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1.  Effect of Low- and High-Glycemic Load on Circulating Incretins in a Randomized Clinical Trial 
Objective
Low-glycemic load diets lower post-prandial glucose and insulin responses; however, the effect of glycemic load on circulating incretin concentrations is unclear. We aimed assess effects of dietary glycemic load on fasting and post-prandial glucose, insulin and incretin (i.e., glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)) concentrations and to examine for effect modification by adiposity.
Materials and Methods
We conducted a single-center, randomized controlled crossover feeding trial in which a subset of participants had post-prandial testing. Participants were recruited from the local Seattle area. We enrolled 89 overweight-obese (BMI 28.0–39.9 kg/m2) and lean (BMI 18.5–25.0 kg/m2) healthy adults. Participants consumed two 28-day, weight-maintaining high- and low-glycemic load controlled diets in random order. Primary outcome measures were post-prandial circulating concentrations of glucose, insulin, GIP and GLP-1, following a test breakfast.
Results
Of the 80 participants completing both diet interventions, 16 had incretin testing and comprise the group for analyses. Following each 28-day high- and low-glycemic load diet, mean fasting concentrations of insulin, glucose, GIP and GLP-1 were not significantly different. Mean integrated post-prandial concentrations of glucose, insulin and GIP were higher (1504±476 mg/dL/min, p<0.01; 2012±644 µU/mL/min, p<0.01 and 15517±4062 pg/ml/min, p<0.01, respectively) and GLP-1 was lower (−81.6±38.5 pmol/L/min, p<0.03) following the high-glycemic load breakfast as compared to the low-glycemic load breakfast. Body fat did not significantly modify the effect of glycemic load on metabolic outcomes.
Conclusions
High-glycemic load diets in weight-maintained healthy individuals leads to higher post-prandial GIP and lower post-prandial GLP-1 concentrations. Future studies evaluating dietary glycemic load manipulation of incretin effects would be helpful for establishing diabetes nutrition guidelines.
doi:10.1016/j.metabol.2012.07.006
PMCID: PMC3519963  PMID: 22959497
glucose-dependent insulinotropic polypeptide (GIP); glucagon-like peptide-1 (GLP-1); glucose; insulin; glycemic index
2.  Effects of Dietary Composition During Weight Loss Maintenance: A Controlled Feeding Study 
Context
Many diets can produce weight loss over the short term, but the biological effects of dietary composition during weight loss maintenance have not been well studied.
Objective
To examine three diets differing widely in macronutrient composition and glycemic load following weight loss.
Design and Setting
Controlled feeding study with a three-way cross-over design conducted in major metropolitan area (June 2006 to June 2010), with recruitment by newspaper advertisements and postings.
Participants
Overweight and obese young adults (n=21).
Interventions
After achieving 10 to 15% weight loss on a run-in diet, participants consumed low-fat (LF; 60% of energy from carbohydrate, 20% fat, 20% protein; high glycemic load), low-glycemic index (LGI; 40%-40%-20%; moderate glycemic load), and very-low-carbohydrate (VLC; 10%-60%-30%; low glycemic load) diets in random order, each for 4 weeks.
Main Outcome Measures
Resting energy expenditure (REE, primary outcome), total energy expenditure (TEE), hormones, and metabolic syndrome components.
Results
The decline in REE (mean [95% CI]) with weight loss was greatest with the LF diet (−205 [−265 to −144] kcal/d), intermediate with the LGI diet (−166 [−227 to −106] kcal/d), and least with the VLC diet (−138 [−198 to −77] kcal/d; P=0.03, P for trend by glycemic load=0.009). The decline in TEE showed a similar pattern (LF: −423 [−606 to −239] kcal/d; LGI:−297 [−479 to −115] kcal/d); VLC: −97 [−281 to +86] kcal/d; P=0.003, P for trend=0.0009). Hormones and metabolic syndrome components also varied during weight maintenance by diet: leptin (P=0.0006); 24-hour urinary cortisol (P=0.005); indexes of peripheral (P=0.02) and hepatic (P=0.03) insulin sensitivity; HDL cholesterol (P<0.0001); non-HDL cholesterol (P=0.0005); triglycerides (P<0.0001); PAI-1 (P for trend=0.04); and CRP (P for trend=0.05).
Conclusions
During isocaloric feeding following weight loss, declines in resting and total energy expenditure varied by dietary glycemic load and were least with the VLC diet, intermediate with the LGI diet, and greatest with the LF diet.
Trial Registration
ClinicalTrials.gov Identifier NCT00315354
doi:10.1001/jama.2012.6607
PMCID: PMC3564212  PMID: 22735432
3.  Glycemic Index, Carbohydrates, Glycemic Load, and the Risk of Pancreatic Cancer in a Prospective Cohort Study 
Diets with high glycemic index and glycemic load have been associated with insulin resistance. Insulin resistance has been implicated in the etiology of pancreatic cancer. We prospectively investigated the associations between glycemic index, carbohydrates, glycemic load, and available carbohydrates dietary constituents (starch and simple sugar) intake and the risk of pancreatic cancer. We followed the participants in the NIH-AARP Diet and Health Study from 1995/1996 through December 2003. A baseline self-administered food frequency questionnaire was used to assess the dietary intake and exposure information. A total of 1,151 exocrine pancreatic cancer cases were identified from 482,362 participants after excluding first-year of follow-up. We used multivariate Cox proportional hazards regression models to calculate relative risks (RR) and 95% confidence intervals (95% CI) for pancreatic cancer. There were no associations between glycemic index, total or available carbohydrates, gycemic load, and pancreatic cancer risk. Participants with high free fructose and glucose intake were at a greater risk of developing pancreatic cancer (highest compared with lowest quintile, RR, 1.29; 95% CI, 1.04–1.59; P trend = 0.004 and RR, 1.35; 95% CI, 1.10–1.67; P trend = 0.005, respectively). There were no statistically significant interactions by body mass index, physical activity, or smoking status. Our results do not support an association between glycemic index, total or available carbohydrate intake, and glycemic load and pancreatic cancer risk. The higher risk associated with high free fructose intake needs further confirmation and elucidation.
doi:10.1158/1055-9965.EPI-08-1135
PMCID: PMC2687095  PMID: 19336549
4.  Effect of the Glycemic Index of Carbohydrates on Acne vulgaris 
Nutrients  2010;2(10):1060-1072.
Acne vulgaris may be improved by dietary factors that increase insulin sensitivity. We hypothesized that a low-glycemic index diet would improve facial acne severity and insulin sensitivity. Fifty-eight adolescent males (mean age ± standard deviation 16.5 ± 1.0 y and body mass index 23.1 ± 3.5 kg/m2) were alternately allocated to high or low glycemic index diets. Severity of inflammatory lesions on the face, insulin sensitivity (homeostasis modeling assessment of insulin resistance), androgens and insulin-like growth factor-1 and its binding proteins were assessed at baseline and at eight weeks, a period corresponding to the school term. Forty-three subjects (n = 23 low glycemic index and n = 20 high glycemic index) completed the study. Diets differed significantly in glycemic index (mean ± standard error of the mean, low glycemic index 51 ± 1 vs. high glycemic index 61 ± 2, p = 0.0002), but not in macronutrient distribution or fiber content. Facial acne improved on both diets (low glycemic index −26 ± 6%, p = 0.0004 and high glycemic index −16 ± 7%, p = 0.01), but differences between diets did not reach significance. Change in insulin sensitivity was not different between diets (low glycemic index 0.2 ± 0.1 and high glycemic index 0.1 ± 0.1, p = 0.60) and did not correlate with change in acne severity (Pearson correlation r = −0.196, p = 0.244). Longer time frames, greater reductions in glycemic load or/and weight loss may be necessary to detect improvements in acne among adolescent boys.
doi:10.3390/nu2101060
PMCID: PMC3257617  PMID: 22253996
glycemic index; carbohydrate; diet; acne vulgaris; adolescent males
5.  Exercise-induced alterations in intramyocellular lipids and insulin resistance: the athlete’s paradox revisited 
We previously reported an “athlete’s paradox” in which endurance-trained athletes, who possess a high oxidative capacity and enhanced insulin sensitivity, also have higher intramyocellular lipid (IMCL) content. The purpose of this study was to determine whether moderate exercise training would increase IMCL, oxidative capacity of muscle, and insulin sensitivity in previously sedentary overweight to obese, insulin-resistant, older subjects. Twenty-five older (66.4 ± 0.8 yr) obese (BMI = 30.3 ± 0.7 kg/m2) men (n = 9) and women (n = 16) completed a 16-wk moderate but progressive exercise training program. Body weight and fat mass modestly but significantly (P < 0.01) decreased. Insulin sensitivity, measured using the euglycemic hyperinsulinemic clamp, was increased (21%, P = 0.02), with modest improvements (7%, P = 0.04) in aerobic fitness (V̇O2peak). Histochemical analyses of IMCL (Oil Red O staining), oxidative capacity [succinate dehydrogenase activity (SDH)], glycogen content, capillary density, and fiber type were performed on skeletal muscle biopsies. Exercise training increased IMCL by 21%. In contrast, diacylglycerol and ceramide, measured by mass spectroscopy, were decreased (n = 13; −29% and −24%, respectively, P < 0.05) with exercise training. SDH (19%), glycogen content (15%), capillary density (7%), and the percentage of type I slow oxidative fibers (from 50.8 to 55.7%), all P ≤ 0.05, were increased after exercise. In summary, these results extend the athlete’s paradox by demonstrating that chronic exercise in overweight to obese older adults improves insulin sensitivity in conjunction with favorable alterations in lipid partitioning and an enhanced oxidative capacity within muscle. Therefore, several key deleterious effects of aging and/or obesity on the metabolic profile of skeletal muscle can be reversed with only moderate increases in physical activity.
doi:10.1152/ajpendo.00769.2007
PMCID: PMC3804891  PMID: 18319352
insulin sensitivity; aging; diacylglycerol; ceramide
6.  Regular Breakfast Consumption and Type 2 Diabetes Risk Markers in 9- to 10-Year-Old Children in the Child Heart and Health Study in England (CHASE): A Cross-Sectional Analysis 
PLoS Medicine  2014;11(9):e1001703.
Angela Donin and colleagues evaluated the association between breakfast consumption and composition and risk markers for diabetes and cardiovascular disease in 9- and 10-year-olds.
Please see later in the article for the Editors' Summary
Background
Regular breakfast consumption may protect against type 2 diabetes risk in adults but little is known about its influence on type 2 diabetes risk markers in children. We investigated the associations between breakfast consumption (frequency and content) and risk markers for type 2 diabetes (particularly insulin resistance and glycaemia) and cardiovascular disease in children.
Methods and Findings
We conducted a cross-sectional study of 4,116 UK primary school children aged 9–10 years. Participants provided information on breakfast frequency, had measurements of body composition, and gave fasting blood samples for measurements of blood lipids, insulin, glucose, and glycated haemoglobin (HbA1c). A subgroup of 2,004 children also completed a 24-hour dietary recall. Among 4,116 children studied, 3,056 (74%) ate breakfast daily, 450 (11%) most days, 372 (9%) some days, and 238 (6%) not usually. Graded associations between breakfast frequency and risk markers were observed; children who reported not usually having breakfast had higher fasting insulin (percent difference 26.4%, 95% CI 16.6%–37.0%), insulin resistance (percent difference 26.7%, 95% CI 17.0%–37.2%), HbA1c (percent difference 1.2%, 95% CI 0.4%–2.0%), glucose (percent difference 1.0%, 95% CI 0.0%–2.0%), and urate (percent difference 6%, 95% CI 3%–10%) than those who reported having breakfast daily; these differences were little affected by adjustment for adiposity, socioeconomic status, and physical activity levels. When the higher levels of triglyceride, systolic blood pressure, and C-reactive protein for those who usually did not eat breakfast relative to those who ate breakfast daily were adjusted for adiposity, the differences were no longer significant. Children eating a high fibre cereal breakfast had lower insulin resistance than those eating other breakfast types (p for heterogeneity <0.01). Differences in nutrient intakes between breakfast frequency groups did not account for the differences in type 2 diabetes markers.
Conclusions
Children who ate breakfast daily, particularly a high fibre cereal breakfast, had a more favourable type 2 diabetes risk profile. Trials are needed to quantify the protective effect of breakfast on emerging type 2 diabetes risk.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, more than 380 million people have diabetes, a disorder that is characterized by high levels of glucose (sugar) in the blood. Blood sugar levels are usually controlled by insulin, a hormone released by the pancreas after meals (digestion of food produces glucose). In people with type 2 diabetes (the commonest type of diabetes) blood sugar control fails because the fat and muscle cells that normally respond to insulin become insulin resistant. Type 2 diabetes can often be controlled initially with diet and exercise and with drugs such as metformin and sulfonylureas. However, many patients eventually need insulin injections to control their blood sugar levels. Long-term complications of diabetes, which include an increased risk of heart disease and stroke (cardiovascular disease), reduce the life expectancy of people with diabetes by about 10 years compared to people without diabetes. Risk factors for the condition include being over 40 years old and being overweight or obese.
Why Was This Study Done?
Experts predict that by 2035 nearly 600 million people will have diabetes so better strategies to prevent diabetes are urgently needed. Eating breakfast regularly—particularly a high fiber, cereal-based breakfast—has been associated with a reduced risk of type 2 diabetes (and a reduced risk of being overweight or obese) in adults. However, little is known about whether breakfast eating habits affect markers of type 2 diabetes risk in children. In this cross-sectional study (an observational investigation that studies a group of individuals at a single time point), the researchers examine the associations between breakfast consumption (both frequency and content) and risk markers for type 2 diabetes, particularly insulin resistance and glycemia (the presence of sugar in the blood), in an ethnically mixed population of children; insulin resistance and glycemia measurements in children provide important information about diabetes development later in life.
What Did the Researchers Do and Find?
The researchers invited 9–10 year old children attending 200 schools in London, Birmingham, and Leicester to participate in the Child Heart and Health Study in England (CHASE), a study examining risk factors for cardiovascular disease and type 2 diabetes in children of South Asian, black African-Caribbean, and white European origin. The researchers measured the body composition of the study participants and the levels of insulin, glucose, and other markers of diabetes risk in fasting blood samples (blood taken from the children 8–10 hours after their last meal or drink). All the participants (4,116 children) reported how often they ate breakfast; 2,004 children also completed a 24-hour dietary recall questionnaire. Seventy-four percent of the children reported that they ate breakfast every day, 11% and 9% reported that they ate breakfast most days and some days, respectively, whereas 6% reported that they rarely ate breakfast. Children who ate breakfast infrequently had higher fasting insulin levels and higher insulin resistance than children who ate breakfast every day. Moreover, the children who ate a high fiber, cereal-based breakfast had lower insulin resistance than children who ate other types of breakfast such as low fiber or toast-based breakfasts.
What Do These Findings Mean?
These findings indicate that children who ate breakfast every day, particularly those who ate a high fiber breakfast, had lower levels of risk markers for type 2 diabetes than children who rarely ate breakfast. Importantly, the association between eating breakfast and having a favorable type 2 diabetes risk profile remained after allowing for differences in socioeconomic status, physical activity levels, and amount of body fat (adiposity); in observational studies, it is important to allow for the possibility that individuals who share a measured characteristic and a health outcome also share another characteristic (a confounder) that is actually responsible for the outcome. Although trials are needed to establish whether altering the breakfast habits of children can alter their risk of developing type 2 diabetes, these findings are encouraging. Specifically, they suggest that if all the children in England who do not eat breakfast daily could be encouraged to do so, it might reduce population-wide fasting insulin levels by about 4%. Moreover, encouraging children to eat a high fiber breakfast instead of a low fiber breakfast might reduce population-wide fasting insulin levels by 11%–12%. Thus, persuading children to eat a high fiber breakfast regularly could be an important component in diabetes preventative strategies in England and potentially worldwide.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001703.
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health-care professionals, and the general public, including detailed information on diabetes prevention (in English and Spanish)
The UK National Health Service Choices website provides information for patients and carers about type 2 diabetes and about living with diabetes; it also provides people's stories about diabetes; Change4Life, a UK campaign that provides tips for healthy living, has a webpage about the importance of a healthy breakfast
The charity Diabetes UK provides detailed information for patients and carers in several languages, including information on healthy lifestyles for people with diabetes
The UK-based non-profit organization Healthtalkonline has interviews with people about their experiences of diabetes
MedlinePlus provides links to further resources and advice about diabetes and diabetes prevention (in English and Spanish)
Kidshealth, a US-based not-for-profit organization provides information for parents about the importance of breakfast and information for children
More information about the Child Heart and Health Study in England (CHASE) is available
doi:10.1371/journal.pmed.1001703
PMCID: PMC4151989  PMID: 25181492
7.  Determinants of Glycemic Control among Insulin Treated Diabetic Patients in Southwest Ethiopia: Hospital Based Cross Sectional Study 
PLoS ONE  2013;8(4):e61759.
Background
Good glycemic control reduces the risk of diabetic complications. Despite this, achieving good glycemic control remains a challenge in diabetic patients. The objective of this study is to identify determinants of glycemic control among insulin treated diabetic patients at Jimma University Hospital, Southwest Ethiopia.
Methods
Hospital-based cross-sectional study was conducted on systematically sampled 284 insulin-treated diabetic patients with a regular follow up. Data was collected by interviewing patients during hospital visits and reviewing respective databases of September 2010 to December 2011. Data collection took place from February 20 to May 20, 2012. Poor glycemic control was defined as fasting blood sugar (FBS) ≥126 mg/dL. Binary logistic regression analysis was conducted to identify predictors of poor glycemic control.
Results
Patients had a mean age of 41.37 (±15.08) years, 58.5% were males, the mean duration of insulin treatment was 4.9 (±5.1) years, 18.3% achieved good glycemic control (FBS≤126 mg/dL), 95% self-reported repeated use of disposable insulin syringe-needle and 48% correctly rotating insulin injection sites. Most (83.1%) of study participants had one or more complications. On multivariable logistic regression analyses, body weight of >70 Kg (AOR = 0.21; P<0.001), total daily dose of insulin ≤35 IU/day (AOR = 0.26; P<0.001), total daily dose variation without checking glycemic level (AOR = 3.39; P = 0.020), knowledge deficit about signs and symptoms of hyperglycemia (AOR = 3.60; P = 0.004), and non-adherence to dietary management (AOR = 0.35; P = 0.005) were independent predictors of poor glycemic control.
Conclusions
The proportion of patients with poor glycemic control was high, which resulted in the development of one or more complications regardless of duration on insulin treatment. Hence, appropriate management of patients focusing on the relevant associated factors and independent predictors of poor glycemic control would be of great benefit in glycemic control.
doi:10.1371/journal.pone.0061759
PMCID: PMC3631159  PMID: 23620789
8.  Dietary Glycemic Load and Risk of Colorectal Cancer in the Women’s Health Study 
Although diet is believed to influence colorectal cancer risk, the long-term effects of a diet with a high glycemic load are unclear. The growing recognition that colorectal cancer may be promoted by hyperinsulinemia and insulin resistance suggests that a diet inducing high blood glucose levels and an elevated insulin response may contribute to a metabolic environment conducive to tumor growth. We prospectively followed a cohort of 38 451 women for an average of 7.9 years and identified 174 with incident colorectal cancer. We used baseline dietary intake measurements, assessed with a semiquantitative food-frequency questionnaire, to examine the associations of dietary glycemic load, overall dietary glycemic index, carbohydrate, fiber, nonfiber carbohydrate, sucrose, and fructose with the subsequent development of colorectal cancer. Cox proportional hazards models were used to estimate relative risks (RRs). Dietary glycemic load was statistically significantly associated with an increased risk of colorectal cancer (adjusted RR = 2.85, 95% confidence interval [CI] = 1.40 to 5.80, comparing extreme quintiles of dietary glycemic load; Ptrend = .004) and was associated, although not statistically significantly, with overall glycemic index (corresponding RR = 1.71, 95% CI = 0.98 to 2.98; Ptrend = .04). Total carbohydrate (adjusted RR = 2.41, 95% CI = 1.10 to 5.27, comparing extreme quintiles of carbohydrate; Ptrend = .02), nonfiber carbohydrate (corresponding RR = 2.60, 95% CI = 1.22 to 5.54; Ptrend = .02), and fructose (corresponding RR = 2.09, 95% CI = 1.13 to 3.87; Ptrend = .08) were also statistically significantly associated with increased risk. Thus, our data indicate that a diet with a high dietary glycemic load may increase the risk of colorectal cancer in women.
PMCID: PMC4165491  PMID: 14759990
9.  Muscle Mitochondrial ATP Synthesis and Glucose Transport/Phosphorylation in Type 2 Diabetes 
PLoS Medicine  2007;4(5):e154.
Background
Muscular insulin resistance is frequently characterized by blunted increases in glucose-6-phosphate (G-6-P) reflecting impaired glucose transport/phosphorylation. These abnormalities likely relate to excessive intramyocellular lipids and mitochondrial dysfunction. We hypothesized that alterations in insulin action and mitochondrial function should be present even in nonobese patients with well-controlled type 2 diabetes mellitus (T2DM).
Methods and Findings
We measured G-6-P, ATP synthetic flux (i.e., synthesis) and lipid contents of skeletal muscle with 31P/1H magnetic resonance spectroscopy in ten patients with T2DM and in two control groups: ten sex-, age-, and body mass-matched elderly people; and 11 younger healthy individuals. Although insulin sensitivity was lower in patients with T2DM, muscle lipid contents were comparable and hyperinsulinemia increased G-6-P by 50% (95% confidence interval [CI] 39%–99%) in all groups. Patients with diabetes had 27% lower fasting ATP synthetic flux compared to younger controls (p = 0.031). Insulin stimulation increased ATP synthetic flux only in controls (younger: 26%, 95% CI 13%–42%; older: 11%, 95% CI 2%–25%), but failed to increase even during hyperglycemic hyperinsulinemia in patients with T2DM. Fasting free fatty acids and waist-to-hip ratios explained 44% of basal ATP synthetic flux. Insulin sensitivity explained 30% of insulin-stimulated ATP synthetic flux.
Conclusions
Patients with well-controlled T2DM feature slightly lower flux through muscle ATP synthesis, which occurs independently of glucose transport /phosphorylation and lipid deposition but is determined by lipid availability and insulin sensitivity. Furthermore, the reduction in insulin-stimulated glucose disposal despite normal glucose transport/phosphorylation suggests further abnormalities mainly in glycogen synthesis in these patients.
Michael Roden and colleagues report that even patients with well-controlled insulin-resistant type 2 diabetes have altered mitochondrial function.
Editors' Summary
Background.
Diabetes mellitus is an increasingly common chronic disease characterized by high blood sugar (glucose) levels. In normal individuals, blood sugar levels are maintained by the hormone insulin. Insulin is released by the pancreas when blood glucose levels rise after eating (glucose is produced by the digestion of food) and “instructs” insulin-responsive muscle and fat cells to take up glucose from the bloodstream. The cells then use glucose as a fuel or convert it into glycogen, a storage form of glucose. In type 2 diabetes, the commonest type of diabetes, the muscle and fat cells become nonresponsive to insulin (a condition called insulin resistance) and consequently blood glucose levels rise. Over time, this hyperglycemia increases the risk of heart attacks, kidney failure, and other life-threatening complications.
Why Was This Study Done?
Insulin resistance is often an early sign of type 2 diabetes, sometimes predating its development by many years, so understanding its causes might provide clues about how to stop the global diabetes epidemic. One theory is that mitochondria—cellular structures that produce the energy (in the form of a molecule called ATP) needed to keep cells functioning—do not work properly in people with insulin resistance. Mitochondria change (metabolize) fatty acids into energy, and recent studies have revealed that fat accumulation caused by poorly regulated fatty acid metabolism blocks insulin signaling, thus causing insulin resistance. Other studies using magnetic resonance spectroscopy (MRS) to study mitochondrial function noninvasively in human muscle indicate that mitochondria are dysfunctional in people with insulin resistance by showing that ATP synthesis is impaired in such individuals. In this study, the researchers have examined both baseline and insulin-stimulated mitochondrial function in nonobese patients with well-controlled type 2 diabetes and in normal controls to discover more about the relationship between mitochondrial dysfunction and insulin resistance.
What Did the Researchers Do and Find?
The researchers determined the insulin sensitivity of people with type 2 diabetes and two sets of people (the “controls”) who did not have diabetes: one in which the volunteers were age-matched to the people with diabetes, and the other containing younger individuals (insulin resistance increases with age). To study insulin sensitivity in all three groups, the researchers used a “hyperinsulinemic–euglycemic clamp.” For this, after an overnight fast, the participants' insulin levels were kept high with a continuous insulin infusion while blood glucose levels were kept normal using a variable glucose infusion. In this situation, the glucose infusion rate equals glucose uptake by the body and therefore measures tissue sensitivity to insulin. Before and during the clamp, the researchers used MRS to measure glucose-6-phosphate (an indicator of how effectively glucose is taken into cells and phosphorylated), ATP synthesis, and the fat content of the participants' muscle cells. Insulin sensitivity was lower in the patients with diabetes than in the controls, but muscle lipid content was comparable and hyperinsulinemia increased glucose-6-phosphate levels similarly in all the groups. Patients with diabetes and the older controls had lower fasting ATP synthesis rates than the young controls and, whereas insulin stimulation increased ATP synthesis in all the controls, it had no effect in the patients with diabetes. In addition, fasting blood fatty acid levels were inversely related to basal ATP synthesis, whereas insulin sensitivity was directly related to insulin-stimulated ATP synthesis.
What Do These Findings Mean?
These findings indicate that the impairment of muscle mitochondrial ATP synthesis in fasting conditions and after insulin stimulation in people with diabetes is not due to impaired glucose transport/phosphorylation or fat deposition in the muscles. Instead, it seems to be determined by lipid availability and insulin sensitivity. These results add to the evidence suggesting that mitochondrial function is disrupted in type 2 diabetes and in insulin resistance, but also suggest that there may be abnormalities in glycogen synthesis. More work is needed to determine the exact nature of these abnormalities and to discover whether they can be modulated to prevent the development of insulin resistance and type 2 diabetes. For now, though, these findings re-emphasize the need for people with type 2 diabetes or insulin resistance to reduce their food intake to compensate for the reduced energy needs of their muscles and to exercise to increase the ATP-generating capacity of their muscles. Both lifestyle changes could improve their overall health and life expectancy.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040154.
The MedlinePlus encyclopedia has pages on diabetes
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information for patients on diabetes and insulin resistance
The US Centers for Disease Control and Prevention has information on diabetes for patients and professionals
American Diabetes Association provides information for patients on diabetes and insulin resistance
Diabetes UK has information for patients and professionals on diabetes
doi:10.1371/journal.pmed.0040154
PMCID: PMC1858707  PMID: 17472434
10.  Continuous Subcutaneous Insulin Infusion (CSII) Pumps for Type 1 and Type 2 Adult Diabetic Populations 
Executive Summary
In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry’s newly released Diabetes Strategy.
After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.
To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,
Diabetes Strategy Evidence Platform: Summary of Evidence-Based Analyses
Continuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based Analysis
Behavioural Interventions for Type 2 Diabetes: An Evidence-Based Analysis
Bariatric Surgery for People with Diabetes and Morbid Obesity: An Evidence-Based Summary
Community-Based Care for the Management of Type 2 Diabetes: An Evidence-Based Analysis
Home Telemonitoring for Type 2 Diabetes: An Evidence-Based Analysis
Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario
Objective
The objective of this analysis is to review the efficacy of continuous subcutaneous insulin infusion (CSII) pumps as compared to multiple daily injections (MDI) for the type 1 and type 2 adult diabetics.
Clinical Need and Target Population
Insulin therapy is an integral component of the treatment of many individuals with diabetes. Type 1, or juvenile-onset diabetes, is a life-long disorder that commonly manifests in children and adolescents, but onset can occur at any age. It represents about 10% of the total diabetes population and involves immune-mediated destruction of insulin producing cells in the pancreas. The loss of these cells results in a decrease in insulin production, which in turn necessitates exogenous insulin therapy.
Type 2, or ‘maturity-onset’ diabetes represents about 90% of the total diabetes population and is marked by a resistance to insulin or insufficient insulin secretion. The risk of developing type 2 diabetes increases with age, obesity, and lack of physical activity. The condition tends to develop gradually and may remain undiagnosed for many years. Approximately 30% of patients with type 2 diabetes eventually require insulin therapy.
CSII Pumps
In conventional therapy programs for diabetes, insulin is injected once or twice a day in some combination of short- and long-acting insulin preparations. Some patients require intensive therapy regimes known as multiple daily injection (MDI) programs, in which insulin is injected three or more times a day. It’s a time consuming process and usually requires an injection of slow acting basal insulin in the morning or evening and frequent doses of short-acting insulin prior to eating. The most common form of slower acting insulin used is neutral protamine gagedorn (NPH), which reaches peak activity 3 to 5 hours after injection. There are some concerns surrounding the use of NPH at night-time as, if injected immediately before bed, nocturnal hypoglycemia may occur. To combat nocturnal hypoglycemia and other issues related to absorption, alternative insulins have been developed, such as the slow-acting insulin glargine. Glargine has no peak action time and instead acts consistently over a twenty-four hour period, helping reduce the frequency of hypoglycemic episodes.
Alternatively, intensive therapy regimes can be administered by continuous insulin infusion (CSII) pumps. These devices attempt to closely mimic the behaviour of the pancreas, continuously providing a basal level insulin to the body with additional boluses at meal times. Modern CSII pumps are comprised of a small battery-driven pump that is designed to administer insulin subcutaneously through the abdominal wall via butterfly needle. The insulin dose is adjusted in response to measured capillary glucose values in a fashion similar to MDI and is thus often seen as a preferred method to multiple injection therapy. There are, however, still risks associated with the use of CSII pumps. Despite the increased use of CSII pumps, there is uncertainty around their effectiveness as compared to MDI for improving glycemic control.
Part A: Type 1 Diabetic Adults (≥19 years)
An evidence-based analysis on the efficacy of CSII pumps compared to MDI was carried out on both type 1 and type 2 adult diabetic populations.
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 1 diabetes?
Are CSII pumps more effective than MDI for improving additional outcomes related to diabetes such as quality of life (QoL)?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, EMBASE, CINAHL
Adults (≥ 19 years)
Type 1 diabetes
Study evaluates CSII vs. MDI
Published between January 1, 2002 – March 24, 2009
Patient currently on intensive insulin therapy
Exclusion Criteria
Studies with <20 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcomes of interest were glycosylated hemoglobin (HbA1c) levels, mean daily blood glucose, glucose variability, and frequency of hypoglycaemic events. Other outcomes of interest were insulin requirements, adverse events, and quality of life.
Search Strategy
The literature search strategy employed keywords and subject headings to capture the concepts of:
1) insulin pumps, and
2) type 1 diabetes.
The search was run on July 6, 2008 in the following databases: Ovid MEDLINE (1996 to June Week 4 2008), OVID MEDLINE In-Process and Other Non-Indexed Citations, EMBASE (1980 to 2008 Week 26), OVID CINAHL (1982 to June Week 4 2008) the Cochrane Library, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment. A search update was run on March 24, 2009 and studies published prior to 2002 were also examined for inclusion into the review. Parallel search strategies were developed for the remaining databases. Search results were limited to human and English-language published between January 2002 and March 24, 2009. Abstracts were reviewed, and studies meeting the inclusion criteria outlined above were obtained. Reference lists were also checked for relevant studies.
Summary of Findings
The database search identified 519 relevant citations published between 1996 and March 24, 2009. Of the 519 abstracts reviewed, four RCTs and one abstract met the inclusion criteria outlined above. While efficacy outcomes were reported in each of the trials, a meta-analysis was not possible due to missing data around standard deviations of change values as well as missing data for the first period of the crossover arm of the trial. Meta-analysis was not possible on other outcomes (quality of life, insulin requirements, frequency of hypoglycemia) due to differences in reporting.
HbA1c
In studies where no baseline data was reported, the final values were used. Two studies (Hanaire-Broutin et al. 2000, Hoogma et al. 2005) reported a slight reduction in HbA1c of 0.35% and 0.22% respectively for CSII pumps in comparison to MDI. A slightly larger reduction in HbA1c of 0.84% was reported by DeVries et al.; however, this study was the only study to include patients with poor glycemic control marked by higher baseline HbA1c levels. One study (Bruttomesso et al. 2008) showed no difference between CSII pumps and MDI on Hba1c levels and was the only study using insulin glargine (consistent with results of parallel RCT in abstract by Bolli 2004). While there is statistically significant reduction in HbA1c in three of four trials, there is no evidence to suggest these results are clinically significant.
Mean Blood Glucose
Three of four studies reported a statistically significant reduction in the mean daily blood glucose for patients using CSII pump, though these results were not clinically significant. One study (DeVries et al. 2002) did not report study data on mean blood glucose but noted that the differences were not statistically significant. There is difficulty with interpreting study findings as blood glucose was measured differently across studies. Three of four studies used a glucose diary, while one study used a memory meter. In addition, frequency of self monitoring of blood glucose (SMBG) varied from four to nine times per day. Measurements used to determine differences in mean daily blood glucose between the CSII pump group and MDI group at clinic visits were collected at varying time points. Two studies use measurements from the last day prior to the final visit (Hoogma et al. 2005, DeVries et al. 2002), while one study used measurements taken during the last 30 days and another study used measurements taken during the 14 days prior to the final visit of each treatment period.
Glucose Variability
All four studies showed a statistically significant reduction in glucose variability for patients using CSII pumps compared to those using MDI, though one, Bruttomesso et al. 2008, only showed a significant reduction at the morning time point. Brutomesso et al. also used alternate measures of glucose variability and found that both the Lability index and mean amplitude of glycemic excursions (MAGE) were in concordance with the findings using the standard deviation (SD) values of mean blood glucose, but the average daily risk range (ADRR) showed no difference between the CSII pump and MDI groups.
Hypoglycemic Events
There is conflicting evidence concerning the efficacy of CSII pumps in decreasing both mild and severe hypoglycemic events. For mild hypoglycemic events, DeVries et al. observed a higher number of events per patient week in the CSII pump group than the MDI group, while Hoogma et al. observed a higher number of events per patient year in the MDI group. The remaining two studies found no differences between the two groups in the frequency of mild hypoglycemic events. For severe hypoglycemic events, Hoogma et al. found an increase in events per patient year among MDI patients, however, all of the other RCTs showed no difference between the patient groups in this aspect.
Insulin Requirements and Adverse Events
In all four studies, insulin requirements were significantly lower in patients receiving CSII pump treatment in comparison to MDI. This difference was statistically significant in all studies. Adverse events were reported in three studies. Devries et al. found no difference in ketoacidotic episodes between CSII pump and MDI users. Bruttomesso et al. reported no adverse events during the study. Hanaire-Broutin et al. found that 30 patients experienced 58 serious adverse events (SAEs) during MDI and 23 patients had 33 SAEs during treatment out of a total of 256 patients. Most events were related to severe hypoglycemia and diabetic ketoacidosis.
Quality of Life and Patient Preference
QoL was measured in three studies and patient preference was measured in one. All three studies found an improvement in QoL for CSII users compared to those using MDI, although various instruments were used among the studies and possible reporting bias was evident as non-positive outcomes were not consistently reported. Moreover, there was also conflicting results in two of the studies using the Diabetes Treatment Satisfaction Questionnaire (DTSQ). DeVries et al. reported no difference in treatment satisfaction between CSII pump users and MDI users while Brutomesso et al. reported that treatment satisfaction improved among CSII pump users.
Patient preference for CSII pumps was demonstrated in just one study (Hanaire-Broutin et al. 2000) and there are considerable limitations with interpreting this data as it was gathered through interview and 72% of patients that preferred CSII pumps were previously on CSII pump therapy prior to the study. As all studies were industry sponsored, findings on QoL and patient preference must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low due to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 1) While blinding of patient to intervention/control was not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. Trials reported consistent results for the outcomes HbA1c, mean blood glucose and glucose variability, but the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as most trials used highly motivated populations with fairly good glycemic control. In addition, the populations in each of the studies varied with respect to prior treatment regimens, which may not be generalizable to the population eligible for pumps in Ontario. For the outcome of hypoglycaemic events the evidence was further downgraded to very low since there was conflicting evidence between studies with respect to the frequency of mild and severe hypoglycaemic events in patients using CSII pumps as compared to CSII (see Table 2). The GRADE quality of evidence for the use of CSII in adults with type 1 diabetes is therefore low to very low and any estimate of effect is, therefore, uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c, Mean Blood Glucose, and Glucose Variability for Adults with Type 1 Diabetes
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
HbA1c: 3/4 studies show consistency however magnitude of effect varies greatly; Single study uses insulin glargine instead of NPH; Mean Blood Glucose: 3/4 studies show consistency however magnitude of effect varies between studies; Glucose Variability: All studies show consistency but 1 study only showed a significant effect in the morning
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
GRADE Quality Assessment for CSII pumps vs. MDI on Frequency of Hypoglycemic
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
Conflicting evidence with respect to mild and severe hypoglycemic events reported in studies
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
Economic Analysis
One article was included in the analysis from the economic literature scan. Four other economic evaluations were identified but did not meet our inclusion criteria. Two of these articles did not compare CSII with MDI and the other two articles used summary estimates from a mixed population with Type 1 and 2 diabetes in their economic microsimulation to estimate costs and effects over time. Included were English articles that conducted comparisons between CSII and MDI with the outcome of Quality Adjusted Life Years (QALY) in an adult population with type 1 diabetes.
From one study, a subset of the population with type 1 diabetes was identified that may be suitable and benefit from using insulin pumps. There is, however, limited data in the literature addressing the cost-effectiveness of insulin pumps versus MDI in type 1 diabetes. Longer term models are required to estimate the long term costs and effects of pumps compared to MDI in this population.
Conclusions
CSII pumps for the treatment of adults with type 1 diabetes
Based on low-quality evidence, CSII pumps confer a statistically significant but not clinically significant reduction in HbA1c and mean daily blood glucose as compared to MDI in adults with type 1 diabetes (>19 years).
CSII pumps also confer a statistically significant reduction in glucose variability as compared to MDI in adults with type 1 diabetes (>19 years) however the clinical significance is unknown.
There is indirect evidence that the use of newer long-acting insulins (e.g. insulin glargine) in MDI regimens result in less of a difference between MDI and CSII compared to differences between MDI and CSII in which older insulins are used.
There is conflicting evidence regarding both mild and severe hypoglycemic events in this population when using CSII pumps as compared to MDI. These findings are based on very low-quality evidence.
There is an improved quality of life for patients using CSII pumps as compared to MDI however, limitations exist with this evidence.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
All studies used crossover design
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations were highly motivated and half of studies used insulin pens as the mode of delivery for MDI
One short-term study concluded that pumps are cost-effective, although this was based on limited data and longer term models are required to estimate the long-term costs and effects of pumps compared to MDI in adults with type 1 diabetes.
Part B: Type 2 Diabetic Adults
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 2 diabetes?
Are CSII pumps more effective than MDI for improving other outcomes related to diabetes such as quality of life?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, Excerpta Medica Database (EMBASE), Cumulative Index to Nursing & Allied Health Literature (CINAHL)
Any person with type 2 diabetes requiring insulin treatment intensive
Published between January 1, 2000 – August 2008
Exclusion Criteria
Studies with <10 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcome of interest was a reduction in glycosylated hemoglobin (HbA1c) levels. Other outcomes of interest were mean blood glucose level, glucose variability, insulin requirements, frequency of hypoglycemic events, adverse events, and quality of life.
Search Strategy
A comprehensive literature search was performed in OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, CINAHL, The Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published between January 1, 2000 and August 15, 2008. Studies meeting the inclusion criteria were selected from the search results. Data on the study characteristics, patient characteristics, primary and secondary treatment outcomes, and adverse events were abstracted. Reference lists of selected articles were also checked for relevant studies. The quality of the evidence was assessed as high, moderate, low, or very low according to the GRADE methodology.
Summary of Findings
The database search identified 286 relevant citations published between 1996 and August 2008. Of the 286 abstracts reviewed, four RCTs met the inclusion criteria outlined above. Upon examination, two studies were subsequently excluded from the meta-analysis due to small sample size and missing data (Berthe et al.), as well as outlier status and high drop out rate (Wainstein et al) which is consistent with previously reported meta-analyses on this topic (Jeitler et al 2008, and Fatourechi M et al. 2009).
HbA1c
The primary outcome in this analysis was reduction in HbA1c. Both studies demonstrated that both CSII pumps and MDI reduce HbA1c, but neither treatment modality was found to be superior to the other. The results of a random effects model meta-analysis showed a mean difference in HbA1c of -0.14 (-0.40, 0.13) between the two groups, which was found not to be statistically or clinically significant. There was no statistical heterogeneity observed between the two studies (I2=0%).
Forrest plot of two parallel, RCTs comparing CSII to MDI in type 2 diabetes
Secondary Outcomes
Mean Blood Glucose and Glucose Variability
Mean blood glucose was only used as an efficacy outcome in one study (Raskin et al. 2003). The authors found that the only time point in which there were consistently lower blood glucose values for the CSII group compared to the MDI group was 90 minutes after breakfast. Glucose variability was not examined in either study and the authors reported no difference in weight gain between the CSII pump group and MDI groups at the end of study. Conflicting results were reported regarding injection site reactions between the two studies. Herman et al. reported no difference in the number of subjects experiencing site problems between the two groups, while Raskin et al. reported that there were no injection site reactions in the MDI group but 15 such episodes among 8 participants in the CSII pump group.
Frequency of Hypoglycemic Events and Insulin Requirements
All studies reported that there were no differences in the number of mild hypoglycemic events in patients on CSII pumps versus MDI. Herman et al. also reported no differences in the number of severe hypoglycemic events in patients using CSII pumps compared to those on MDI. Raskin et al. reported that there were no severe hypoglycemic events in either group throughout the study duration. Insulin requirements were only examined in Herman et al., who found that daily insulin requirements were equal between the CSII pump and MDI treatment groups.
Quality of Life
QoL was measured by Herman et al. using the Diabetes Quality of Life Clinical Trial Questionnaire (DQOLCTQ). There were no differences reported between CSII users and MDI users for treatment satisfaction, diabetes impact, and worry-related scores. Patient satisfaction was measured in Raskin et al. using a patient satisfaction questionnaire, whose results indicated that patients in the CSII pump group had significantly greater improvement in overall treatment satisfaction at the end of the study compared to the MDI group. Although patient preference was also reported, it was only examined in the CSII pump group, thus results indicating a greater preference for CSII pumps in this groups (as compared to prior injectable insulin regimens) are biased and must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low according to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 3). While blinding of patient to intervention/control is not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. ITT was not clearly explained in one study and heterogeneity between study populations was evident from participants’ treatment regimens prior to study initiation. Although trials reported consistent results for HbA1c outcomes, the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as trials required patients to adhere to an intense SMBG regimen. This suggests that patients were highly motivated. In addition, since prior treatment regimens varied between participants (no requirement for patients to be on MDI), study findings may not be generalizable to the population eligible for a pump in Ontario. The GRADE quality of evidence for the use of CSII in adults with type 2 diabetes is, therefore, low and any estimate of effect is uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c Adults with Type 2 Diabetes
Inadequate or unknown allocation concealment (all studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; ITT not well explained in 1 of 2 studies
Indirect due to lack of generalizability of findings since participants varied with respect to prior treatment regimens and intensive SMBG suggests highly motivated populations used in trials.
Economic Analysis
An economic analysis of CSII pumps was carried out using the Ontario Diabetes Economic Model (ODEM) and has been previously described in the report entitled “Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario”, part of the diabetes strategy evidence series. Based on the analysis, CSII pumps are not cost-effective for adults with type 2 diabetes, either for the age 65+ sub-group or for all patients in general. Details of the analysis can be found in the full report.
Conclusions
CSII pumps for the treatment of adults with type 2 diabetes
There is low quality evidence demonstrating that the efficacy of CSII pumps is not superior to MDI for adult type 2 diabetics.
There were no differences in the number of mild and severe hypoglycemic events in patients on CSII pumps versus MDI.
There are conflicting findings with respect to an improved quality of life for patients using CSII pumps as compared to MDI.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations may not reflect eligible patient population in Ontario (participants not necessarily on MDI prior to study initiation, pen used in one study and frequency of SMBG required during study was high suggesting highly motivated participants)
Based on ODEM, insulin pumps are not cost-effective for adults with type 2 diabetes either for the age 65+ sub-group or for all patients in general.
PMCID: PMC3377523  PMID: 23074525
11.  Comparison of multiple and novel measures of dietary glycemic carbohydrate with insulin resistant status in older women 
Background
Previous epidemiological investigations of associations between dietary glycemic intake and insulin resistance have used average daily measures of glycemic index (GI) and glycemic load (GL). We explored multiple and novel measures of dietary glycemic intake to determine which was most predictive of an association with insulin resistance.
Methods
Usual dietary intakes were assessed by diet history interview in women aged 42-81 years participating in the Longitudinal Assessment of Ageing in Women. Daily measures of dietary glycemic intake (n = 329) were carbohydrate, GI, GL, and GL per megacalorie (GL/Mcal), while meal based measures (n = 200) were breakfast, lunch and dinner GL; and a new measure, GL peak score, to represent meal peaks. Insulin resistant status was defined as a homeostasis model assessment (HOMA) value of >3.99; HOMA as a continuous variable was also investigated.
Results
GL, GL/Mcal, carbohydrate (all P < 0.01), GL peak score (P = 0.04) and lunch GL (P = 0.04) were positively and independently associated with insulin resistant status. Daily measures were more predictive than meal-based measures, with minimal difference between GL/Mcal, GL and carbohydrate. No significant associations were observed with HOMA as a continuous variable.
Conclusion
A dietary pattern with high peaks of GL above the individual's average intake was a significant independent predictor of insulin resistance in this population, however the contribution was less than daily GL and carbohydrate variables. Accounting for energy intake slightly increased the predictive ability of GL, which is potentially important when examining disease risk in more diverse populations with wider variations in energy requirements.
doi:10.1186/1743-7075-7-25
PMCID: PMC2859357  PMID: 20370933
12.  A low glycemic diet lifestyle intervention improves fat utilization during exercise in older obese humans 
Obesity (Silver Spring, Md.)  2013;21(11):2272-2278.
Objective
To determine the influence of dietary glycemic index on exercise training-induced adaptations in substrate oxidation in obesity.
Design and Methods
Twenty older, obese individuals undertook 3-months of fully-supervised aerobic exercise and were randomised to low (LoGIX) or high glycemic (HiGIX) diets. Changes in indirect calorimetry (VO2; VCO2) were assessed at rest, during a hyperinsulinemic-euglycemic clamp, and during submaximal exercise (walking: 65% VO2max, 200 kcal energy expenditure). Intramyocellular lipid (IMCL) was measured by 1H-magnetic resonance spectroscopy.
Results
Weight loss (−8.6±1.1%) and improvements (P<0.05) in VO2max, glycemic control, fasting lipemia, and metabolic flexibility were similar for both LoGIX and HiGIX groups. During submaximal exercise, energy expenditure was higher following the intervention (P<0.01) in both groups. Respiratory exchange ratio (RER) during exercise was unchanged in the LoGIX group but increased in the HiGIX group (P<0.05). However, fat oxidation during exercise expressed relative to changes in body weight was increased in the LoGIX group (+10.6±3.6%; P<0.05). Fasting IMLC was unchanged, however extramyocellular lipid was reduced (P<0.05) after LoGIX.
Conclusions
A low glycemic diet/exercise weight-loss intervention increases fat utilization during exercise independent of changes in energy expenditure. This highlights the potential therapeutic value of low glycemic foods for reversing metabolic defects in obesity.
doi:10.1002/oby.20411
PMCID: PMC3696477  PMID: 23512711
glycemic index; weight loss; obesity; type 2 diabetes; exercise training; energy expenditure; fat oxidation
13.  Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets 
Background
PCSK9 (Proprotein Convertase Subtilisin Kexin type 9) is a circulating protein that promotes hypercholesterolemia by decreasing hepatic LDL receptor protein. Under non interventional conditions, its expression is driven by sterol response element binding protein 2 (SREBP2) and follows a diurnal rhythm synchronous with cholesterol synthesis. Plasma PCSK9 is associated to LDL-C and to a lesser extent plasma triglycerides and insulin resistance. We aimed to verify the effect on plasma PCSK9 concentrations of dietary interventions that affect these parameters.
Methods
We performed nutritional interventions in young healthy male volunteers and offspring of type 2 diabetic (OffT2D) patients that are more prone to develop insulin resistance, including: i) acute post-prandial hyperlipidemic challenge (n=10), ii) 4 days of high-fat (HF) or high-fat/high-protein (HFHP) (n=10), iii) 7 (HFruc1, n=16) or 6 (HFruc2, n=9) days of hypercaloric high-fructose diets. An acute oral fat load was also performed in two patients bearing the R104C-V114A loss-of-function (LOF) PCSK9 mutation. Plasma PCSK9 concentrations were measured by ELISA. For the HFruc1 study, intrahepatocellular (IHCL) and intramyocellular lipids were measured by 1H magnetic resonance spectroscopy. Hepatic and whole-body insulin sensitivity was assessed with a two-step hyperinsulinemic-euglycemic clamp (0.3 and 1.0 mU.kg-1.min-1).
Findings
HF and HFHP short-term diets, as well as an acute hyperlipidemic oral load, did not significantly change PCSK9 concentrations. In addition, post-prandial plasma triglyceride excursion was not altered in two carriers of PCSK9 LOF mutation compared with non carriers. In contrast, hypercaloric 7-day HFruc1 diet increased plasma PCSK9 concentrations by 28% (p=0.05) in healthy volunteers and by 34% (p=0.001) in OffT2D patients. In another independent study, 6-day HFruc2 diet increased plasma PCSK9 levels by 93% (p<0.0001) in young healthy male volunteers. Spearman’s correlations revealed that plasma PCSK9 concentrations upon 7-day HFruc1 diet were positively associated with plasma triglycerides (r=0.54, p=0.01) and IHCL (r=0.56, p=0.001), and inversely correlated with hepatic (r=0.54, p=0.014) and whole-body (r=−0.59, p=0.0065) insulin sensitivity.
Conclusions
Plasma PCSK9 concentrations vary minimally in response to a short term high-fat diet and they are not accompanied with changes in cholesterolemia upon high-fructose diet. Short-term high-fructose intake increased plasma PCSK9 levels, independent on cholesterol synthesis, suggesting a regulation independent of SREBP-2. Upon this diet, PCSK9 is associated with insulin resistance, hepatic steatosis and plasma triglycerides.
doi:10.1186/1743-7075-10-4
PMCID: PMC3548771  PMID: 23298392
Nutrition; Dietary intervention; PCSK9; Insulin resistance; Liver steatosis
14.  Association between Dietary Carbohydrates and Body Weight 
American journal of epidemiology  2005;161(4):359-367.
The role of dietary carbohydrates in weight loss has received considerable attention in light of the current obesity epidemic. The authors investigated the association of body mass index (weight (kg)/height (m)2) with dietary intake of carbohydrates and with measures of the induced glycemic response, using data from an observational study of 572 healthy adults in central Massachusetts. Anthropometric measurements, 7-day dietary recalls, and physical activity recalls were collected quarterly from each subject throughout a 1-year study period. Data were collected between 1994 and 1998. Longitudinal analyses were conducted, and results were adjusted for other factors related to body habitus. Average body mass index was 27.4 kg/m2 (standard deviation, 5.5), while the average percentage of calories from carbohydrates was 44.9 (standard deviation, 9.6). Mean daily dietary glycemic index was 81.7 (standard deviation, 5.5), and glycemic load was 197.8 (standard deviation, 105.2). Body mass index was found to be positively associated with glycemic index, a measure of the glycemic response associated with ingesting different types of carbohydrates, but not with daily carbohydrate intake, percentage of calories from carbohydrates, or glycemic load. Results suggest that the type of carbohydrate may be related to body weight. However, further research is required to elucidate this association and its implications for weight management.
doi:10.1093/aje/kwi051
PMCID: PMC1199523  PMID: 15692080
body mass index; carbohydrates; glycemic index; BMI, body mass index; FFQ, food frequency questionnaire; SD, standard deviation; 7DDR, 7-day dietary recall
15.  Hemoglobin A1c Levels and Risk of Severe Hypoglycemia in Children and Young Adults with Type 1 Diabetes from Germany and Austria: A Trend Analysis in a Cohort of 37,539 Patients between 1995 and 2012 
PLoS Medicine  2014;11(10):e1001742.
In a cohort study, Beate Karges and colleagues find that the association between low hemoglobin A1C and severe hypoglycemia in children and young adults with type 1 diabetes has decreased over the period between 1995 and 2012.
Please see later in the article for the Editors' Summary
Background
Severe hypoglycemia is a major complication of insulin treatment in patients with type 1 diabetes, limiting full realization of glycemic control. It has been shown in the past that low levels of hemoglobin A1c (HbA1c), a marker of average plasma glucose, predict a high risk of severe hypoglycemia, but it is uncertain whether this association still exists. Based on advances in diabetes technology and pharmacotherapy, we hypothesized that the inverse association between severe hypoglycemia and HbA1c has decreased in recent years.
Methods and Findings
We analyzed data of 37,539 patients with type 1 diabetes (mean age ± standard deviation 14.4±3.8 y, range 1–20 y) from the DPV (Diabetes Patienten Verlaufsdokumentation) Initiative diabetes cohort prospectively documented between January 1, 1995, and December 31, 2012. The DPV cohort covers an estimated proportion of >80% of all pediatric diabetes patients in Germany and Austria. Associations of severe hypoglycemia, hypoglycemic coma, and HbA1c levels were assessed by multivariable regression analysis. From 1995 to 2012, the relative risk (RR) for severe hypoglycemia and coma per 1% HbA1c decrease declined from 1.28 (95% CI 1.19–1.37) to 1.05 (1.00–1.09) and from 1.39 (1.23–1.56) to 1.01 (0.93–1.10), respectively, corresponding to a risk reduction of 1.2% (95% CI 0.6–1.7, p<0.001) and 1.9% (0.8–2.9, p<0.001) each year, respectively. Risk reduction of severe hypoglycemia and coma was strongest in patients with HbA1c levels of 6.0%–6.9% (RR 0.96 and 0.90 each year) and 7.0%–7.9% (RR 0.96 and 0.89 each year). From 1995 to 2012, glucose monitoring frequency and the use of insulin analogs and insulin pumps increased (p<0.001). Our study was not designed to investigate the effects of different treatment modalities on hypoglycemia risk. Limitations are that associations between diabetes education and physical activity and severe hypoglycemia were not addressed in this study.
Conclusions
The previously strong association of low HbA1c with severe hypoglycemia and coma in young individuals with type 1 diabetes has substantially decreased in the last decade, allowing achievement of near-normal glycemic control in these patients.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, more than 380 million people have diabetes, a chronic disorder characterized by high levels of glucose (sugar) in the blood. Blood sugar levels are usually controlled by insulin, a hormone produced by the pancreas. In people with diabetes, blood sugar control fails because they make no insulin (type 1 diabetes) or because the cells that normally respond to insulin by removing sugar from the blood have become insulin-resistant (type 2 diabetes). Type 1 diabetes, which tends to develop in childhood or early adulthood, is responsible for about 10% of cases of diabetes in adults and is treated with injections of insulin. Type 2 diabetes can usually be treated with diet, exercise, and antidiabetic drugs. With both types of diabetes, it is important to keep blood sugar levels within the normal range (good glycemic control) to reduce the long-term complications of diabetes, which include kidney failure, blindness, and an increased risk of cardiovascular disease.
Why Was This Study Done?
Patients with type 1 diabetes can achieve strict glycemic control using intensive insulin therapy, but such treatment is associated with a risk of severe or fatal hypoglycemia (low blood sugar). Past studies have found an association between low levels of hemoglobin A1c (HbA1c, a marker of average blood sugar levels over the past 2–3 months; a low HbA1c percentage indicates good glycemic control) and a high risk of severe hypoglycemia. Because of this inverse association, people at risk of severe hypoglycemia are advised to aim for an HbA1c of 7.5% or less, which puts them at risk of diabetic complications (most adults with diabetes aim for an HbA1c of 6.5% or less; people without diabetes have Hb1Ac readings below 6.05%). With recent improvements in insulin therapy, it is not clear whether the inverse association between the incidence of severe hypoglycemia and HbA1c levels still exists. In this trend analysis, the researchers investigate the association over time between HbA1C levels and the risk of severe hypoglycemia in a large cohort (group) of Austrian and German children and young adults with type 1 diabetes.
What Did the Researchers Do and Find?
The researchers analyzed data on Hb1Ac levels and on incidents of severe hypoglycemia and hypoglycemic coma collected from 37,539 children and young adults with type 1 diabetes between 1995 and 2012 by the DPV (Diabetes Patienten Verlaufsdokumentation) Initiative for diabetes care. The DPV cohort includes around 80% of all children and young adults with type 1 diabetes in Germany and Austria. Over the study period, the use of insulin analogs (compounds related to insulin that keep blood sugar levels steadier than regular insulin injections) and of insulin pumps (which deliver constant amounts of short-acting insulin analogs to the body) increased, and there was an increase in how often patients monitored their blood sugar level. Notably, between 1995 and 2012, the relative risk for severe hypoglycemia per 1% decrease in Hb1Ac declined from 1.28 to 1.05, and the relative risk for hypoglycemic coma per 1% decrease in Hb1Ac declined from 1.39 to 1.01. That is, the strength of the inverse association between severe hypoglycemia or coma and HbA1c decreased during the study period. Expressed another way, between 1995 and 2012, the relative risk for severe hypoglycemia and coma per 1% HbA1c decrease dropped by 1.2% and 1.9%, respectively, each year.
What Do These Findings Mean?
These findings reveal a substantial decrease since 1995 in the previously strong inverse association between low HbA1c levels and severe hypoglycemia and hypoglycemic coma in this cohort of young Germans and Austrians with type 1 diabetes. This decrease mainly occurred because of substantial reductions in the risk of hypoglycemia in patients with HbA1c levels between 6.0% and 7.9%, but the study provides no information about the drivers of this reduction. Moreover, these findings may apply only to young type 1 diabetes patients of European descent, and their accuracy may be limited by other aspects of the study design. However, by showing that HbA1c has become a minor predictor for severe hypoglycemia in this group of patients, these findings suggest that strict glycemic control in young patients with type 1 diabetes has become safer in recent years. Thus, it should now be possible to reduce the risk of long-term diabetic complications in such patients through achievement of near-normal glycemic control without increasing patients' risk of severe hypoglycemia.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001742.
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health care professionals, and the general public (in English and Spanish), including information on the HbA1c test and a description of a trial that compared the effects of intensive versus conventional treatment of blood glucose levels on the development of diabetic complications in patients with type 1 diabetes
The UK National Health Service Choices website provides information for patients and carers about type 1 diabetes, including a video that describes parents' experiences caring for a child with type 1 diabetes, and information about treating type 1 diabetes that includes a short video about HbA1c
The charity Diabetes UK provides detailed information about type 1 diabetes for patients and carers
The UK-based non-profit organization Healthtalkonline provides information about type 1 diabetes and young people, including interviews with young people about their experiences of the condition
MedlinePlus provides links to further resources and advice about type 1 diabetes (in English and Spanish)
Information about the DPV Initiative is available (mainly in German)
doi:10.1371/journal.pmed.1001742
PMCID: PMC4188517  PMID: 25289645
16.  Muscle-Strengthening and Conditioning Activities and Risk of Type 2 Diabetes: A Prospective Study in Two Cohorts of US Women 
PLoS Medicine  2014;11(1):e1001587.
Anders Grøntved and colleagues examined whether women who perform muscle-strengthening and conditioning activities have an associated reduced risk of type 2 diabetes mellitus.
Please see later in the article for the Editors' Summary
Background
It is well established that aerobic physical activity can lower the risk of type 2 diabetes (T2D), but whether muscle-strengthening activities are beneficial for the prevention of T2D is unclear. This study examined the association of muscle-strengthening activities with the risk of T2D in women.
Methods and Findings
We prospectively followed up 99,316 middle-aged and older women for 8 years from the Nurses' Health Study ([NHS] aged 53–81 years, 2000–2008) and Nurses' Health Study II ([NHSII] aged 36–55 years, 2001–2009), who were free of diabetes, cancer, and cardiovascular diseases at baseline. Participants reported weekly time spent on resistance exercise, lower intensity muscular conditioning exercises (yoga, stretching, toning), and aerobic moderate and vigorous physical activity (MVPA) at baseline and in 2004/2005. Cox regression with adjustment for major determinants for T2D was carried out to examine the influence of these types of activities on T2D risk. During 705,869 person years of follow-up, 3,491 incident T2D cases were documented. In multivariable adjusted models including aerobic MVPA, the pooled relative risk (RR) for T2D for women performing 1–29, 30–59, 60–150, and >150 min/week of total muscle-strengthening and conditioning activities was 0.83, 0.93, 0.75, and 0.60 compared to women reporting no muscle-strengthening and conditioning activities (p<0.001 for trend). Furthermore, resistance exercise and lower intensity muscular conditioning exercises were each independently associated with lower risk of T2D in pooled analyses. Women who engaged in at least 150 min/week of aerobic MVPA and at least 60 min/week of muscle-strengthening activities had substantial risk reduction compared with inactive women (pooled RR = 0.33 [95% CI 0.29–0.38]). Limitations to the study include that muscle-strengthening and conditioning activity and other types of physical activity were assessed by a self-administered questionnaire and that the study population consisted of registered nurses with mostly European ancestry.
Conclusions
Our study suggests that engagement in muscle-strengthening and conditioning activities (resistance exercise, yoga, stretching, toning) is associated with a lower risk of T2D. Engagement in both aerobic MVPA and muscle-strengthening type activity is associated with a substantial reduction in the risk of T2D in middle-aged and older women.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, more than 370 million people have diabetes mellitus, a disorder characterized by poor glycemic control—dangerously high amounts of glucose (sugar) in the blood. Blood sugar levels are normally controlled by insulin, a hormone released by the pancreas. In people with type 2 diabetes (the commonest form of diabetes), blood sugar control fails because the fat and muscle cells that normally respond to insulin by removing excess sugar from the blood become less responsive to insulin. Type 2 diabetes, which was previously known as adult-onset diabetes, can often initially be controlled with diet and exercise, and with antidiabetic drugs such as metformin and sulfonylureas. However, as the disease progresses, the pancreatic beta cells, which make insulin, become impaired and patients may eventually need insulin injections. Long-term complications of diabetes, which include an increased risk of cardiovascular problems such as heart disease and stroke, reduce the life expectancy of people with diabetes by about 10 years compared to people without diabetes.
Why Was This Study Done?
Type 2 diabetes is becoming increasingly common worldwide so better preventative strategies are essential. It is well-established that regular aerobic exercise—physical activity in which the breathing and heart rate increase noticeably such as jogging, brisk walking, and swimming—lowers the risk of type 2 diabetes. The World Health Organization currently recommends that adults should do at least 150 min/week of moderate-to-vigorous aerobic physical activity to reduce the risk of diabetes and other non-communicable diseases. It also recommends that adults should undertake muscle-strengthening and conditioning activities such as weight training and yoga on two or more days a week. However, although studies have shown that muscle-strengthening activity improves glycemic control in people who already have diabetes, it is unclear whether this form of exercise prevents diabetes. In this prospective cohort study (a study in which disease development is followed up over time in a group of people whose characteristics are recorded at baseline), the researchers investigated the association of muscle-strengthening activities with the risk of type 2 diabetes in women.
What Did the Researchers Do and Find?
The researchers followed up nearly 100,000 women enrolled in the Nurses' Health Study (NHS) and the Nurses' Health Study II (NHSII), two prospective US investigations into risk factors for chronic diseases in women, for 8 years. The women provided information on weekly participation in muscle-strengthening exercise (for example, weight training), lower intensity muscle-conditioning exercises (for example, yoga and toning), and aerobic moderate and vigorous physical activity (aerobic MVPA) at baseline and 4 years later. During the study 3,491 women developed diabetes. After allowing for major risk factors for type 2 diabetes (for example, diet and a family history of diabetes) and for aerobic MVPA, compared to women who did no muscle-strengthening or conditioning exercise, the risk of developing type 2 diabetes among women declined with increasing participation in muscle-strengthening and conditioning activity. Notably, women who did more than 150 min/week of these types of exercise had 40% lower risk of developing diabetes as women who did not exercise in this way at all. Muscle-strengthening and muscle-conditioning exercise were both independently associated with reduced diabetes risk, and women who engaged in at least 150 min/week of aerobic MVPA and at least 60 min/week of muscle-strengthening exercise were a third as likely to develop diabetes as inactive women.
What Do These Findings Mean?
These findings show that, among the women enrolled in NHS and NHSII, engagement in muscle-strengthening and conditioning activities lowered the risk of type 2 diabetes independent of aerobic MVPA. That is, non-aerobic exercise provided protection against diabetes in women who did no aerobic exercise. Importantly, they also show that doing both aerobic exercise and muscle-strengthening exercise substantially reduced the risk of type 2 diabetes. Because nearly all the participants in NHS and NHSII were of European ancestry, these results may not be generalizable to women of other ethnic backgrounds. Moreover, the accuracy of these findings may be limited by the use of self-administered questionnaires to determine how much exercise the women undertook. Nevertheless, these findings support the inclusion of muscle-strengthening and conditioning exercises in strategies designed to prevent type 2 diabetes in women, a conclusion that is consistent with current guidelines for physical activity among adults.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001587.
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health-care professionals and the general public, including information on diabetes prevention (in English and Spanish)
The UK National Health Service Choices website provides information for patients and carers about type 2 diabetes and explains the benefits of regular physical activity
The World Health Organization provides information about diabetes and about physical activity and health (in several languages); its 2010 Global Recommendations on Physical Activity for Health are available in several languages
The US Centers for Disease Control and Prevention provides information on physical activity for different age groups; its Physical Activity for Everyone web pages include guidelines, instructional videos and personal success stories
More information about the Nurses Health Study and the Nurses Health Study II is available
The UK charity Healthtalkonline has interviews with people about their experiences of diabetes
MedlinePlus provides links to further resources and advice about diabetes and about physical exercise and fitness (in English and Spanish)
doi:10.1371/journal.pmed.1001587
PMCID: PMC3891575  PMID: 24453948
17.  Habitually Higher Dietary Glycemic Index During Puberty Is Prospectively Related to Increased Risk Markers of Type 2 Diabetes in Younger Adulthood 
Diabetes Care  2013;36(7):1870-1876.
OBJECTIVE
Carbohydrate nutrition during periods of physiological insulin resistance such as puberty may affect future risk of type 2 diabetes. This study examined whether the amount or the quality (dietary glycemic index [GI], glycemic load [GL], and added sugar, fiber, and whole-grain intake) of carbohydrates during puberty is associated with risk markers of type 2 diabetes in younger adulthood.
RESEARCH DESIGN AND METHODS
The analysis was based on 226 participants (121 girls and 105 boys) from the Dortmund Nutritional and Anthropometric Longitudinally Designed Study (DONALD) with an average of five 3-day weighed dietary records (range 2–6) during puberty (girls, age 9–14 years; boys, age 10–15 years) and fasting blood samples in younger adulthood (age 18–36 years) (average duration of follow-up 12.6 years). Multivariable linear regression was used to analyze the associations between carbohydrate nutrition and homeostasis model assessment–insulin resistance (HOMA-IR) as well as the liver enzymes alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT) (n = 214).
RESULTS
A higher dietary GI was prospectively related to greater values of HOMA-IR (Ptrend = 0.03), ALT (Ptrend = 0.02), and GGT (Ptrend = 0.04). After adjustment for sex, adult age, baseline BMI, and early life and socioeconomic factors as well as protein and fiber intake, predicted mean HOMA-IR values in energy-adjusted tertiles of GI were 2.37 (95% CI 2.16–2.60), 2.47 (2.26–2.71), and 2.59 (2.35–2.85). The amount of carbohydrates, GL, and added sugar, fiber, and whole-grain intake were not related to the analyzed markers.
CONCLUSIONS
Our data indicate that a habitually higher dietary GI during puberty may adversely affect risk markers of type 2 diabetes in younger adulthood.
doi:10.2337/dc12-2063
PMCID: PMC3687320  PMID: 23349549
18.  PTEN Mutations as a Cause of Constitutive Insulin Sensitivity and Obesity 
The New England journal of medicine  2012;367(11):1002-1011.
BACKGROUND
Epidemiologic and genetic evidence links type 2 diabetes, obesity, and cancer. The tumor-suppressor phosphatase and tensin homologue (PTEN) has roles in both cellular growth and metabolic signaling. Germline PTEN mutations cause a cancer-predisposition syndrome, providing an opportunity to study the effect of PTEN haploinsufficiency in humans.
METHODS
We measured insulin sensitivity and beta-cell function in 15 PTEN mutation carriers and 15 matched controls. Insulin signaling was measured in muscle and adipose-tissue biopsy specimens from 5 mutation carriers and 5 well-matched controls. We also assessed the effect of PTEN haploinsufficiency on obesity by comparing anthropometric indexes between the 15 patients and 2097 controls from a population-based study of healthy adults. Body composition was evaluated by means of dual-emission x-ray absorptiometry and skinfold thickness.
RESULTS
Measures of insulin resistance were lower in the patients with a PTEN mutation than in controls (e.g., mean fasting plasma insulin level, 29 pmol per liter [range, 9 to 99] vs. 74 pmol per liter [range, 22 to 185]; P = 0.001). This finding was confirmed with the use of hyperinsulinemic euglycemic clamping, showing a glucose infusion rate among carriers 2 times that among controls (P = 0.009). The patients’ insulin sensitivity could be explained by the presence of enhanced insulin signaling through the PI3K-AKT pathway, as evidenced by increased AKT phosphorylation. The PTEN mutation carriers were obese as compared with population-based controls (mean body-mass index [the weight in kilograms divided by the square of the height in meters], 32 [range, 23 to 42] vs. 26 [range, 15 to 48]; P<0.001). This increased body mass in the patients was due to augmented adiposity without corresponding changes in fat distribution.
CONCLUSIONS
PTEN haploinsufficiency is a monogenic cause of profound constitutive insulin sensitization that is apparently obesogenic. We demonstrate an apparently divergent effect of PTEN mutations: increased risks of obesity and cancer but a decreased risk of type 2 diabetes owing to enhanced insulin sensitivity. (Funded by the Wellcome Trust and others.)
doi:10.1056/NEJMoa1113966
PMCID: PMC4072504  PMID: 22970944
19.  Body composition, dietary composition, and components of metabolic syndrome in overweight and obese adults after a 12-week trial on dietary treatments focused on portion control, energy density, or glycemic index 
Nutrition Journal  2012;11:57.
Background
Given the rise in obesity and associated chronic diseases, it is critical to determine optimal weight management approaches that will also improve dietary composition and chronic disease risk factors. Few studies have examined all these weight, diet, and disease risk variables in subjects participating in recommended multi-disciplinary weight loss programs using different dietary strategies.
Methods
This study compared effects of three dietary approaches to weight loss on body composition, dietary composition and risk factors for metabolic syndrome (MetS). In a 12-week trial, sedentary but otherwise healthy overweight and obese adults (19 M & 138 F; 38.7 ± 6.7 y; BMI 31.8 ± 2.2) who were attending weekly group sessions for weight loss followed either portion control, low energy density, or low glycemic index diet plans. At baseline and 12 weeks, measures included anthropometrics, body composition, 3-day food diaries, blood pressure, total lipid profile, HOMA, C-reactive protein, and fasting blood glucose and insulin. Data were analyzed by repeated measures analysis of variance.
Results
All groups significantly reduced body weight and showed significant improvements in body composition (p < 0.001), and components of metabolic syndrome (p < 0.027 to 0.002), although HDL decreased (p < 0.001). Dietary energy, %fat and %saturated fat decreased while protein intake increased significantly (p < 0.001). There were no significant differences among the three groups in any variable related to body composition, dietary composition, or MetS components.
Conclusion
Different dietary approaches based on portion control, low energy density, or low glycemic index produced similar, significant short-term improvements in body composition, diet compositin, and MetS components in overweight and obese adults undergoing weekly weight loss meetings. This may allow for flexibility in options for dietary counseling based on patient preference.
doi:10.1186/1475-2891-11-57
PMCID: PMC3464127  PMID: 22925169
Weight loss; Chronic diseases; Blood lipids; Risk factors
20.  Lower Dipeptidyl peptidase-4 following exercise training plus weight loss is related to increased insulin sensitivity in adults with metabolic syndrome 
Peptides  2013;47:10.1016/j.peptides.2013.07.008.
Dipeptidyl peptidase-4 (DPP-4) is a circulating glycoprotein that impairs insulin-stimulated glucose uptake and is linked to obesity and metabolic syndrome. However, the effect of exercise on plasma DPP-4 in adults with metabolic syndrome is unknown. Therefore, we determined the effect of exercise on DPP-4 and its role in explaining exercise-induced improvements in insulin sensitivity. Fourteen obese adults (67.9±1.2yr, BMI: 34.2±1.1kg/m2) with metabolic syndrome (ATP III criteria) underwent a 12-week supervised exercise intervention (60 min/d for 5 d/wk at ~85% HRmax). Plasma DPP-4 was analyzed using an enzyme-linked immunosorbent assay. Insulin sensitivity was measured using the euglycemic-hyperinsulinemic clamp (40mU/m2/min) and estimated by HOMA-IR. Visceral fat (computerized tomography), 2-hour glucose levels (75g oral glucose tolerance), and basal fat oxidation as well as aerobic fitness (indirect calorimetry) were also determined before and after exercise. The intervention reduced visceral fat, lowered blood pressure, glucose and lipids, and increased aerobic fitness (P<0.05). Exercise improved clamp-derived insulin sensitivity by 75% (P<0.001) and decreased HOMA-IR by 15% (P<0.05). Training decreased plasma DPP-4 by 10% (421.8±30.1 vs. 378.3±32.5ng/ml; P<0.04), and the decrease in DPP-4 was associated with clamp-derived insulin sensitivity (r=−0.59; P<0.04), HOMA-IR (r=0.59; P<0.04) and fat oxidation (r=−0.54; P<0.05). Increased fat oxidation also correlated with lower 2-hour glucose levels (r=−0.64; P<0.02). Exercise training reduces plasma DPP-4, which may be linked to elevated insulin sensitivity and fat oxidation. Maintaining low plasma DPP-4 concentrations is a potential mechanism whereby exercise plus weight loss prevents/delays the onset of type 2 diabetes in adults with metabolic syndrome.
doi:10.1016/j.peptides.2013.07.008
PMCID: PMC3825405  PMID: 23872069
impaired glucose tolerance; obesity; cytokine; diabetes
21.  Chronologically scheduled snacking with high-protein products within the habitual diet in type-2 diabetes patients leads to a fat mass loss: a longitudinal study 
Nutrition Journal  2011;10:74.
Background
Obesity is the most relevant overnutrition disease worldwide and is associated to different metabolic disorders such as insulin resistance and type-2 diabetes. Low glycemic load foods and diets and moderately high protein intake have been shown to reduce body weight and fat mass, exerting also beneficial effects on LDL-cholesterol, triglyceride concentrations, postprandial glucose curve and HDL-cholesterol levels. The present study aimed at studying the potential functionality of a series of low glycemic index products with moderately high protein content, as possible coadjuvants in the control of type-2 diabetes and weight management following a chronologically planned snacking offer (morning and afternoon).
Methods
The current trial followed a single group, sequential, longitudinal design, with two consecutive periods of 4 weeks each. A total of 17 volunteers participated in the study. The first period was a free living period, with volunteers' habitual ad libitum dietary pattern, while the second period was a free-living period with structured meal replacements at breakfast, morning snack and afternoon snack, which were exchanged by specific products with moderately high protein content and controlled low glycemic index, following a scheduled temporal consumption. Blood extractions were performed at the beginning and at the end of each period (free-living and intervention). Parameters analysed were: fasting glucose, insulin, glycosylated hemoglobin, total-, HDL- and LDL-cholesterol, triglyceride, C - reactive protein and Homocysteine concentrations. Postprandial glucose and insulin were also measured. Anthropometrical parameters were monitored each 2 weeks during the whole study.
Results
A modest but significant (p = 0.002) reduction on body weight (1 kg) was observed during the intervention period, mainly due to the fat mass loss (0.8 kg, p = 0.02). This weight reduction was observed without apparently associated changes in total energy intake. None of the biochemical biomarkers measured was altered throughout the whole study.
Conclusions
Small changes in the habitual dietary recommendations in type-2 diabetes patients by the inclusion of specific low-glycemic, moderately high-protein products in breakfast, morning and afternoon snacks may promote body weight and fat-mass loss, without apparently altering biochemical parameters and cardiovascular risk-related factors.
Trial Registration
Trial registered at clinicaltrials.gov NCT01264523.
doi:10.1186/1475-2891-10-74
PMCID: PMC3155966  PMID: 21756320
22.  Sucralose Affects Glycemic and Hormonal Responses to an Oral Glucose Load 
Diabetes Care  2013;36(9):2530-2535.
OBJECTIVE
Nonnutritive sweeteners (NNS), such as sucralose, have been reported to have metabolic effects in animal models. However, the relevance of these findings to human subjects is not clear. We evaluated the acute effects of sucralose ingestion on the metabolic response to an oral glucose load in obese subjects.
RESEARCH DESIGN AND METHODS
Seventeen obese subjects (BMI 42.3 ± 1.6 kg/m2) who did not use NNS and were insulin sensitive (based on a homeostasis model assessment of insulin resistance score ≤2.6) underwent a 5-h modified oral glucose tolerance test on two separate occasions preceded by consuming either sucralose (experimental condition) or water (control condition) 10 min before the glucose load in a randomized crossover design. Indices of β-cell function, insulin sensitivity (SI), and insulin clearance rates were estimated by using minimal models of glucose, insulin, and C-peptide kinetics.
RESULTS
Compared with the control condition, sucralose ingestion caused 1) a greater incremental increase in peak plasma glucose concentrations (4.2 ± 0.2 vs. 4.8 ± 0.3 mmol/L; P = 0.03), 2) a 20 ± 8% greater incremental increase in insulin area under the curve (AUC) (P < 0.03), 3) a 22 ± 7% greater peak insulin secretion rate (P < 0.02), 4) a 7 ± 4% decrease in insulin clearance (P = 0.04), and 5) a 23 ± 20% decrease in SI (P = 0.01). There were no significant differences between conditions in active glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, glucagon incremental AUC, or indices of the sensitivity of the β-cell response to glucose.
CONCLUSIONS
These data demonstrate that sucralose affects the glycemic and insulin responses to an oral glucose load in obese people who do not normally consume NNS.
doi:10.2337/dc12-2221
PMCID: PMC3747933  PMID: 23633524
23.  Dietary Glycemic Index, Glycemic Load, and Risk of Coronary Heart Disease, Stroke, and Stroke Mortality: A Systematic Review with Meta-Analysis 
PLoS ONE  2012;7(12):e52182.
Background
The relationship between dietary glycemic index, glycemic load and risk of coronary heart disease (CHD), stroke, and stroke-related mortality is inconsistent.
Methods
We systematically searched the MEDLINE, EMBASE, and Science Citation Index Expanded databases using glycemic index, glycemic load, and cardiovascular disease and reference lists of retrieved articles up to April 30, 2012. We included prospective studies with glycemic index and glycemic load as the exposure and incidence of fatal and nonfatal CHD, stroke, and stroke-related mortality as the outcome variable. Pooled relative risks (RR) and 95% confidence intervals (CI) were calculated using random-effects models.
Results
Fifteen prospective studies with a total of 438,073 participants and 9,424 CHD cases, 2,123 stroke cases, and 342 deaths from stroke were included in the meta-analysis. Gender significantly modified the effects of glycemic index and glycemic load on CHD risk, and high glycemic load level was associated with higher risk of CHD in women (RR = 1.49, 95%CI 1.27−1.73), but not in men (RR = 1.08, 95%CI 0.91−1.27). Stratified meta-analysis by body mass index indicated that among overweight and obese subjects, dietary glycemic load level were associated with increased risk of CHD (RR = 1.49, 95%CI 1.27−1.76; P for interaction = 0.003). Higher dietary glycemic load, but not glycemic index, was positively associated with stroke (RR = 1.19, 95% CI 1.00−1.43). There is a linear dose-response relationship between dietary glycemic load and increased risk of CHD, with pooled RR of 1.05 (95%CI 1.02−1.08) per 50-unit increment in glycemic load level.
Conclusion
High dietary glycemic load is associated with a higher risk of CHD and stroke, and there is a linear dose-response relationship between glycemic load and CHD risk. Dietary glycemic index is slightly associated with risk of CHD, but not with stroke and stroke-related death. Further studies are needed to verify the effects of gender and body weight on cardiovascular diseases.
doi:10.1371/journal.pone.0052182
PMCID: PMC3527433  PMID: 23284926
24.  The effect of 12 weeks of aerobic, resistance or combination exercise training on cardiovascular risk factors in the overweight and obese in a randomized trial 
BMC Public Health  2012;12:704.
Background
Evidence suggests that exercise training improves CVD risk factors. However, it is unclear whether health benefits are limited to aerobic training or if other exercise modalities such as resistance training or a combination are as effective or more effective in the overweight and obese. The aim of this study is to investigate whether 12 weeks of moderate-intensity aerobic, resistance, or combined exercise training would induce and sustain improvements in cardiovascular risk profile, weight and fat loss in overweight and obese adults compared to no exercise.
Methods
Twelve-week randomized parallel design examining the effects of different exercise regimes on fasting measures of lipids, glucose and insulin and changes in body weight, fat mass and dietary intake. Participants were randomized to either: Group 1 (Control, n = 16); Group 2 (Aerobic, n = 15); Group 3 (Resistance, n = 16); Group 4 (Combination, n = 17). Data was analysed using General Linear Model to assess the effects of the groups after adjusting for baseline values. Within-group data was analyzed with the paired t-test and between-group effects using post hoc comparisons.
Results
Significant improvements in body weight (−1.6%, p = 0.044) for the Combination group compared to Control and Resistance groups and total body fat compared to Control (−4.4%, p = 0.003) and Resistance (−3%, p = 0.041). Significant improvements in body fat percentage (−2.6%, p = 0.008), abdominal fat percentage (−2.8%, p = 0.034) and cardio-respiratory fitness (13.3%, p = 0.006) were seen in the Combination group compared to Control. Levels of ApoB48 were 32% lower in the Resistance group compared to Control (p = 0.04).
Conclusion
A 12-week training program comprising of resistance or combination exercise, at moderate-intensity for 30 min, five days/week resulted in improvements in the cardiovascular risk profile in overweight and obese participants compared to no exercise. From our observations, combination exercise gave greater benefits for weight loss, fat loss and cardio-respiratory fitness than aerobic and resistance training modalities. Therefore, combination exercise training should be recommended for overweight and obese adults in National Physical Activity Guidelines.
This clinical trial was registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), registration number: ACTRN12609000684224.
doi:10.1186/1471-2458-12-704
PMCID: PMC3487794  PMID: 23006411
Obesity; Overweight; Cardiovascular risk factors; Exercise training
25.  Dietary Carbohydrate, Glycemic Index, and Glycemic Load in Relation to Colorectal Cancer Risk in the Women’s Health Initiative 
Cancer causes & control : CCC  2008;19(10):10.1007/s10552-008-9200-3.
Evidence implicating hyperinsulinemia and insulin resistance in the etiology of colorectal cancer suggests that a diet characterized by a high glycemic index and load may increase the risk of this disease, but previous studies have yielded inconsistent results. We assessed the association between intake of total carbohydrates, sugars, fiber, and the glycemic index (GI) and glycemic load (GL) of individual diets, and risk of developing colorectal cancer among 158,800 participants in the Women’s Health Initiative (WHI). We used a GI/GL database developed specifically for the WHI food-frequency questionnaire. Over an average of 7.8 years of follow-up, 1,476 incident cases of colorectal cancer were identified. Cox proportional hazards models were used to estimate the association between dietary factors classified by quintiles and risk of colorectal cancer, with adjustment for covariates. Total carbohydrate intake, glycemic index, glycemic load, and intake of sugars and fiber showed no association with colorectal cancer. Analyses by cancer subsite yielded null results, with the exception of a borderline positive association between glycemic load and rectal cancer (HR for the highest vs. lowest quintile 1.84, 95% confidence interval 0.95–3.56, p for trend 0.05). Analyses stratified by tertiles of body mass index and physical activity showed no evidence of effect modification by these factors. Results of this large study do not support of a role of a diet characterized by a high glycemic index or load in colorectal carcinogenesis in postmenopausal women.
doi:10.1007/s10552-008-9200-3
PMCID: PMC3856717  PMID: 18618276

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