Polycystic ovary syndrome (PCOS) is a reproductive and metabolic disorder associated with obesity and insulin resistance that often precedes the development of type-2 diabetes. Rats continuously exposed to dihydrotestosterone from prepuberty display typical reproductive and metabolic PCOS characteristics including anovulation, polycystic ovaries, insulin resistance, and obesity.
Our aim was to investigate if resveratrol improves reproductive and metabolic functions in PCOS rats. The effect was compared to exercise.
Control and PCOS rats were treated with vehicle or resveratrol (400 mg · kg−1 · day−1) for 5-6 weeks. Another group of PCOS rats received vehicle treatment and exercised for 5-6 weeks. Insulin sensitivity was determined by euglycemic-hyperinsulinemic clamp.
The glucose infusion rate was lower in the PCOS-vehicle group compared to control-vehicle rats (P < 0.05). Exercise increased insulin sensitivity compared with PCOS-vehicle rats (P < 0.05), but resveratrol did not. Resveratrol treatment and exercise resulted in smaller adipocytes, upregulated estrogen-related receptor α gene expression in subcutaneous fat, and improved estrus cyclicity in the previously acyclic PCOS rats.
Although resveratrol had positive effects on adiposity and cyclicity in a similar manner to exercise, resveratrol does not seem to be a good candidate for treating insulin resistance associated with PCOS because no improvement in insulin sensitivity was observed in PCOS rats on normal chow.
Exercise improves insulin resistance and is a first line for the prevention and treatment of type 2 diabetes. The extent, however, to which these response are dose-dependent is not known. The purpose of this study was to examine whether or not exercise dose was associated with improvements in insulin sensitivity following four months of exercise training in previously sedentary adults.
Fifty-five healthy volunteers participated in a 16-week supervised endurance exercise intervention with a pre/post intervention design. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp, peak oxygen uptake by a graded exercise test and body composition by DXA. The exercise intervention consisted of 3 to 5 sessions/week with a minimum of 3 sessions supervised. A ramped exercise prescription protocol was used to achieve 75% of peak HR for 45 minutes/session. Exercise dose, expressed as average kcal expended per week, was computed as the product of exercise intensity, duration and frequency.
Improved insulin sensitivity was significantly related to exercise dose in a graded dose-response relationship. No evidence of threshold or maximal dose-response effect was observed. Age and gender did not influence this dose-response relationship. Exercise intensity was also significantly related to improvements in insulin sensitivity, while frequency was not.
This study identifies a graded dose-response relationship between exercise dose and improvements in insulin sensitivity. The implication of this observation is of importance for the adaptation of exercise prescription in clinical situations.
Exercise dose-response; insulin resistance; obesity; type 2 diabetes; exercise prescription
Insulin resistance in skeletal muscle is an early phenomenon in the pathogenesis of type 2 diabetes. Muscle is mainly responsible for insulin-stimulated glucose clearance from the bloodstream. Thus, regulation of gene expression in muscle tissue may be involved in the pathogenesis of insulin resistance. The objective was to investigate gene expression and metabolic pathways alterations in skeletal muscle tissue following an euglycemic-hyperinsulinemic clamp in obese insulin-resistant subjects. We carried out a transcriptome comparison of skeletal muscle tissue before and after a 3-h euglycemic-hyperinsulinemic clamp following 8-week supplementation with n-3 polyunsaturated fatty acid (PUFA) (1.8 g/day) with or without a supplement of fish gelatin (FG) (25 % of daily protein intake) in 16 obese insulin-resistant subjects. Results indicate that approximately 5 % (1932) of expressed transcripts were significantly changed after the clamp in both n-3 PUFA and n-3 PUFA + FG supplementation periods. Of these differentially expressed transcripts, 1394 genes associated with enzymes, transcription and translation regulators, transporters, G protein-coupled receptors, cytokines, and ligand-dependent nuclear receptors were modified. Metabolic pathways that were significantly modified included liver X receptor/retinoid X receptors (RXR) activation, vitamin D receptor/RXR activation, interleukin (IL)-8, acute phase response, IL10, triggering receptor expressed on myeloid cells 1, peroxisome proliferator-activated receptor, G-beta/gamma and hepatocyte growth factor and IL6 signaling. Taken together, results suggest that mainly inflammatory and transcription factors are modified following clamp in obese insulin-resistant subjects. Overall, understanding the changes in metabolic pathways due to insulin may be a potential target for the management of insulin resistance.
Diabetes; Obesity; Microarray; Gene expression; Metabolic pathways
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.
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.
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.
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.
The prevalence of insulin resistance, metabolic syndrome, and cardiovascular disease is greatest in older obese patients, and effective evidence-based treatment strategies are lacking.
A prospective controlled study was conducted on 24 older (65.5 ± 5.0 years) obese (body mass index, 34.3 ± 5.2 kg/m2) adults with clinically diagnosed metabolic syndrome. We examined the effect of exercise alone (EX) or exercise combined with moderate caloric restriction (−500 kcal, EX + CR) on metabolic and cardiovascular risk factors. Measures of insulin sensitivity assessed by euglycemic hyperinsulinemic clamp and by oral glucose tolerance test, lipid profiles, blood pressure, body composition, abdominal fat, and aerobic capacity were all obtained before and after the interventions.
Both groups experienced significant weight loss, but the reduction was greater in the EX + CR group than in the EX group (−6.8 ± 2.7 kg vs −3.7 ± 3.4 kg, respectively, p = .02). Both interventions improved insulin sensitivity (2.4 ± 2.4 mg/kg FFM/min and 1.4 ± 1.7 mg/kgFFM/min, respectively, p < .001) and indices of metabolic syndrome (systolic/diastolic blood pressure, waist circumference, glucose, and triglycerides; p < .05). High-density lipoprotein levels remained unchanged. Total abdominal, subcutaneous, and visceral fat; aerobic capacity; and total and low-density lipoprotein cholesterol were also improved. With the exception of weight loss and subcutaneous fat, there was no difference in the magnitude of improvement between the interventions.
These data suggest that exercise alone is an effective nonpharmacological treatment strategy for insulin resistance, metabolic syndrome, and cardiovascular disease risk factors in older obese adults.
Aging; Obesity; Diabetes; Impaired glucose tolerance
Low levels of osteocalcin (OCN), an osteoblast-specific hormone, have recently been associated with insulin resistance (homeostasis model assessment-insulin resistance (HOMA-IR)) and obesity, particularly in older adults. The aim of this study was to determine whether low levels of OCN would be associated with insulin resistance, obesity, and greater cardiovascular (CV) risk in young adults just emerging from adolescence. Undercarboxylated OCN and carboxylated OCN levels were measured on stored serum samples (total OCN = undercarboxylated OCN + carboxylated OCN) on 137 participants (67 males) at mean age 18.6 years (range 17–22 years). Insulin resistance was measured by hyperinsulinemic–euglycemic clamp (Mlbm). Multivariable regression analyses with ln(OCN) as the independent variable were adjusted for age, sex, ethnicity, and BMI as indicated. Total OCN was inversely related to BMI, waist circumference, systolic blood pressure (SBP), interleukin (IL)-6, and directly related to Mlbm; only SBP remained significant (with Mlbm
P = 0.0560) after further adjustment for BMI. Carboxylated OCN was inversely related to BMI, waist circumference, SBP, low-density lipoprotein cholesterol (LDL-C), and directly related to adiponectin; SBP and adiponectin remained significant after further adjustment for BMI. There were no significant associations with undercarboxylated OCN. In summary, most associations with OCN were mediated via BMI. However, the significant associations of OCN with SBP, obesity, and adiponectin and borderline with Mlbm, suggest a potential role for OCN in the development of insulin resistance and CV risk that becomes more apparent with aging into older adulthood.
Growing evidence indicates that metabolic syndrome is rooted in fetal life with a potential key role of nutrition during pregnancy. The objective of the study was to assess the possible associations between the dietary glycemic index (GI) and glycemic load (GL) during pregnancy and biomarkers of the metabolic syndrome in young adult offspring.
Dietary GI and GL were assessed by questionnaires and interviews in gestation week 30 and offspring were clinically examined at the age of 20 years. Analyses based on 428 mother-offspring dyads were adjusted for maternal smoking during pregnancy, height, pre-pregnancy body mass index (BMI), education, energy intake, and the offspring’s ambient level of physical activity. In addition, possible confounding by gestational diabetes mellitus was taken into account.
Waist circumference, blood pressure, HOMA insulin resistance (HOMA-IR) and plasma levels of fasting glucose, triglycerides, HDL cholesterol, LDL cholesterol, total cholesterol, insulin, and leptin were measured in the offspring.
Significant associations were found between dietary GI in pregnancy and HOMA-IR (the relative increase in HOMA-IR per 10 units’ GI increase was 1.09 [95% CI: 1.01, 1.16], p = 0.02), insulin (1.09 [95% CI: 1.02, 1.16], p = 0.01) and leptin (1.21 [95% CI: 1.06, 1.38], p = 0.01) in the offspring; whereas no associations were detected for GL.
Our data suggests that high dietary GI in pregnancy may affect levels of markers for the metabolic syndrome in young adult offspring in a potentially harmful direction.
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.
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.
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).
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.
Obesity; Overweight; Cardiovascular risk factors; Exercise training
Low-fat hypocaloric diets reduce insulin resistance and prevent type 2 diabetes in those at risk. Low-carbohydrate, high-fat diets are advocated as an alternative, but reciprocal increases in dietary fat may have detrimental effects on insulin resistance and offset the benefits of weight reduction.
RESEARCH DESIGN AND METHODS
We investigated a low-fat (20% fat, 60% carbohydrate) versus a low-carbohydrate (60% fat, 20% carbohydrate) weight reduction diet in 24 overweight/obese subjects ([mean ± SD] BMI 33.6 ± 3.7 kg/m2, aged 39 ± 10 years) in an 8-week randomized controlled trial. All food was weighed and distributed, and intake was calculated to produce a 500 kcal/day energy deficit. Insulin action was assessed by the euglycemic clamp and insulin secretion by meal tolerance test. Body composition, adipokine levels, and vascular compliance by pulse-wave analysis were also measured.
Significant weight loss occurred in both groups (P < 0.01), with no difference between groups (P = 0.40). Peripheral glucose uptake increased, but there was no difference between groups (P = 0.28), and suppression of endogenous glucose production was also similar between groups. Meal tolerance–related insulin secretion decreased with weight loss with no difference between groups (P = 0.71). The change in overall systemic arterial stiffness was, however, significantly different between diets (P = 0.04); this reflected a significant decrease in augmentation index following the low-fat diet, compared with a nonsignificant increase within the low-carbohydrate group.
This study demonstrates comparable effects on insulin resistance of low-fat and low-carbohydrate diets independent of macronutrient content. The difference in augmentation index may imply a negative effect of low-carbohydrate diets on vascular risk.
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.
Chronic insulin resistance contributes to subclinical inflammation, thrombosis/impaired fibrinolysis, and dyslipidemia. The effect of dietary carbohydrate, specifically of glycemic index (GI) and glycemic load (GL), on established and emerging coronary heart disease (CHD) risk factors has not been elucidated fully. We conducted a randomized, cross-over feeding study of matched diets differing only in GI and GL in 24 overweight or obese but otherwise healthy men to investigate the effects on insulin sensitivity, inflammation, thrombosis/fibrinolysis, lipoproteins/lipids, and body composition. All meals for the high- and low-GI/GL diets were prepared in a metabolic kitchen. Each participant consumed both diets in random order for 4 weeks each, with a 4-week wash-out period in between. Each participant underwent a frequently-sampled intravenous glucose tolerance test for assessment of insulin sensitivity; blood sampling for the measurement of inflammatory markers, coagulation factors, and lipoproteins/lipids; and dual-energy x-ray absorptiometry for assessment of body composition at the beginning and end of each dietary period. There were no statistically significant differences in glucose metabolism factors, inflammatory markers, or coagulation factors following 4 weeks on the high- and low-GI/GL diets. The high-GI/GL diet resulted in a slightly greater reduction in fat mass and a slightly greater increase in lean mass compared to the low-GI/GL diet. The high-GI/GL diet resulted in significant, but unexpected, reductions in total and LDL cholesterol, while HDL cholesterol concentration was significantly reduced on the high-GI/GL diet compared to the low-GI/GL diet. Overall, high- and low-GI/GL diets of 4-weeks duration had no consistent effects on CHD risk factors in this group of overweight/obese men.
Comprehensive lifestyle interventions are effective in preventing diabetes and restoring glucose regulation; however, the key stimulus for change has not been identified and effects in older individuals are not established. The aim of the study was to investigate the independent and combined effects of dietary weight-loss and exercise on insulin sensitivity and restoration of normal fasting glucose in mid-aged and older women.
Four-arm RCT, conducted between 2005 and 2009 and data analyzed in 2010.
439 inactive, overweight/obese postmenopausal women. Interventions: Women were assigned to: dietary weight loss (n=118), exercise (n=117), exercise+diet (n=117), or control (n=87). The diet intervention was a group-based reduced-calorie program with a 10% weight-loss goal. The exercise intervention was 45 min/day, 5 days/week of moderate-to-vigorous intensity aerobic activity.
Main outcome measures
12-month change in serum insulin, C-peptide, fasting glucose, and whole body insulin resistance (HOMA-IR).
A significant improvement in HOMA-IR was detected in the diet (−24%, p<0.001) and exercise+ diet (−26%, p<0.001) groups, but not in the exercise (−9%, p=0.22) group compared to controls (−2%); these effects were similar in middle-aged (50–60 years) and older women (aged 60–75 years). Among those with impaired fasting glucose (5.6–6.9 mmol/L) at baseline (n=143; 33%), the odds (95% CI) of regressing to normal fasting glucose after adjusting for weight loss and baseline levels were: 2.5 (0.8, 8.4), 2.76 (0.8, 10.0), and 3.1 (1.0, 9.9) in the diet, exercise+diet, and exercise group, respectively, compared to controls.
Dietary weight loss, with or without exercise, significantly improved insulin resistance. Older women derived as much benefit as did the younger postmenopausal women.
The “Carnivore Connection” hypothesizes that, during human evolution, a scarcity of dietary carbohydrate in diets with low plant : animal subsistence ratios led to insulin resistance providing a survival and reproductive advantage with selection of genes for insulin resistance. The selection pressure was relaxed at the beginning of the Agricultural Revolution when large quantities of cereals first entered human diets. The “Carnivore Connection” explains the high prevalence of intrinsic insulin resistance and type 2 diabetes in populations that transition rapidly from traditional diets with a low-glycemic load, to high-carbohydrate, high-glycemic index diets that characterize modern diets. Selection pressure has been relaxed longest in European populations, explaining a lower prevalence of insulin resistance and type 2 diabetes, despite recent exposure to famine and food scarcity. Increasing obesity and habitual consumption of high-glycemic-load diets worsens insulin resistance and increases the risk of type 2 diabetes in all populations.
The putative blunted thermogenesis in obesity may be related to insulin resistance, but insulin sensitivity and obesity are potentially confounding factors. To determine the independent effects of obesity and insulin resistance on the thermic effect of food, at rest and after exercise, lean and obese men were matched at two levels of insulin sensitivity determined by insulin-stimulated glucose disposal (milligrams per kilogram fat-free mass [FFM] per minute) during the euglycemic, hyperinsulinemic (40 mU/m2.min) clamp: 5.4 mg/kg FFM for the lean and obese groups with low insulin sensitivity, and 8.1 mg/kg FFM for the groups with high insulin sensitivity. The two lean groups were matched for percent fat (approximately 15 +/- 1% fat), as were the two obese groups (approximately 33 +/- 2% fat). Energy expenditure was measured for 3 h in the fasting state and for 3 h after a 720-kcal mixed meal, each at rest and immediately after 1 h of cycling at 100 W. The thermic effect of food (TEF) was calculated as the postprandial minus fasting energy expenditure (kcal/3 h) during rest and after exercise. During rest, TEF was blunted by both obesity (24 +/- 5 and 34 +/- 6 kcal/3 h for obese groups with low and high insulin sensitivity vs. 56 +/- 6 and 74 +/- 6 kcal/3 h for the lean groups with low and high insulin sensitivity; P less than 0.01 lean vs. obese) and insulin resistance (insulin-resistant less than insulin-sensitive, at both levels of obesity; P less than 0.01). After exercise, TEF was also impaired in the obese (47 +/- 6 and 44 +/- 5 kcal/3 h for the insulin-resistant and -sensitive groups) and in the lean insulin-resistant (55 +/- 5 kcal/3 h), compared with the lean insulin-sensitive men (71 +/- 3 kcal/3 h), P less than 0.01. Compared with rest, TEF after exercise was improved, but not normalized, in both obese groups (P less than 0.05), but unchanged in the lean groups. These results suggest that both insulin resistance and obesity are independently associated with impaired TEF at rest, but the responsiveness of thermogenesis to exercise before a meal is related to the obese state and not independently to insulin resistance per se.
Insulin resistance is commonly associated with obesity. Studies conducted in obese mouse models found that endoplasmic reticulum (ER) stress contributes to insulin resistance, and treatment with tauroursodeoxycholic acid (TUDCA), a bile acid derivative that acts as a chemical chaperone to enhance protein folding and ameliorate ER stress, increases insulin sensitivity. The purpose of this study was to determine the effect of TUDCA therapy on multiorgan insulin action and metabolic factors associated with insulin resistance in obese men and women.
RESEARCH DESIGN AND METHODS
Twenty obese subjects ([means ± SD] aged 48 ± 11 years, BMI 37 ± 4 kg/m2) were randomized to 4 weeks of treatment with TUDCA (1,750 mg/day) or placebo. A two-stage hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled tracer infusions and muscle and adipose tissue biopsies were used to evaluate in vivo insulin sensitivity, cellular factors involved in insulin signaling, and cellular markers of ER stress.
Hepatic and muscle insulin sensitivity increased by ∼30% (P < 0.05) after treatment with TUDCA but did not change after placebo therapy. In addition, therapy with TUDCA, but not placebo, increased muscle insulin signaling (phosphorylated insulin receptor substrateTyr and AktSer473 levels) (P < 0.05). Markers of ER stress in muscle or adipose tissue did not change after treatment with either TUDCA or placebo.
These data demonstrate that TUDCA might be an effective pharmacological approach for treating insulin resistance. Additional studies are needed to evaluate the target cells and mechanisms responsible for this effect.
OBJECTIVE—Skeletal muscle–specific LPL knockout mouse (SMLPL−/−) were created to study the systemic impact of reduced lipoprotein lipid delivery in skeletal muscle on insulin sensitivity, body weight, and composition.
RESEARCH DESIGN AND METHODS—Tissue-specific insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp and 2-deoxyglucose uptake. Gene expression and insulin-signaling molecules were compared in skeletal muscle and liver of SMLPL−/− and control mice.
RESULTS—Nine-week-old SMLPL−/− mice showed no differences in body weight, fat mass, or whole-body insulin sensitivity, but older SMLPL−/− mice had greater weight gain and whole-body insulin resistance. High-fat diet feeding accelerated the development of obesity. In young SMLPL−/− mice, insulin-stimulated glucose uptake was increased 58% in the skeletal muscle, but was reduced in white adipose tissue (WAT) and heart. Insulin action was also diminished in liver: 40% suppression of hepatic glucose production in SMLPL−/− vs. 90% in control mice. Skeletal muscle triglyceride was 38% lower, and insulin-stimulated phosphorylated Akt (Ser473) was twofold greater in SMLPL−/− mice without changes in IRS-1 tyrosine phosphorylation and phosphatidylinositol 3-kinase activity. Hepatic triglyceride and liver X receptor, carbohydrate response element–binding protein, and PEPCK mRNAs were unaffected in SMLPL−/− mice, but peroxisome proliferator–activated receptor (PPAR)-γ coactivator-1α and interleukin-1β mRNAs were higher, and stearoyl–coenzyme A desaturase-1 and PPARγ mRNAs were reduced.
CONCLUSIONS—LPL deletion in skeletal muscle reduces lipid storage and increases insulin signaling in skeletal muscle without changes in body composition. Moreover, lack of LPL in skeletal muscle results in insulin resistance in other key metabolic tissues and ultimately leads to obesity and systemic insulin resistance.
The purpose of this pilot study was to assess the feasibility and effectiveness of an intense health promotion program in older adults with diabetes. The program combined individually prescribed and supervised exercise with nutrition and education programs on glycemic control and aerobic fitness.
Various recruitment and retention strategies were analyzed for effectiveness. Out of 28 potential subjects assessed for eligibility, 6 subjects with type 2 diabetes (2 male and 4 female; all white; age, 60.2 ± 4.7 years) participated in the 10-week intervention. Aerobic and resistance exercise was performed on alternate days (3-4 days per week), with individualized nutrition counseling and diabetes health education sessions once weekly. The primary outcome measures were aerobic fitness and glycemic control (A1C), and secondary outcome measures included body mass index (BMI), self-efficacy, and symptoms of neuropathy. Changes in outcomes were assessed using descriptive statistics and paired t test analysis (α = .05).
Following the intervention, subjects had improvements that approached significance in A1C and pain, with significant improvements in self-efficacy.
A systematic approach to analysis of feasibility revealed issues with recruitment and retention that would need to be addressed for future studies or clinical implementation of this program. However, for the subset of subjects who did complete the intervention, adherence was excellent, and satisfaction with the program was confirmed by exit interview comments. Following participation in this pilot health promotion program, subjects had meaningful improvements in glycemic control, pain, and self-efficacy.
It is unclear whether immediate dietary effects on blood glucose influence risk of developing type 2 diabetes.
The objective of this study was to examine whether the dietary glycemic index (GI) and glycemic load (GL) were associated with risk of type 2 diabetes in older adults.
The Health, Aging and Body Composition Study is a prospective cohort study of 3075 adults age 70 to 79 at baseline (n=1898 for this analysis). Intake of specific nutrients and food groups and risk of type 2 diabetes over a 4-year period were examined according to dietary GI and GL.
Dietary GI was positively associated with dietary carbohydrate, and negatively associated with intake of protein, total fat, saturated fat, alcohol, vegetables and fruit. Dietary GL was positively associated with dietary carbohydrate, fruit and fiber, and negatively associated with intake of protein, total fat, saturated fat and alcohol. Persons in the higher quintiles of dietary GI or GL did not show a significantly higher incidence of type 2 diabetes.
This study does not support a relationship between dietary GI or GL and risk of type 2 diabetes in older adults. Because dietary GI and GL show strong nutritional correlates, the overall dietary pattern should be considered.
diet; glycemic index; glycemic load; type 2 diabetes; older adults
We aim to investigate the effectiveness of a 10-week lifestyle intervention focusing on physical activity and high fiber intake for reducing indicators for metabolic syndrome in overweight-obese individuals. A prospective study of 50 overweight (OW) adults (22 in the general educational group - G1; 28 in the high fiber nutrition group - G2) was performed. Both groups were offered dietary counseling and supervised exercise. Clinical, anthropometric, dietary and plasma biochemical tests were performed at baseline - time 0 (T0) and after 10 weeks - time 1 (T1). Both groups improved their dietary quality, but only G2 presented higher intake of fruit and vegetables (servings/day), higher plasma β-carotene levels and a 24% reduction of MetS incidence. Additionally G2 showed greater reductions in body fat (4%), and waist circumference (7%), obesity class III (2%) and obesity class II (14%) rate. Lifestyle intervention, including a high dietary fiber intake, improved healthy eating index and decreased body fat composition and plasma lipid concentrations leading to MetS incidence reduction.
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).
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.
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.
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 registered at clinicaltrials.gov NCT01264523.
Reductions in insulin sensitivity in conjunction with muscle mitochondrial dysfunction have been reported to occur in many conditions including aging. The objective was to determine whether insulin resistance and mitochondrial dysfunction are directly related to chronological age or are related to age-related changes in body composition.
RESEARCH DESIGN AND METHODS
Twelve young lean, 12 young obese, 12 elderly lean, and 12 elderly obese sedentary adults were studied. Insulin sensitivity was measured by a hyperinsulinemic-euglycemic clamp, and skeletal muscle mitochondrial ATP production rates (MAPRs) were measured in freshly isolated mitochondria obtained from vastus lateralis biopsy samples using the luciferase reaction.
Obese participants, independent of age, had reduced insulin sensitivity based on lower rates of glucose infusion during a hyperinsulinemic-euglycemic clamp. In contrast, age had no independent effect on insulin sensitivity. However, the elderly participants had lower muscle MAPRs than the young participants, independent of obesity. Elderly participants also had higher levels inflammatory cytokines and total adiponectin. In addition, higher muscle MAPRs were also noted in men than in women, whereas glucose infusion rates were higher in women.
The results demonstrate that age-related reductions in insulin sensitivity are likely due to an age-related increase in adiposity rather than a consequence of advanced chronological age. The results also indicate that an age-related decrease in muscle mitochondrial function is neither related to adiposity nor insulin sensitivity. Of interest, a higher mitochondrial ATP production capacity was noted in the men, whereas the women were more insulin sensitive, demonstrating further dissociation between insulin sensitivity and muscle mitochondrial function.
Several reports have suggested that conditions associated with hyperinsulinemia and insulin resistance, such as diets high in carbohydrates, may influence the risk of pancreatic cancer, although results from prior studies have been mixed.
We utilized data from the population-based women’s health initiative (WHI) cohort to determine whether dietary factors that are associated with increased postprandial blood glucose levels are also associated with an increased risk of pancreatic cancer. The WHI included 161,809 postmenopausal women of ages 50–79, in which 332 cases of pancreatic cancer were identified over a median of 8 years of follow-up; 287 of these cases met the criteria for analysis. A validated 122-item food frequency questionnaire was used to estimate dietary glycemic load (GL), glycemic index (GI), total and available carbohydrates, fructose and sucrose. Baseline questionnaires and physical exams provided information on demographic, medical, lifestyle, and anthropometric characteristics. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between the exposures of interest and pancreatic cancer risk, with adjustment for potential confounders.
Dietary GL, GI, carbohydrates, fructose, and sucrose were not associated with increased risk of pancreatic cancer. The multivariable adjusted HR for the highest vs. the lowest quartile of GL was 0.80 (95% CI = 0.55–1.15, trend p = 0.31) and 1.13 (95% CI = 0.78–1.63, trend p = 0.94) for GI. The results remained negative when individuals with a history of diabetes were excluded.
Our results do not support the hypothesis that dietary intake of carbohydrates is associated with increased risk of pancreatic cancer.
Glycemic index; Glycemic load; Pancreatic neoplasms; Prospective cohort
Hyperinsulinemia is a common feature of many obesity syndromes. We investigated whether suppression of insulin secretion, without dietary or exercise intervention, could promote weight loss and alter food intake and preference in obese adults.
Suppression of insulin secretion was achieved using octreotide-LAR 40 mg IM q28d for 24 weeks in 44 severely obese adults (89% female, 39% minority). Oral glucose tolerance testing was performed before and after treatment, indices of β-cell activity (CIRgp), insulin sensitivity (CISI), and clearance (CP/I AUC) were computed, and leptin levels, 3-day food records and carbohydrate-craving measurements were obtained. DEXA evaluations were performed pre- and post-therapy in an evaluable subgroup.
For the entire cohort, significant insulin suppression was achieved with simultaneous improvements in insulin sensitivity, weight loss, and body mass index (BMI). Leptin, fat mass, total caloric intake, and carbohydrate craving significantly decreased. When grouped by BMI response, high responders (HR; ΔBMI < −3 kg/m2) and low responders (LR; ΔBMI between −3 and −0.5) exhibited higher suppression of CIRgp and IAUC than nonresponders (NR; ΔBMI > −0.5). CISI improved and significant declines in leptin and fat mass occurred only in HR and LR. Conversely, both leptin and fat mass increased in NR. Carbohydrate intake was markedly suppressed in HR only, while carbohydrate-craving scores decreased in HR and LR. For the entire cohort, ΔBMI correlated with ΔCISI, Δfat mass, and Δleptin. ΔFat mass also correlated with ΔIAUC and ΔCISI.
In a subcohort of obese adults, suppression of insulin secretion was associated with loss of body weight and fat mass and with concomitant modulation of caloric intake and macronutrient preference.
obesity; insulin; somatostatin; octreotide; weight loss
BACKGROUND & AIMS
Obesity-related insulin resistance contributes to cardiovascular disease. Cannabinoid receptor-1 (CB1) blockade improves insulin sensitivity in obese animals and people, suggesting endocannabinoid involvement. We explored the role of hepatic CB1 in insulin resistance and inhibition of insulin signaling pathways.
Wild-type mice and mice with disruption of CB1 (CB1−/− mice) or with hepatocyte-specific deletion or transgenic overexpression of CB1 were maintained on regular chow or a high-fat diet (HFD) to induce obesity and insulin resistance. Hyperinsulinemic-euglycemic clamp analysis was used to analyze the role of the liver and hepatic CB1 in HFD-induced insulin resistance. The cellular mechanisms of insulin resistance were analyzed in mouse and human isolated hepatocytes using small interfering or short hairpin RNAs and lentiviral knockdown of gene expression.
The HFD induced hepatic insulin resistance in wild-type mice, but not in CB1−/− mice or mice with hepatocyte-specific deletion of CB1. CB1−/− mice that overexpressed CB1 specifically in hepatocytes became hyperinsulinemic as a result of reduced insulin clearance due to down-regulation of the insulin-degrading enzyme. However, they had increased hepatic glucose production due to increased glycogenolysis, indicating hepatic insulin resistance; this was further increased by the HFD. In mice with hepatocytes that express CB1, the HFD or CB1 activation induced the endoplasmic reticulum stress response via activation of the Bip-PERK-eIF2α protein translation pathway. In hepatocytes isolated from human or mouse liver, CB1 activation caused endoplasmic reticulum stress-dependent suppression of insulin-induced phosphorylation of akt-2 via phosphorylation of IRS1 at serine-307 and by inducing the expression of the serine and threonine phosphatase Phlpp1. Expression of CB1 was up-regulated in samples from patients with nonalcoholic fatty liver disease.
Endocannabinoids contribute to diet-induced insulin resistance in mice via hepatic CB1-mediated inhibition of insulin signaling and clearance.
NASH; Signal Transduction; Mouse Model; Liver Disease
Background & Aims
Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) reduce weight and improve glucose metabolism in obese patients, although it is not clear if metabolic changes are independent of weight loss. We investigated alterations in glucose metabolism in rats following RYGB or VSG.
Rats underwent RYGB or VSG and were compared to sham-operated rats that were fed ad lib or pair-fed with animals that received RYGB. Intraperitoneal glucose tolerance and insulin sensitivity tests were performed to assess glycemic function, independent of the incretin response. A hyperinsulinemic euglycemic clamp was used to compare tissue-specific changes in insulin sensitivity following each procedure. A mixed-meal tolerance tests was used to assess the effect of each surgery on post-prandial release of GLP-1(7–36) and glucose tolerance, and were also performed in rats given the GLP-1 receptor antagonist exendin9–39.
Following RYGB or VSG, glucose tolerance and insulin sensitivity improved, in proportion to weight loss. Hepatic insulin sensitivity was significantly better in rats that received RYGB or VSG, compared with rats fed ad lib or pair-fed, whereas glucose clearance was similar in all groups. During the mixed-meal tolerance test, plasma levels of GLP-1(7–36) and insulin were greatly and comparably increased in rats that received RYGB and VSG, compared with those that were pair-fed or fed ad lib. Administration of a GLP-1 receptor antagonist prevented improvements in glucose and insulin responses after a meal among rats that received RYGB or VSG.
In obese rats, VSG is as effective as RYGB at increasing secretion of GLP-1 and insulin secretion and at improving hepatic sensitivity to insulin; these effects are independent of weight loss.
obesity; surgery; weight reduction; diabetes