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1.  Vitamin D metabolism-related genetic variants, dietary protein intake and improvement of insulin resistance in a 2 year weight-loss trial: POUNDS Lost 
Diabetologia  2015;58(12):2791-2799.
Vitamin D and related genetic variants are associated with obesity and insulin resistance. We aimed to examine whether vitamin D metabolism-related variants affect changes in body weight and insulin resistance in response to weight-loss diets varying in macronutrient content.
Three vitamin D metabolism-related variants, DHCR7 rs12785878, CYP2R1 rs10741657 and GC rs2282679, were genotyped in 732 overweight/obese participants from a 2 year weight-loss trial (POUNDS Lost). We assessed genotype effects on changes in body weight, fasting levels of glucose and insulin, and HOMA-IR at 6 months (up to 656 participants) and 2 years (up to 596 participants) in response to low-protein vs high-protein diets, and low-fat vs high-fat diets.
We found significant interactions between DHCR7 rs12785878 and diets varying in protein, but not in fat, on changes in insulin and HOMA-IR at both 6 months (p for interaction <0.001) and 2 years (p for interaction ≤0.03). The T allele (vitamin-D-increasing allele) of DHCR7 rs12785878 was associated with greater decreases in insulin and HOMA-IR (p<0.002) in response to high-protein diets, while there was no significant genotype effect on changes in these traits in the low-protein diet group. Generalised estimating equation analyses indicated significant genotype effects on trajectory of changes in insulin resistance over the 2 year intervention in response to high-protein diets (p<0.001). We did not observe significant interaction between the other two variants and dietary protein or fat on changes in these traits.
Our data suggest that individuals carrying the T allele of DHCR7 rs12785878 might benefit more in improvement of insulin resistance than noncarriers by consuming high-protein weight-loss diets.
Trial registration NCT00072995
PMCID: PMC4631625  PMID: 26416604
Diet intervention; Genetic variants; Insulin resistance; Vitamin D; Weight loss
2.  Testosterone and depressive symptoms among men in the Diabetes Prevention Program 
Psychoneuroendocrinology  2016;72:63-71.
Structured Abstract
We examined associations between randomization to intensive lifestyle intervention (ILS) and changes in testosterone and associations with mood among middle-aged men.
Secondary analysis of men (n=886) participating in the Diabetes Prevention Program which randomized glucose-intolerant, overweight men to ILS, metformin, or placebo.
Main Outcome Measures
Changes in testosterone between baseline and 1-year follow-up and associations of these changes with mood measures (Beck Depression Inventory [BDI], Beck Anxiety Inventory [BAI])
Median baseline testosterone was 10.98 nmol/l and 44% (n=385) had testosterone < 10.41 nmol/l or 300 ng/dl, a common threshold for biochemical hypogonadism. Testosterone increases were greater among men randomized to ILS vs. metformin vs. placebo (1.15 nmol/l vs. −0.12 nmol/l vs. −0.27 nmol/l, p<0.001). The association between changes in testosterone and mood differed by randomization arm (p<0.001 for interaction); there were no significant associations between changes in testosterone and mood changes among men randomized to ILS or placebo. Among men randomized to metformin, increases in testosterone were significantly associated with decreases in BDI (improved depressive symptoms) (β-coefficient −0.2336, p=0.0002) indicating a 0.23 decrease in BDI for every 1 nmol/l increase in testosterone and decreases in BAI (improved anxiety symptoms) (β-coefficient −0.2147, p=0.0014). Similar patterns were observed for bioavailable testosterone.
Among overweight middle-aged men with glucose-intolerance, ILS increased endogenous testosterone slightly but without significant improvements in mood. Metformin did not increase testosterone, but among participants randomized to metformin, testosterone increases were associated with improvements in mood. Thus, interventions that increase endogenous testosterone may not also improve mood.
PMCID: PMC5070975  PMID: 27371769
testosterone; androgens; mood; glucose-intolerance
3.  R1 - Eight Weeks of Dietary Overfeeding Increases Renal Filtration Rates in Humans: Implications for the Pathogenesis of Diabetic Hyperfiltration 
Journal of internal medicine  2015;278(4):396-400.
Diabetic nephropathy is characterized at its onset by glomerular hyperfiltration. Prospective studies in humans measuring filtration rates with weight gain are lacking. We investigated renal filtration following weight gain induced by overfeeding.
Eight week of overfeeding (40 percent above energy requirements; 44 percent fat, 15 percent protein and 41 percent carbohydrate) as well as a six month follow-up after the overfeeding intervention.
Thirty-five participants (age: 26.7 ± 5.3 yrs; BMI: 25.5 ± 2.2 kg/m2; 29m/6f).
Creatinine clearance rate (Ccr) from 24-hour urine collection, estimated glomerular filtration rate (eGFR) from the modification of diet in renal disease (MDRD), insulin sensitivity/glucose disposal rate (GDR) by a euglycemic-hyperinsulinemic clamp, components from basic metabolic panels, and serum lipid panels
Both eGFR and Ccr increased with overfeeding (p = 0.04) and serum lipids (all p < 0.05), along with a decrease in insulin sensitivity (p = 0.003). Fasting glucose concentration was not affected (p = 0.98), but the percent change in Ccr correlated positively with the change in GDR with overfeeding (r = 0.39, p = 0.02). Six months following overfeeding, serum glucose was maintained, and no evidence of urinary glucose was observed at any time point.
This data suggests that renal hyperfiltration may act as a mechanism to preserve insulin sensitivity through maintenance of systemic glucose homeostasis with caloric excess.
PMCID: PMC4560986  PMID: 25903638
Glomerular Filtration Rate; End stage renal disease; type 2 diabetes; insulin resistance
4.  Self-Reported Gastrointestinal Symptoms in Type 2 Diabetes Improve With an Intensive Lifestyle Intervention: Results From the Action for Health in Diabetes (Look AHEAD) Clinical Trial 
In Brief This article reports on an investigation of whether an intensive lifestyle intervention (ILI) would reduce gastrointestinal symptoms over 4 years of follow-up for participants in the Action for Health in Diabetes (Look AHEAD) trial compared to a diabetes support and education (DSE) group. Look AHEAD is a randomized, multicenter trial comparing overweight and obese adults with type 2 diabetes treated with ILI versus DSE. ILI, and weight loss in general, had beneficial effects on gastrointestinal (GI) symptoms, with some variability in the strength of the effect depending on the specific symptom and time course. Potential modifiers were analyzed, yet ILI retained an association with improvement in GI symptoms.
PMCID: PMC4608270  PMID: 26487792
5.  Body Weight Dynamics Following Intentional Weight Loss and Physical Performance: The Look AHEAD Movement and Memory Study 
Obesity science & practice  2015;1(1):12-22.
To explore the impact of body weight change following intentional weight loss on measures of physical performance in adults with diabetes.
Design and methods
450 individuals with type 2 diabetes (age: 59.0±6.9 years, BMI: 35.5±5.9 kg/m2) who participated in the Look AHEAD Movement and Memory Study and lost weight one year after being randomized to an intensive lifestyle intervention were assessed. Body weight was measured annually, and participants were categorized as continued losers/maintainers, regainers, or cyclers based on a ±5% annual change in weight. Objective measures of physical performance were measured at the year 8/9 visit.
Forty-four, 38 and 18% of participants were classified as regainers, cyclers, and continued losers/maintainers. In women, weight cycling and regain was associated with worse follow-up expanded physical performance battery score (1.46±0.07 and 1.48±0.07 vs. 1.63±0.07, both p≤0.02) and slower 20-meter walking speed (1.10±0.04 and 1.08±0.04 m/s vs. 1.17±0.04 m/s, both p<0.05) compared to continued or maintained weight loss. Male cyclers presented with weaker grip strength compared to regainers or continued losers/maintainers (30.12±2.21 kg versus 34.46±2.04 and 37.39±2.26 kg; both p<0.01).
Weight cycling and regain following intentional weight loss in older adults with diabetes was associated with worse physical function in women and grip strength in men.
PMCID: PMC4950993  PMID: 27453790
Weight loss; Weight cycling; Physical performance; Type 2 diabetes mellitus
6.  Genetic variation of fasting glucose and changes in glycemia in response to 2-year weight-loss diet intervention: the POUNDS Lost trial 
Weight loss intervention through diet modification has been widely used to improve obesity-related hyperglycemia; however, little is known about whether genetic variation modifies the intervention effect. We examined the interaction between weight-loss diets and genetic variation of fasting glucose on changes in glycemic traits in a dietary intervention trial.
Research Design and Methods
The Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial is a randomized, controlled 2-year weight-loss trial. We assessed overall genetic variation of fasting glucose by calculating a genetic risk score (GRS) based on 14 fasting glucose-associated single nucleotide polymorphisms, and examined the progression in fasting glucose and insulin levels, and insulin resistance and insulin sensitivity in 733 adults from this trial.
The GRS was associated with 6-month changes in fasting glucose (P<0.001), fasting insulin (P=0.042), homeostasis model assessment of insulin resistance (HOMA-IR, P=0.009) and insulin sensitivity (HOMA-S, P=0.043). We observed significant interaction between the GRS and dietary fat on 6-month changes in fasting glucose, HOMA-IR and HOMA-S after multivariable adjustment (P-interaction=0.007, 0.045, and 0.028, respectively). After further adjustment for weight loss, the interaction remained significant on change in fasting glucose (P=0.015). In the high-fat diet group, participants in the highest GRS tertile showed increased fasting glucose, whereas participants in the lowest tertile showed decreased fasting glucose (P-trend<0.001); in contrast, the genetic association was not significant in the low-fat diet group (P-trend=0.087).
Our data suggest that participants with a higher genetic risk may benefit more by eating a low-fat diet to improve glucose metabolism.
PMCID: PMC4935586  PMID: 27113490
7.  Update on Prevention of Cardiovascular Disease in Adults With Type 2 Diabetes Mellitus in Light of Recent Evidence: A Scientific Statement From the American Heart Association and the American Diabetes Association 
Diabetes Care  2015;38(9):1777-1803.
Cardiovascular disease risk factor control as primary prevention in patients with type 2 diabetes mellitus has changed substantially in the past few years. The purpose of this scientific statement is to review the current literature and key clinical trials pertaining to blood pressure and blood glucose control, cholesterol management, aspirin therapy, and lifestyle modification. We present a synthesis of the recent literature, new guidelines, and clinical targets, including screening for kidney and subclinical cardiovascular disease for the contemporary management of patients with type 2 diabetes mellitus.
PMCID: PMC4876675  PMID: 26246459
8.  Advances in the Science, Treatment, and Prevention of the Disease of Obesity: Reflections From a Diabetes Care Editors’ Expert Forum 
Diabetes Care  2015;38(8):1567-1582.
As obesity rates increase, so too do the risks of type 2 diabetes, cardiovascular disease, and numerous other detrimental conditions. The prevalence of obesity in U.S. adults more than doubled between 1980 and 2010, from 15.0 to 36.1%. Although this trend may be leveling off, obesity and its individual, societal, and economic costs remain of grave concern. In June 2014, a Diabetes Care Editors’ Expert Forum convened to review the state of obesity research and discuss the latest prevention initiatives and behavioral, medical, and surgical therapies. This article, an outgrowth of the forum, offers an expansive view of the obesity epidemic, beginning with a discussion of its root causes. Recent insights into the genetic and physiological factors that influence body weight are reviewed, as are the pathophysiology of obesity-related metabolic dysfunction and the concept of metabolically healthy obesity. The authors address the crucial question of how much weight loss is necessary to yield meaningful benefits. They describe the challenges of behavioral modification and predictors of its success. The effects of diabetes pharmacotherapies on body weight are reviewed, including potential weight-neutral combination therapies. The authors also summarize the evidence for safety and efficacy of pharmacotherapeutic and surgical obesity treatments. The article concludes with an impassioned call for researchers, clinicians, governmental agencies, health policymakers, and health-related industries to collectively embrace the urgent mandate to improve prevention and treatment and for society at large to acknowledge and manage obesity as a serious disease.
PMCID: PMC4831905  PMID: 26421334
9.  Ankle-brachial index and inter-artery blood pressure differences as predictors of cognitive function in overweight and obese older adults with diabetes: Results from the Action for Health in Diabetes Movement and Memory Study 
Ankle-brachial index (ABI) and inter-artery systolic blood pressure differences, as markers of vascular disease, are plausible risk factors for deficits in cognitive function among overweight and obese adults with type 2 diabetes.
ABI and maximum inter-artery differences (MIAD) in systolic blood pressures were assessed annually for five years among 479 participants assigned to the control condition in a randomized clinical trial of a behavioral weight loss intervention. A battery of standardized cognitive function tests was administered four to five years later. Analyses of covariance were used to assess relationships that ABI, MIAD, and progression of ABI and MIAD had with cognitive function.
There was a curvilinear relationship between ABI and a composite index of cognitive function (p=0.03), with lower ABI being associated with poorer function. In graded fashions, both greater MIAD and increases in MIAD over time also had modest relationships with poorer verbal memory (both p≤0.05), processing speed (both p≤0.05), and composite cognitive function (both p≤0.04). These relationships were independent of each other and remained evident after extensive covariate adjustment.
In overweight and obese adults with type 2 diabetes, lower ABI and larger inter-artery systolic blood pressure differences have modest, independent, graded relationships with poorer cognitive function 4–5 year later.
PMCID: PMC4964588  PMID: 25546032
Cognitive function; Arterial disease; Diabetes; Obesity
11.  Catechol-O-methyltransferase association with hemoglobin A1c 
Catecholamines have metabolic effects on blood pressure, insulin sensitivity and blood glucose. Genetic variation in catechol-O-methyltransferase (COMT), an enzyme that degrades catecholamines, is associated with cardiometabolic risk factors and incident cardiovascular disease (CVD). Here we examined COMT effects on glycemic function and type 2 diabetes.
We tested whether COMT polymorphisms were associated with baseline HbA1c in the Women’s Genome Health Study (WGHS), and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), and with susceptibility to type 2 diabetes in WGHS, DIAbetes Genetics Replication And Meta-analysis consortium (DIAGRAM), and the Diabetes Prevention Program (DPP). Given evidence that COMT modifies some drug responses, we examined association with type 2 diabetes and randomized metformin and aspirin treatment.
COMT rs4680 high-activity G-allele was associated with lower HbA1c in WGHS (β = −0.032% [0.012], p = 0.008) and borderline significant in MAGIC (β = −0.006% [0.003], p = 0.07). Combined COMT per val allele effects on type 2 diabetes were significant (OR = 0.98 [0.96–0.998], p = 0.03) in fixed-effects analyses across WGHS, DIAGRAM, and DPP. Similar results were obtained for 2 other COMT SNPs rs4818 and rs4633. In the DPP, the rs4680 val allele was borderline associated with lower diabetes incidence among participants randomized to metformin (HR = 0.81 [0.65–1.00], p = 0.05).
COMT rs4680 high-activity G-allele was associated with lower HbA1c and modest protection from type 2 diabetes. The directionality of COMT associations was concordant with those previously observed for cardiometabolic risk factors and CVD.
PMCID: PMC4924514  PMID: 27282867
12.  The impact of lifestyle intervention on sedentary time in individuals at high risk of diabetes 
Diabetologia  2015;58(6):1198-1202.
The Diabetes Prevention Program (DPP) lifestyle intervention successfully achieved its goal of increasing leisure physical activity levels. This current study examines whether the lifestyle intervention also changed time spent being sedentary and the impact of sedentary time on diabetes development in this cohort.
3232 DPP participants provided baseline data. Sedentary behaviour was assessed via an interviewer-administered questionnaire and reported as time spent watching television specifically (or combined with sitting at work). Mean change in sedentary time was examined using repeated measures ANCOVA. The relationship between sedentary time and diabetes incidence was determined using Cox proportional hazards models.
During the DPP follow-up (mean: 3.2 years), sedentary time declined more in the lifestyle than the metformin or placebo participants (p <0.05). For the lifestyle group, the decrease in reported mean television watching time (22 [95% CI 26, 17] min/day) was greater than in the metformin or placebo groups (p< 0.001). Combining all participants together, there was a significantly increased risk of developing diabetes with increased television watching (3.5% per h spent watching television), after controlling for age, sex, treatment arm and leisure physical activity (p< 0.01), which was attenuated when time-dependent weight was added to the model.
In the DPP, the lifestyle intervention was effective at reducing sedentary time, which was not a primary goal. In addition, in all treatment arms, individuals with lower levels of sedentary time had a significantly lower risk of developing diabetes. Future lifestyle intervention programmes should emphasise reducing television watching and other sedentary behaviours in addition to increasing physical activity.
Trial registration NCT00004992
PMCID: PMC4417075  PMID: 25851102
Diabetes Prevention Program; Sedentary behaviour; Television watching; Type 2 diabetes
13.  Aging and Physical Function in Type 2 Diabetes: 8 Years of an Intensive Lifestyle Intervention 
Compared with adults without type 2 diabetes mellitus, those with the disease experience more limitations in their physical functioning (PF). Look AHEAD is a large multicenter trial that examined the effects of an intensive lifestyle intervention (ILI) for weight loss on cardiovascular outcomes compared with diabetes support and education (DSE). Although the current study compared treatment differences between ILI and DSE on PF, the primary goal was to examine whether this effect was moderated by age and history of cardiovascular disease at enrollment.
Overweight or obese adults with type 2 diabetes mellitus (n = 5,145) were randomly assigned to either ILI or DSE. The mean (±SD) age and % females in ILI was 58.9 years (±6.9) and 59.8%; it was 58.6 years (6.8) and 59.5% in DSE. Analysis in 4,998 participants assessed the differential rates of decline in PF across a period of 8 years for the ILI and DSE groups.
ILI resulted in improved PF compared with DSE after 1 year (p < .0001) and was maintained across time. Within the ILI, older adults experienced greater improvements than younger adults (p < .0001). By year 2, persons in ILI with preexisting cardiovascular disease were no different in PF than in DSE participants with preexisting cardiovascular disease.
With the exception of persons who had a history of cardiovascular disease, ILI slowed the decline in PF with type 2 diabetes mellitus despite weight regain, an effect that was stronger for older than younger participants and could translate into reductions in falls and disability.
PMCID: PMC4351390  PMID: 24986062
Diabetes; Obesity; Functional performance.
14.  Changes in Body Composition over Eight Years in a Randomized Trial of a Lifestyle Intervention: The Look AHEAD Study 
Obesity (Silver Spring, Md.)  2015;23(3):565-572.
To determine the effects of an intensive lifestyle intervention vs. a comparison group on body composition in obese or overweight persons with type 2 diabetes at baseline and at 1, 4, and 8 years.
Design and Methods
Body composition was measured by dual energy X-ray absorptiometry in a subset of 1019 Look Ahead study volunteers randomized to intervention or comparison groups. The intervention was designed to achieve and maintain ≥7% weight loss through increased physical activity and reduced caloric intake. The comparison group received social support and diabetes education.
At 1 year, the intervention group lost fat (5.6 ± 0.2 kg) and lean mass (2.3 ± 0.1 kg) but regained fat (~100%), and lost lean mass between years 1 and 8. Between baseline and year-8, weight-loss was greater in intervention vs. comparison groups (4.0 ± 0.4 vs. 2.3 ± 0.4 kg); comparison group weight-loss was mostly lean mass (2.1 ± 0.17 kg). Fat mass in the intervention group was lower than that of the comparison group at all post-baseline time points.
Reduced FM may place the intervention group at a lower risk of obesity-linked sequelae, a hypothesis that can be tested by future studies of this cohort.
Trial Registration Identifier: NCT00017953
PMCID: PMC4707962  PMID: 25707379
Obesity; diabetes; body composition; weight loss
15.  Factors Affecting the Decline in Incidence of Diabetes in the Diabetes Prevention Program Outcomes Study (DPPOS) 
Diabetes  2014;64(3):989-998.
During the first 7 years of the Diabetes Prevention Program Outcomes Study (DPPOS), diabetes incidence rates, when compared with the Diabetes Prevention Program (DPP), decreased in the placebo (−42%) and metformin (−25%), groups compared with the rates in the intensive lifestyle intervention (+31%) group. Participants in the placebo and metformin groups were offered group intensive lifestyle intervention prior to entering the DPPOS. The following two hypotheses were explored to explain the rate differences: “effective intervention” (changes in weight and other factors due to intensive lifestyle intervention) and “exhaustion of susceptible” (changes in mean genetic and diabetes risk scores). No combination of behavioral risk factors (weight, physical activity, diet, smoking, and antidepressant or statin use) explained the lower DPPOS rates of diabetes progression in the placebo and metformin groups, whereas weight gain was the factor associated with higher rates of progression in the intensive lifestyle intervention group. Different patterns in the average genetic risk score over time were consistent with exhaustion of susceptibles. Results were consistent with exhaustion of susceptibles for the change in incidence rates, but not the availability of intensive lifestyle intervention to all persons before the beginning of the DPPOS. Thus, effective intervention did not explain the lower diabetes rates in the DPPOS among subjects in the placebo and metformin groups compared with those in the DPP.
PMCID: PMC4338587  PMID: 25277389
16.  PCSK7 Genotype Modifies Effect of a Weight-Loss Diet on 2-Year Changes of Insulin Resistance: The POUNDS LOST Trial 
Diabetes Care  2014;38(3):439-444.
A common variant rs236918 in the PCSK7 gene has the strongest association with iron homeostasis and is related to insulin resistance. Dietary carbohydrate (CHO) modulates the genetic effect on insulin resistance. We examined whether 2-year weight-loss diets modify the effect of PCSK7 genetic variants on changes in fasting insulin levels and insulin resistance in a randomized, controlled trial.
Data were analyzed in the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial, which is a randomized, controlled 2-year weight-loss trial using diets that differed in macronutrient proportions. PCSK7 rs236918 was genotyped in 730 overweight or obese adults (80% whites) in this trial. We assessed the progression in fasting insulin and glucose levels, and insulin resistance by genotypes.
During the 6-month weight-loss phase, the PCSK7 rs236918 G allele was significantly associated with greater decreases in fasting insulin levels in the high–dietary CHO group (P for interaction = 0.04), while the interaction for changes in HOMA-insulin resistance (HOMA-IR) (P for interaction = 0.06) did not reach significant levels in white subjects. The G allele was significantly associated with a greater decrease in fasting insulin levels and HOMA-IR in response to high dietary CHO levels (P = 0.02 and P = 0.03, respectively). From 6 months to 2 years (weight-regain phase), the interactions became attenuated due to the regaining of weight (P for interactions = 0.08 and 0.06, respectively). In addition, we observed similar and even stronger results in the whole-study samples from the trial.
Our data suggest that PCSK7 genotypes may interact with dietary CHO intake on changes in insulin sensitivity in the white Americans.
PMCID: PMC4876697  PMID: 25504030
17.  A Long-Term Intensive Lifestyle Intervention and Physical Function: the Look AHEAD Movement and Memory Study 
Obesity (Silver Spring, Md.)  2014;23(1):77-84.
To assess the long-term effects of an intensive lifestyle intervention on physical function using a randomized post-test design in the Look AHEAD trial.
Overweight and obese (BMI ≥25 kg/m2) middle-aged and older adults (aged 45–76 years at enrollment) with type 2 diabetes (n=964) at four clinics in Look AHEAD, a trial evaluating an intensive lifestyle intervention (ILI) designed to achieve weight loss through caloric restriction and increased physical activity compared to diabetes support and education (DSE), underwent standardized assessments of performance-based physical function including an expanded short physical performance battery (SPPBexp), 20-m and 400-m walk, and grip and knee extensor strength 8 years post-randomization, during the trial’s weight maintenance phase.
Eight years post-randomization, individuals randomized to ILI had better SPPBexp scores (adjusted mean (SE) difference: 0.055 (0.022), p=0.01) and faster 20-m and 400-m walk speeds (0.032 (0.012) m/sec, p=0.01, and 0.025 (0.011) m/sec, p=0.02, respectively) compared to those randomized to DSE. Achieved weight loss greatly attenuated the group differences in physical function and the intervention effect was no longer significant.
An intensive lifestyle intervention has long-term benefits for mobility function in overweight and obese middle-aged and older individuals with type 2 diabetes.
PMCID: PMC4276480  PMID: 25452229
diabetes; lifestyle modifications; weight loss; functional disability
18.  Prevention of Diabetes Through the Lifestyle Intervention: Lessons Learned from the Diabetes Prevention Program and Outcomes Study and its Translation to Practice 
Current nutrition reports  2014;3(4):364-378.
A number of strategies have been used to delay or prevent the development of type 2 diabetes mellitus (T2D) in high-risk adults. Among them were diet, exercise, medications and surgery. This report focuses on the nutritional lessons learned from implementation of the Intensive Lifestyle Intervention (ILI) in the DPP and its follow-up DPPOS that looked at weight loss through modification of diet and exercise. The Diabetes Prevention Program (DPP) is a large clinical trial, sponsored by the National Institutes of Health, designed to look at several strategies to prevent conversion to type 2 diabetes (T2D) by adults with prediabetes (IGT/IFG) including an Intensive Lifestyle Intervention (ILI). The ∼3800 ethnically diverse participants (46% reported non-white race) were overweight, had impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). Treatments were assigned randomly. The Diabetes Prevention Program Outcomes Study (DPPOS) is a follow up study evaluating the long-term outcomes of the clinical trial.
PMCID: PMC4221569  PMID: 25383256
Lifestyle intervention; Diabetes prevention; weight loss; physical activity; prevention; diabetes; overweight; type 2 diabetes; nutrition; lifestyle; diet; genetics
19.  The Look AHEAD Trial: Bone Loss at 4-Year Follow-up in Type 2 Diabetes 
Diabetes Care  2014;37(10):2822-2829.
To determine whether an intensive lifestyle intervention (ILI) designed to sustain weight loss and improve physical fitness in overweight or obese persons with type 2 diabetes was associated with bone loss after 4 years of follow-up.
This randomized controlled trial of intensive weight loss compared an ILI with a diabetes support and education (DSE) group among 1,309 overweight or obese subjects. Bone mineral density was assessed at baseline and after 1 year and 4 years of intervention.
ILI was effective in producing significant weight loss (5.3% vs. 1.8% in ILI and DSE, respectively; P < 0.01) and increased fitness (6.4% vs. −0.8%) at year 4. In men, ILI participants had a greater rate of bone loss during the first year (−1.66% vs. −0.09% per year in ILI and DSE, respectively). Differences between groups were diminished by one-half after 4 years (−0.88% vs. −0.05% per year in ILI and DSE, respectively) but remained significant (P < 0.01). The difference in rate of hip bone loss between groups over 4 years was related to increased weight loss in ILI. Among women, the rate of bone loss did not differ between ILI and DSE after 4 years.
A 4-year weight loss intervention was significantly associated with a modest increase in bone loss at the hip in men but not in women.
PMCID: PMC4170123  PMID: 25048381
20.  Effects of Weight Loss, Weight Cycling, and Weight Loss Maintenance on Diabetes Incidence and Change in Cardiometabolic Traits in the Diabetes Prevention Program 
Diabetes Care  2014;37(10):2738-2745.
This study examined specific measures of weight loss in relation to incident diabetes and improvement in cardiometabolic risk factors.
This prospective, observational study analyzed nine weight measures, characterizing baseline weight, short- versus long-term weight loss, short- versus long-term weight regain, and weight cycling, within the Diabetes Prevention Program (DPP) lifestyle intervention arm (n = 1,000) for predictors of incident diabetes and improvement in cardiometabolic risk factors over 2 years.
Although weight loss in the first 6 months was protective of diabetes (hazard ratio [HR] 0.94 per kg, 95% CI 0.90, 0.98; P < 0.01) and cardiometabolic risk factors (P < 0.01), weight loss from 0 to 2 years was the strongest predictor of reduced diabetes incidence (HR 0.90 per kg, 95% CI 0.87, 0.93; P < 0.01) and cardiometabolic risk factor improvement (e.g., fasting glucose: β = −0.57 mg/dL per kg, 95% CI −0.66, −0.48; P < 0.01). Weight cycling (defined as number of 5-lb [2.25-kg] weight cycles) ranged 0–6 times per participant and was positively associated with incident diabetes (HR 1.33, 95% CI 1.12, 1.58; P < 0.01), fasting glucose (β = 0.91 mg/dL per cycle; P = 0.02), HOMA-IR (β = 0.25 units per cycle; P = 0.04), and systolic blood pressure (β = 0.94 mmHg per cycle; P = 0.01). After adjustment for baseline weight, the effect of weight cycling remained statistically significant for diabetes risk (HR 1.22, 95% CI 1.02, 1.47; P = 0.03) but not for cardiometabolic traits.
Two-year weight loss was the strongest predictor of reduced diabetes risk and improvements in cardiometabolic traits.
PMCID: PMC4170126  PMID: 25024396
21.  Impact of an Intensive Lifestyle Intervention on Use and Cost of Medical Services Among Overweight and Obese Adults With Type 2 Diabetes: The Action for Health in Diabetes 
Diabetes Care  2014;37(9):2548-2556.
To assess the relative impact of an intensive lifestyle intervention (ILI) on use and costs of health care within the Look AHEAD trial.
A total of 5,121 overweight or obese adults with type 2 diabetes were randomly assigned to an ILI that promoted weight loss or to a comparison condition of diabetes support and education (DSE). Use and costs of health-care services were recorded across an average of 10 years.
ILI led to reductions in annual hospitalizations (11%, P = 0.004), hospital days (15%, P = 0.01), and number of medications (6%, P < 0.001), resulting in cost savings for hospitalization (10%, P = 0.04) and medication (7%, P < 0.001). ILI produced a mean relative per-person 10-year cost savings of $5,280 (95% CI 3,385–7,175); however, these were not evident among individuals with a history of cardiovascular disease.
Compared with DSE over 10 years, ILI participants had fewer hospitalizations, fewer medications, and lower health-care costs.
PMCID: PMC4140155  PMID: 25147253
22.  Long-term Impact of Behavioral Weight Loss Intervention on Cognitive Function 
It is unknown whether intentional weight loss provides long-term benefits for cognitive function.
An ancillary study to a randomized controlled clinical trial was conducted in overweight and obese individuals (N = 978), aged 45–76 years at enrollment, with type 2 diabetes. An intensive behavioral intervention designed to promote and maintain weight loss through caloric restriction and increased physical activity was compared with diabetes support and education. Standardized assessments of cognitive function were collected an average of 8.1 years after trial enrollment.
Participants assigned to intensive lifestyle intervention lost a mean (SE) 11.1% (0.4%) and 7.2% (0.5%) of weight at Years 1 and 8, respectively, compared with 1.0% (0.2%) and 3.3% (0.5%) in the control group (p < .001). Covariate-adjusted mean composite cognitive function test scores were similar for the two groups (p = .69), and no significant differences were found for any individual cognitive test. There was some evidence of a differential effect (nominal interaction p = .008) for a prespecified comparison: Intensive lifestyle intervention was associated with a relative mean benefit for composite cognitive function of 0.276 (95% confidence interval: 0.033, 0.520) SDs among individuals with body mass index less than 30kg/m2 at baseline compared with a relative mean deficit of 0.086 (−0.021, 0.194) SDs among individuals with body mass more than or equal to 30kg/m2.
Eight years of intensive lifestyle intervention did not alter cognitive function in obese adults with type 2 diabetes; however, there was evidence for benefit among overweight but not obese individuals. Changes in cognition were not assessed in this cross-sectional study.
PMCID: PMC4158413  PMID: 24619151
Cognition; Obesity; Diabetes; Clinical trials.
23.  Treatment-Induced Changes in Plasma Adiponectin Do Not Reduce Urinary Albumin Excretion in the Diabetes Prevention Program Cohort 
PLoS ONE  2015;10(8):e0136853.
Background and Objectives
Molecular data suggests that adiponectin may directly regulate urinary albumin excretion. In the Diabetes Prevention Program (DPP) we measured adiponectin and albuminuria before and after intervention, and we previously reported increases in adiponectin with interventions. Here we have used the DPP dataset to test the hypothesis that treatment-related increases in adiponectin may reduce albuminuria in obesity.
Design, Setting, Participants and Methods
We evaluated cross-sectional correlations between plasma adiponectin and urinary albumin excretion at baseline, and the relationship of treatment-related changes in adiponectin and albuminuria. Baseline and follow-up urine albumin to creatinine ratios (ACR (albumin to creatinine ratio)) and plasma adiponectin concentration were available in 2553 subjects.
Adjusting for age, sex and race/ethnicity, we observed a statistically significant but weak inverse relationship between adiponectin and ACR at baseline (conditional Spearman’s rho = (-) 0.04, p = 0.04). Although DPP treatments significantly increased plasma adiponectin, there were no treatment effects on ACR and no differences in ACR across treatment groups. There was a weak direct (not inverse) association between change in adiponectin and change in albuminuria (adjusted Spearman’s rho = (+) 0.04, p = 0.03).
In a large, well-characterized cohort of obese dysglycemic subjects we observed a weak inverse association between circulating adiponectin concentrations and urinary albumin excretion at baseline. Contrary to the hypothesized effect, treatment-related increases in plasma adiponectin were not associated with a reduction in ACR. The association of change in adiponectin with change in ACR should be assessed in populations with overt albuminuria before excluding a beneficial effect of increasing adiponectin to reduce ACR in obesity.
PMCID: PMC4551844  PMID: 26312480
24.  Overfeeding of Polyunsaturated Versus Saturated Fatty Acids Reduces Ectopic Fat 
Diabetes  2014;63(7):2222-2224.
PMCID: PMC4392897  PMID: 24962923
25.  Baseline Adiponectin Levels Do Not Influence the Response to Pioglitazone in ACT NOW 
Diabetes Care  2014;37(6):1706-1711.
Plasma adiponectin levels are reduced in type 2 diabetes mellitus (T2DM) and other insulin-resistant states. We examined whether plasma adiponectin levels at baseline and after pioglitazone treatment in impaired glucose tolerance (IGT) subjects were associated with improved insulin sensitivity (SI) and glucose tolerance status.
A total of 602 high-risk IGT subjects in ACT NOW were randomized to receive pioglitazone or placebo with a median follow-up of 2.4 years.
Pioglitazone reduced IGT conversion to diabetes by 72% in association with improved β-cell function by 64% (insulin secretion/insulin resistance index) and increased tissue sensitivity by 88% (Matsuda index). In pioglitazone-treated subjects, plasma adiponectin concentration increased threefold from 13 ± 0.5 to 38 ± 2.5 μg/mL (P < 0.001) and was strongly correlated with the improvement in SI (r = 0.436, P < 0.001) and modestly correlated with glucose area under the curve during oral glucose tolerance test (r = 0.238, P < 0.005) and insulin secretion/insulin resistance index (r = 0.306, P < 0.005). The increase in adiponectin was a strong predictor of reversion to normal glucose tolerance and prevention of T2DM. In the placebo group, plasma adiponectin did not change and was not correlated with changes in glucose levels. There was an inverse association between baseline plasma adiponectin concentration and progression to diabetes in the placebo group but not in the pioglitazone group.
Baseline adiponectin does not predict the response to pioglitazone. The increase in plasma adiponectin concentration after pioglitazone therapy in IGT subjects is strongly related to improved glucose tolerance status and enhanced tissue sensitivity to insulin.
PMCID: PMC4179517  PMID: 24705615

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