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Weight Loss and Exercise Differentially Affect Insulin Sensitivity, Body Composition, Cardiorespiratory Fitness, and Muscle Strength in Older Adults With Obesity: A Randomized Controlled Trial.
Brennan, AM, Standley, RA, Anthony, SJ, Grench, KE, Helbling, NL, DeLany, JP, Cornnell, HH, Yi, F, Stefanovic-Racic, M, Toledo, FGS, et al
The journals of gerontology. Series A, Biological sciences and medical sciences. 2022;77(5):1088-1097
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Aging is marked by increased risk for type 2 diabetes, reduced muscle mass and strength (ie, sarcopenia), decreased physical function and cardiorespiratory fitness, ectopic fat deposition, and insulin resistance all of which increase the risk for physical disability, morbidity, and mortality. These adverse health consequences associated with advanced age are exacerbated with obesity and physical inactivity. The aim of this study was to investigate the effects of weight loss with or without exercise on skeletal muscle insulin sensitivity, exclusively in obese older adults. This study is a 2-site, 6-month randomized controlled trial with a parallel group design. Eighty-six older (60–80 years of age), physically inactive men and women with obesity were randomised into one of the 3 treatments (1:1:1 allocation ratio): control (health education), calorie restriction-induced weight loss, and weight loss with exercise. Results suggest that weight loss via calorie restriction alone is insufficient to significantly improve skeletal muscle insulin sensitivity and requires the addition of exercise to incur benefit, which was also true for clinical measures of insulin resistance including haemoglobin A1C [a blood test that measures the average blood sugar levels over a period of 3 months] and fasting insulin. Authors conclude that regular exercise should be considered as a useful and manageable adjunct to traditional weight loss therapies for older adults with obesity to mitigate risk for chronic disease and maintain functional independence and quality of life.
Abstract
BACKGROUND Aging-related disease risk is exacerbated by obesity and physical inactivity. It is unclear how weight loss and increased activity improve risk in older adults. We aimed to determine the effects of diet-induced weight loss with and without exercise on insulin sensitivity, VO2peak, body composition, and physical function in older obese adults. METHODS Physically inactive older (68.6 ± 4.5 years) obese (body mass index 37.4 ± 4.9 kg/m2) adults were randomized to health education control (HEC; n = 25); diet-induced weight loss (WL; n = 31); or weight loss and exercise (WLEX; n = 28) for 6 months. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp, body composition by dual-energy X-ray absorptiometry and MRI, strength by isokinetic dynamometry, and VO2peak by graded exercise test. RESULTS WLEX improved (p < .05) peripheral insulin sensitivity (+75 ± 103%) versus HEC (+12 ± 67%); WL (+36 ± 47%) versus HEC did not reach statistical significance. WLEX increased VO2peak (+7 ± 12%) versus WL (-2 ± 24%) and prevented reductions in strength and lean mass induced by WL (p < .05). WLEX decreased abdominal adipose tissue (-16 ± 9%) versus HEC (-3 ± 8%) and intermuscular adipose tissue (-15 ± 13%) versus both HEC (+9 ± 15%) and WL (+2 ± 11%; p < .01). CONCLUSIONS Exercise with weight loss improved insulin sensitivity and VO2peak, decreased ectopic fat, and preserved lean mass and strength. Weight loss alone decreased lean mass and strength. Older adults intending to lose weight should perform regular exercise to promote cardiometabolic and functional benefits, which may not occur with calorie restriction-induced weight loss alone.
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Lipids activate skeletal muscle mitochondrial fission and quality control networks to induce insulin resistance in humans.
Axelrod, CL, Fealy, CE, Erickson, ML, Davuluri, G, Fujioka, H, Dantas, WS, Huang, E, Pergola, K, Mey, JT, King, WT, et al
Metabolism: clinical and experimental. 2021;121:154803
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Insulin resistance is a key pathophysiological mechanism in the development and progression of type 2 diabetes. Abnormalities in lipid metabolism and ectopic lipid accumulation are known to directly contribute to the onset of insulin resistance. Authors hypothesised that lipid infusion would increase dynamin related protein 1 [a type of protein]-mediated mitochondrial fission in skeletal muscle independent of function and content, consequently reducing peripheral insulin sensitivity. The study included sedentary but otherwise healthy adults who were prospectively randomized to receive either lipid or saline infusion to isolate the direct contribution of fatty acids to skeletal muscle mitochondrial dynamics. Results show that mitochondrial fission and quality control networks are activated in response to lipid infusion which occurs independent of changes in mitochondrial content or capacity and contributes to the onset of insulin resistance in healthy humans. Authors conclude that treatments that limit lipid-induced activation of mitochondrial fission and/or quality control processes may have therapeutic value in the treatment of insulin resistance.
Abstract
BACKGROUND AND AIMS A diminution in skeletal muscle mitochondrial function due to ectopic lipid accumulation and excess nutrient intake is thought to contribute to insulin resistance and the development of type 2 diabetes. However, the functional integrity of mitochondria in insulin-resistant skeletal muscle remains highly controversial. METHODS 19 healthy adults (age:28.4 ± 1.7 years; BMI:22.7 ± 0.3 kg/m2) received an overnight intravenous infusion of lipid (20% Intralipid) or saline followed by a hyperinsulinemic-euglycemic clamp to assess insulin sensitivity using a randomized crossover design. Skeletal muscle biopsies were obtained after the overnight lipid infusion to evaluate activation of mitochondrial dynamics proteins, ex-vivo mitochondrial membrane potential, ex-vivo oxidative phosphorylation and electron transfer capacity, and mitochondrial ultrastructure. RESULTS Overnight lipid infusion increased dynamin related protein 1 (DRP1) phosphorylation at serine 616 and PTEN-induced kinase 1 (PINK1) expression (P = 0.003 and P = 0.008, respectively) in skeletal muscle while reducing mitochondrial membrane potential (P = 0.042). The lipid infusion also increased mitochondrial-associated lipid droplet formation (P = 0.011), the number of dilated cristae, and the presence of autophagic vesicles without altering mitochondrial number or respiratory capacity. Additionally, lipid infusion suppressed peripheral glucose disposal (P = 0.004) and hepatic insulin sensitivity (P = 0.014). CONCLUSIONS These findings indicate that activation of mitochondrial fission and quality control occur early in the onset of insulin resistance in human skeletal muscle. Targeting mitochondrial dynamics and quality control represents a promising new pharmacological approach for treating insulin resistance and type 2 diabetes. CLINICAL TRIAL REGISTRATION NCT02697201, ClinicalTrials.gov.
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Effect of time restricted eating on body weight and fasting glucose in participants with obesity: results of a randomized, controlled, virtual clinical trial.
Peeke, PM, Greenway, FL, Billes, SK, Zhang, D, Fujioka, K
Nutrition & diabetes. 2021;11(1):6
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Time-restricted eating (TRE) has been identified as an effective method of losing weight in the face of rising obesity worldwide. Fasting for at least 12 hours has a beneficial effect on weight management and cardiometabolic health. Overnight fasting longer than 12 hours may result in fat-burning or ketosis. A high-fat, low-protein, low-carbohydrate snack during a 14-hour fast is believed not to raise blood sugar levels and helps with hunger management. This 8-week virtual, pilot, randomised, comparator-controlled clinical trial evaluated the benefits of following a commercial weight loss programme combined with TRE on body weight and fasting blood glucose (FBG) levels. The commercial weight loss programme included calculated calories and macronutrient content in their customised meal plans, as well as coaching and troubleshooting sessions. The participants were randomly assigned to 14-hour fasting (14:10) or 12-hour fasting (control). The 14:10 group also consumed 200 kcal of mixed nuts as a snack at hour 12 to determine the effect on blood glucose levels. After the intervention for 8 weeks, the 14:10 group showed a significant reduction in body weight (11kg) and FBG (8mg/dl), and the 12:12 group significantly lost 9kg of body weight and showed a non-significant reduction in FBG (3mg/dl). Participants with higher baseline FBG levels showed a greater reduction in FBG, indicating potential greater improvements in people with diabetes. A comparison of the two groups did not show a statistically significant difference in intervention effects. A fasting snack at 12 hours did not affect FBG in the 14:10 group, which may help adherence. Due to the exploratory nature of this study, larger robust studies are needed to assess the effectiveness of 14:10 and 12:12 time-restricted fasting regimens with commercial weight loss programmes. However, healthcare professionals can use the results of this study to understand the beneficial effects of different time-restricted fasting regimens on cardiometabolic health.
Abstract
BACKGROUND Time restricted eating (TRE) is an emerging dietary intervention for weight loss that is hypothesized to reinforce the metabolic benefits of nightly fasting/ketosis. This pilot study investigated the effectiveness of a daily 14-h metabolic fast (14:10 TRE beginning after dinner, a "fasting snack" at hour 12, and ending with breakfast 14 h later) combined with a commercial weight management program on body weight and fasting blood glucose (FBG) in individuals with obesity. We also investigated the effect of the low-calorie, high-fat, low-carbohydrate, and low-protein "fasting snack" on blood glucose. METHODS This 8-week, randomized, controlled, clinical trial included men and women (BMI ≥ 30 kg/m2) between June and October 2020. Study procedures were conducted remotely. Participants were randomized to 14:10 or 12-h TRE (12:12, active comparator) and prescribed a diet (controlled for calories and macronutrient composition) and exercise program that included weekly customized counseling and support. The primary outcome was change from baseline in body weight in the 14:10 group. RESULTS Of the 78 randomized participants, 60 (n = 30/group) completed 8 weeks. The LS mean change from baseline in weight in the 14:10 group was -8.5% (95% CI -9.6 to -7.4; P < 0.001) and -7.1% (-8.3 to -5.8; P < 0.001) in the 12:12 group (between group difference -1.4%; -2.7 to -0.2; P < 0.05). There was a statistically significant LS mean change from baseline to week 8 in FBG in the 14:10 group of -7.6 mg/dl (95% CI -15.1 to -0.1; P < 0.05) but not in the 12:12 group (-3.1 mg/dl, -10.0 to 3.7; P = NS). Both interventions resulted in a larger reduction in FBG in participants with elevated FBG (≥100 mg/dl) at baseline (both P < 0.05). CONCLUSIONS In participants with obesity who completed 8 weeks of the 14:10 TRE schedule combined with a commercial weight loss program, there was statistically significant and clinically meaningful weight loss and improvements in FBG.
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Interaction Between Type 2 Diabetes Prevention Strategies and Genetic Determinants of Coronary Artery Disease on Cardiometabolic Risk Factors.
Merino, J, Jablonski, KA, Mercader, JM, Kahn, SE, Chen, L, Harden, M, Delahanty, LM, Araneta, MRG, Walford, GA, Jacobs, SBR, et al
Diabetes. 2020;69(1):112-120
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Individual risk of Coronary Artery Disease (CAD) and type 2 diabetes reflects the interplay between lifestyle behaviours acting on a backdrop of genetic predisposition. The aim of this study was to examine whether type 2 diabetes prevention strategies, either an intensive lifestyle intervention (ILS) or metformin treatment (MET), modify the association between CAD genetic risk and cardiometabolic risk factors (CRFs) in participants at high risk of type 2 diabetes. The study is a randomised controlled trial were participants were randomly allocated to one of the three groups; ILS (n = 1,079), MET (850 mg twice daily [n = 1,073]), or placebo (n = 1,082). Results indicate that there weren’t major significant differences in baseline characteristics, except for lower high-density lipoprotein and higher triglyceride in the placebo individuals compared with individuals assigned to MET or ILS. In fact, either an ILS or MET has a beneficial effect on 1-year change in different CRFs. Authors conclude that type 2 diabetes–preventive strategies for individuals at high risk of type 2 diabetes provide beneficial effects on CRFs regardless of CAD genetic risk profile.
Abstract
Coronary artery disease (CAD) is more frequent among individuals with dysglycemia. Preventive interventions for diabetes can improve cardiometabolic risk factors (CRFs), but it is unclear whether the benefits on CRFs are similar for individuals at different genetic risk for CAD. We built a 201-variant polygenic risk score (PRS) for CAD and tested for interaction with diabetes prevention strategies on 1-year changes in CRFs in 2,658 Diabetes Prevention Program (DPP) participants. We also examined whether separate lifestyle behaviors interact with PRS and affect changes in CRFs in each intervention group. Participants in both the lifestyle and metformin interventions had greater improvement in the majority of recognized CRFs compared with placebo (P < 0.001) irrespective of CAD genetic risk (P interaction > 0.05). We detected nominal significant interactions between PRS and dietary quality and physical activity on 1-year change in BMI, fasting glucose, triglycerides, and HDL cholesterol in individuals randomized to metformin or placebo, but none of them achieved the multiple-testing correction for significance. This study confirms that diabetes preventive interventions improve CRFs regardless of CAD genetic risk and delivers hypothesis-generating data on the varying benefit of increasing physical activity and improving diet on intermediate cardiovascular risk factors depending on individual CAD genetic risk profile.
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Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures.
Elhassan, YS, Kluckova, K, Fletcher, RS, Schmidt, MS, Garten, A, Doig, CL, Cartwright, DM, Oakey, L, Burley, CV, Jenkinson, N, et al
Cell reports. 2019;28(7):1717-1728.e6
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As the body ages, there is a decline in muscle mass and function, which can be combatted with diet, exercise, and supplementation. Nicotinamide riboside (NR) or vitamin B3 has been shown in animal studies to promote healthy muscle, however its effects in human muscle are unknown. This randomised control trial of overweight older men aimed to determine if NR can be used by muscle and whether it has any effect on muscle function. The results showed that NR supplementation (1 g/day) for 3 weeks can be used by the muscle but had no effect on muscle function as shown by the hand grip test. Supplementation also decreased energy production in muscle and had anti-inflammatory effects. It was concluded that NR is available to muscle and that it may have anti-inflammatory properties, which may be of benefit to older individuals.
Abstract
Nicotinamide adenine dinucleotide (NAD+) is modulated by conditions of metabolic stress and has been reported to decline with aging in preclinical models, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome and if it can alter muscle mitochondrial bioenergetics. We supplemented 12 aged men with 1 g NR per day for 21 days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways, without altering mitochondrial bioenergetics. NR also depressed levels of circulating inflammatory cytokines. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR.
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Inflammation and glucose homeostasis are associated with specific structural features among adults without knee osteoarthritis: a cross-sectional study from the osteoarthritis initiative.
Stout, AC, Barbe, MF, Eaton, CB, Amin, M, Al-Eid, F, Price, LL, Lu, B, Lo, GH, Zhang, M, Pang, J, et al
BMC musculoskeletal disorders. 2018;19(1):1
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Individuals with osteoarthritis (OA) typically present with greater systemic inflammation and impaired glucose homeostasis. Currently it is unclear whether these factors are associated with early-stage OA, namely bone marrow lesions and swelling. The purpose of this cross-sectional study was to investigate the role of inflammation and glucose homeostasis in early-stage OA. Using baseline data from the Osteoarthritis Initiative, 343 participants were enrolled and tested for markers of inflammation and impaired glucose homeostasis. Bone marrow lesions and swelling were also assessed through imaging results. Results indicate that among individuals without OA, those with greater systemic inflammation were more likely to have bone marrow lesions and knee swelling. According to these results, the authors conclude that systemic inflammation and glucose homeostasis are related to structural features of osteoarthritis. Future studies should explore whether these factors are predictive of OA in order to identify therapeutic targets to prevent or delay the onset of knee OA.
Abstract
BACKGROUND Greater age and body mass index are strong risk factors for osteoarthritis (OA). Older and overweight individuals may be more susceptible to OA because these factors alter tissue turnover in menisci, articular cartilage, and bone via altered glucose homeostasis and inflammation. Understanding the role of inflammation and glucose homeostasis on structural features of early-stage OA may help identify therapeutic targets to delay or prevent the onset of OA among subsets of adults with these features. We examined if serum concentrations of glucose homeostasis (glucose, glycated serum protein [GSP]) or inflammation (C-reactive protein [CRP]) were associated with prevalent knee bone marrow lesions (BMLs) or effusion among adults without knee OA. METHODS We conducted a cross-sectional study using baseline data from the Osteoarthritis Initiative. We selected participants who had no radiographic knee OA but were at high risk for knee OA. Blinded staff conducted assays for CRP, GSP, and glucose. Readers segmented BML volume and effusion using semi-automated programs. Our outcomes were prevalent BML (knee with a BML volume > 1 cm3) and effusion (knee with an effusion volume > 7.5 cm3). We used logistic regression models with CRP, GSP, or glucose concentrations as the predictors. We adjusted for age, sex, body mass index (BMI), and Physical Activity Scale for the Elderly (PASE) scores. RESULTS We included 343 participants: mean age = 59 ± 9 years, BMI = 27.9 ± 4.5 kg/m2, PASE score = 171 ± 82, and 64% female. Only CRP was associated with BML prevalence (odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.09 to 1.87). For effusion, we found an interaction between BMI and CRP: only among adults with a BMI <25 kg/m2 was there a significant trend towards a positive association between CRP and effusion (OR = 1.40, 95% CI = 1.00 to 1.97). We detected a U-shaped relationship between GSP and effusion prevalence. Fasting glucose levels were not significantly associated with the presence of baseline effusion or BML. CONCLUSIONS Among individuals without knee OA, CRP may be related to the presence of BMLs and effusion among normal weight individuals. Abnormal GSP may be associated with effusion. Future studies should explore whether inflammation and glucose homeostasis are predictive of symptomatic knee OA.
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Changes in Visceral Adiposity, Subcutaneous Adiposity, and Sex Hormones in the Diabetes Prevention Program.
Kim, C, Dabelea, D, Kalyani, RR, Christophi, CA, Bray, GA, Pi-Sunyer, X, Darwin, CH, Yalamanchi, S, Barrett-Connor, E, Golden, SH, et al
The Journal of clinical endocrinology and metabolism. 2017;102(9):3381-3389
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It is not currently known to what extent changes in different types of fat stores (visceral fat that surrounds organs and subcutaneous fat that sits under the surface of the skin) relate to changes in sex hormones. This study was a secondary analysis of a randomised controlled trial including 555 individuals. It examined whether changes to visceral and subcutaneous fat were associated with changes in sex hormones (DHEA, testosterone, oestrogen and sex hormone binding globulin - SHBG) among overweight individuals with glucose intolerance under the care of a diabetes program. Participants were randomly assigned to an intensive lifestyle modification programme (goals for weight reduction and 150 mins exercise weekly), medication (metformin) or placebo for 12 months. The authors found that among men, reductions in both types of fat were associated with significant increases in total testosterone and SHBG. Among women, reductions in both types of fat were associated with increases in SHBG and associations with estrone differed by menopausal status. No associations were found between changes in fat stores and estradiol or DHEA. The authors conclude that weight loss may affect sex hormone profiles via reductions in visceral and subcutaneous fat. -
Abstract
Context: The degree to which changes in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) relate to corresponding changes in plasma sex steroids is not known. Objective: We examined whether changes in VAT and SAT areas assessed by computed tomography were associated with changes in sex hormones [dehydroepiandrosterone sulfate (DHEAS), testosterone, estradiol, estrone, and sex hormone binding globulin (SHBG)] among Diabetes Prevention Program participants. Design: Secondary analysis of a randomized trial. Participants: Overweight and glucose-intolerant men (n = 246) and women (n = 309). Interventions: Intensive lifestyle change with goals of weight reduction and 150 min/wk of moderate intensity exercise or metformin administered 850 mg twice a day or placebo. Main Outcome Measures: Associations between changes in VAT, SAT, and sex hormone changes over 1 year. Results: Among men, reductions in VAT and SAT were both independently associated with significant increases in total testosterone and SHBG in fully adjusted models. Among women, reductions in VAT and SAT were both independently associated with increases in SHBG and associations with estrone differed by menopausal status. Associations were similar by race/ethnicity and by randomization arm. No significant associations were observed between change in fat depot with change in estradiol or DHEAS. Conclusions: Among overweight adults with impaired glucose intolerance, reductions in either VAT and SAT were associated with increased total testosterone in men and higher SHBG in men and women. Weight loss may affect sex hormone profiles via reductions in visceral and subcutaneous fat.
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Effect of weight loss, exercise, or both on cognition and quality of life in obese older adults.
Napoli, N, Shah, K, Waters, DL, Sinacore, DR, Qualls, C, Villareal, DT
The American journal of clinical nutrition. 2014;100(1):189-98
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Obese adults may be at increased risk of dementia. Lifestyle interventions and weight loss are recommended for obese individuals, however, this may not be applicable to older obese individuals as extra weight could be protective against health risks in the older generation. This randomised controlled trail aimed to evaluate the combined and independent effect of weight loss and exercise on cognition & mood in 107 obese older adults over a one year period. The study found that diet and exercise both independently had a statistically significant impact on mood and quality of life. Exercise had the most significant impact, with the combination of diet and exercise being equal to the impact of exercise alone.
Abstract
BACKGROUND Obesity impairs cognition and health-related quality of life (HRQOL) in older adults; however, the appropriate treatment of obese older adults remains controversial. OBJECTIVE The objective was to determine the independent and combined effects of weight loss and exercise on cognition, mood, and HRQOL in obese older adults. DESIGN One hundred seven frail, obese older adults were randomly assigned to a control, weight-management (diet), exercise, or weight-management-plus-exercise (diet-exercise) group for 1 y. In this secondary analysis, main outcomes were Modified Mini-Mental State Examination (3MS) and total Impact of Weight on Quality of Life-Lite (IWQOL) scores. Other outcomes included Word Fluency Test, Trail Making Test Parts A and B, and Geriatric Depression Scale (GDS) scores. RESULTS Scores on the 3MS improved more in the diet (mean ± SE: 1.7 ± 0.4), exercise (2.8 ± 0.4), and diet-exercise (2.9 ± 0.4) groups than in the control group (0.1 ± 0.4) (between-group P = 0.0001-0.04); scores in the diet-exercise group improved more than in the diet group but not more than in the exercise group. Scores on the Word Fluency Test improved more in the exercise (4.1 ± 0.8) and diet-exercise (4.2 ± 0.7) groups than in the control group (-0.8 ± 0.8; both P = 0.001). For the Trail Making Test Part A, scores in the diet-exercise group (-11.8 ± 1.9) improved more than in the control group (-0.8 ± 1.9) (P = 0.001); a similar finding was observed for the Trail Making Test Part B. Scores on the IWQOL improved more in the diet (7.6 ± 1.6), exercise (10.1 ± 1.6), and diet-exercise (14.0 ± 1.4) groups than in the control group (0.3 ± 1.6) (P = 0.0001-0.03); scores in the diet-exercise group improved more than in the diet group but not more than in the exercise group. In the diet-exercise group, peak oxygen consumption and strength changes were independent predictors of 3MS changes; weight and strength changes were independent predictors of IWQOL changes. GDS scores did not change. CONCLUSIONS Weight loss and exercise each improve cognition and HRQOL, but their combination may provide benefits similar to exercise alone. These findings could inform practice guidelines with regard to optimal treatment strategies for obese older adults. This trial was registered atclinicaltrials.govas NCT00146107.
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Glycemic index, glycemic load, and risk of type 2 diabetes: results from 3 large US cohorts and an updated meta-analysis.
Bhupathiraju, SN, Tobias, DK, Malik, VS, Pan, A, Hruby, A, Manson, JE, Willett, WC, Hu, FB
The American journal of clinical nutrition. 2014;100(1):218-32
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Carbohydrates are the principle dietary components that effect blood glucose concentrations. The association between Type 2 diabetes (T2D) and diets with different levels of sugars and carbohydrates has been controversial in the prevention of T2D. Foods can be measured for their impact on blood glucose concentration using the Glycaemic Index (GI) and the Glycaemic Load (GL). The objective of this meta-analysis was to update previous studies and evaluate the association between the GI and GL of dietary intake and the risk of T2D. The authors found a significant association between the GI and GL of food intake and T2D risk and conclude that high GI and GL foods increase the risk of T2D. However, GI is more strongly associated to T2D than GL.
Abstract
BACKGROUND Epidemiologic evidence for the relation between carbohydrate quality and risk of type 2 diabetes (T2D) has been mixed. OBJECTIVE We prospectively examined the association of dietary glycemic index (GI) and glycemic load (GL) with T2D risk. DESIGN We prospectively followed 74,248 women from the Nurses' Health Study (1984-2008), 90,411 women from the Nurses' Health Study II (1991-2009), and 40,498 men from the Health Professionals Follow-Up Study (1986-2008) who were free of diabetes, cardiovascular disease, and cancer at baseline. Diet was assessed by using a validated questionnaire and updated every 4 y. We also conducted an updated meta-analysis, including results from our 3 cohorts and other studies. RESULTS During 3,800,618 person-years of follow-up, we documented 15,027 cases of incident T2D. In pooled multivariable analyses, those in the highest quintile of energy-adjusted GI had a 33% higher risk (95% CI: 26%, 41%) of T2D than those in the lowest quintile. Participants in the highest quintile of energy-adjusted GL had a 10% higher risk (95% CI: 2%, 18%) of T2D. Participants who consumed a combination diet that was high in GI or GL and low in cereal fiber had an ~50% higher risk of T2D. In the updated meta-analysis, the summary RRs (95% CIs) comparing the highest with the lowest categories of GI and GL were 1.19 (1.14, 1.24) and 1.13 (1.08, 1.17), respectively. CONCLUSION The updated analyses from our 3 cohorts and meta-analyses provide further evidence that higher dietary GI and GL are associated with increased risk of T2D.