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Healthy dietary patterns rich in legumes can improve metabolic health, although their additional benefits in conjunction with calorie restriction have not been well-established. We investigated effects of a calorie-restricted, legume-enriched, multicomponent intervention diet compared with a calorie-restricted control diet in 127 Chinese prediabetes participants, living in Singapore. The study was a 16-week, single-blind, parallel-design, randomized controlled trial (n = 63 intervention group (IG), n = 64 control group (CG); mean ± SD age 62.2 ± 6.3 years, BMI 23.8 ± 2.6 kg/m 2 ). Primary outcomes were markers of glycemia and all measurements were taken at 2 or 4-weekly intervals. At the end of 16 weeks, both groups had significantly lower BMI ( q ( Time )  = 1.92 ×10 -42 , β   = -0.02) compared with baseline, with minimal difference between groups. The IG had significantly greater reductions in LDL cholesterol ( q ( Treatment×Time )  = 0.01, β   = -0.16), total cholesterol ( q ( Treatment×Time )  = 0.02, β   = -0.3) and HbA1c ( q ( Treatment×Time )  = 0.04, β   = -0.004) compared with CG, alongside increases in fiber degrading species in IG, mediated through metabolites such as bile acids and amino acids. A legume-enriched, multicomponent intervention diet can improve metabolic health in a prediabetes population, in addition to benefits obtained from calorie restriction alone, partially mediated through changes in gut microbial composition and function. Trial registration: Clinical Trials NCT04745702. Prediabetics have an increased risk of type 2 diabetes. In this parallel-design, randomized controlled trial, the authors show improvements in metabolic health in a prediabetes population consuming a legume-rich diet, which are mediated through favorable changes in gut microbiome.

Aims/hypothesis Although the Diabetes Prevention Program (DPP) established lifestyle changes (diet, exercise and weight loss) as the ‘gold standard’ preventive therapy for diabetes, the relative contribution of exercise alone to the overall utility of the combined diet and exercise effect of DPP is unknown; furthermore, the optimal intensity of exercise for preventing progression to diabetes remains very controversial. To establish clinical efficacy, we undertook a study (2009 to 2013) to determine: how much of the effect on measures of glucose homeostasis of a 6 month programme modelled after the first 6 months of the DPP is due to exercise alone; whether moderate- or vigorous-intensity exercise is better for improving glucose homeostasis; and to what extent amount of exercise is a contributor to improving glucose control. The primary outcome was improvement in fasting plasma glucose, with improvement in plasma glucose AUC response to an OGTT as the major secondary outcome. Methods The trial was a parallel clinical trial. Sedentary, non-smokers who were 45–75 year old adults ( n  = 237) with elevated fasting glucose (5.28–6.94 mmol/l) but without cardiovascular disease, uncontrolled hypertension, or diabetes, from the Durham area, were studied at Duke University. They were randomised into one of four 6 month interventions: (1) low amount (42 kJ kg body weight −1 week −1 [KKW])/moderate intensity: equivalent of expending 42 KKW (e.g. walking ∼16 km [8.6 miles] per week) with moderate-intensity (50% V . O 2 reserve ) exercise; (2) high amount (67 KKW)/moderate intensity: equivalent of expending 67 KKW (∼22.3 km [13.8 miles] per week) with moderate-intensity exercise; (3) high amount (67 KKW)/vigorous intensity: equivalent to group 2, but with vigorous-intensity exercise (75% V . O 2 reserve ); and (4) diet + 42 KKW moderate intensity: same as group 1 but with diet and weight loss (7%) to mimic the first 6 months of the DPP. Computer-generated randomisation lists were provided by our statistician (G. P. Samsa). The randomisation list was maintained by L. H. Willis and C. A. Slentz with no knowledge of or input into the scheduling, whereas all scheduling was done by L. A. Bateman, with no knowledge of the randomisation list. Subjects were automatically assigned to the next group listed on the randomisation sheet (with no ability to manipulate the list order) on the day that they came in for the OGTT, by L. H. Willis. All plasma analysis was done blinded by the individuals doing the measurements (i.e. lipids, glucose, insulin). Subjects and research staff (other than individuals analysing the blood) were not blinded to the group assignments. Results Number randomised, completers and number analysed with complete OGTT data for each group were: low-amount/moderate-intensity (61, 43, 35); high-amount/moderate-intensity (61, 44, 40); high-amount/vigorous-intensity (61, 43, 38); diet/exercise (54, 45, 37), respectively. Only the diet and exercise group experienced a decrease in fasting glucose ( p  < 0.001). The means and 95% CIs for changes in fasting glucose (mmol/l) for each group were: high-amount/moderate-intensity −0.07 (−0.20, 0.06); high-amount/vigorous 0.06 (−0.07, 0.19); low-amount/moderate 0.05 (−0.05, 0.15); and diet/exercise −0.32 (−0.46, −0.18). The effects sizes for each group (in the same order) were: 0.17, 0.15, 0.18 and 0.71, respecively. For glucose tolerance (glucose AUC of OGTT), similar improvements were observed for the diet and exercise (8.2% improvement, effect size 0.73) and the 67 KKW moderate-intensity exercise (6.4% improvement, effect size 0.60) groups; moderate-intensity exercise was significantly more effective than the same amount of vigorous-intensity exercise ( p  < 0.0207). The equivalent amount of vigorous-intensity exercise alone did not significantly improve glucose tolerance (1.2% improvement, effect size 0.21). Changes in insulin AUC, fasting plasma glucose and insulin did not differ among the exercise groups and were numerically inferior to the diet and exercise group. Conclusions/interpretation In the present clinical efficacy trial we found that a high amount of moderate-intensity exercise alone was very effective at improving oral glucose tolerance despite a relatively modest 2 kg change in body fat mass. These data, combined with numerous published observations of the strong independent relation between postprandial glucose concentrations and prediction of future diabetes, suggest that walking ∼18.2 km (22.3 km prescribed with 81.6% adherence in the 67 KKW moderate-intensity group) per week may be nearly as effective as a more intensive multicomponent approach involving diet, exercise and weight loss for preventing the progression to diabetes in prediabetic individuals. These findings have important implications for the choice of clinical intervention to prevent progression to type 2 diabetes for those at high risk. Trial registration : ClinicalTrials.gov NCT00962962 Funding : The study was funded by National Institutes for Health National Institute of Diabetes and Digestive and Kidney Diseases (NIH-NDDK) (R01DK081559)

Reverse causality has made it difficult to establish the causal directions between obesity and prediabetes and obesity and insulin resistance. To disentangle whether obesity causally drives prediabetes and insulin resistance already in non-diabetic individuals, we utilized the UK Biobank and METSIM cohort to perform a Mendelian randomization (MR) analyses in the non-diabetic individuals. Our results suggest that both prediabetes and systemic insulin resistance are caused by obesity (p = 1.2×10-3 and p = 3.1×10-24). As obesity reflects the amount of body fat, we next studied how adipose tissue affects insulin resistance. We performed both bulk RNA-sequencing and single nucleus RNA sequencing on frozen human subcutaneous adipose biopsies to assess adipose cell-type heterogeneity and mitochondrial (MT) gene expression in insulin resistance. We discovered that the adipose MT gene expression and body fat percent are both independently associated with insulin resistance (p≤0.05 for each) when adjusting for the decomposed adipose cell-type proportions. Next, we showed that these 3 factors, adipose MT gene expression, body fat percent, and adipose cell types, explain a substantial amount (44.39%) of variance in insulin resistance and can be used to predict it (p≤2.64×10-5 in 3 independent human cohorts). In summary, we demonstrated that obesity is a strong determinant of both prediabetes and insulin resistance, and discovered that individuals' adipose cell-type composition, adipose MT gene expression, and body fat percent predict their insulin resistance, emphasizing the critical role of adipose tissue in systemic insulin resistance.

The timing of dietary total fat intake influences glucose homeostasis, however, the impact of unsaturated fat (USFA) intake has yet to be explored. This 12-week, double-blind, randomized, controlled, 2 × 2 factorial-designed feeding trial investigated the effects of timing (lunch or dinner) and types of dietary USFA (high monounsaturated fat or polyunsaturated fat diet) intake on glucose metabolism in seventy prediabetes participants (mean age, 57 years). Sixty participants with completed fecal samples were included in the final analysis ( n  = 15 for each group). Postprandial serum glucose was first primary outcome, postprandial insulin levels and insulin sensitivity indices were co-primary outcomes Secondary outcomes were continuous glucose levels, serum fatty acid profile, gut microbiome (metagenomic sequencing) and fecal metabolites. Results showed no significant differences in postprandial glucose between groups. However, USFA intake at lunch (vs. dinner) improved insulin sensitivity and reduced postprandial insulin and serum free saturated fatty acid ( P timing  < 0.05, P type  > 0.05, P interaction  > 0.05), which was associated with alterations in gut microbiome and bile acid metabolism, regardless of USFA type. In summary, these results suggest that advancing timing of USFA intake improves insulin sensitivity through the gut microbiome and bile acid metabolism. Trial registration: ChiCTR2100045645. Here, Ying Li et al. present the results of a randomized controlled feeding trial in prediabetes participants, finding that advancing timing of unsaturated fat (USFA) intake improves insulin sensitivity through the gut microbiome and bile acid metabolism, regardless of USFA type.

To investigate the effectiveness of long-term Baduanjin and aerobic training on the 10-year risk of atherosclerotic cardiovascular disease in prediabetic patients. This study was single-blind randomized controlled trial. A total of 98 participants with prediabetes were randomly divided into three groups: the BDJ (n = 34), AT (n = 32), and control (n = 32) groups. Participants in the BDJ and AT groups underwent one year of supervised group exercise, consisting of 60 min/session every other day. The primary outcomes were metabolic control and the 10-year risk of ASCVD. The secondary outcome was a change in blood glucose status. After the intervention, various metabolic indexes were significantly improved in the two exercise groups relative to the control group and baseline measurements ( p  < 0.05). Compared with no exercise, BDJ and AT had significant preventive and protective effects against the risk of ASCVD in patients with prediabetes ( p  < 0.001). The overall effects of the two exercise groups were similar ( p  > 0.05). Long-term BDJ training can effectively reduce the risk of type 2 diabetes mellitus (T2DM) and its cardiovascular complications in prediabetic patients. The effect of BDJ is similar to that of moderate-intensity aerobic exercise.

To examine whether combined vitamin D and calcium supplementation improves insulin sensitivity, insulin secretion, β-cell function, inflammation and metabolic markers. 6-month randomized, placebo-controlled trial. Ninety-five adults with serum 25-hydroxyvitamin D [25(OH)D] ≤55 nmol/L at risk of type 2 diabetes (with prediabetes or an AUSDRISK score ≥15) were randomized. Analyses included participants who completed the baseline and final visits (treatment n = 35; placebo n = 45). Daily calcium carbonate (1,200 mg) and cholecalciferol [2,000-6,000 IU to target 25(OH)D >75 nmol/L] or matching placebos for 6 months. Insulin sensitivity (HOMA2%S, Matsuda index), insulin secretion (insulinogenic index, area under the curve (AUC) for C-peptide) and β-cell function (Matsuda index x AUC for C-peptide) derived from a 75 g 2-h OGTT; anthropometry; blood pressure; lipid profile; hs-CRP; TNF-α; IL-6; adiponectin; total and undercarboxylated osteocalcin. Participants were middle-aged adults (mean age 54 years; 69% Europid) at risk of type 2 diabetes (48% with prediabetes). Compliance was >80% for calcium and vitamin D. Mean serum 25(OH)D concentration increased from 48 to 95 nmol/L in the treatment group (91% achieved >75 nmol/L), but remained unchanged in controls. There were no significant changes in insulin sensitivity, insulin secretion and β-cell function, or in inflammatory and metabolic markers between or within the groups, before or after adjustment for potential confounders including waist circumference and season of recruitment. In a post hoc analysis restricted to participants with prediabetes, a significant beneficial effect of vitamin D and calcium supplementation on insulin sensitivity (HOMA%S and Matsuda) was observed. Daily vitamin D and calcium supplementation for 6 months may not change OGTT-derived measures of insulin sensitivity, insulin secretion and β-cell function in multi-ethnic adults with low vitamin D status at risk of type 2 diabetes. However, in participants with prediabetes, supplementation with vitamin D and calcium may improve insulin sensitivity. Australian New Zealand Clinical Trials Registry ACTRN12609000043235.

Aims/hypothesisPancreatic fat accumulation may contribute to the development of beta cell dysfunction. Exercise training improves whole-body insulin sensitivity, but its effects on pancreatic fat content and beta cell dysfunction are unclear. The aim of this parallel-group randomised controlled trial was to evaluate the effects of exercise training on pancreatic fat and beta cell function in healthy and prediabetic or type 2 diabetic participants and to test whether the responses were similar regardless of baseline glucose tolerance.MethodsUsing newspaper announcements, a total of 97 sedentary 40–55-year-old individuals were assessed for eligibility. Prediabetes (impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes were defined by ADA criteria. Of the screened candidates, 28 healthy men and 26 prediabetic or type 2 diabetic men and women met the inclusion criteria and were randomised into 2-week-long sprint interval or moderate-intensity continuous training programmes in a 1:1 allocation ratio using random permuted blocks. The primary outcome was pancreatic fat, which was measured by magnetic resonance spectroscopy. As secondary outcomes, beta cell function was studied using variables derived from OGTT, and whole-body insulin sensitivity and pancreatic fatty acid and glucose uptake were measured using positron emission tomography. The measurements were carried out at the Turku PET Centre, Finland. The analyses were based on an intention-to-treat principle. Given the nature of the intervention, blinding was not applicable.ResultsAt baseline, the group of prediabetic or type 2 diabetic men had a higher pancreatic fat content and impaired beta cell function compared with the healthy men, while glucose and fatty acid uptake into the pancreas was similar. Exercise training decreased pancreatic fat similarly in healthy (from 4.4% [3.0%, 6.1%] to 3.6% [2.4%, 5.2%] [mean, 95% CI]) and prediabetic or type 2 diabetic men (from 8.7% [6.0%, 11.9%] to 6.7% [4.4%, 9.6%]; p = 0.036 for time effect) without any changes in pancreatic substrate uptake (p ≥ 0.31 for time effect in both insulin-stimulated glucose and fasting state fatty acid uptake). In prediabetic or type 2 diabetic men and women, both exercise modes similarly improved variables describing beta cell function.Conclusions/interpretationTwo weeks of exercise training improves beta cell function in prediabetic or type 2 diabetic individuals and decreases pancreatic fat regardless of baseline glucose tolerance. This study shows that short-term training efficiently reduces ectopic fat within the pancreas, and exercise training may therefore reduce the risk of type 2 diabetes.Trial registrationClinicalTrials.gov NCT01344928FundingThis study was funded by the Emil Aaltonen Foundation, the European Foundation for the Study of Diabetes, the Finnish Diabetes Foundation, the Orion Research Foundation, the Academy of Finland (grants 251399, 256470, 281440, and 283319), the Ministry of Education of the State of Finland, the Paavo Nurmi Foundation, the Novo Nordisk Foundation, the Finnish Cultural Foundation, the Hospital District of Southwest Finland, the Turku University Foundation, and the Finnish Medical Foundation.

Aims/hypothesisPrediabetes is associated with postprandial hypertriacylglycerolaemia. Resistance exercise acutely lowers postprandial plasma triacylglycerol (TG); however, the changes in lipid metabolism that mediate this reduction are poorly understood. The aim of this study was to identify the constitutive metabolic mechanisms underlying the changes in postprandial lipid metabolism after resistance exercise in obese men with prediabetes.MethodsWe evaluated the effect of a single bout of whole-body resistance exercise (seven exercises, three sets, 10–12 repetitions at 80% of one-repetition maximum) on postprandial lipid metabolism in ten middle-aged (50 ± 9 years), overweight/obese (BMI: 33 ± 3 kg/m2), sedentary men with prediabetes (HbA1c >38 but <48 mmol/mol [>5.7% but <6.5%]), or fasting plasma glucose >5.6 mmol/l but <7.0 mmol/l or 2 h OGTT glucose >7.8 mmol/l but <11.1 mmol/l). We used a randomised, crossover design with a triple-tracer mixed meal test (ingested [(13C4)3]tripalmitin, i.v. [U-13C16]palmitate and [2H5]glycerol) to evaluate chylomicron-TG and total triacylglycerol-rich lipoprotein (TRL)-TG kinetics. We used adipose tissue and skeletal muscle biopsies to evaluate the expression of genes regulating lipolysis and lipid oxidation, skeletal muscle respirometry to evaluate oxidative capacity, and indirect calorimetry to assess whole-body lipid oxidation.ResultsThe single bout of resistance exercise reduced the lipaemic response to a mixed meal in obese men with prediabetes without changing chylomicron-TG or TRL-TG fractional clearance rates. However, resistance exercise reduced endogenous and meal-derived fatty acid incorporation into chylomicron-TG and TRL-TG. Resistance exercise also increased whole-body lipid oxidation, skeletal muscle mitochondrial respiration, oxidative gene expression in skeletal muscle, and the expression of key lipolysis genes in adipose tissue.Conclusions/interpretationA single bout of resistance exercise improves postprandial lipid metabolism in obese men with prediabetes, which may mitigate the risk for cardiovascular disease and type 2 diabetes.

Vitamin D deficiency may contribute to etiology of type 2 diabetes in Asian Indians. The objectives of this study was to evaluate effect of vitamin D supplementation on glycemic profile and body composition in prediabetic and vitamin D deficient overweight/obese Asian Indian women. In this open-label randomized placebo-controlled trial (78 weeks duration), 121 females (aged 20–60 years) with prediabetes and vitamin D deficiency were randomly allocated in intervention (n, 61) and placebo (n, 60) groups. The primary outcome variables were fasting blood glucose (FBG), 2-h blood glucose post OGTT (2-h BG), hemoglobin A1c (HbA1C), and reversal to normoglycemia. In Intention-to-treat analysis, at the end of intervention, we observed significant decrease in FBG [−5.0 (−12.6–2.4), p = 0.04], 2-h blood glucose post OGTT [−11(−49.3–26.9), p = 0.02], hemoglobin A1c [−0.41 (5.89, 6.55), p = 0.05] and increase in 25(OH) D [7.5 (−6.0–20.9), p = 0.002] levels in intervention as compared to the placebo group. Changes in glycemic category based on FBG were as follows; intervention group: normal FBG, 58.6%; impaired fasting glucose (IFG), 39%; and type 2 diabetes mellitus (T2DM), 2.4%; placebo group: normal FBG, 48.8%; IFG, 46.3%; and T2DM, 4.9%. Changes in category of 2-hour glucose post OGTT after intervention were as follows; intervention group: normal glucose tolerance (NGT) 51.2% and prediabetes, 48.8%; placebo group: NGT, 43.9%; prediabetes, 53.7% and T2DM, 2.4%. After intervention, subscapular skinfold (visit I st compared to visit III rd ) and suprailiac skinfold (visit II nd compared to visit III rd ) were significantly lower in intervention group vs . control group. In conclusion, we observed significant reduction in FBG, 2-hour glucose post OGTT, HbA1c, and truncal subcutaneous fat and reversal to normoglycemia in overweight/obese prediabetic vitamin D deficient Asian Indian women after 78 weeks of vitamin D supplementation.

OBJECTIVE: We evaluated the metabolic effects and tolerability of GFT505, a novel dual peroxisome proliferator–activated receptor α/δ agonist, in abdominally obese patients with either combined dyslipidemia or prediabetes. RESEARCH DESIGN AND METHODS: The S1 study was conducted in 94 patients with combined dyslipidemia while the S2 study was conducted in 47 patients with prediabetes. Participants were randomly assigned in a double-blind manner to GFT505 at 80 mg/day or placebo for 28 (S1) or 35 (S2) days. Primary efficacy end points were changes from baseline at week 4 in both fasting plasma triglycerides and HDL cholesterol in the S1 group and 2-h glucose upon oral glucose tolerance test in the S2 group. RESULTS: In comparison with placebo, GFT505 significantly reduced fasting plasma triglycerides (S1: least squares means –16.7% [95% one-sided CI –∞ to –5.3], P = 0.005; S2: –24.8% [–∞ to –10.5], P = 0.0003) and increased HDL cholesterol (S1: 7.8% [3.0 to ∞], P = 0.004; S2: 9.3% [1.7 to ∞], P = 0.009) in both studies, whereas LDL cholesterol only decreased in S2 (–11.0% [ –∞ to –3.5], P = 0.002). In S2, GFT505 did not reduce 2-h glucose (–0.52 mmol/L [–∞ to 0.61], P = 0.18) but led to a significant decrease of homeostasis model assessment of insulin resistance (–31.4% [–∞ to 12.5], P = 0.001), fasting plasma glucose (–0.37 mmol/L [–∞ to –0.10], P = 0.01) and fructosamine (–3.6% [–∞ to –0.20], P = 0.02). GFT505 also reduced γ glutamyl transferase levels in both studies (S1: –19.9% [–∞ to –12.8], P < 0.0001; S2: –15.1% [–∞ to –1.1], P = 0.004). No specific adverse safety signals were reported during the studies. CONCLUSIONS: GFT505 may be considered a new drug candidate for the treatment of lipid and glucose disorders associated with the metabolic syndrome.