Greater Improvement In Insulin Sensitivity Research Articles

Effects of Tirzepatide vs Semaglutide on β-cell Function, Insulin Sensitivity, and Glucose Control During a Meal Test.

In a clinical study, tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1RA), provided superior glycemic control vs the GLP-1RA semaglutide. The physiologic mechanisms are incompletely understood. To evaluate treatment effects by model-based analyses of mixed-meal tolerance test (MMTT) data. A 28-week double-blind, randomized, placebo-controlled trial. Two clinical research centers in Germany. Patients with type 2 diabetes treated with metformin. Tirzepatide 15 mg, semaglutide 1 mg, placebo. Glycemic control, model-derived β-cell function indices including insulin secretion rate (ISR) at 7.2-mmol/L glucose (ISR7.2), β-cell glucose (β-CG) sensitivity, insulin sensitivity, and estimated hepatic insulin-to-glucagon ratio. Tirzepatide significantly reduced fasting glucose and MMTT total glucose area under the curve (AUC) vs semaglutide (P < 0.01). Incremental glucose AUC did not differ significantly between treatments; therefore, greater total glucose AUC reduction with tirzepatide was mainly attributable to greater suppression of fasting glucose. A greater reduction in total ISR AUC was achieved with tirzepatide vs semaglutide (P < 0.01), in the context of greater improvement in insulin sensitivity with tirzepatide (P < 0.01). ISR7.2 was significantly increased with tirzepatide vs semaglutide (P < 0.05), showing improved β-CG responsiveness. MMTT-derived β-CG sensitivity was increased but not significantly different between treatments. Both treatments reduced fasting glucagon and total glucagon AUC, with glucagon AUC significantly reduced with tirzepatide vs semaglutide (P < 0.01). The estimated hepatic insulin-to-glucagon ratio did not change substantially with either treatment. These results suggest that the greater glycemic control observed for tirzepatide manifests as improved fasting glucose and glucose excursion control, due to improvements in ISR, insulin sensitivity, and glucagon suppression.

Dietary weight loss-induced improvements in metabolic function are enhanced by exercise in people with obesity and prediabetes.

The additional therapeutic effects of regular exercise during a dietary weight loss program in people with obesity and prediabetes are unclear. Here, we show that whole-body (primarily muscle) insulin sensitivity (primary outcome) was 2-fold greater (P = 0.006) after 10% weight loss induced by calorie restriction plus exercise training (Diet+EX; n = 8, 6 women) than 10% weight loss induced by calorie restriction alone (Diet-ONLY; n = 8, 4 women) in participants in two concurrent studies. The greater improvement in insulin sensitivity was accompanied by increased muscle expression of genes involved in mitochondrial biogenesis, energy metabolism and angiogenesis (secondary outcomes) in the Diet+EX group. There were no differences between groups in plasma branched-chain amino acids or markers of inflammation, and both interventions caused similar changes in the gut microbiome. Few adverse events were reported. These results demonstrate that regular exercise during a diet-induced weight loss program has profound additional metabolic benefits in people with obesity and prediabetes.Trial Registration: ClinicalTrials.gov (NCT02706262 and NCT02706288).

Cardiometabolic health improvements upon dietary intervention are driven by tissue-specific insulin resistance phenotype: A precision nutrition trial

Precision nutrition based on metabolic phenotype may increase the effectiveness of interventions. In this proof-of-concept study, we investigated the effect of modulating dietary macronutrient composition according to muscle insulin-resistant (MIR) or liver insulin-resistant (LIR) phenotypes on cardiometabolic health. Women and men with MIR or LIR (n= 242, body mass index [BMI] 25-40kg/m2, 40-75 years) were randomized to phenotype diet (PhenoDiet) group A or B and followed a 12-week high-monounsaturated fatty acid (HMUFA) diet or low-fat, high-protein, and high-fiber diet (LFHP) (PhenoDiet group A, MIR/HMUFA and LIR/LFHP; PhenoDiet group B, MIR/LFHP and LIR/HMUFA). PhenoDiet group B showed no significant improvements in the primary outcome disposition index, but greater improvements in insulin sensitivity, glucose homeostasis, serum triacylglycerol, and C-reactive protein compared with PhenoDiet group A were observed. We demonstrate that modulating macronutrient composition within the dietary guidelines based on tissue-specific insulin resistance (IR) phenotype enhances cardiometabolic health improvements. Clinicaltrials.gov registration: NCT03708419, CCMO registration NL63768.068.17.

714-P: Greater Improvement in Insulin Sensitivity Per Unit Weight Loss with Tirzepatide Compared with Selective GLP-1 Receptor Agonism

Tirzepatide (TZP) , a novel GIP-GLP-1 dual agonist, improved fasting measures of insulin sensitivity partially attributable to weight loss in Phase 2 studies. Studies in mice demonstrated that GIP receptor agonism with TZP improved insulin sensitivity independent of weight loss. To further evaluate insulin-sensitizing actions of TZP, we measured insulin sensitivity with hyperinsulinemic euglycemic clamps (M-value) in a 28-week double-blind randomized controlled trial comparing effects of TZP 15mg with placebo or semaglutide 1mg (SEMA) , a selective GLP-1RA, all subcutaneous QW. Linear regression was used to compare relationships of change in M-value versus change in weight across treatment groups. Change in M-value was related to absolute change and % change in weight (Figure) . Slopes of linear relationships with absolute and % weight change differed between TZP and SEMA (absolute change: p=0.015; % change: p=0.03) . Larger negative slopes were observed for TZP compared with SEMA on change in M-value related to absolute change and to % change in weight. These results suggest that TZP may provide greater improvement in insulin sensitivity than a selective GLP-1RA per unit weight loss, most evident in subjects with greater weight loss. Disclosure K.J.Mather: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. M.K.Thomas: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A.Mari: Consultant; Lilly, Research Support; Lilly. J.Li: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. T.Heise: Advisory Panel; Novo Nordisk A/S, Research Support; ADOCIA, AstraZeneca, Biocon, Boehringer Ingelheim International GmbH, Crinetics Pharmaceuticals, Inc., Eli Lilly and Company, Gan &amp; Lee Pharmaceuticals, Genova, Nestlé, Neuraly Inc., Novo Nordisk A/S, Sanofi, Zealand Pharma A/S, Speaker's Bureau; Eli Lilly and Company, Gan &amp; Lee Pharmaceuticals, Novo Nordisk A/S. J.De vries: Advisory Panel; ADOCIA, Novo Nordisk A/S, Zealand Pharma A/S, Speaker's Bureau; Novo Nordisk A/S. S.Urva: Employee; Eli Lilly and Company. T.Coskun: Employee; Eli Lilly and Company. Z.Milicevic: Employee; Eli Lilly and Company. A.Haupt: Employee; Lilly, Stock/Shareholder; Lilly. Funding Eli Lilly and Company

Effects Of Moderate Versus Vigorous Intensity Exercise Training In Older Adults With Prediabetes

PURPOSE: Aerobic exercise is recommended to improve glycemic control; however, the optimal intensity of exercise for older adults with prediabetes is unknown. The objective of this pilot study was to compare the effects of moderate vs. vigorous intensity aerobic exercise on glycemic control and non-exercise physical activity (NEPA). METHODS: 19 older adults (14F; 68.1 ± 5.8 yrs) with prediabetes (HbA1c 5.7-6.4% or fasting glucose 100-125 mg/dl) were randomized to 12-weeks of supervised aerobic exercise (45-min sessions 4 days/wk) at either moderate (MOD: 60-65% HRmax) or vigorous (VIG: 80-85% HRmax) intensity. Free-living glycemic control (24h mean; percent of day ≥140 mg/dL) was measured using continuous glucose monitors (CGM, Dexcom). NEPA (>1.5 METs, excluding exercise sessions) was assessed using a thigh worn accelerometer (ActivPAL v4). A 3h Oral glucose tolerance test (OGTT, 75g) was performed at baseline and following the exercise intervention (72-96h following the last exercise bout) to compare to free-living CGM and as measure of insulin sensitivity (Matsuda Index). Data are presented as mean±SE. RESULTS: Adherence rates to the exercise interventions were 85±9% and 89±3% in MOD and VIG with mean heart rates during exercise of 99±1 bpm (65% HRmax) and 123±4 bpm (79% HRmax), respectively. Mean 24h glucose (-8.4±6.4 vs. -2.2±6.7 mg/dl) and percent of day >140 mg/dL (-9.7±11.0% vs. 0.7±4.6%) did not significantly change in MOD or VIG, respectively. However, there was a significant group by time interaction (p=0.05) for change in insulin sensitivity in MOD (+2.4±1.1) and VIG (-0.6±0.8).There were no differences between groups for change in NEPA, fasting glucose, or 2h glucose. Changes in free-living CGM were not significantly correlated with changes in OGTT outcomes. CONCLUSION: In older men and women with prediabetes, both MOD and VIG had minimal effects on free-living glycemic control, but MOD induced greater improvements in insulin sensitivity. These preliminary results suggest that a more comprehensive lifestyle intervention combining dietary intervention and exercise may be needed to improve glycemic control in this population.

1029 Objectively-Measured Sleep Following a Time Restricted Eating Intervention in Adults With Obesity

Abstract Introduction Time-restricted eating (TRE), limiting food intake to a consistent daily window, is emerging as a novel weight loss intervention but impact of TRE on sleep remains unclear. Prior studies reported mixed results but are limited by subjective sleep measurements and lack of a randomized control group. Thus, we examined changes in actigraphy-measured sleep following a 12-week TRE protocol. Methods Participants were 20 adults ages 18-65 years with BMI ≥24kg/m2. Participants were randomized to either TRE (8-hour eating window) or non-TRE (typical eating). At baseline and follow-up, all participants had anthropometric measurements, oral glucose tolerance test, logged eating occasions in a smartphone application, and wore an ActiGraph Link for two weeks. Independent samples t-tests compared groups on actigraphy-estimated sleep variables. Pearson correlations examined associations between sleep variables with health outcomes. Results The TRE (N=11) and non-TRE groups (N=9) were predominantly female and had a baseline eating window of approximately 15 hours. There were no differences in actigraphy-assessed sleep variables at baseline or follow-up between groups. Participants did not significantly change their sleep from baseline to follow-up. Median weekday sleep duration was 6.2 hours at follow-up for all participants, suggesting insufficient sleep compared to the recommended 7-9 hours of sleep. Participants who obtained greater than the median weekday sleep duration at follow-up had significantly lower BMI, better insulin sensitivity (HOMA and Matsuda Index), and greater percent improvement in insulin sensitivity. Conclusion Our data show that TRE does not significantly alter sleep behaviors in participants with obesity. However, longer sleep duration at follow-up was associated with lower BMI, better insulin sensitivity, and greater improvement in insulin sensitivity, indicating that sleep may be an important variable to consider in dietary interventions. Future research examining behavioral sleep strategies in combination with TRE is needed to evaluate whether improved sleep leads to better weight loss and glycemic outcomes for individuals with obesity. Support This work was support by the Healthy Foods Healthy Lives program (17SFR-2YR50LC to LC) and the National Institutes of Health (NIH National Center for Advancing Translational Sciences, UL1TR002494).

Biliopancreatic Diversion Induces Greater Metabolic Improvement Than Roux-en-Y Gastric Bypass

Diabetes remission is greater after biliopancreatic diversion (BPD) than Roux-en-Y gastric bypass (RYGB) surgery. We used a mixed-meal test with ingested and infused glucose tracers and the hyperinsulinemic-euglycemic clamp procedure with glucose tracer infusion to assess the effect of 20% weight loss induced by either RYGB or BPD on glucoregulation in people with obesity (ClinicalTrials.gov number: NCT03111953). The rate of appearance of ingested glucose into the circulation was much slower, and the postprandial increases in plasma glucose and insulin concentrations were markedly blunted after BPD compared to after RYGB. Insulin sensitivity, assessed as glucose disposal rate during insulin infusion, was ∼45% greater after BPD than RYGB, whereas β cell function was not different between groups. These results demonstrate thatcompared with matched-percentage weight loss induced by RYGB, BPD has unique beneficial effects on glycemic control, manifested by slower postprandial glucose absorption, blunted postprandial plasma glucose and insulin excursions, and greater improvement in insulin sensitivity.

PPARG Pro12Ala Ala carriers exhibit greater improvements in peripheral insulin sensitivity in response to 12 weeks of aerobic exercise training.

The Ala allele of PPARG Pro12Ala ( rs1801282 ) is associated with greater improvements to the glucose metabolism in exercise studies, but whether this extends to peripheral insulin sensitivity is unknown. Our objective was to investigate the effect of PPARG Pro12Ala on exercise-induced changes in peripheral insulin sensitivity. A total of 124 (91 Pro homozygotes and 33 Ala carriers) previously physically inactive healthy young men and women with overweight or class 1 obesity who completed a 12 wk aerobic exercise intervention were included in the analysis. All participants underwent a hyperinsulinemic euglycemic clamp before and after the 12 wk intervention. The prescribed exercise frequency was 5-7 days/wk, and the exercise energy expenditure was 2,100 4,200 kcal/wk for men and 1,600 kcal/wk for women. Insulin sensitivity improved significantly in both genotype groups. However, Ala carriers had a 1.13-fold (95% confidence interval 1.01; 1.26, P = 0.032) greater improvement in insulin sensitivity from baseline compared with Pro homozygotes. Our data support that PPARG Pro12Ala modifies the effect of aerobic exercise on peripheral insulin sensitivity.

Similar Weight Loss Induces Greater Improvements in Insulin Sensitivity and Liver Function among Individuals with NAFLD Compared to Individuals without NAFLD.

Background: Preliminary evidence suggests that weight loss among obese has differential metabolic effects depending on the presence of non-alcoholic fatty liver disease (NAFLD). We assessed whether NAFLD predisposes to differential changes in liver fat content, liver function, and metabolic parameters upon diet-induced weight loss in a 50-week intervention trial. Methods: 143 overweight and obese non-smokers underwent a 12-week dietary intervention and a 38-week follow-up. Diet-induced changes in anthropometric measures, circulating biomarkers, and magnetic resonance (MR)-derived liver fat content and adipose tissue volumes were evaluated by mixed linear models stratifying by NAFLD at baseline. Results: The prevalence of NAFLD at baseline was 52%. Diet-induced weight loss after 12 (NAFLD: 4.8 ± 0.5%, No NAFLD: 5.1 ± 0.5%) and 50 weeks (NAFLD: 3.5 ± 0.7%, No NAFLD: 3.5 ± 0.9%) was similar in both groups, while the decrease in liver fat was significantly greater in the NAFLD group (week 12: 32.9 ± 9.5% vs. 6.3 ± 4.0%; week 50: 23.3 ± 4.4% vs. 5.0 ± 4.2%). Decreases in biomarkers of liver dysfunction (GGT, ALT, AST) and HOMA IR were also significantly greater in the NAFLD group. Other metabolic parameters showed no significant differences. Conclusion: Our data suggest that individuals with NAFLD show greater improvements of liver function and insulin sensitivity after moderate diet-induced weight loss than individuals without NAFLD.

Effects of aerobic training with and without weight loss on insulin sensitivity and lipids.

PurposeThe purpose of this study is to evaluate the effect of exercise training with modest or greater weight loss (≥3%) or not (<3%) on insulin sensitivity, lipoprotein concentrations, and lipoprotein particle size in overweight and obese participants.MethodsAdults (N = 163, body mass index: 25–37 [kg/m2]) participated in 8 months of exercise training. Insulin sensitivity, lipid concentrations, lipid particle size and other cardiometabolic variables were measured at baseline and follow-up. Participants were categorized by whether they achieved at least modest weight loss (≥ 3%) or not (<3%) following the intervention.ResultsA greater improvement in insulin sensitivity was observed in adults performing exercise training with at least modest weight loss (2.2 mU·l-1 ·min -1, CI: 1.5 to 2.8) compared to those who did not (0.8 mU·l-1 ·min -1, CI: 0.5 to 1.2). Similar results were observed for acute insulin response, triglycerides, non-HDL cholesterol concentration, low density lipoprotein (LDL) particle size and high density lipoprotein (HDL) particle size (p<0.05), when all exercise groups were combined. No significant results across weight loss categories were observed for LDL, HDL, glucose, or insulin levels.ConclusionThe present study suggests that aerobic exercise combined with at least modest weight loss leads to greater improvements in insulin sensitivity, triglycerides as well as other non-traditional lipid risk factors (non-HDL cholesterol, HDL/LDL particle size). Clinicians should advocate patients who are overweight/obese to exercise and obtain modest weight loss for improved cardiovascular benefits.

Effects of Short-Term Exercise in Overweight/Obese Adults with Insulin Resistance or Type 2 Diabetes: A Systematic Review of Randomized Controlled Trials

Background: Chronic exercise training is associated with improvements in body composition and/aerobic fitness. This presents a challenge to study effects of exercise in isolation. Metabolic effects of short-term exercise training (≤ 12 weeks) are unclear, with studies reporting improvements or no change in insulin sensitivity and/or glucose control. This review systemically examined randomized controlled trials (RCTs) to establish whether short-term exercise training improves insulin resistance and type 2 diabetes (diabetes). Methods: Following the PRISMA guidelines, a systematic review was conducted on nine electronic databases (BMC Endocrine Disorders, Clinical Key, Cochrane Library, EBSChost, PubMed, Scopus, Sabinet_SA Publications, The Lancet and Web of Science) to identify randomized controlled human trials (2005-2018) examining effects of short-term exercise training (≤ 12 weeks) in overweight/obese adults with insulin resistance or diabetes. Search terms included: insulin resistance, type 2 diabetes, short-term, exercise or energy expenditure and randomized controlled trial. Studies were only included if they provided sufficient data on: insulin sensitivity, glycemic control, body composition and aerobic fitness. Results: From 374 articles, three met the inclusion criteria. Of these, two prescribed moderate intensity training (MIT); rate of perceived exertion (RPE) 12-13 and 60% lactic threshold (LT) for four and twelve weeks, respectively while one prescribed vigorous exercise training at 70% VO2max for seven days. Duration of exercise sessions was 40-60 minutes. Twelve weeks of MIT was associated with improved glycemic control vs. no change in the 7-d and four weeks studies. Seven days of vigorous training was associated with greater improvement in insulin sensitivity, 44.4% vs. no change in the four- and twelve-weeks studies. Conclusion: Short-term exercise appears to improve insulin sensitivity and glucose control independent of body fat loss or gains in aerobic fitness. Vigorous exercise training was associated with superior improvements in insulin sensitivity. More RCTs are needed to confirm these findings.

Obesity in coronary heart disease: An unaddressed behavioral risk factor

Obesity is an independent risk factor for the development and progression of coronary heart disease (CHD). Over 80% of patients with CHD are overweight or obese. While obesity is often considered a relatively "minor" CHD risk factor, weight loss is a broadly effective risk-factor intervention. Weight loss can profoundly influence a number of "major" risk factors including: hypertension, dyslipidemia and insulin resistance/type 2 diabetes mellitus. Despite its prominence as a risk factor most cardiac rehabilitation (CR) programs do not have a specific, targeted intervention to assist patients with weight loss. Consequently, the weight loss that occurs during CR is quite small and unlikely to appreciably alter risk factors. Relying on CR associated exercise as a sole intervention is an ineffective strategy to promote weight loss. There is evidence, however, that behavioral weight loss (BWL) interventions can be effectively employed in the CR setting. In contrast to programs that do not offer a targeted intervention, studies show that participants in CR-related BWL programs lose significantly more weight. The additional weight loss from the BWL intervention is associated with greater improvements in insulin sensitivity and other components of the metabolic syndrome such as hypertension and lipid abnormalities. As a means of maximizing CHD risk factor reduction CR programs need to incorporate BWL programs as a standard programming for overweight/obese patients.

Impact of Endurance Exercise Training in the Fasted State on Muscle Biochemistry and Metabolism in Healthy Subjects: Can These Effects be of Particular Clinical Benefit to Type2 Diabetes Mellitus and Insulin-Resistant Patients?

Exercise trainingintervention is a cornerstone in the care of type2 diabetes mellitus (T2DM) and insulin resistance (IR), and it is pursued in order to optimize exercise interventions for these patients. In this regard, the nutritional state of patients during exercise (being in the fed or fasted state) can be of particular interest. The aim of the present review is to describe the impact of endurance exercise (training) in the fasted versus fed state on parameters of muscle biochemistry and metabolism linked to glycemic control or insulin sensitivity in healthy subjects. From these data it can then be deduced whether exercise training in the fasted state may be relevant to patients with T2DM or IR. In healthy subjects, acute endurance exercise in the fasted state is accompanied by lower blood insulin and elevated blood free fatty acid concentrations, stable blood glucose concentrations (in the first 60-90min), superior intramyocellular triacylglycerol oxidation and whole-body lipolysis, and muscle glycogen preservation. Long-term exercise training in the fasted state in healthy subjects is associated with greater improvements in insulin sensitivity, basal muscle fat uptake capacity, and oxidation. Therefore, promising results of exercise (training) in the fasted state have been found in healthy subjects on parameters of muscle biochemistry and metabolism linked to insulin sensitivity and glycemic control. Whether exercise training intervention in which exercise sessions are organized in the fasted state may be more effective in improving insulin sensitivity or glycemic control in T2DM patients and insulin-resistant individuals warrants investigation.

The effects of aerobic, resistance, and combination training on insulin sensitivity and secretion in overweight adults from STRRIDE AT/RT: a randomized trial

Most health organizations recommend a combination of aerobic training (AT) and resistance training (RT), yet few studies have compared their acute (within 24 h of the last exercise bout) and sustained (after 14 days of no exercise training) effects alone and in combination on glucose metabolism. The present study (Studies Targeting Risk Reduction Interventions through Defined Exercise-Aerobic Training and/or Resistance Training) compared the effects of AT, RT, and the combination (AT/RT) on insulin action at both acute and sustained phases. Subjects (N = 196) were 18-70 yr old (mean age = 50 yr), overweight (mean body mass index = 30 kg/m2), sedentary with moderate dyslipidemia, and were randomized into one of three 8-mo exercise groups: 1) RT: 3 days/wk, 8 exercises, 3 sets/exercise, 8-12 repetitions/set; 2) AT: equivalent to ∼19.2 km/wk (12 miles/wk) at 75% peak O2 consumption; 3) AT/RT: the combination of AT and RT. One hundred forty-four subjects completed the intervention. Eighty-eight subjects completed all pre- and postintervention testing visits. Insulin sensitivity, glucose effectiveness, and disposition index were measured via a frequently sampled intravenous glucose tolerance test with subsequent minimal model analyses. AT/RT resulted in greater improvements in insulin sensitivity, β-cell function (disposition index), and glucose effectiveness than either AT or RT alone (all P < 0.05). Approximately 52% of the improvement in insulin sensitivity by AT/RT was retained 14 days after the last exercise training bout. Neither AT or RT led to acute or chronic improvement in sensitivity index. In summary, only AT/RT (which required twice as much time as either alone) led to significant acute and sustained benefits in insulin sensitivity

Akkermansia Muciniphila and Gut Microbiota Richness are Associated with Improved Metabolic Status after Calorie Restriction

Populations with obesity and Type 2 Diabetes differ from healthy populations in the abundance of certain gut microbial species and microbial gene richness (MGR). Abundance of Akkermansia muciniphila (Akk) has been inversely associated to fat mass and glucose intolerance in mice. More evidence is needed in humans as well as on the impact of diet and weight loss on Akk abundance. Our aim was to evaluate the association between fecal Akk abundance and MGR, host characteristics, and their changes as a result of calorie restriction (CR) for 6 weeks followed by weight stabilization (WS) for 6 weeks in 49 overweight/obese adults. Fecal Akk, MGR, diet and bioclinical parameters were measured at baseline (BS) and after CR and WS. At BS Akk was inversely related to fasting glucose, waist‐to‐hip ratio, and adipocyte diameter in subcutaneous white adipose tissue. Subjects with higher MGR and Akk had the healthiest metabolic status, particularly in fasting glucose, triglycerides and body composition. Higher BS Akk was associated with greater improvement in insulin sensitivity and other clinical parameters after CR. Akk is associated with a healthier metabolic status and outcomes after CR in this population. Further studies are required to establish underlying mechanisms in humans. Support: ANR MICRO‐Obes, KOT‐Ceprodi, Fondation Coeur et Arteres, Metacardis HEALTH‐F4‐2012‐305312, FRS‐FNRS, ERC Starting grant 336452‐ENIGMO).

Morning Meal More Efficient for Fat Loss in a 3-Month Lifestyle Intervention

Objective: To evaluate the effects of 2 low-calorie diets but with different distributions of calories throughout the day on weight loss and other major obesity-related metabolic parameters.Methods: We randomly assigned 42 nonsmoking homemakers (age = 46.3 ± 2.3 years, body mass index [BMI] = 35.7 ± 0.8 kg/m2, mean ± SD) in 2 groups of 21 subjects (G1 and G2). The participants underwent a 3 month individualized Mediterranean-style diet (55% carbohydrate, 30% fat, 15% protein and fiber > 30 g), calorie (600 kcal daily deficit compared to the total energy expenditure measured by a metabolic Holter). Diets consisted of the same food and complied with cardiovascular disease prevention guidelines but differed in the distribution of calories throughout the day (G1: 70% breakfast, morning snack, lunch and 30% afternoon snack and dinner; G2: 55 breakfast, morning snack, lunch and 45% afternoon snack and dinner). Dual-energy X-ray absorptiometry was used for pre- and postintervention body composition assessment.Results: Thirty-six subjects completed the study (G1 = 18, G2 = 18). Both groups had significant improvements in body composition and metabolic parameters but G1 had enhanced results for weight loss (G1: −8.2 ± 3.0 kg; G2: −6.5 ± 3.4 kg; p = 0.028), waist circumference reduction (G1: −7 ± 0.6 cm; G2: −5 ± 0.3 cm; p = 0.033), and fat mass loss (G1: −6.8 ± 2.1 kg, G2: −4.5 ± 2.9 kg, p = 0.031; mean ± SD). Improvements were detected in both groups for blood pressure and blood and lipid parameters. G1 subjects showed a greater improvement in insulin sensitivity measured by homeostasis model assessment–estimated insulin resistance (G1: −1.37 ± 0.27, G2: −0.74 ± 0.12, p = 0.017).Conclusions: These data suggest that a low-calorie Mediterranean diet with a higher amount of calories in the first part of the day could establish a greater reduction in fat mass and improved insulin sensitivity than a typical daily diet.

Effects of different periods of hypoxic training on glucose metabolism and insulin sensitivity

This study examined the effects of different periods of hypoxic training on glucose metabolism. Sedentary subjects underwent hypoxic training (FiO2 = 15.0%) for either 2 weeks (2-week group; n = 11) or 4 weeks (4-week group; n = 10). The 2-week group conducted training sessions on 6 days week(-1) for 2 weeks, whereas the 4-week group conducted training sessions on 3 days week(-1) for 4 weeks. Body fat mass or abdominal fat area did not change after training period in either group. VO2max increased in both groups after training period (42 ± 2 versus 43 ± 2 ml min(-1) kg(-1) in 2-week group, 41 ± 1 versus 42 ± 2 ml min(-1) kg(-1) in 4-week group). Both groups showed a reduction in mean blood pressure after training period (92 ± 3 versus 90 ± 3 mmHg in 2-week group, 91 ± 2 versus 87 ± 2 mmHg in 4-week group, P ≤ 0.05). No change was observed in blood glucose response after glucose ingestion after training period. However, area under the curve for serum insulin concentrations after glucose ingestion significantly decreased in only 4-week group (6910 ± 763 versus 5812 ± 872 μIU ml(-1) 120 min, P ≤ 0.05). In conclusion, hypoxic training reduced blood pressure with independent on training duration. However, a longer period of hypoxic training led to greater improvements in insulin sensitivity compared with equivalent training over a shorter period, suggesting that hypoxic training programmes for more than 4 weeks might be more beneficial for improving insulin sensitivity.

Effects of Metformin, Metformin Plus Rosiglitazone, and Metformin Plus Lifestyle on Insulin Sensitivity and β-Cell Function in TODAY

OBJECTIVEThe Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial demonstrated that combination therapy with metformin plus rosiglitazone provided superior durability of glycemic control compared with metformin alone, with significantly lower treatment failure rates (38.6 vs. 51.7%), and metformin plus lifestyle was intermediate. Herein we describe the temporal changes in measures of β-cell function and insulin sensitivity over a 4-year period among the three treatments.RESEARCH DESIGN AND METHODSTODAY participants (699) were tested periodically with an oral glucose tolerance test to determine insulin sensitivity (1/fasting insulin [1/IF]), insulinogenic index (△I30/△G30) or C-peptide index (△C30/△G30), and β-cell function relative to insulin sensitivity (oral disposition index [oDI]).RESULTSDuring the first 6 months, metformin plus rosiglitazone exhibited a significantly greater improvement in insulin sensitivity and oDI versus metformin alone and versus metformin plus lifestyle; these improvements were sustained over 48 months of TODAY. Irrespective of treatment, those who failed to maintain glycemic control had significantly lower β-cell function (∼50%), higher fasting glucose concentration, and higher HbA1c at randomization compared with those who did not fail.CONCLUSIONSThe beneficial change in insulin sensitivity and the resultant lower burden on β-cell function achieved in the first 6 months with metformin plus rosiglitazone appear to be responsible for its superior glycemic durability over metformin alone and metformin plus lifestyle. However, initial β-cell reserve and HbA1c at randomization are independent predictors of glycemic durability. Therefore, efforts to preserve β-cell function before significant loss occurs and to reduce HbA1c may be beneficial in the treatment of youth with type 2 diabetes.

The effect of intermittent energy and carbohydrate restrictionv. daily energy restriction on weight loss and metabolic disease risk markers in overweight women

Intermittent energy restriction may result in greater improvements in insulin sensitivity and weight control than daily energy restriction (DER). We tested two intermittent energy and carbohydrate restriction (IECR) regimens, including one which allowed ad libitum protein and fat (IECR+PF). Overweight women (n 115) aged 20 and 69 years with a family history of breast cancer were randomised to an overall 25 % energy restriction, either as an IECR (2500-2717 kJ/d, < 40 g carbohydrate/d for 2 d/week) or a 25 % DER (approximately 6000 kJ/d for 7 d/week) or an IECR+PF for a 3-month weight-loss period and 1 month of weight maintenance (IECR or IECR+PF for 1 d/week). Insulin resistance reduced with the IECR diets (mean - 0·34 (95% CI - 0·66, - 0·02) units) and the IECR+PF diet (mean - 0·38 (95% CI - 0·75, - 0·01) units). Reductions with the IECR diets were significantly greater compared with the DER diet (mean 0·2 (95% CI - 0·19, 0·66) μU/unit, P= 0·02). Both IECR groups had greater reductions in body fat compared with the DER group (IECR: mean - 3·7 (95% CI - 2·5, - 4·9) kg, P= 0·007; IECR+PF: mean - 3·7 (95% CI - 2·8, - 4·7) kg, P= 0·019; DER: mean - 2·0 (95% CI - 1·0, 3·0) kg). During the weight maintenance phase, 1 d of IECR or IECR+PF per week maintained the reductions in insulin resistance and weight. In the short term, IECR is superior to DER with respect to improved insulin sensitivity and body fat reduction. Longer-term studies into the safety and effectiveness of IECR diets are warranted.

Association of vitamin D receptor gene polymorphisms with insulin resistance and response to vitamin D

The objectives of the study were to determine associations between single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) gene and insulin resistance and the effects of these SNPs on changes in insulin sensitivity in response to vitamin D supplementation. The research described here was an extension of the Surya study. Genotyping of the Cdx-2, FokI, BsmI, ApaI, and TaqI SNPs was carried out on 239 South Asian women in New Zealand using polymerase chain reaction–based techniques. Associations of these genotypes and 3′ end haplotypes with insulin resistance were determined using multiple regression analysis. Associations between SNP genotypes and responses in insulin sensitivity to vitamin D supplementation (4000 IU vitamin D3 per day) were also determined for a subset (81) of these women. BsmI BB, ApaI AA, and TaqI tt genotypes were significantly associated with lower insulin resistance compared with BsmI bb, ApaI aa, and TaqI TT, respectively, in the cohort of 239 women. Furthermore, homozygosity of the haplotypes baT and BAt was associated with higher and lower insulin resistance, respectively, compared with no copies of their respective alleles. Of the 81 subjects who were supplemented with vitamin D, women with the FokI Ff genotype showed a significantly greater improvement in insulin sensitivity (increase of 29.4 [2.9, 38.1]) compared with women with the FokI FF genotype (increase of 2.3 [−11.5, 10.1]). This study has highlighted the association of vitamin D responsiveness and insulin resistance with VDR gene polymorphisms. This is the first study to determine associations between all three. Genotyping of the VDR gene may provide a predictive measure for insulin resistance in response to vitamin D intervention.