Insulin Sensitivity In People Research Articles

The effects of different intermittent fasting regimens in people with type 2 diabetes: a network meta-analysis

ObjectiveTo compare the effects of four intermittent fasting regimens on blood glucose and insulin sensitivity in people with type 2 diabetes.MethodsRandomized controlled trials of intermittent fasting in the treatment of patients with type 2 diabetes mellitus in PubMed, the Cochrane Library, Embase, ScienceDirect, Web of Science, CNKI, VIP Database, and WANFANG Database were searched for from the library to September 2023. 2 review authors independently screened studies and extracted data. RevMan 5.4 was used for direct comparison of meta-results. Network meta-analysis was performed using Stata16 software.Results13 studies with a total of 867 patients were included. The intervention effects of twice-per-week fasting, fasting-mimicking diet, time-restricted eating, and peridic fasting were better than that of conventional diet. The results of the network comparison showed that there was no significant difference in the intervention effect of the intermittent fasting regimens. SUCRA ranking results showed that the twice-per-week fasting was best for comprehensive interventions for improvement.ConclusionFrom the perspective of fasting blood glucose, glycated hemoglobin and insulin resistance, the twice-per-week fasting intervention has a good effect, which can be used as a reference for patients with inter-type 2 diabetes to choose intermittent fasting regimen. However, more clinical trials are needed to verify this at a later stage.

Tirzepatide Improved Markers of Islet Cell Function and Insulin Sensitivity in People With T2D (SURPASS-2).

In previous SURPASS studies tirzepatide reduced HbA1c and body weight and improved markers of insulin sensitivity (IS) and beta-cell function to a greater extent than comparators. Explore changes in biomarkers of beta-cell function and IS and in efficacy profiles in baseline biomarker quartile analyses with tirzepatide compared to semaglutide. Post-hoc analysis of SURPASS-2 Phase 3 trial (participants randomly assigned to receive weekly subcutaneous tirzepatide or semaglutide for 40 weeks). Post-hoc analysis of 128 sites in 8 countries. 1879 participants with T2D. Once-weekly tirzepatide (5, 10, 15 mg) or semaglutide 1 mg. Change in HOMA2-B, HOMA2-IR, fasting glucagon, fasting C-peptide, and fasting insulin. At week 40, greater increase in HOMA2-B was seen with tirzepatide (5, 10, 15 mg) doses (96.9 to 120.4%) than with semaglutide 1 mg (84.0%) [p<0.05]. There was a greater reduction in HOMA2-IR with all doses of tirzepatide (15.5 to 24.0%) than with semaglutide 1 mg (5.1%) [p<0.05]. Tirzepatide 10 and 15 mg resulted a significant reduction in both fasting C-peptide (5.2 to 6.0%) and fasting glucagon (53.0 to 55.3%) compared to an increase of C-peptide (3.3%) and a reduction of glucagon (47.7%) with semaglutide 1 mg [p<0.05]. HbA1c and body weight reductions were greater with all tirzepatide doses than semaglutide within each HOMA2-B and HOMA2-IR baseline quartile. In this post-hoc analysis improvements in HbA1c and weight loss were consistent and significantly higher with tirzepatide, irrespective of baseline beta cell function and insulin resistance, compared to semaglutide.

Exercise under hypoxia on glucose tolerance in type 2 diabetes mellitus risk individuals: A systematic review and meta-analysis.

To analyze the impact of exercise under hypoxic exposure versus normoxic exposure on blood glucose level, insulin level, and insulin sensitivity in people at risk of Type 2 diabetes mellitus (T2DM). We systematically performed electronic searching on PubMed, Web of Science, ProQuest, and Scopus. Primary studies that met the inclusion criteria were analyzed using Revman 5.4.1. Nine randomized controlled trials were included in this meta-analysis. We found that physical exercise under hypoxic exposure had no significant effect on improving blood glucose levels, insulin levels, and insulin sensitivity in the elderly and sedentary people compared to normoxic condition. However, physical exercise during hypoxic exposure had a significant effect on lowering blood glucose levels in overweight/obese individuals (pooled Standardized Mean Difference = 0.29; 95% confidence interval = 0.01-0.57; P = 0.04). Exercising under hypoxic exposure can be an alternative strategy for reducing blood glucose levels in overweight/obese people. Nevertheless, in other populations at risk of T2DM, exercising in hypoxic conditions gives similar results to normoxic conditions.

Obesity blunts insulin sensitivity improvements and attenuates strength gains following resistance training in nondiabetic men.

Impaired insulin sensitivity is central in the etiology of type 2 diabetes in people with obesity. The effectiveness of resistance training (RE) alone in improving insulin sensitivity in people with obesity is undetermined. This study aimed to determine the influence of obesity on insulin sensitivity responses to RE. Nineteen sedentary men were allocated to Lean (BMI 22.7 ± 2.5 kgm-2; n = 10) or Obese group (BMI 33.2 ± 3.2 kgm-2; n = 9). Participants were evaluated before and after a 10-weeksupervised progressive RE (3 sets of 10 repetition maximum (RM), 3 d/wk) for insulin sensitivity indexes using an oral glucose tolerance test, body composition using anthropometrics, and strength using 1RM. Groups were matched at baseline for all variables except for body composition and absolute strength. Body fat was not changed in both groups. Matsuda insulin sensitivity index, hepatic insulin resistance, and insulin area under the curve improved by 64.3 ± 61.9 unit, - 58.2 ± 102.9 unit, 2.3 ± 4.1 unit, and - 721.6 ± 858.2 µU/ml, respectively, only in the Lean group. The increased1RM% for leg press was greater in the Lean (49.5 ± 18.7%) than in the Obese (31.5 ± 13.9), but not different for bench press (18.0 ± 9.1% vs. 16.4 ± 6.0%, respectively). Sustained obesity precludes insulin sensitivity improvements and attenuates strength gains in response to progressive RE. Additional strategies such as caloric restriction might be necessary for RE to improve insulin sensitivity, particularly at high levels of obesity.

Higher Short-Chain Fermentable Carbohydrates Are Associated with Lower Body Fat and Higher Insulin Sensitivity in People with Prediabetes.

The quality of carbohydrates has metabolic consequences in people with prediabetes. However, the causality of short-chain fermentable carbohydrate intakes and metabolic parameters has not been explored in the prediabetic or diabetic population. We investigated associations between different types of carbohydrates, including fermentable oligosaccharides, disaccharides, monosaccharides, polyols (FODMAPs), and polysaccharides (dietary fibre), and body composition and glucose/insulin responses in subjects with prediabetes. In this prospective cross-sectional study, 177 subjects with impaired glucose tolerance (IGT) (mean age: 60 (54-62) years, 41% men) underwent an assessment of body composition and completed six-point oral glucose tolerance tests (OGTT), Homeostatic Model Assessment of Insulin Resistance (HOMA2-IR), insulin sensitivity, detailed 3-day food records, and physical activity questionnaire. Daily habitual FODMAP intake decreased progressively with increasing BMI, ranging from 7.9 (6.2-12.7) g/d in subjects with normal BMI and 6.6 (4.6-9.9) g/d in subjects with overweight to 5.8 (3.8-9.0) g/d in subjects with obesity (p = 0.038). After adjustment for age and gender, galactooligosaccharides (GOSs) were negatively correlated with body fat (Standardised Beta coefficient β = -0.156, p = 0.006) and positively associated with insulin sensitivity (β = 0.243, p = 0.001). This remained significant after adjustment for macronutrients, fibre, and physical activity (p = 0.035 and p = 0.010, respectively). In individuals with IGT, higher dietary GOS intake was associated with lower body fat and higher insulin sensitivity independent of macronutrients and fibre intake, calling for interventional studies to evaluate the effect of FODMAP intake in prediabetes.

Oral magnesium supplementation does not affect insulin sensitivity in people with insulin-treated type 2 diabetes and a low serum magnesium: a randomised controlled trial

Aims/hypothesisHypomagnesaemia has been associated with insulin resistance and an increased risk of type 2 diabetes. Whether magnesium supplementation improves insulin sensitivity in people with type 2 diabetes and a low serum magnesium level is unknown.MethodsUsing a randomised, double-blind (both participants and investigators were blinded to the participants’ treatment sequences), placebo-controlled, crossover study design, we compared the effect of oral magnesium supplementation (15 mmol/day) for 6 weeks with that of matched placebo in individuals with insulin-treated type 2 diabetes (age ≥18 years, BMI 18–40 kg/m2, HbA1c <100 mmol/mol [11.3%], serum magnesium ≤0.79 mmol/l). Participants were recruited from the outpatient clinic and through advertisements. Randomisation to a treatment sequence order was done using a randomisation list. We used block randomisation and the two possible treatment sequences were evenly distributed among the trial population. The primary outcome was the mean glucose infusion rate during the final 30 min of a hyperinsulinaemic–euglycaemic clamp (i.e. M value). Secondary outcomes included variables of glucose control, insulin need, BP, lipid profile and hypomagnesaemia-related symptoms during follow-up.ResultsWe recruited 14 participants (50% women, 100% White, mean ± SD age 67±6 years, BMI 31±5 kg/m2, HbA1c 58±9 mmol/mol [7.4±0.9%]) with insulin-treated type 2 diabetes. Magnesium supplementation increased both mean ± SEM serum magnesium level (0.75±0.02 vs 0.70±0.02 mmol/l, p=0.016) and urinary magnesium excretion (magnesium/creatinine ratio, 0.23±0.02 vs 0.15±0.02, p=0.005), as compared with placebo. The M value of the glucose clamp did not differ between the magnesium and placebo study arms (4.6±0.5 vs 4.4±0.6 mg kg−1 min−1, p=0.108). During the 6 weeks of treatment, continuous glucose monitoring outcomes, HbA1c, insulin dose, lipid profile and BP also did not differ, except for a lower HDL-cholesterol concentration after magnesium compared with placebo (1.14±0.08 vs 1.20±0.09 mmol/l, p=0.026). Symptoms potentially related to hypomagnesaemia were similar for both treatment arms.Conclusions/interpretationDespite an albeit modest increase in serum magnesium concentration, oral magnesium supplementation does not improve insulin sensitivity in people with insulin-treated type 2 diabetes and low magnesium levels.Trial registrationEudraCT number 2021-001243-27.FundingThis study was supported by a grant from the Dutch Diabetes Research Foundation (2017–81–014).Graphical

FRI032 Cellular Insights Into Metabolically Healthy And Unhealthy Obesity

Abstract Disclosure: M.C. Petersen: None. G.I. Smith: None. J. Yu: None. R.A. Barve: Other; Self; Royalties; PercayAI. J. Yoshino: None. G.I. Shulman: None. S. Klein: Advisory Board Member; Self; Merck, Altimmune. Some people with obesity are resistant to the adverse metabolic effects of excess adiposity and are considered to have “metabolically healthy obesity” (MHO). However, the mechanisms responsible for MHO are not clear. We evaluated whole-body insulin sensitivity (glucose infusion rate/plasma insulin during a hyperinsulinemic-euglycemic clamp) and several putative factors that regulate insulin action, including skeletal muscle diacylglycerol (DAG) and ceramide content and transcriptomic profiles in abdominal subcutaneous adipose tissue (ASAT) and muscle, in three groups separated by adiposity and metabolic function: i) 20 adults with MHO (BMI = 38.6 ± 1.2 kg/m2, normal fasting glucose, oral glucose tolerance, hemoglobin A1c, and intrahepatic triglyceride content); ii) 20 adults with MUO (BMI= 39.5 ± 1.1 kg/m2, prediabetes and hepatic steatosis); and iii) 15 adults who were metabolically-healthy and lean (MHL, BMI= 22.7 ± 0.4 kg/m2). Insulin sensitivity progressively decreased from MHL to MHO to MUO [109 ± 7 to 72 ± 7 to 30 ± 2 (μg glucose/kg FFM/min)/(μU/mL), respectively]. Muscle plasma membrane and total cellular sn-1,2-DAG contents were greater in the MHO and MUO groups compared with the MHL group, with no difference between MHO and MUO groups. In contrast, muscle ceramide content in multiple compartments progressively increased from MHL to MHO to MUO and were inversely correlated with insulin sensitivity among all subjects (plasma membrane, r = -0.61; mitochondria, r = -0.56; endoplasmic reticulum, r = -0.51, all P &amp;lt; 0.001). In ASAT, the expression of genes involved in extracellular matrix (ECM) remodeling and inflammation were greater in MUO than MHO, whereas the expression of genes involved in lipogenesis was greater in MHO than MUO. Sparse partial least-squares discriminant analysis, a classification algorithm, was used to identify the features that best discriminated the MHO and MUO groups. Of 125 variables, fasting plasma C-peptide concentration and skeletal muscle mitochondrial ceramide content were the best discriminants of MHO and MUO. Muscle mitochondrial ceramide content was negatively correlated with muscle transcripts involved in mitochondrial structure/function (e.g., ATP5MG [r = -0.69, P &amp;lt; 0.0001] and MPC1 [r = -0.67, P &amp;lt; 0.0001]) and PAQR4 (r = -0.71, P &amp;lt; 0.0001), which encodes a ceramidase in the adiponectin receptor family. In addition, the muscle transcripts that positively correlated with muscle mitochondrial ceramide content were strongly enriched for ECM and TGFβ-related pathways. Conclusions: Greater whole-body insulin sensitivity in people with MHO than MUO is associated with alterations in adipose tissue and skeletal muscle biology, namely decreased markers of ASAT ECM remodeling and inflammation, decreased skeletal muscle ceramide content, and increased skeletal muscle expression of PAQR4 and genes associated with mitochondrial content/function. Presentation: Friday, June 16, 2023

Intramyocellular Triglyceride Content During the Early Course of Type 1 and Type 2 Diabetes Mellitus.

Intramyocellular lipid content (IMCL) is elevated in insulin-resistant humans, but its changes over time and relationships with comorbidities remain unclear. We examined IMCL during the initial course of diabetes and its associations with complications. Participants of the German Diabetes Study (GDS) with recent-onset type 1 (n=132) or type 2 diabetes (n=139) and glucosetolerant controls (n=128) underwent 1H-magnetic resonance spectroscopy to measure IMCL and muscle volume, whole-body insulin sensitivity (hyperinsulinemic-euglycemic clamps; Mvalue) and cycling spiroergometry (VO2max). Subgroups underwent the same measurements after 5 years. At baseline, IMCL was ∼30% higher in type 2 diabetes than in other groups independently of age, sex, BMI and muscle volume. In type 2 diabetes, M-value was ∼36% and ∼62% lower compared to type 1 diabetes and controls, respectively. After 5 years, M-value decreased by ∼29% in type 1 and ∼13% in type 2 diabetes, whereas IMCL remained unchanged. The correlation of IMCL and M-value in type 2 diabetes at baseline was modulated by VO2max. IMCL also associated with microalbuminuria, Framingham risk score for cardiovascular disease and cardiac autonomic neuropathy. Changes in IMCL within 5 years after diagnosis do not mirror progression of insulin resistance in type 2 diabetes but associate with early diabetesrelated complications.

P22-026-23 Effect of Dairy Fat Consumption on Insulin Sensitivity in People With Overweight or Obesity With Prediabetes: A 12-Week Randomized Controlled Trial Protocol

P22-026-23 Effect of Dairy Fat Consumption on Insulin Sensitivity in People With Overweight or Obesity With Prediabetes: A 12-Week Randomized Controlled Trial Protocol

GDF15 promotes weight loss by enhancing energy expenditure in muscle

Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake4–7. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL–β-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15–GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.

Heterogeneity in the effect of marked weight loss on metabolic function in women with obesity.

BACKGROUNDThere is considerable heterogeneity in the effect of weight loss on metabolic function in people with obesity.METHODSWe evaluated muscle and liver insulin sensitivity, body composition, and circulating factors associated with insulin action before and after approximately 20% weight loss in women identified as "Responders" (n = 11) or "Non-responders" (n = 11), defined as the top (>75% increase) and bottom (<5% increase) quartiles of the weight loss-induced increase in glucose disposal rate (GDR) during a hyperinsulinemic-euglycemic clamp procedure, among 43 women with obesity (BMI: 44.1 ± 7.9 kg/m2).RESULTSAt baseline, GDR, which provides an index of muscle insulin sensitivity, and the hepatic insulin sensitivity index were more than 50% lower in Responders than Non-responders, but both increased much more after weight loss in Responders than Non-responders, which eliminated the differences between groups. Weight loss also caused greater decreases in intrahepatic triglyceride content and plasma adiponectin and PAI-1 concentrations in Responders than Non-responders and greater insulin-mediated suppression of plasma free fatty acids, branched-chain amino acids, and C3/C5 acylcarnitines in Non-responders than Responders, so that differences between groups at baseline were no longer present after weight loss. The effect of weight loss on total body fat mass, intra-abdominal adipose tissue volume, adipocyte size, and circulating inflammatory markers were not different between groups.CONCLUSIONThe results from our study demonstrate that the heterogeneity in the effects of marked weight loss on muscle and hepatic insulin sensitivity in people with obesity is determined by baseline insulin action, and reaches a ceiling when "normal" insulin action is achieved.TRIAL REGISTRATIONNCT00981500, NCT01299519, NCT02207777.FUNDINGNIH grants P30 DK056341, P30 DK020579, P30 DK052574, UL1 TR002345, and T32 HL13035, the American Diabetes Association (1-18-ICTS-119), the Longer Life Foundation (2019-011), and the Atkins Philanthropic Trust.

1517-P: Interactive Calculator to Estimate Insulin Sensitivity (IS) in Type 1 Diabetes

Introduction: Euglycemic hyperinsulinemic clamps, although costly, time- and labor-intensive, are “gold standard” in measuring insulin sensitivity (IS). Several formulae to estimate IS in people with Type 1 diabetes (T1D) exist (DOI: 10.1007/978-3-030-81303-1_18-1), using various routine and research assays, and with wide ranging IS results. Aim: To develop a free online tool to estimate IS using different metrics and existent formulae and compare estimated IS with measured glucose disposal rate (GDR) from 104 clamp studies. Methods: We prepared an online tool for calculating IS using 17 formulae. Suitable formula(e) are suggested based on available (clinical and research) data. We also compare calculated IS with measured IS (GDR) from clamp studies in 104 adults with T1D (mean±SD) age 34±7 yrs, T1D duration 10±4 yrs, HbA1c 7.7±1.5%, 33 with microvascular complications). Logistic regression was used to infer probability of calculated IS being below GDR=4.45 mg/kg/min or above GDR=6.5 mg/kg/min, which represent respectively the median and 75th percentile of measured GDR values. Results: A calculator is available at www.bit.ly/estimated-GDR and an example result in the Figure 1. Estimated IS varied widely, but results interpretation is generally consistent. Conclusion: We developed an interactive tool to estimate IS in T1D for clinical and research use. Disclosure A.S.Januszewski: None. P.Niedzwiecki: None. N.Sachithanandan: None. G.M.Ward: None. D.N.O'neal: None. D.Zozulinska-ziolkiewicz: Advisory Panel; Abbott, Lilly, Lilly, Novo Nordisk, Medtronic, Speaker's Bureau; Abbott, Ascensia Diabetes Care, Novo Nordisk, Medtronic, Boehringer-Ingelheim, AstraZeneca. A.Uruska: Other Relationship; Lilly, Boehringer-Ingelheim, AstraZeneca, Ascensia Diabetes Care, Sanofi. A.Jenkins: Advisory Panel; Insulet Corporation, Board Member; Insulin for Life, Research Support; Abbott Diabetes, Medtronic, Hemsley Charitable Trust, Juvenile Diabetes Research Foundation (JDRF), National Institutes of Health.

Sedentary Time is Independently Related to Adipose Tissue Insulin Resistance in Adults with or at Risk of Type 2 Diabetes.

This cross-sectional study examined associations of device-measured sedentary time and moderate-to-vigorous physical activity (MVPA) with adipose tissue insulin resistance in people with or at high-risk of type 2 diabetes (T2DM). Data were combined from six previous experimental studies (within our group) involving patients with T2DM or primary risk factors (median (IQR) age 66.2 (66.0 - 70.8) years, body mass index (BMI) 31.1 (28.0 - 34.4) kg.m-2, 62% male, n = 179). Adipose tissue insulin resistance was calculated as the product of fasted circulating insulin and non-esterified fatty acids (ADIPO-IR), while sedentary time and MVPA were determined from wrist-worn accelerometery. Generalised linear models examined associations of sedentary time and MVPA with ADIPO-IR with interaction terms added to explore the moderating influence of ethnicity (white European vs. south Asian), BMI, age, and sex. In finally-adjusted models, sedentary time was positively associated with ADIPO-IR, with every 30-min of sedentary time associated with a 1.80 (95% CI: 0.51 to 3.06; P = 0.006) unit higher ADIPO-IR. This relationship strengthened as BMI increased (β = 3.48 [95%CI = 1.50 to 5.46], P = 0.005 in the upper BMI tertile [≥ 33.2 kg.m-2]). MVPA was unrelated to ADIPO-IR. These results were consistent in sensitivity analyses that excluded participants taking statins and/or metformin (n = 126) and when separated into the participants with T2DM (n = 32) and those at-high-risk (n = 147). Sedentary time is positively related to adipose tissue insulin sensitivity in people with or at high-risk of T2DM. This relationship strengthens as BMI increases and may help explain established relationships between greater sedentary time, ectopic lipid, and hyperglycaemia.

Circulating and adipose tissue immune cells in tissue-specific insulin resistance in humans with overweight and obesity.

A proinflammatory adipose tissue (AT) microenvironment and systemic low-grade inflammation may differentially affect tissue-specific insulin sensitivity. This study investigated the relationships of abdominal subcutaneous AT (aSAT) and circulating immune cells, aSAT gene expression, and circulating inflammatory markers with liver and skeletal muscle insulin sensitivity in people with overweight and obesity. Individuals with overweight and obesity from the PERSonalized Glucose Optimization Through Nutritional Intervention (PERSON) Study (n=219) and the Maastricht Study (replication cohort; n=1256) underwent a seven-point oral glucose tolerance test to assess liver and muscle insulin sensitivity, and circulating inflammatory markers were determined. In subgroups, flow cytometry was performed to identify circulating and aSAT immune cells, and aSAT gene expression was evaluated. The relative abundances of circulating T cells, nonclassical monocytes, and CD56dim CD16+ natural killer cells were inversely associated with liver, but not muscle, insulin sensitivity in the PERSON Study. The inverse association between circulating (classical) monocytes and liver insulin sensitivity was confirmed in the Maastricht Study. In aSAT, immune cell populations were not related to insulin sensitivity. Furthermore, aSAT gene expression of interleukin 6 and CD14 was positively associated with muscle, but not liver, insulin sensitivity. The present findings demonstrate that circulating immune cell populations and inflammatory gene expression in aSAT show distinct associations with liver and muscle insulin sensitivity.

High-Intensity Interval Training is Safe, Feasible and Efficacious in Nonalcoholic Steatohepatitis: A Randomized Controlled Trial

BackgroundHigh-Intensity Interval Training (HIIT) involves bursts of high-intensity exercise interspersed with lower-intensity exercise recovery. HIIT may benefit cardiometabolic health in people with nonalcoholic steatohepatitis (NASH).AimsWe aimed to examine the safety, feasibility, and efficacy of 12-weeks of supervised HIIT compared with a sham-exercise control (CON) for improving aerobic fitness and peripheral insulin sensitivity in biopsy-proven NASH.MethodsParticipants based in the community [(n = 14, 56 ± 10 years, BMI 39.2 ± 6.7 kg/m2, 64% male), NAFLD Activity Score 5 (range 3–7)] were randomized to 12-weeks of supervised HIIT (n = 8, 4 × 4 min at 85–95% maximal heart rate, interspersed with 3 min active recovery; 3 days/week) or CON (n = 6, stretching; 3 days/week). Safety (adverse events) and feasibility determined as ≥ 70% program completion and ≥ 70% global adherence (including session attendance, interval intensity adherence, and duration adherence) were assessed. Changes in cardiorespiratory fitness (V̇O2peak), exercise capacity (time-on-test) and peripheral insulin sensitivity (euglycemic hyperinsulinemic clamp) were assessed. Data were analysed using ANCOVA with baseline value as the covariate.ResultsThere were no HIIT-related adverse events and HIIT was globally feasible [program completion 75%, global adherence 100% (including adherence to session 95.4 ± 7.3%, interval intensity 95.3 ± 6.0% and duration 96.8 ± 2.4%)]. A large between-group effect was observed for exercise capacity [mean difference 134.2 s (95% CI 19.8, 248.6 s), ƞ2 0.44, p = 0.03], improving in HIIT (106.2 ± 97.5 s) but not CON (− 33.4 ± 43.3 s), and for peripheral insulin sensitivity [mean difference 3.4 mg/KgLegFFM/min (95% CI 0.9,6.8 mg/KgLegFFM/min), ƞ2 0.32, p = 0.046], improving in HIIT (1.0 ± 0.8 mg/KgLegFFM/min) but not CON (− 3.1 ± 1.2 mg/KgLegFFM/min).ConclusionsHIIT is safe, feasible and efficacious for improving exercise capacity and peripheral insulin sensitivity in people with NASH.Clinical Trial Registration NumberAustralian New Zealand Clinical Trial Registry (anzctr.org.au) identifier ACTRN12616000305426 (09/03/2016).Graphical

Independent euglycaemic hyperinsulinaemic clamp studies validate clinically applicable formulae to estimate insulin sensitivity in people with type 1 diabetes

Background and aimLow insulin sensitivity (IS) increases Type 1 diabetes (T1D) complication risk and can be estimated by simple formulae developed from complex euglycemic hyperinsulinaemic clamp studies. We aimed to validate these formulae using independent clamp data. MethodsClamps were performed in 104 T1D adults. Measured glucose disposal rate (GDR) was correlated with eGDR and eLog10 M/I calculated by five IS formulae. ResultsCorrelations ranged between 0.23–0.40. Two IS formulae (by the authors), using age, sex, HDL-C, HbA1c, pulse pressure, BMI, and waist-hip-ratio had the highest correlation with measured GDR and the best performance in detecting low IS.

715-P: Tirzepatide as Monotherapy Improved Markers of Beta-Cell Function and Insulin Sensitivity in People with Type 2 Diabetes (SURPASS-1)

Tirzepatide (TZP) , a novel dual GIP/GLP-1 receptor agonist, led to greater HbA1c, fasting serum glucose and body weight reductions vs. placebo (PBO) in people with early T2D (baseline mean T2D duration 4.7 y and 54% no prior diabetes medications) from the 40-wk SURPASS-1 trial. In a Phase 2b trial, TZP also improved β-cell function and insulin sensitivity (IS) vs. PBO and selective GLP-1 receptor agonist, dulaglutide 1.5 mg. Similarly, in SURPASS-1, TZP improved β-cell function, as indicated by a 75-80% increase in HOMA2-B, and insulin resistance, as indicated by a 2-12% decrease in fasting insulin and 8-20% decrease in HOMA2-IR. In this analysis, we aimed to explore changes in additional biomarkers of β-cell function and IS after TZP monotherapy (5, and 15 mg) . At 40 wks, proinsulin/C-peptide ratios, a marker of insulin processing, β-cell stress and β-cell function improved with decrease by 47-49% with TZP vs. -0.1% with PBO (p&amp;lt;0.001, all doses) (Table) . Fasting proinsulin decreased by 49-55% with TZP vs. no change with PBO (p&amp;lt;0.001, all doses) . Decreases in fasting C-peptide by 3-9% with TZP did not differ vs. PBO. TZP vs. PBO improved biomarkers of IS evidenced by increases in adiponectin (16-23% vs. -0.2%; p≤0.028, all doses) and IGFBP-2 (38-70% vs. 4.1%; p&amp;lt;0.001, all doses) . As a monotherapy for early T2D, TZP achieved significant improvement in markers of β-cell function and IS. Disclosure C.Lee: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. H.Mao: Employee; Eli Lilly and Company. V.Thieu: None. M.K.Thomas: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company

561-P: The Effect of Time-Restricted Eating on Glycemic Control and Insulin Sensitivity in Women with Prediabetes: A Pilot Study

Time-restricted eating (TRE) is a dietary pattern in which daily food intake is restricted to a 6-h period without any caloric intake for the rest of the day. TRE improves glucose homeostasis in animal models even independent of weight loss and calorie intake. However, the weight-loss independent effect of TRE on glucose homeostasis in people remains debatable. We conducted a pilot study to investigate whether TRE without weight loss improves glycemic control and insulin sensitivity in women with prediabetes. Participants were randomized to the TRE (9-h daily eating period) or Control group (15-h daily eating period) for 12 weeks. We studied five participants (TRE n = 3 and Control n = 2) with overweight/obesity, prediabetes, and habitual daily eating period greater than 14 hours ([means and SD] age 50 ± 16 years, BMI 31 ± 5 kg/m2) . The daily eating period decreased in the TRE group (13.8 ± 0.5 vs. 8.5 ± 0.5 h) , but not in the Control group (13.9 ± 0.9 vs. 14.1 ± 1.1 h) . Participants’ weight, diet composition, and number of eating occasions remained unchanged during the study period for both groups. Glycemic control in free-living conditions assessed by using continuous glucose monitoring tended to improve in the TRE group (24-h area under the curve for interstitial glucose concentration: 2572 ± 286 vs. 2161 ± 216 mg/dl/24 h) , but not in the Control group (23± 59 vs. 2374 ± 2mg/dl/24 h) . Skeletal muscle insulin sensitivity assessed by using a hyperinsulinemic-euglycemic clamp procedure tended to increase in the TRE group (median and IQR: 27 (21, 37) vs. 34 (27, 41) μmol/kg/min) , but not in the Control group (41 ± 9 vs. 36 ± μmol/kg/min) . These preliminary results suggest that TRE may lead to weight-loss-independent improvements in glycemic control and insulin sensitivity in women with prediabetes. Further ongoing research will establish the effect of TRE without weight loss on glucose homeostasis and insulin sensitivity in people at high risk for type 2 diabetes mellitus. Disclosure M.Chondronikola: None. S.Zhu: None. P.Surampudi: n/a. B.Roshanravan: None. C.Sanchez: None. Funding NIH-UL1-TR001860, Clinical and Translational Science Center-Highly Innovative Pilot Award and USDA NationalInstitute of Food and Agriculture, Hatch project numberCA-D-NTR-2618-H

Subcutaneous Adipose Tissue Metabolic Function and Insulin Sensitivity in People With Obesity.

We used stable isotope-labeled glucose and palmitate tracer infusions, a hyperinsulinemic-euglycemic clamp, positron emission tomography of muscles and adipose tissue after [18F]fluorodeoxyglucose and [15O]water injections, and subcutaneous adipose tissue (SAT) biopsy to test the hypotheses that 1) increased glucose uptake in SAT is responsible for high insulin-stimulated whole-body glucose uptake in people with obesity who are insulin sensitive and 2) putative SAT factors thought to cause insulin resistance are present in people with obesity who are insulin resistant but not in those who are insulin sensitive. We found that high insulin-stimulated whole-body glucose uptake in insulin-sensitive participants with obesity was not due to channeling of glucose into SAT but, rather, was due to high insulin-stimulated muscle glucose uptake. Furthermore, insulin-stimulated muscle glucose uptake was not different between insulin-sensitive obese and lean participants even though adipocytes were larger, SAT perfusion and oxygenation were lower, and markers of SAT inflammation, fatty acid appearance in plasma in relation to fat-free mass, and plasma fatty acid concentration were higher in the insulin-sensitive obese than in lean participants. In addition, we observed only marginal or no differences in adipocyte size, SAT perfusion and oxygenation, and markers of SAT inflammation between insulin-resistant and insulin-sensitive obese participants. Plasma fatty acid concentration was also not different between insulin-sensitive and insulin-resistant obese participants, even though SAT was resistant to the inhibitory effect of insulin on lipolysis in the insulin-resistant obese group. These data suggest that several putative SAT factors commonly implicated in causing insulin resistance are normal consequences of SAT expansion unrelated to insulin resistance.

Associations Among Adipose Tissue Immunology, Inflammation, Exosomes and Insulin Sensitivity in People With Obesity and Nonalcoholic Fatty Liver Disease

Insulin resistance is a key factor in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We evaluated the importance of subcutaneous abdominal adipose tissue (SAAT) inflammation and both plasma and SAAT-derived exosomes in regulating insulin sensitivity in people with obesity and NAFLD. Adipose tissue inflammation (macrophage and T-cell content and expression of proinflammatory cytokines), liver and whole-body insulin sensitivity (assessed using a hyperinsulinemic-euglycemic clamp and glucose tracer infusion), and 24-hour serial plasma cytokine concentrations were evaluated in 3 groups stratified by adiposity and intrahepatic triglyceride (IHTG) content: (1) lean with normal IHTG content (LEAN; N= 14); (2) obese with normal IHTG content (OB-NL; N= 28); and (3) obese with NAFLD (OB-NAFLD; N= 28). The effect of plasma and SAAT-derived exosomes on insulin-stimulated Akt phosphorylation in human skeletal muscle myotubes and mouse primary hepatocytes was assessed in a subset of participants. Proinflammatory macrophages, proinflammatory CD4 and CD8 T-cell populations, and gene expression of several cytokines in SAAT were greater in the OB-NAFLD than the OB-NL and LEAN groups. However, with the exception of PAI-1, which was greater in the OB-NAFLD than the LEAN and OB-NL groups, 24-hour plasma cytokine concentration areas-under-the-curve were not different between groups. The percentage of proinflammatory macrophages and plasma PAI-1 concentration areas-under-the-curve were inversely correlated with both hepatic and whole-body insulin sensitivity. Compared with exosomes from OB-NL participants, plasma and SAAT-derived exosomes from the OB-NAFLD group decreased insulin signaling in myotubes and hepatocytes. Systemic insulin resistance in people with obesity and NAFLD is associated with increased plasma PAI-1 concentrations and both plasma and SAAT-derived exosomes. ClinicalTrials.gov number: NCT02706262 (https://clinicaltrials.gov/ct2/show/NCT02706262).