Decreased Fasting Insulin Research Articles

High-intensity Interval Training Improves Lipocalin-2 and Omentin-1 Levels in Men with Obesity.

We investigated the effects of 12 weeks of high-intensity interval training (HIIT) on selected circulating adipokines and other cardiovascular diseases risks factors in men with obesity. Thirty men with obesity (age: 24.96±3.11 year, BMI: 30.92±1.04 kg/m2) were randomly assigned to HIIT and control groups. The HIIT group participated in a 12-week HIIT program (5×2 min interval bout at an intensity of 85-95% HRmax interspersed by 1 min passive recovery, three times per week), while the control group maintained their usual lifestyles. Blood lipids, insulin resistance, and select serum adipokines were assessed before and after 12 weeks of the intervention period. HIIT improved body composition and lipid profiles (p<0.05) and also decreased fasting insulin levels (p=0.001) and HOMA-IR (p=0.002) levels. Furthermore, HIIT increased levels of lipocalin-2 (p=0.002) while decreasing omentin-1 levels (p=0.001) in men with obesity. Changes in lcn2 and omentin-1 concentrations correlated with the changes in risk factors in the HIIT group (p<0.05). The results indicate that 12 weeks of supervised HIIT significantly improves both circulating concentrations of lcn2 and omentin-1, two recently described adipokines, and risk markers of cardiovascular diseases in men with obesity. Further research is necessary to understand the molecular mechanisms involved with these changes.

PSVI-9 Effects of dietary boron supplementation on growth performance, fasting and postprandial serum insulin, and glucose concentration of pigs

Abstract A 49-d experiment evaluated the effects of supplemental boron (B) on growth, and serum insulin and glucose concentration of pigs. Crossbred pigs [n = 48; initial body weight (BW) 19.18 ± 0.29 kg] were randomly allotted to 1 of 4 diets based on BW and sex. Diets were corn-SBM-based, formulated to meet NRC (2012) nutrient requirement estimates, and were supplemented with 0, 25, 50, or 100 mg B/kg diet as sodium tetraborate decahydrate. On d 20 and 41, blood samples were collected. Fasting samples were collected following an overnight fast; then a postprandial sample was taken approximately 50 minutes after the pigs had 10 minutes of ad libitum access to feed. Samples were processed and serum analyzed for insulin and glucose concentration. Increasing B levels resulted in a linear decrease for overall ADG (0.87, 0.86, 0.85, and 0.82 kg, P = 0.02). On d 20, supplemental B resulted in a quadratic response on fasting serum glucose concentration (5.25, 4.80, 4.65, and 5.01, P = 0.03) and a linear decrease in postprandial serum insulin concentration (29.1, 25.5, 18.2, and 18.1 µU/mL, P = 0.02). Furthermore, there was a tendency for a linear decrease in fasting insulin:glucose ratio (0.85, 0.84, 0.42, and 0.59, P = 0.08), which became more noticeable during the postprandial state (3.96, 3.63, 2.63, and 2.73, P = 0.02). Again on d 41, there was a quadratic response on fasting serum glucose concentration (4.32, 4.07, 3.91, and 4.68, P = 0.01) with supplemental B. Results suggest that supplemental boron may impact serum insulin and glucose concentrations by reducing the amount of insulin needed to maintain glucose concentrations. However, higher levels of supplemental boron did result in suppressed growth performance. Thus, additional research is warranted to determine the optimum level of supplemental B.

Dietary Supplementation with Inulin Modulates the Gut Microbiota and Improves Insulin Sensitivity in Prediabetes.

Aims Accumulating evidence indicates gut microbiota dysbiosis is involved in metabolic disorders, including prediabetes. The prebiotic inulin has been frequently reported to exert beneficial effects on the host metabolism. Here, we aimed to evaluate whether dietary supplementation with inulin modulates gut microbiota structure in prediabetes, affecting glucose and lipid metabolism. Methods We performed a prospective single-arm study. A total of 49 subjects with prediabetes (WHO 1999 criteria) were voluntarily enrolled. Each subject received a daily supplement with 15 g of inulin for 6 months. Glucose and lipid metabolic parameters and gut microbiota were analyzed at baseline and at 3 and 6 months after inulin intervention. Intestinal microbiota profile was evaluated using the Illumina MiSeq platform based on V3-V4 bacterial 16S rRNA gene. Results The mean age of 49 subjects was 56.6 ± 6.9 years and BMI was 25.07 ± 3.02 kg/m2. After 24 weeks of prevention, inulin significantly decreased fasting insulin (2.38 ± 0.50 vs. 2.22 ± 0.62, P=0.03) and 2-hour post-OGTT insulin (4.01 ± 0.77 vs. 3.74 ± 0.76, P=0.02) and improved HOMA-IR (1.05 ± 0.53 vs. 0.85 ± 0.66, P=0.03). Gut microbiota analysis indicated that inulin supplement resulted in an increase in the relative abundance of Actinobacteria, Bifidobacteriales, Bifidobacteriaceae, Lactobacillaceae, Bifidobacterium, Lactobacillus, and Anaerostipes both at 3 and 6 months, while with a decrease in the relative abundance of Alistipes. Spearman correlation analysis revealed altered microbial community was associated with glucose and lipids metabolic parameters. Conclusions Inulin supplementation improves insulin resistance of prediabetes and exerts beneficial effects on modulating the intestinal microbiota composition. These findings suggest that insulin may be a potentially novel and inexpensive intervention for prediabetes.

Effects of hormone replacement therapy on glucose and lipid metabolism in peri- and postmenopausal women with a history of menstrual disorders

BackgroundPrevious studies have indicated that women with a history of menstrual disorders have an increased risk of metabolic and cardiovascular diseases. This has been attributed to the high proportion of polycystic ovary syndrome (PCOS) among this group. The favorable effects of hormone replacement therapy (HRT) on serum lipid profiles and glucose homeostasis in postmenopausal women is widely accepted. Whether HRT can also show positive effects on metabolic homeostasis in menopausal women with prior menstrual disorders (a putative PCOS phenotype) has not been reported yet. The aim of the study was to compare the effects of HRT on glucose and lipid metabolism in peri- and postmenopausal women with prior menstrual disorders and controls who did not have prior menstrual disorders.MethodsA retrospective multicenter study was conducted including 595 peri- and postmenopausal women who received HRT at four hospitals in the Zhejiang Province from May 31, 2010 to March 8, 2021. Participants were divided into the Normal menstruation group and the Menstrual disorders group according to their prior usual menstrual cycle pattern. Glucose and lipid metabolism indicators were assessed at baseline and after HRT. The results were compared between and within the groups, and data from peri- and postmenopausal women were analyzed separately.ResultsHRT significantly decreased fasting insulin and homeostasis model assessment of insulin resistance in perimenopausal users, and fasting plasma glucose levels in postmenopausal users with prior menstrual disorders, compared with baseline. Furthermore, HRT decreased low-density lipoprotein cholesterol, total cholesterol, fasting insulin, fasting plasma glucose and homeostasis model assessment of insulin resistance in both peri- and postmenopausal controls, compared with baseline. Nevertheless, no significant differences were observed in any of the glucose or lipid metabolism indicators at baseline and follow-up, as well as changes from baseline levels between menopausal women with and without prior menstrual disorders.ConclusionsHRT shows more obvious within-group improvements in glucose and lipid metabolism in controls, but there is no significant between-group difference. Further prospective studies are required for confirmation.

Chardonnay Grape Marc Powder Supplementation May Increase Insulin Sensitivity in Obese and Overweight Men and Women

Abstract Objectives Chardonnay grape marc (CM) is the remaining skins and seeds from winemaking that offers a rich source of phytonutrients. The objective was to evaluate glucose metabolism following the addition of CM to the diet. Methods Overweight or obese men and women with mild hyperlipidemia between 35–65 y were recruited for this double-blinded 16-week crossover study. Subjects consumed 1500mg of 1) microcrystalline cellulose (MCC), 2) high chardonnay seed extract/WellVine™ marc blend (HE) or 3) high WellVine™ chardonnay marc/seed extract blend (HM) in a randomized order. Each intervention arm lasted 3 weeks and included two 3-week washout periods. Following each intervention, fasting blood was drawn and assayed for glucose and insulin. Indexes of insulin resistance (HOMA-IR, McAuley) and insulin sensitivity (QUICKI) were calculated. Data were transformed before conducting analyses, when appropriate. Analyses were conducted with 24 completed subjects and intention to treat (ITT) with 3 subjects who withdrew using linear mixed model ANOVA. Results In the ITT analysis, fasting glucose and insulin showed a significant main effect of intervention (P = 0.04 and P = 0.03, respectively). For both glucose and insulin, pairwise comparisons showed a significant difference between HM and MCC (P = 0.03 and P = 0.03, respectively). The indexes, HOMA-IR and QUICKI showed a significant main effect of intervention (P = 0.04 and P = 0.03, respectively), whereas there was no effect with the McAuley index. For HOMA-IR and QUICKI, pairwise comparisons showed a significant difference between HM and MCC (P = 0.04 and P = 0.03, respectively). Conclusions There was an increase in QUICKI, indicating an increase in insulin sensitivity following the HM arm compared to MCC. This has important implications if it is followed up in a larger cohort. Following the HM arm there was also a decrease in fasting insulin and decrease in HOMA-IR compared to the MCC arm; in this case, the magnitude of these changes are not sufficient to suggest improvement in insulin resistance by clinical definitions. This was a proof of concept study, thus future studies should further explore these findings. Funding Sources NIFA Phase II Small Business Innovation Research Grant awarded to Sonomaceuticals, LLC, USDA CRIS 2032–51,530-025–00D.

Continuous energy restriction (CER) plus 16/8 time-restricted feeding improve body composition and metabolic parameters in overweight and obese, but no more than CER alone

BACKGROUND: Current guidelines recommend continuous energy restriction (CER) and lifestyle change as the basis of obesity treatment. Recently, several intermittent fasting protocols have received considerable interest as an alternative weight loss strategy. OBJECTIVE: This study compared the effects of 8-week CER versus CER along with 16/8 time-restricted feeding (16/8 TRF) on body composition and metabolic markers in excess weight physically active subjects. METHODS: Twenty-four physically active obese or overweight adults, from both genders, were split into two groups: CER plus 16/8 TRF (CER + TRF) and CER. Both groups consumed a 20%energy restriction diet. CER plus 16/8 TRF were asked to consume their meals during an 8-hour open window (12 to 20 pm). We evaluated body composition and metabolic biomarkers before and after the intervention. RESULTS: We observed a reduction in body weight (BW), body mass index (BMI), waist circumference (WC), and fat mass (FM) in both groups. However, a decrease in fat-free mass (FFM) and skeletal muscle mass (SMM) was seen only in the CER. Although fasting glucose did not change, we observed a decrease in fasting insulin and HOMA-IR in both groups. Leptin decrease in both treatments. Cortisol levels increased only in the CER group. CONCLUSIONS: We can conclude that CER + TRF is as effective as CER to promote weight and fat loss, but, CER + TRF seems to be more efficient in maintaining lean body mass.

Metformin Affects Gut Microbiome Composition and Function and Circulating Short-Chain Fatty Acids: A Randomized Trial.

OBJECTIVETo determine the longer-term effects of metformin treatment and behavioral weight loss on gut microbiota and short-chain fatty acids (SCFAs).RESEARCH DESIGN AND METHODSWe conducted a 3-parallel-arm, randomized trial. We enrolled overweight/obese adults who had been treated for solid tumors but had no ongoing cancer treatment and randomized them (n = 121) to either 1) metformin (up to 2,000 mg), 2) coach-directed behavioral weight loss, or 3) self-directed care (control) for 12 months. We collected stool and serum at baseline (n = 114), 6 months (n = 109), and 12 months (n = 105). From stool, we extracted microbial DNA and conducted amplicon and metagenomic sequencing. We measured SCFAs and other biochemical parameters from fasting serum.RESULTSOf the 121 participants, 79% were female and 46% were Black, and the mean age was 60 years. Only metformin treatment significantly altered microbiota composition. Compared with control, metformin treatment increased amplicon sequence variants for Escherichia (confirmed as Escherichia coli by metagenomic sequencing) and Ruminococcus torques and decreased Intestinibacter bartlettii at both 6 and 12 months and decreased the genus Roseburia, including R. faecis and R. intestinalis, at 12 months. Effects were similar in comparison of the metformin group with the behavioral weight loss group. Metformin versus control also increased butyrate, acetate, and valerate at 6 months (but not at 12 months). Behavioral weight loss versus control did not significantly alter microbiota composition but did increase acetate at 6 months (but not at 12 months). Increases in acetate were associated with decreases in fasting insulin. Additional whole-genome metagenomic sequencing of a subset of the metformin group showed that metformin altered 62 metagenomic functional pathways, including an acetate-producing pathway and three pathways in glucose metabolism.CONCLUSIONSMetformin, but not behavioral weight loss, impacted gut microbiota composition at 6 months and 12 months. Both metformin and behavioral weight loss altered circulating SCFAs at 6 months, including increasing acetate, which correlated with lower fasting insulin. Future research is needed to elucidate whether the gut microboime mediates or modifies metformin’s health effects.

High-Protein, Low-Glycaemic Meal Replacement Decreases Fasting Insulin and Inflammation Markers-A 12-Month Subanalysis of the ACOORH Trial.

Lifestyle interventions, including meal replacement, are effective in the prevention and treatment of type-2-diabetes and obesity. Since insulin is the key weight regulator, we hypothesised that the addition of meal replacement to a lifestyle intervention reduces insulin levels more effectively than lifestyle intervention alone. In the international multicentre randomised controlled ACOORH (Almased Concept against Overweight and Obesity and Related Health Risk) trial, overweight or obese persons who meet the criteria for metabolic syndrome (n = 463) were randomised into two groups. Both groups received nutritional advice focusing on carbohydrate restriction and the use of telemonitoring devices. The intervention group substituted all three main meals per day in week 1, two meals per day in weeks 2–4, and one meal per day in weeks 5–26 with a protein-rich, low-glycaemic meal replacement. Data were collected at baseline and after 1, 3, 6 and 12 months. All datasets providing insulin data (n = 446) were included in this predefined subanalysis. Significantly higher reductions in insulin (−3.3 ± 8.7 µU/mL vs. −1.6 ± 9.8 µU/mL), weight (−6.1 ± 5.2 kg vs. −3.2 ± 4.6 kg), and inflammation markers were observed in the intervention group. Insulin reduction correlated with weight reduction and the highest amount of weight loss (−7.6 ± 4.9 kg) was observed in those participants with an insulin decrease > 2 µU/mL. These results underline the potential for meal replacement-based lifestyle interventions in diabetes prevention, and measurement of insulin levels may serve as an indicator for adherence to carbohydrate restriction.

Uric acid lowering improves insulin sensitivity and lowers blood pressure: a meta-analysis of randomized parallel-controlled clinical trials.

This meta-analysis aimed to investigate whether uric acid lowering treatment can improve β-cell function and insulin sensitivity. PubMed, Cochrane Library, EMBASE and China Biology Medicine were searched up to March 1, 2020. Randomized controlled clinical trials of urate lowering therapy in hyperuricemia patients were included in meta-analysis. Effect size was estimated as mean difference with 95% confidence interval (CI). Our search yielded 7 eligible trials with 503 participants. This meta-analysis showed that uric acid-lowering therapy decreased fasting insulin -1.43 µIU/ml (weighted mean differences (WMD, 95% CI -2.78 to -0.09), homeostasis model assessment of insulin resistance -0.65 (WMD, 95% CI -1.05 to -0.24), systolic blood pressure -2.45 mm Hg (WMD, 95%CI -4.57 to -0.33) and diastolic blood pressure -3.41 mm Hg (WMD, 95%CI -3.87 to -2.95). However, the treatment had no significant effect on fasting plasma glucose (WMD -0.19 mmol/L, 95%CI -0.42 to 0.05), homeostasis model assessment of β-cell function index (WMD -0.02, 95%CI -0.28 to 0.24), total cholesterol (WMD 0.18 mg/dl; 95%CI, -1.39 to 1.75) and triglyceride (WMD 3.15 mg/dl, 95% CI -9.83 to 16.14). Uric acid-lowering therapies might improve insulin sensitivity and lower blood pressure, but had no significant effect on HOMA-β and serum lipids.

Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes.

ContextNovel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control and weight loss (WL) compared with selective GLP-1RA dulaglutide.ObjectiveExplore mechanisms of glucose control by tirzepatide.DesignPost hoc analyses of fasting biomarkers and multiple linear regression analysis.SettingForty-seven sites in 4 countries.Patients or other ParticipantsThree hundred and sixteen subjects with type 2 diabetes.InterventionsTirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo.Main Outcome MeasuresAnalyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks.ResultsHomeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (P ≤ .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (P ≤ .007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (P ≤ .033) and tirzepatide 10 mg significantly decreased HOMA2-IR (P = .004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by 1 or more doses of tirzepatide (P < .05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and glycated hemoglobin A1c was conducted. WL significantly (P ≤ .028) explained only 13% and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg, respectively.ConclusionsTirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.

A ketogenic diet combined with exercise alters mitochondrial function in human skeletal muscle while improving metabolic health.

Animal data indicate that ketogenic diets are associated with improved mitochondrial function, but human data are lacking. We aimed to characterize skeletal muscle mitochondrial changes in response to a ketogenic diet combined with exercise training in healthy individuals. Twenty-nine physically active adults completed a 12-wk supervised exercise program after self-selection into a ketogenic diet (KD, n = 15) group or maintenance of their habitual mixed diet (MD, n = 14). Measures of metabolic health and muscle biopsies (vastus lateralis) were obtained before and after the intervention. Mitochondria were isolated from muscle and studied after exposure to carbohydrate (pyruvate), fat (palmitoyl-l-carnitine), and ketone (β-hydroxybutyrate+acetoacetate) substrates. Compared with MD, the KD resulted in increased whole body resting fat oxidation (P < 0.001) and decreased fasting insulin (P = 0.019), insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR), P = 0.022], and visceral fat (P < 0.001). The KD altered mitochondrial function as evidenced by increases in mitochondrial respiratory control ratio (19%, P = 0.009), ATP production (36%, P = 0.028), and ATP/H2O2 (36%, P = 0.033) with the fat-based substrate. ATP production with the ketone-based substrate was four to eight times lower than with other substrates, indicating minimal oxidation. The KD resulted in a small decrease in muscle glycogen (14%, P = 0.035) and an increase in muscle triglyceride (81%, P = 0.006). These results expand our understanding of human adaptation to a ketogenic diet combined with exercise. In conjunction with weight loss, we observed altered skeletal muscle mitochondrial function and efficiency, an effect that may contribute to the therapeutic use of ketogenic diets in various clinical conditions, especially those associated with insulin resistance.

Physical activity impacts insulin sensitivity post metabolic bariatric surgery in adolescents with severe obesity.

Background/Objectives:We hypothesized that physical activity (PA) improves insulin sensitivity in adolescents with severe obesity beyond that attributable to metabolic bariatric surgery (MBS).Subjects/Methods:StepWatch™ monitors objectively measured PA in 88 participants in the Teen Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. Primary outcomes included absolute change in fasting insulin, HOMA-IR, and fasting glucose from pre-surgery (baseline) to 6, 12, 24, and 36 months post-MBS. SAS PROC TRAJ generated activity trajectories based on probability and individual participant step count trajectories. Linear regression models were used, adjusted for baseline value, visit, surgical procedure, sex, and percent change in BMI. Additional models adjusted for percent change in iliac waist circumference (IWC) or percent body fat (BF), measured by bio-impedance.Results:Two activity trajectories were identified: more active (MA, n=13) and less active (LA, n=75). MA baseline mean daily step count was >6 000, increasing to > 9 000 at 2 years. LA mean daily step count remained at approximately 4 000. Few participants recorded moderate step activity (cadence >80 steps/minute). Still, fasting insulin and HOMA-IR differed in association with activity trajectory. MA was associated with a greater absolute decrease in fasting insulin (−7.8μU/ml [95% CI: (−11.8, −3.7)], p =<0.001) and a greater decrease in HOMA- IR (−1.9 [95% CI: (−3.0, −0.7)], p = 0.001), when adjusted for percent change in BMI. The significant independent effect of MA remained when adjusted for percent change in IWC or percent BF. Clinically, 100% of MA trajectory participants normalized fasting insulin, HOMA-IR and fasting glucose by 6 months and normalization remained throughout the 36 month follow up. In contrast, 76.3% and 65.8% of LA trajectory participants normalized fasting insulin and HOMA-IR, respectively, by 12 months with 28.6% of both remaining normalized at 36 months.Conclusion:PA is independently associated with improved insulin sensitivity beyond that attributable to MBS in adolescents with severe obesity.

Effects of a whole diet approach on metabolic flexibility, insulin sensitivity and postprandial glucose responses in overweight and obese adults - A randomized controlled trial.

Metabolic flexibility is the ability to adapt fuel oxidation to fuel availability. Metabolic inflexibility has been associated with obesity, the metabolic syndrome and insulin resistance, and can be improved by exercise or weight loss. Dietary changes can modulate metabolic flexibility; however, the effect of a whole diet approach on metabolic flexibility has never been studied. Therefore, our objective was to assess the effect of a healthy diet (HD), as compared to a typical Western diet (WD), on several fasting and postprandial markers of metabolic flexibility and insulin sensitivity. In this parallel randomized trial, overweight or obese men and women (50-70 years; BMI 25-35kg/m2) consumed a healthy diet (HD; high in fruits and vegetables, pulses, fibers, nuts, fatty fish, and low in high-glycemic carbohydrates; n=19) or a typical Western diet (WD; n=21) for six weeks, following a two-week run-in period. The change in respiratory quotient upon insulin stimulation (ΔRQ), and insulin sensitivity, expressed as the M-value, were both determined with a hyperinsulinemic euglycemic clamp. Additionally, other fasting and postprandial markers of metabolic flexibility were assessed during a 5-h high-fat high-glycemic mixed meal challenge. ΔRQ (p=0.730) and insulin sensitivity (p=0.802) were not significantly affected by diet. Postprandial RQ did also not show significant differences (p=0.610), whereas postprandial glucose excursions were significantly higher in the HD group at T30 (p=0.014) and T45 (p=0.026) after mixed meal ingestion (p=0.037). Fasting glucose (p=0.530) and HbA1c (p=0.124) remained unchanged, whereas decreases in fasting insulin (p=0.038) and the HOMA-IR (p=0.050) were significantly more pronounced with the HD. A healthy diet for six weeks, without further life-style changes, did not improve metabolic flexibility and whole-body insulin sensitivity, when compared to a Western-style diet. It remains to be determined whether the short time increase in postprandial glucose is physiologically relevant or detrimental to metabolic health. This trial was registered at clinicaltrials.gov as NCT02519127.

Ultra-Early and Early Changes in Bile Acids and Insulin After Sleeve Gastrectomy Among Obese Patients.

Background and Objective: In obese patients, sleeve gastrectomy (SG) has shown mixed results on bile acid (BA) values. The aim of our study was to examine the potential ultra-early and early changes of the circulating total BA in relation with the changes of insulin resistance (IR) in obese patients submitted to laparoscopic SG. Materials and Methods: Twenty-four obese subjects were investigated for body mass index (BMI), total fasting BA, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and leptin before and at 7 and 30 d after SG. Results: After surgery, mean BMI decreased at the first (p < 0.001) and at the second time point (p < 0.001) relative to baseline. Total fasting BA values did not change significantly at 7 d (p = 0.938) and at 30 d (p = 0.289) after SG. No significant changes were found at 7 d (p = 0.194, p = 0.34) and 30 d (p = 0.329, p = 0.151) after surgery regarding fasting insulin and HOMA-IR, respectively. However, a trend of increased total fasting BA and decreased fasting insulin and HOMA- after laparoscopic SG has been found. Negative correlations between total fasting BA and insulin (r = −0.807, p = 0.009), HOMA-IR (r = −0.855, p = 0.014), and blood glucose (r = −0.761, p = 0.047), respectively, were observed at one month after SG. Conclusion: In conclusion, here, we found a lack of significant changes in total fasting BA, insulin, and HOMA-IR ultra-early and early after SG, which precluded us to consider a possible relation between the variations of BA and IR. However, the presence of the tendency for total fasting BA to increase and for insulin and HOMA-IR to decrease, as well as of the negative correlations one month after laparoscopic SG, suggest that this surgery brings about some changes that point towards the existence, and possibly towards the restoration, at least to some extent, of the link between BA and glucose metabolism.

Reduction in Thyroid-Stimulating Hormone Correlated with Improved Inflammation Markers in Chinese Patients with Morbid Obesity Undergoing Laparoscopic Sleeve Gastrectomy.

Bariatric surgery has a significant impact on levels of thyroid hormones and various inflammatory markers in obesity. The relationship between changes in thyroid hormones and inflammatory markers after bariatric surgery is unknown. We aimed to investigate the changes in thyroid hormones and their relations to inflammatory changes after laparoscopic sleeve gastrectomy (LSG) in Chinese patients with morbid obesity. Eighty-eight patients with morbid obesity (56.8% female; age 30.9 ± 9.5years; BMI 39.9 ± 5.7kg/m2) submitted to LSG were selected. Patients were subdivided into euthyroid group and subclinical hypothyroidism (SH) group. Thyroid-stimulating hormone (TSH), free thyroxine (FT4), inflammatory markers, and related metabolic indexes were analyzed pre- and 12months post-LSG. SH patients presented significantly higher interleukin (IL)-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) than euthyroid patients. Twelve-month post-surgery, the SH incidence decreased from 31.8 to 2.3% (P < 0.001). TSH levels were declined significantly in both groups but were more pronounced in SH group (P < 0.001), whereas no change in FT4 in either group. Additionally, we observed marked reduction of IL-6, TNF-α, and CRP in SH group, as well as TNF-α and CRP in euthyroid group. After adjusting for age, baseline BMI, and changes in BMI, decrease in TSH correlated significantly with decreased HOMA-IR and TNF-α in euthyroid group and decreased fasting insulin (FINS), IL-6, TNF-α, and CRP in SH group. LSG promotes TSH reduction in patients with morbid obesity that is more pronounced in patients with SH and correlated with improved inflammatory state after surgery.

Effect Of Breaking-up Sedentary Activity On Metabolic Flexibility And Glycemia In Free-living Overweight/obese Adults

PURPOSE: Sedentary behavior (SB) triggers an inability to adjust substrate use to substrate availability (metabolic flexibility, MF), which may precede glucose intolerance in the pathogenesis of insulin resistance. We and others have shown that frequent interruptions in SB leads to improved glycemic control, however the underlying role of MF in this process is unknown. This study examined the effects of breaking up SB on MF and glucose metabolism in free-living overweight and obese adults. To distinguish effects of breaking up SB from being physically active, we also studied a group where participants performed a single energy matched continuous bout of exercise. METHODS: Physically inactive, adults (12F/7M, mean±SD; 33±8 yrs, BMI = 29.5±3.3kg/m2) were randomly assigned to a 4 week intervention consisting of brisk walking for 5 min each hour for 10h, 5 d/wk (MICRO), or 4 weeks of an intervention consisting of one continuous 45 min bout of exercise per day, 5d/wk (ONE). Outcomes assessed at baseline and after each intervention included: MF (waking respiratory quotient,RQ, minus sleeping RQ as measured in a whole room calorimeter), insulin sensitivity (SI, IVGTT), 24h glycaemia (continuous glucose monitor), 24h glucose oxidation (U13C glucose tracer), SB, time spent stepping, and performing moderate to vigorous activity (MVPA; ActivPAL and ActiGraph). Groups were similar on all outcome variables at baseline. Linear mixed models evaluated intervention and intervention-by-group effects. RESULTS: MICRO and ONE decreased time sitting (-43.5±93.4 min), increased time stepping (+26.3±44.0 min) and time spent in MVPA (+9.8±17.6 min) (p<0.05 for all). No significant changes were observed in SI, but both interventions decreased fasting insulin and HOMA IR (p<0.05 for both). Compared to ONE, MICRO improved the acute insulin response to glucose (AIRg), lowered 24h glycemic variability, maintained exogenous glucose oxidation, and improved MF (interaction: p<0.05 for all). Improvements in MF were positively associated with changes in SI (r=0.59, p=0.02). CONCLUSIONS: Independent of time sitting and stepping, breaking up SB improves glucose homeostasis and MF. The effects of such an intervention in persons with type 2 diabetes warrants further study.

980-P: Tirzepatide, a Dual GIP and GLP-1 Receptor Agonist, Improves Markers of Beta-Cell Function and Insulin Sensitivity in Type 2 Diabetes Patients

Tirzepatide (TZP), a novel dual GIP and GLP-1 receptor agonist (RA), showed significantly greater glucose control and weight loss compared to the selective GLP-1 RA dulaglutide (DU) in a 26-week, randomized, double-blind Phase 2b study of type 2 diabetes patients. TZP doses tested were 1, 5, 10, and 15 mg versus placebo (PB) and DU 1.5 mg. Fasting markers of beta cell function and insulin sensitivity were analyzed by mixed model repeated measures to explore differentiated mechanisms of glucose control by TZP. Biomarkers of beta cell function were improved by TZP. Proinsulin to insulin ratios, insulin processing markers of beta cell stress, were significantly reduced by TZP 10 and 15 mg compared with PB and DU. HOMA2-B significantly increased with DU and TZP 5, 10, and 15 mg compared with PB. TZP 10 mg significantly improved insulin sensitivity as reflected by lower HOMA2-IR compared with PB and DU. TZP 10 and 15 mg significantly decreased fasting insulin compared with PB and DU, consistent with reduced insulin resistance. To evaluate weight loss contributions to improvements in insulin sensitivity with TZP, multiple linear regression with potential confounding variables age, sex, metformin use, and baseline HbA1c was conducted. An intercept-free model with weight loss as the only covariate was selected as the most significant of all possible models. Weight loss significantly (p&amp;lt;0.004) explained 22% and 28% of variation in HOMA2-IR with TZP 15 and 10 mg, respectively, suggesting the insulin sensitizing effects of TZP are only partly attributable to weight loss. Multiple markers associated with improved insulin sensitivity were significantly increased by one or more doses of TZP compared with PB or DU, including adiponectin, IGFBP1, and IGFBP2. These data suggest that, compared with the selective GLP-1 RA dulaglutide, TZP has a greater impact on insulin sensitivity and beta cell function, resulting in improved glycemic control. Disclosure M.K. Thomas: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. A. Nikooienejad: Research Support; Self; Eli Lilly and Company. R. Bray: Employee; Self; Eli Lilly and Company. X. Cui: Employee; Self; Eli Lilly and Company. J.M. Wilson: Employee; Self; Eli Lilly and Company. K.L. Duffin: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Pfizer Inc. Z. Milicevic: Employee; Self; Eli Lilly and Company. A. Haupt: Employee; Self; Lilly Diabetes. Stock/Shareholder; Self; Lilly Diabetes. D.A. Robins: Employee; Self; Eli Lilly and Company. Funding Eli Lilly and Company

Effects of Different Fasting Durations on Glucose and Lipid Metabolism in Sprague Dawley Rats.

Overnight fasting of varying length is common practice when studying glucose and lipid metabolism in rats. However, prolonged fasting may influence insulin sensitivity, and it is unknown to which extent different fasting durations affect postprandial metabolism in rats. The purpose of this study was to investigate the effect of different fasting durations (6-, 12-, or 18-h) on fat tolerance and glucose tolerance in male Sprague Dawley rats. We also aimed to examine the effect of two test fats with different fatty acid composition on postprandial triglycerides. We conducted a fat tolerance test, where butterfat or rapeseed oil was administered in a crossover design (experiment 1), and an oral glucose tolerance test (experiment 2). Regarding the fat tolerance test, we found no effects of fasting duration on triglycerides or free fatty acids, whereas the 18-h fast resulted in reduced glucose and insulin area under the curves. We did not find differential effects of butterfat and rapeseed oil on the outcomes. We found decreased fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR), and increased beta-hydroxybutyric acid concentrations after 18-h fast compared with shorter fasting durations. Regarding the oral glucose tolerance test, both 12-h and 18-h fast resulted in greater peak insulin concentrations than 6-h fast, and peak glucose concentrations were higher after 18-h than 12-h fast. We found no effects of fasting on the insulin sensitivity index. In conclusion, extending the fasting duration had an impact on glucose metabolism in rats, but did not appear to influence fat tolerance.

OR28-6 Short-Term Mifepristone Treatment Improves Hepatic and Adipose Tissue Insulin Sensitivity in Overweight and Obese Subjects with Glucose Intolerance

Background: Increased tissue cortisol availability and enhanced glucocorticoid action have been implicated in abnormal glucose and fat metabolism in patients with obesity, metabolic syndrome, and type 2 diabetes. Objective: To test the hypothesis that blockade of glucocorticoid receptor (GR) with mifepristone ameliorates insulin resistance in overweight/obese subjects with glucose intolerance. Design: We conducted a randomized, placebo-controlled, double-blind, crossover trial of mifepristone (50 mg orally, every six hr) in overweight/obese subjects (BMI 25-37 kg/m2), with abnormal glucose tolerance (n=16, women=7). Participants (age:56 ± 8 yr) had prediabetes (n=12) or mild type 2 DM (n=4, A1c < 7%) on diet control or stable dose of metformin for 3 months (n=2). Mifepristone or placebo treatment for one week was followed by a 6-8-week washout and crossover to the other arm. At baseline, and after each treatment period, insulin sensitivity was assessed by a frequently sampled intravenous glucose tolerance test (FSIVGTT) and an oral glucose tolerance test (OGTT). Whole body glucose disposal index of insulin sensitivity (SI) was derived using a Minimal model analysis. Adipose tissue-SI, which reflects insulin-induced free fatty acid (FFA) suppression, was estimated by the log-linear slope of FFA levels during the FSIVGTT. Matsuda index, oral glucose insulin sensitivity index (OGIS, ml/min/m2), and hepatic insulin resistance index (HIRI, mg/dL×µU/mL×105) were derived from OGTT. Adipo-IR, a surrogate measure of adipocyte insulin resistance, was calculated by multiplying fasting concentrations of FFA and insulin (mmol×pmol/L). Comparison of various post-treatment parameters was performed using crossover ANOVA. This analysis takes into account specific treatment arm, treatment order, and treatment effects. Thus, we explicitly tested for carryover effects in our crossover study. Results: GR blockade did not affect body weight (p=0.56) or fasting glucose (p=0.67), but significantly decreased fasting insulin levels when compared with placebo [mean (95%CI): -40.7 (-68.53 to -12.91), p=0.007]. Mifepristone administration for one week did not alter whole body glucose disposal indices of insulin sensitivity (FSIVGTT-Si: p=0.52, Matsuda Index: p=0.74; and OGIS: p=0.75). However, GR blockade reduced HIRI [-19.80 (-40.76 to 1.15), p=0.05], Adipo-IR [-15.54 (-31.47 to 0.37), p=0.04], and improved Adipose-SI [-19.75 (-31.41 to -8.08), p=0.003]. Conclusions: In patients with abnormal glucose tolerance, short-term GR blockade improved hepatic and adipose tissue insulin sensitivity without significantly altering whole-body insulin sensitivity. These findings suggest that GR may be a therapeutic target in insulin-resistant states. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Abstract P039: Change in Blood Pressure and Glucose Are Major Determinants of Increasing Carotid IMT in Young Adults

Increased carotid intima-media thickness (cIMT) is associated with CV events in adults and thicker cIMT is found in youth with CV risk factors including obesity. Which risk factors have the most direct effect upon cIMT in youth and whether obesity has direct or indirect effects is not known. We used structural equation modeling to elucidate direct and indirect pathways through which obesity and other risk factors were associated with increase in cIMT. Demographics, anthropometrics, laboratory and carotid ultrasound data were collected on 426 participants aged 17.5 at baseline (32% type 2 diabetes) and after 5 years of follow-up. Latent change score variables were defined by baseline and follow-up measurements. Latent baseline and follow-up cIMT, glucose variables were defined for each cIMT segmemt (common, bulb and internal), HbA1c, and fasting glucose. SAS 9.4 CALIS procedure was used for analyses with maximal likelihood estimation. Comparative fit index (CFI &gt;0.9) and root mean squared error of approximation (RMSEA &lt;0.1) were considered good model fit. At follow up, there were increases in BMI, MAP, LDL, TG, HDL, CRP and fasting glucose, decrease in fasting insulin and HbA1c (all p≤0.05). There was no increase in common, but significant increase in bulb (0.031 mm) and internal (0.027 mm) cIMT (all p ≤0.001). Significant direct effects on changes of cIMT were baseline MAP (β 0.23) and BMI z-score (β 0.16) plus change in glucose (β 0.37) and age (β 0.37; all p≤0.05). Change in MAP showed a trend in the model (β 0.14, p=0.10). BMI also had significant indirect effect (b 0.17) while non-HDL demonstrated no significant effect. We conclude that baseline adiposity drives increasing BP and glucose in high risk youth leading to accelerated accumulation of carotid atherosclerosis. Prevention of acquisition of obesity is critical in slowing development of CV disease. NIH R01 HL105591 (Urbina) and UL1 TR001425.