Changes In Insulin Sensitivity Research Articles

Exploring interindividual differences in fasting and postprandial insulin sensitivity adaptations in response to sprint interval exercise training

ABSTRACT Previous studies have concluded that wide variance in changes in insulin sensitivity markers following exercise training demonstrates heterogeneity in individual trainability. However, these studies frequently don’t account for technical, biological, and random within-subject measurement error. We used the standard deviation of individual responses (SDIR) to determine whether interindividual variability in trainability exists for fasting and postprandial insulin sensitivity outcomes following low-volume sprint interval training (SIT). We pooled data from 63 untrained participants who completed 6 weeks of SIT (n = 49; VO2max: 35 (7) mL⋅kg−1⋅min−1) or acted as no-intervention controls (n = 14; VO2max: 34 (6) mL⋅kg−1⋅min−1). Fasting and oral glucose tolerance test (OGTT)-derived measures of insulin sensitivity were measured pre- and post-intervention. SDIR values were positive and exceeded a small effect size threshold for changes in fasting glucose (SDIR = 0.27 [95%CI 0.07,0.38] mmol⋅L−1), 2-h OGTT glucose (SDIR = 0.89 [0.22,1.23] mmol⋅L−1), glucose area-under-the-curve (SDIR = 66.4 [−81.5,124.3] mmol⋅L−1⋅120min−1) and The Cederholm Index (SDIR = 7.2 [−16.0,19.0] mg⋅l2⋅mmol−1⋅mU−1⋅min−1), suggesting meaningful individual responses to SIT, whilst SDIR values were negative for fasting insulin, fasting insulin resistance and insulin AUC. For all variables, the 95% CIs were wide and/or crossed zero, highlighting uncertainty about the existence of true interindividual differences in exercise trainability. Only 2–22% of participants could be classified as responders or non-responders with more than 95% certainty. Our findings demonstrate it cannot be assumed that variation in changes in insulin sensitivity following SIT is attributable to inherent differences in trainability, and reiterate the importance of accounting for technical, biological, and random error when examining heterogeneity in health-related training adaptations. Highlights This study tested whether true interindividual variability exists for changes in insulin sensitivity and glyceamic control following 6-weeks of low volume sprint interval training (SIT). The high level of technical, biological, and random error associated with repeated measurements of insulin sensitivity and glycaemic control, means we can neither confidently conclude that there is evidence of true interindividual differences in the trainability of these outcomes following SIT, nor confidently identify responders or non-responders for such parameters. Researchers contrasting responders vs. non-responders for a given parameter, either to understand mechanisms of adaptation and/or develop physiological/genetic/epigenetic predictors of response, need to be aware that identification of responders and non-responders with sufficient certainty may not be achievable for parameters with a high level of technical, biological, and random error.

Upregulation of hepatic de novo lipogenesis dissociates from changes in liver fat content and insulin sensitivity in healthy humans

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Dietary advanced glycation products and their associations with insulin sensitivity and body weight: A 16-week randomized clinical trial.

Evidence suggests that changes in advanced glycation end-products (AGEs) may influence body weight. Previous studies have focused on cooking methods as the primary way how to reduce the dietary AGEs but little is known about the effects of a change in diet composition. The aim of this study was to assess the effects of a low-fat plant-based diet on dietary AGEs and test the association with body weight, body composition, and insulin sensitivity. Participants who were overweight (n=244) were randomly assigned to an intervention (low-fat plant-based) (n=122) or control group (n=122) for 16weeks. Before and after the intervention period, body composition was measured by dual X-ray absorptiometry. Insulin sensitivity was assessed with the predicted insulin sensitivity index (PREDIM). Three-day diet records were analyzed using the Nutrition Data System for Research software and dietary AGEs were estimated, using a database. Repeated measure ANOVA was used for statistical analysis. Dietary AGEs decreased in the intervention group by 8768 ku/day on average (95% -9611 to -7925; p<0.001), compared with the control group (-1608; 95% CI -2709 to -506; p=0.005; treatment effect -7161 ku/day [95% CI -8540 to -5781]; Gxt, p<0.001). Body weight decreased by 6.4kg in the intervention group, compared with 0.5kg in the control group (treatment effect -5.9kg [95% CI -6.8 to -5.0]; Gxt, p<0.001), largely due to a reduction in fat mass, notably visceral fat. PREDIM increased in the intervention group (treatment effect +0.9 [95% CI+0.5 to +1.2]; p<0.001). Changes in dietary AGEs correlated with changes in body weight (r=+0.41; p<0.001), fat mass (r=+0.38; p<0.001), visceral fat (r=+0.23; p<0.001), and PREDIM (r=-0.28; p<0.001), and remained significant even after adjustment for changes in energy intake (r=+0.35; p<0.001 for body weight; r=+0.34; p<0.001 for fat mass; r=+0.15; p=0.03 for visceral fat; and r=-0.24; p<0.001 for PREDIM). Dietary AGEs decreased on a low-fat plant-based diet, and this decrease was associated with changes in body weight, body composition, and insulin sensitivity, independent of energy intake. These findings demonstrate positive effects of qualitative dietary changes on dietary AGEs and cardiometabolic outcomes. NCT02939638.

Perhexiline Therapy in Patients with Type 2 Diabetes: Incremental Insulin Resistance despite Potentiation of Nitric Oxide Signaling.

Perhexiline (Px) inhibits carnitine palmitoyltransferase 1 (CPT1), which controls uptake of long chain fatty acids into mitochondria. However, occasional cases of hypoglycaemia have been reported in Px-treated patients, raising the possibility that Px may also increase sensitivity to insulin. Furthermore, Px increases anti-aggregatory responses to nitric oxide (NO), an effect which may theoretically parallel insulin sensitization. We therefore sought to examine these relationships in patients with stable Type 2 diabetes (T2D) and cardiovascular disease (n = 30). Px was initiated, and dosage was titrated, to reach the therapeutic range and thus prevent toxicity. Investigations were performed before and after 2 weeks, to examine changes in insulin sensitivity and, utilizing aggregometry in whole blood, platelet responsiveness to the anti-aggregatory effects of the NO donor sodium nitroprusside (SNP). Other parameters that affect may affect NO signalling were also evaluated. Px substantially potentiated inhibition of platelet aggregation by SNP (from 16.7 ± 3.0 to 27.3 ± 3.7%; p = 0.005). Px did not change fasting blood glucose concentrations but reduced insulin sensitivity (HOMA-IR score increased from median of 4.47 to 6.08; p = 0.028), and increased fasting plasma insulin concentrations (median 16.5 to 19.0 mU/L; p = 0.014). Increases in SNP responses tended (r = −0.30; p = 0.11) to be reciprocally related to increases in HOMA-IR, and increases in HOMA-IR were greater (p = 0.002) in patients without NO-sensitizing effects. No patient developed symptomatic hypoglycaemia, nor was there any other short-term toxicity of Px. Thus, in patients with stable T2D and cardiovascular disease, Px increases anti-aggregatory responsiveness to NO, but is not an insulin sensitizer, and does not induce hypoglycaemia. Absence of NO-sensitizing effect occurs in approximately 30% of Px-treated patients with T2D, and is associated with induction of insulin resistance in these patients.

DASH diet vs. DASH diet plus physical activity in older patients with type 2 diabetes and high blood pressure: A randomized clinical trial.

To evaluate the effect of lifestyle modification by adopting a DASH diet, with and without physical activity guidance, on blood pressure, glycemic control, lipid profile, weight, and body composition in older patients with type 2 diabetes mellitus (T2DM) and hypertension. For this randomized clinical trial, we recruited patients aged 60 years or older with T2DM and uncontrolled hypertension. One group (DASH) received only DASH dietary guidance, while the other group (DASHPED) received dietary guidance and encouragement to walk with a pedometer. Outcomes of interest were (1) blood pressure, (2) physical activity, (3) weight, body mass index (BMI), and body composition, and (4) biochemical variables. Measurements were taken at baseline and 16 weeks after the intervention. We included 35 patients in the analysis. At the end of the study, the DASHPED group had an mean increase in physical activity of 1721 steps/day. Both groups displayed significantly reduced weight, BMI, and waking diastolic pressures on ambulatory blood pressure monitoring after the intervention. A trend of reduced sleeping diastolic pressure was found in the DASHPED group. Changes in weight, BMI, muscle mass, body fat, waist-hip ratio, glycemic control, lipid profile, and insulin sensitivity did not differ between the groups. There was no difference in outcomes between the group that only dieted and the group that also performed increased physical activity, despite a significant increase in exercise. This reinforces the importance of dietary changes in immediate blood pressure control.

Changes in circulating bile acid subtypes in response to weight-loss diets are associated with improvements in glycemic status and insulin resistance: The POUNDS Lost trial

ObjectiveVarious primary and secondary bile acids (BAs) may play pivotal roles in glucose/insulin metabolism. We investigated whether changes in specific BA subtypes were associated with long-term changes in glucose and insulin sensitivity. MethodsThis study included 515 adults with overweight or obesity who participated in a 2-year intervention study of weight-loss diets with different macronutrient intakes. Circulating primary and secondary unconjugated BAs and their taurine-/glycine-conjugates were measured at baseline and 6 months after the interventions. We analyzed associations of changes in BA subtypes with two-year changes in fasting glucose, insulin, and insulin resistance (HOMA-IR). ResultsGreater decreases in primary and secondary BA subtypes induced by the interventions were significantly associated with greater reductions of fasting insulin and HOMA-IR at 6 months, showing various effects across the BA subtypes. The reductions of specific BA subtypes (chenodeoxycholate [CDCA], taurocholate [TCA], taurochenodeoxycholate [TCDCA], and taurodeoxycholate [TDCA]) were significantly related to improved glucose levels at 6 months. The initial (6-month) decreases in primary and secondary BA subtypes (glycochenodeoxycholate [GCDCA], TCDCA, and glycoursodeoxycholate [GUDCA]) were also significantly associated with long-term improvements in glucose and insulin metabolism over 2 years. We found significant interactions between dietary fat intake and changes in the BA subtypes for changes in glucose metabolism (Pinteraction < 0.05). ConclusionsWeight-loss diet-induced changes in distinct subtypes of circulating BAs were associated with improved glucose metabolism and insulin sensitivity in adults with overweight or obesity. Dietary fat intake may modify the associations of changes in BA metabolism with glucose metabolism.

Assessing the efficacy of spironolactone on adult acne in subjects with polycystic ovary syndrome

Aim: The present prospective clinical study was conducted to assess the long‑term spironolactone therapy and its effect with and without dietary‑induced weight‑loss, on insulin levels, lipid profile, and clinical features in females with PCOS (polycystic ovary syndrome). Methods: The present study included 22 females 12 normal weight and 10 obese within the age of 17-32 years having symptoms of PCOS including hyperandrogenism with clinical or biochemical evidence with amenorrhea and/or oligomenorrhea. These subjects were assessed before spironolactone therapy and after 100mg/day spironolactone orally for 12 months. Lifestyle modification was advised for obese females. Before starting and following antiandrogen therapy, metabolic, endocrine, and clinical parameters were assessed. Results: Spironolactone orally resulted in a significant reduction of triglycerides in overweight females and an increase in HDL (high-density lipoproteins) in subjects who were lean and have normal weight. After 12 months of oral spironolactone therapy, the area under the curve of insulin, insulin resistance with hemostasis model, and levels of insulin during OGTT at 60 minutes were significantly reduced in obese females. In females with PCOS following therapy, no negative change in insulin sensitivity and secretion and weight loss was seen after pharmacologic treatment.

Assessing the efficacy of spironolactone on adult acne in subjects with polycystic ovary syndrome

Aim: The present prospective clinical study was conducted to assess the long‑term spironolactone therapy and its effect with and without dietary‑induced weight‑loss, on insulin levels, lipid profile, and clinical features in females with PCOS (polycystic ovary syndrome). Methods: The present study included 22 females 12 normal weight and 10 obese within the age of 17-32 years having symptoms of PCOS including hyperandrogenism with clinical or biochemical evidence with amenorrhea and/or oligomenorrhea. These subjects were assessed before spironolactone therapy and after 100mg/day spironolactone orally for 12 months. Lifestyle modification was advised for obese females. Before starting and following antiandrogen therapy, metabolic, endocrine, and clinical parameters were assessed. Results: Spironolactone orally resulted in a significant reduction of triglycerides in overweight females and an increase in HDL (high-density lipoproteins) in subjects who were lean and have normal weight. After 12 months of oral spironolactone therapy, the area under the curve of insulin, insulin resistance with hemostasis model, and levels of insulin during OGTT at 60 minutes were significantly reduced in obese females. In females with PCOS following therapy, no negative change in insulin sensitivity and secretion and weight loss was seen after pharmacologic treatment.

Caloric Restriction and Weight Loss Are Primary Factors in the Early Tissue-Specific Metabolic Changes After Bariatric Surgery.

OBJECTIVETo evaluate changes in insulin sensitivity, hormone secretion, and hepatic steatosis immediately after caloric restriction, vertical sleeve gastrectomy (VSG), and Roux-en-Y gastric bypass (RYGB).RESEARCH DESIGN AND METHODSObese subjects were assessed for 1) insulin sensitivity with hyperinsulinemic-euglycemic clamp with glucose tracer infusion, 2) adipokine concentrations with serum and subcutaneous adipose interstitial fluid sampling, and 3) hepatic fat content with MRI before and 7–10 days after VSG, RYGB, or supervised caloric restriction.RESULTSEach group exhibited an ∼5% total body weight loss, accompanied by similar improvements in hepatic glucose production and hepatic, skeletal muscle, and adipose tissue insulin sensitivity. Leptin concentrations in plasma and adipose interstitial fluid were equally decreased, and reductions in hepatic fat were similar.CONCLUSIONSThe improvements in insulin sensitivity and adipokine secretion observed early after bariatric surgery are replicated by equivalent caloric restriction and weight loss.

Three weeks of time-restricted eating improves glucose homeostasis in adults with type 2 diabetes but does not improve insulin sensitivity: a randomised crossover trial

Aims/hypothesisTime-restricted eating (TRE) is suggested to improve metabolic health by limiting food intake to a defined time window, thereby prolonging the overnight fast. This prolonged fast is expected to lead to a more pronounced depletion of hepatic glycogen stores overnight and might improve insulin sensitivity due to an increased need to replenish nutrient storage. Previous studies showed beneficial metabolic effects of 6–8 h TRE regimens in healthy, overweight adults under controlled conditions. However, the effects of TRE on glucose homeostasis in individuals with type 2 diabetes are unclear. Here, we extensively investigated the effects of TRE on hepatic glycogen levels and insulin sensitivity in individuals with type 2 diabetes.MethodsFourteen adults with type 2 diabetes (BMI 30.5±4.2 kg/m2, HbA1c 46.1±7.2 mmol/mol [6.4±0.7%]) participated in a 3 week TRE (daily food intake within 10 h) vs control (spreading food intake over ≥14 h) regimen in a randomised, crossover trial design. The study was performed at Maastricht University, the Netherlands. Eligibility criteria included diagnosis of type 2 diabetes, intermediate chronotype and absence of medical conditions that could interfere with the study execution and/or outcome. Randomisation was performed by a study-independent investigator, ensuring that an equal amount of participants started with TRE and CON. Due to the nature of the study, neither volunteers nor investigators were blinded to the study interventions. The quality of the data was checked without knowledge on intervention allocation. Hepatic glycogen levels were assessed with 13C-MRS and insulin sensitivity was assessed using a hyperinsulinaemic–euglycaemic two-step clamp. Furthermore, glucose homeostasis was assessed with 24 h continuous glucose monitoring devices. Secondary outcomes included 24 h energy expenditure and substrate oxidation, hepatic lipid content and skeletal muscle mitochondrial capacity.ResultsResults are depicted as mean ± SEM. Hepatic glycogen content was similar between TRE and control condition (0.15±0.01 vs 0.15±0.01 AU, p=0.88). M value was not significantly affected by TRE (19.6±1.8 vs 17.7±1.8 μmol kg−1 min−1 in TRE vs control, respectively, p=0.10). Hepatic and peripheral insulin sensitivity also remained unaffected by TRE (p=0.67 and p=0.25, respectively). Yet, insulin-induced non-oxidative glucose disposal was increased with TRE (non-oxidative glucose disposal 4.3±1.1 vs 1.5±1.7 μmol kg−1 min−1, p=0.04). TRE increased the time spent in the normoglycaemic range (15.1±0.8 vs 12.2±1.1 h per day, p=0.01), and decreased fasting glucose (7.6±0.4 vs 8.6±0.4 mmol/l, p=0.03) and 24 h glucose levels (6.8±0.2 vs 7.6±0.3 mmol/l, p<0.01). Energy expenditure over 24 h was unaffected; nevertheless, TRE decreased 24 h glucose oxidation (260.2±7.6 vs 277.8±10.7 g/day, p=0.04). No adverse events were reported that were related to the interventions.Conclusions/interpretationWe show that a 10 h TRE regimen is a feasible, safe and effective means to improve 24 h glucose homeostasis in free-living adults with type 2 diabetes. However, these changes were not accompanied by changes in insulin sensitivity or hepatic glycogen.Trial registrationClinicalTrials.gov NCT03992248FundingZonMW, 459001013Graphical abstract

Therapeutic effects of aqueous extract of bioactive active component of Ageratum conyzoides on the ovarian-uterine and hypophysis-gonadal axis in rat with polycystic ovary syndrome: Histomorphometric evaluation and biochemical assessment

BackgroundPolycystic ovary syndrome (PCOS) is an endocrine disorder, affecting women of reproductive age. Ageratum conyzoïdes (AGC) is used traditionally in the treatment of fever, rheumatism, and ulcer. This study investigates the effects of AGC on ovarian-uterine in PCOS rats. MethodsFemale rats were randomized into four groups (n = 6). Group A control received 2 ml distilled water. Group B received a single dose of 4 mg/kg body weight (bwt) i.p estradiol valerate (EV). Group C received 500 mg/kg bwt AGC and group D received a single dose of 4 mg/kg bwt i.p EV followed by 500 mg/kg bwt AGC orally for 30 days. Parameters tested include follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), estradiol (E2), progesterone (P), C-reactive protein (CRP), interleukin (IL)-6, IL-18 and tumor necrosis factor (TNF)- α, malondialdehyde (MDA), superoxide dismutase (SOD), Catalase (CAT), total protein (TP), total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and ovary and uterus histomorphometric. ResultsAgeratum conyzoides decrease insulin resistance, obesity indices, TC, TG, LDL, MDA, T, LH, FSH, CRP, IL-6, IL-18, and TNF- α in PCOS rats. And increase HDL, E2, P, TP, CAT, and SOD in PCOS rats. AGC improved ovary and uterus histo-architecture, tertiary, and Graafian follicles, corpus luteum and endometrial thickness increased,and cystic and atretic follicles decreased. ConclusionAgeratum conyzoides improved insulin sensitivity, antioxidant activities, hormonal imbalance, inflammatory makers, and histological changes in PCOS rats. Therefore AGC can be used as a potential adjuvant agent in the treatment of PCOS.

Altered Insulin Clearance after Gastric Bypass and Sleeve Gastrectomy in the Fasting and Prandial Conditions.

Background: The liver has the capacity to regulate glucose metabolism by altering the insulin clearance rate (ICR). The decreased fasting insulin concentrations and enhanced prandial hyperinsulinemia after Roux-en-Y gastric-bypass (GB) surgery and sleeve gastrectomy (SG) are well documented. Here, we investigated the effect of GB or SG on insulin kinetics in the fasting and fed states. Method: ICR was measured (i) during a mixed-meal test (MMT) in obese non-diabetic GB (n = 9) and SG (n = 7) subjects and (ii) during a MMT combined with a hyperinsulinemic hypoglycemic clamp in the same GB and SG subjects. Five BMI-matched and non-diabetic subjects served as age-matched non-operated controls (CN). Results: The enhanced ICR during the fasting state after GB and SC compared with CN (p < 0.05) was mainly attributed to augmented hepatic insulin clearance rather than non-liver organs. The dose-response slope of the total insulin extraction rate (InsExt) of exogenous insulin per circulatory insulin value was greater in the GB and SG subjects than in the CN subjects, despite the similar peripheral insulin sensitivity among the three groups. Compared to the SG or the CN subjects, the GB subjects had greater prandial insulin secretion (ISR), independent of glycemic levels. The larger post-meal ISR following GB compared with SG was associated with a greater InsExt until it reached a plateau, leading to a similar reduction in meal-induced ICR among the GB and SG subjects. Conclusions: GB and SG alter ICR in the presence or absence of meal stimulus. Further, altered ICR after bariatric surgery results from changes in hepatic insulin clearance and not from a change in peripheral insulin sensitivity.

Risk of Type 2 Diabetes Among Individuals with Excess Weight: Weight Trajectory Effects.

Increased risk of type 2 diabetes mellitus (T2D) among individuals with overweight or obesity is well-established; however, questions remain about the temporal dynamics of weight change (gain or loss) on the natural course of T2D in this at-risk population. Existing epidemiologic evidence is limited to studies that discretely sample and assess excess weight and T2D risk at different ages with limited follow-up, yet changes in weight may have time-varying and possibly non-linear effects on T2D risk. Predicting the impact of weight change on the risk of T2D is key to informing primary prevention. We critically review the relationship between weight change, trajectory groups (i.e., distinct weight change patterns), and T2D risk among individuals with excess weight in recently published T2D prevention randomized controlled trials (RCTs) and longitudinal cohort studies. Overall, weight trajectory groups have been shown to differ by age of onset, sex, and patterns of insulin resistance or beta-cell function biomarkers. Lifestyle (diet and physical activity), pharmacological, and surgical interventions can modify an individual's weight trajectory. Adolescence is a critical etiologically relevant window during which onset of excess weight may be associated with higher risk of T2D. Changes in insulin resistance and beta-cell function biomarkers are distinct but related correlates of weight trajectory groups that evolve contemporaneously over time. These multi-trajectory markers are differentially associated with T2D risk. T2D risk may differ by the age of onset and duration of excess body weight, and the type of weight loss intervention. A better understanding of the changes in weight, insulin sensitivity, and beta-cell function as distinct but related correlates of T2D risk that evolve contemporaneously over time has important implications for designing and targeting primary prevention efforts.

Effects of oral N-acetyl cysteine on pain and plasma biochemical parameters in fibrocystic breast disorder: A randomized controlled trial

BackgroundFibrocystic change is the most common benign lesion in breasts of a woman in her reproductive age. It is an outcome of estrogen excess due to sex hormone imbalance. Cyclical pain as the most common symptom worsens life quality, compels patient to seek health care support continuously, and imposes large amounts of expense to both patient and health system. Current study aims to evaluate effects of N-acetyl cysteine on decreasing pain and changes in plasma biochemistry. MethodA total of 64 eligible women participated in this double-blinded randomized controlled trial. They were between 18 and 40 years. Participants were randomly allocated into oral N-acetyl cysteine and placebo receivers. Intervention and follow-up lasted for, respectively, a 12-week drugs-on and 12-month drugs-off period. Visual analog scaling was applied to measure severity of pain. Peripheral venous plasma was extracted and compared for inflammatory parameters including high-sensitivity C-reactive protein, total antioxidant capacity, malondialdehyde, total plasma glutathione, lipid profile, and fasting blood sugar. ResultsOral N-acetyl cysteine significantly decreased feeling of cyclical mastalgia (P < .01) after 12 weeks of consumption. In addition to lowering of plasma level of high-sensitivity C-reactive protein (P = .008), total plasma glutathione significantly increased (P = .02) among N-acetyl cysteine receivers. No change in lipid profile and insulin sensitivity was seen. ConclusionN-Acetyl cysteine could mitigate cyclical mastalgia. Inflammation as a considered reason for cyclical mastalgia also was halted by N-acetyl cysteine consumption.

(-)-Epicatechin Reverses Glucose Intolerance in Rats Housed at Thermoneutrality.

Diabetes is a life-threatening and debilitating disease with pathological hallmarks, including glucose intolerance and insulin resistance. Plant compounds are a source of novel and effective therapeutics, and the flavonoid (−)-epicatechin, common to popular foods worldwide, has been shown to improve carbohydrate metabolism in both clinical studies and preclinical models. We hypothesized that (−)-epicatechin would alleviate thermoneutral housing-induced glucose intolerance. Male rats were housed at either thermoneutral (30 °C) or room temperature (24 °C) for 16 weeks and gavaged with either 1 mg/kg body weight or vehicle for the last 15 days before sacrifice. Rats housed at thermoneutrality had a significantly elevated serum glucose area under the curve (p < 0.05) and reduced glucose-mediated insulin secretion. In contrast, rats at thermoneutrality treated with (−)-epicatechin had improved glucose tolerance and increased insulin secretion (p < 0.05). Insulin tolerance tests revealed no differences in insulin sensitivity in any of the four groups. Pancreatic immunohistochemistry staining showed significantly greater islet insulin positive cells in animals housed at thermoneutrality. In conclusion, (−)-epicatechin improved carbohydrate tolerance via increased insulin secretion in response to glucose challenge without a change in insulin sensitivity.

Assessing the Pathophysiology of Hyperglycemia in the Diabetes RElated to Acute Pancreatitis and Its Mechanisms Study: From the Type 1 Diabetes in Acute Pancreatitis Consortium.

The metabolic abnormalities that lead to diabetes mellitus (DM) after an episode of acute pancreatitis (AP) have not been extensively studied. This article describes the objectives, hypotheses, and methods of mechanistic studies of glucose metabolism that comprise secondary outcomes of the DREAM (Diabetes RElated to Acute pancreatitis and its Mechanisms) Study. Three months after an index episode of AP, participants without preexisting DM will undergo baseline testing with an oral glucose tolerance test. Participants will be followed longitudinally in three subcohorts with distinct metabolic tests. In the first and largest subcohort, oral glucose tolerance tests will be repeated 12 months after AP and annually to assess changes in β-cell function, insulin secretion, and insulin sensitivity. In the second, mixed meal tolerance tests will be performed at 3 and 12 months, then annually, and following incident DM to assess incretin and pancreatic polypeptide responses. In the third, frequently sampled intravenous glucose tolerance tests will be performed at 3 months and 12 months to assess the first-phase insulin response and more precisely measure β-cell function and insulin sensitivity. The DREAM study will comprehensively assess the metabolic and endocrine changes that precede and lead to the development of DM after AP.

Differences in levothyroxine action on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity between metformin- and myo-inositol-treated women with autoimmune subclinical hypothyroidism.

Insulin resistance impairs the impact of levothyroxine on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity. Both metformin and myo-inositol were found to improve insulin sensitivity and to reduce thyrotropin levels in individuals with hypothyroidism. The aim of the present study was to compare the effect of levothyroxine on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity between women receiving metformin and myo-inositol. The study included two groups of women with autoimmune hypothyroidism, treated for at least 6 months with either metformin (group A; n= 25) or myo-inositol (group B; n= 25). Both groups were matched for age, insulin sensitivity, hormone levels and antibody titers. For the following 6 months, all women received levothyroxine. Plasma levels of glucose, insulin, thyrotropin, free thyroid hormones, prolactin, 25-hydroxyvitamin D and high-sensitivity C-reactive protein (hsCRP), as well as titers of thyroid peroxidase and thyroglobulin antibodies were assessed at the beginning and at the end of the study. At baseline there were not differences between the study groups. Although levothyroxine reduced thyrotropin levels, increased free thyroid hormone levels and decreased antibody titers in both study groups, these effects were more pronounced in group A than group B. Only in group A, levothyroxine increased 25-hydroxyvitamin D, decreased hsCRP and improved insulin sensitivity. The impact of levothyroxine on thyrotropin and free thyroid hormones correlated with treatment-induced changes in insulin sensitivity, antibody titers, 25-hydroxyvitamin D and hsCRP. The present study suggests that the impact of levothyroxine on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity is stronger in women receiving metformin than in women treated with myo-inositol.

Acute effects of prior dietary fat ingestion on postprandial metabolic responses to protein and carbohydrate co-ingestion in overweight and obese men: A randomised crossover trial

Obesity and insulin resistance are associated with an impaired sensitivity to anabolic stimuli such as dietary protein (anabolic resistance). Omega-3 polyunsaturated fatty acids (n-3 PUFA) may be protective against the deleterious effects of saturated fatty acids (SFA) on insulin resistance. However, the contribution of excess fat consumption to anabolic and insulin resistance and the interaction between SFA and n-3 PUFA is not well studied. The primary aim of this study was to investigate the effects of an oral fat pre-load, with or without the partial substitution of SFA with fish oil (FO)-derived n-3 PUFA, on indices of insulin and anabolic sensitivity in response to subsequent dietary protein and carbohydrate (dextrose) co-ingestion. Eight middle-aged males with overweight or obesity (52.8±2.0yr, BMI 31.8±1.4kg·m-2) ingested either an SFA, or isoenergetic SFA and FO emulsion (FO), or water/control (Con), 4h prior to a bolus of milk protein and dextrose. Lipid ingestion (in particular FO) impaired the early postprandial uptake of branched chain amino acids (BCAA) into the skeletal muscle in response to protein and dextrose, and attenuated the peak glycaemic response, but was not accompanied by differences in whole body (Matsuda Index: Con: 4.66±0.89, SFA: 5.10±0.94 and FO: 4.07±0.59) or peripheral (forearm glucose netAUC: Con: 521.7±101.7; SFA: 470.2±125.5 and FO: 495.3±101.6μmol·min-1·100g lean mass·min [t=240-420min]) insulin sensitivity between visits. Postprandial whole body fat oxidation was affected by visit (P=0.024) with elevated rates in SFA and FO, relative to Con (1.85±0.55; 2.19±0.21 and 0.65±0.35kJ·h-1·kg-1 lean body mass, respectively), however muscle uptake of free fatty acids (FFA) was unaffected. Oral lipid preloads, consisting of SFA and FO, impair the early postprandial BCAA uptake into skeletal muscle, which occurs independent of changes in insulin sensitivity. ClinicalTrials.gov Identifier NCT03146286.

Changes in Insulin Sensitivity and Lipid Profile Markers Following Initial and Secondary Bouts of Multiple Eccentric Exercises.

An acute bout of eccentric exercise affects insulin sensitivity and lipid profile, but how the magnitude of muscle damage affects them is not clear. We compared changes in blood insulin sensitivity and lipid markers after the first (EC1) and second (EC2) eccentric exercise bouts. Fifteen sedentary young men performed arm, leg and trunk muscle eccentric exercises, and repeated them 2 weeks later. Fasting blood samples were taken before, 2 h and 1–5 days after each exercise bout to analyze plasma creatine kinase (CK) activity, serum glucose (GLU), insulin, homeostasis model assessment (HOMA), triacylglycerols (TG), total (TC) and low- (LDLC) and high-density lipoprotein cholesterol (HDLC) concentrations as well as TC/HDLC ratio. Changes in these measures were compared between bouts and relationships to peak plasma CK activity were analyzed. Plasma CK activity increased (p < 0.05) after EC1 (peak: 101,668 ± 58,955 IU/L) but not after EC2. The magnitude of changes in GLU (peak after EC1: 26 ± 10% vs. EC2: 7 ± 6%), insulin (46 ± 27% vs. 15 ± 8%), HOMA (86 ± 48% vs. 24 ± 15%), TC (−20 ± 5% vs. −6 ± 4%), TG (−32 ± 11% vs. −6 ± 3%), LDHC (−47 ± 15% vs. −12 ± 9%), HDLC (35 ± 26% vs. 7 ± 4%), and TC/HDLC ratio (−139 ± 13% vs. −11 ± 7%) were significantly greater after EC1 than EC2. Peak plasma CK activity was significantly (p < 0.05) correlated with the peak changes in blood insulin sensitivity and lipid markers for the combined data of EC1 and EC2. These results suggest that the greater the magnitude of muscle damage, the greater the magnitude of changes in the insulin sensitivity to a negative direction and lipid markers to a positive direction.

395-P: BeAM Value and Glycemia Assessed by Continuous Glucose Monitoring among Participants with Type 2 Diabetes and Chronic Kidney Disease

Introduction: The difference between bedtime and morning glucose levels (BeAM value) is a clinically relevant measure that can guide clinicians regarding insulin titrations. As chronic kidney disease (CKD) develops, changes in insulin sensitivity and kinetics and limitations to available medications may contribute to over-basalization, insufficient prandial control, and large BeAM. We hypothesized that CKD and less time in range (TIR) derived from continuous glucose monitoring (CGM) are associated with large BeAM in T2DM. Methods: This was a prospective observational cohort study of 1people with T2DM treated with insulin or sulfonylurea, 81 participants with CKD (eGFR &amp;lt;60 mL/min/1.73 m2) , and 24 controls with eGFR ≥60 frequency matched on age, duration of diabetes, HbA1c, and glucose-lowering medications. Each participant wore a CGM for two 6-day periods. BeAM was calculated as the difference between mean bedtime sensor glucose values and mean morning sensor values, with large BeAM defined as ≥30 mg/dL glucose drop from bedtime to morning. Results: Participants had a mean age of 68 years, diabetes duration years and HbA1c 7.7%. CKD and controls had a mean eGFR 38 and 83 mL/min/1.73 m2 respectively. Median (IQR) BeAM was 29 (9-52) mg/dL for participants with CKD and (-4-31) mg/dL for controls (p = 0.11) . Forty participants with CKD (49%) and 7 controls (29%) had a large BeAM. Those with a large BeAM had less TIR (58 v 68%) , higher HbA1c (8.0 vs. 7.5%) , and higher glucose management indicator (GMI, 7.5 vs. 7.2%) compared to those with BeAM &amp;lt;30 mg/dL (each p&amp;lt;0.05, adjusting for age, sex, and race) . Coefficient of variation, diabetes duration, and insulin dose (total or basal) did not correlate with BeAM. Conclusions: Large BeAM was common among participants with long-standing T2DM and CKD and was associated with less TIR and higher GMI. These data suggest that there is opportunity for improvement in daytime and prandial diabetes management among patients with CKD. Disclosure L.Mayeda: None. L.Zelnick: None. S.Trikudanathan: Research Support; Bionic pancreas, Bionic pancreas , Insulet Corporation, Insulet Corporation. I.B.Hirsch: Consultant; Abbott Diabetes, Bigfoot Biomedical, Inc., GWave, Roche Diabetes Care, Research Support; Beta Bionics, Inc., Insulet Corporation, Medtronic. I.De boer: Advisory Panel; AstraZeneca, Bayer AG, Cyclerion Therapeutics, Inc., George Clinical, Goldfinch Bio, Inc., Other Relationship; American Society of Nephrology, Research Support; Dexcom, Inc. Funding American Diabetes Association (4-15-CKD-20) ; National Institute of Diabetes and Digestive and Kidney Diseases (R01DK088762, R01087726)