Changes In Insulin Sensitivity Research Articles

1349-P: Bariatric Surgery Causes an Early Improvement in the Lipidomic Profile and a Decrease in Plasma Ceramides and Diacylglycerols in Patients with Type 2 Diabetes and NAFLD

Bariatric surgery (BarS) is known to improve insulin resistance (IR) , atherogenic dyslipidemia and steatohepatitis in patients (pts) with type 2 diabetes (T2D) . Total ceramides (Cer) and diacylglycerols (DAGs) have been implicated in the development of IR and nonalcoholic fatty liver disease (NAFLD) , but the impact of BarS on their plasma concentration remains unclear. The aim of this study was to assess early changes in the plasma lipidome, before and 3-6 months post BarS. To this end, we recruited 17 pts with NAFLD who underwent BarS (age 47±3, BMI 46±2 kg/m2, 76% with T2D) , and 6 controls without T2D (baseline data only, age 47±6, BMI 31.2±2.1 kg/m2) . Global lipidomic profiling was performed on orbitrap mass spectrometer with UHPLC. Data was analysed using LipidMatch software. Plasma levels of total lipids (TL) (34%; p=0.01) , Cer (20%; p=0.31) , DAGs (50%; p=0.03) and total triglycerides (TG) (79%; p=0.01) were higher in pts with NAFLD compared to controls. Bariatric surgery reduced plasma TL (-26%) , Cer (-31%) , DAGs (-34%) and TG (-43%) levels (all p<0.01) . In pts with vs. without T2D, plasma TL were higher (28%; p=0.01) . There was a reduction in TL (-29%; p<0.01) , Cer (-22%; 0.27) , DAGs (-41%; p=0.02) and TG (-52%; p<0.01) post BarS and a similar pattern was observed across the lipidomic profile (cholesterol esters, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol) . Reduction in weight after BarS correlated with lower DAGs (r=0.81; p=0.03) and TG (r=0.66; p=0.07) . Reduction in Cer correlated with improved HOMA-IR (r= 0.71; p=0.04) and Adipo-IR (r= 0.63; p=0.09) . In conclusion, pts with NAFLD and T2D have a significantly worse lipidomic profile compared to pts without T2D. The unfavorable lipidomic profile was normalized after BarS, in particular Cer and DAG levels, known to be linked to IR. Assessment of the lipidomic profile may provide further insights into insulin sensitivity changes after BarS. Disclosure S.Kalavalapalli: None. A.Zarrinpar: None. K.Cusi: Consultant; Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Fractyl Health, Inc., Genentech, Inc., Hanmi Pharm. Co., Ltd., Intercept Pharmaceuticals, Inc., Novo Nordisk. D.Barb: None. R.E.Dillard: None. E.Godinez: None. J.Friedman: n/a. N.Fanous: None. C.O.Warren: None. F.Bril: None. R.Lomonaco: None.

252-LB: GRK2 Participates in Islet Function and Glucose-Stimulated Insulin Secretory Responses

Insulin deficiency is central to diabetes and diabetes-related cardiac dysfunction. GPCRs are known modulators of insulin secretion and a main pharmacological target in various tissues, including the heart. GPCR kinase 2 (GRK2) phosphorylates activated GPCRs, targeting receptors for recycling or degradation. Notably, we and others have shown that GRK2 can also localize to the cardiac mitochondria where it participates in substrate utilization, particularly in response to cellular stress. GRK2 is downregulated in the pancreas of diabetogenic mice, and we have shown that pancreatic loss of GRK2 impairs insulin secretion in normal and high fat diet. Mice with pancreatic-specific GRK2 KO showed glucose intolerance (AUC WT 8691 vs. KO 14766 mg/dl*min, n=22/group, p<.05) due to significant decrease in insulin secretion following glucose administration (after 15 minutes WT 2.35 vs. KO 1.616 ng/ml, N=16-19/group, P<.0001) without changes in islet size or cell distribution. Using a model of high fat diet, we observed an impairment in glucose-stimulated insulin release in pancreatic GRK2 KO animals when compared to control animals without significant changes in fasting insulin secretion or insulin sensitivity. To further dissect the role of islet GRK2 in α- or β-cells, we have constructed two novel mouse models of inducible cell type-specific GRK2 KO. Our preliminary studies reveal that β-cell GRK2 deficient animals are prone to glucose intolerance and decreased glucose-induced insulin secretion when exposed to high fat high sucrose diet. This suggests that GRK2 plays a role in islet adaptation to metabolic challenge. Further studies will delineate the mechanistic role of GRK2 in mediating metabolism and calcium influx in β-cells regulating insulin secretion, and subsequently the impact to the heart in the presence or absence of TAC. Our studies will provide new GRK2 mechanistic insight that could be explored as new pharmacological strategies to delay diabetes disease progression. Disclosure J. W. Snyder: None. S. K. Montgomery: None. N. M. Doliba: None. J. Roman: None. Y. Tian: None. P. Y. Sato: None. W. L. Holland: None. R. Choi: None. Funding National Institutes of Health (1R56HL149887) ; University of Pennsylvania Diabetes Research Center Pilot and Feasibility Grant (P30-DK019525) ; American Heart Association Scientist Development Grant (17SDG33660407)

Evaluation of thyroid function and metabolic parameters in obese and overweight children: A prospective case-control study.

Obesity is considered an important global public health challenge, and its prevalence is rapidly increasing in children. We investigated in this study if the upper-normal TSH level may be associated with metabolic syndrome parameters, including obesity, high blood pressure, and dyslipidemia and changes in insulin sensitivity in overweight and obese children. We also investigated whether there is a relationship between BMI and these parameters. This prospective case-control study comprised 145 participants (74 females, 71 males) aged 5–18 years. Participants were divided into three groups according to their BMI z-score, as overweight, obese and control. The control group included 35 age and sex-matched healthy subjects. Thyroid stimulating hormone levels of control, overweight and obese groups were 2.14 ± 1.27, 2.97 ± 1.26 and 3.13 ± 1.11, respectively (p<0.05). There was a significant positive correlation between TSH and the BMI, BMI z-scores between overweight and obese groups (r=0.302, p=0.000), (r=0.121, p=0.004), respectively. The current study suggests that increased serum TSH levels, even within the normal range, in overweight and obese children is associated with the impairment of metabolic parameters, including dyslipidemia and insulin sensitivity. For that reason, TSH levels in the high-normal range should be considered as a risk factor for metabolic syndrome and its components.

Evolution of Mitochondrially Derived Peptides Humanin and MOTSc, and Changes in Insulin Sensitivity during Early Gestation in Women with and without Gestational Diabetes.

Our purpose is to study the evolution of mitochondrially derived peptides (MDPs) and their relationship with changes in insulin sensitivity from the early stages of pregnancy in a cohort of pregnant women with and without gestational diabetes (GDM). MDPs (humanin and MOTSc) were assessed in the first and second trimesters of gestation in 28 pregnant women with gestational diabetes mellitus (GDM) and a subgroup of 45 pregnant women without GDM matched by BMI, age, previous gestations, and time of sampling. Insulin resistance (IR) was defined as a HOMA-IR index ≥70th percentile. We observed a significant reduction in both humanin and MOTSc levels from the first to the second trimesters of pregnancy. After adjusting for predefined variables, including BMI, statistically nonsignificant associations between lower levels of humanin and the occurrence of a high HOMA-IR index were obtained (adjusted OR = 2.63 and 3.14 for the first and second trimesters, linear p-trend 0.260 and 0.175, respectively). Regarding MOTSc, an association was found only for the second trimester: adjusted OR = 7.68 (95% CI 1.49–39.67), linear p-trend = 0.012. No significant associations were observed in humanin change with insulin resistance throughout pregnancy, but changes in MOTSc levels were significantly associated with HOMA-IR index: adjusted OR 3.73 (95% CI 1.03–13.50). In conclusion, MOTSc levels, especially a strong decrease from the first to second trimester of gestation, may be involved in increasing insulin resistance during early gestation.

Age, Body Mass Index, and Waist-to-Hip Ratio Related Changes in Insulin Secretion and Insulin Sensitivity in Women with Polycystic Ovary Syndrome: Minimal Model Analyses.

Insulin resistance is believed to be an integral component of the polycystic ovary syndrome (PCOS). Beta (ß) cell dysfunction is also found in PCOS. In the study, we determined the influence of age, body mass index (BMI), and waist-to-hip ratio (WHR) on insulin response to oral glucose load (OGTT) and on insulin sensitivity (Si) and ß-cell function in young women with PCOS. One hundred fourteen patients with PCOS and 41 controls with normal basal plasma glucose were studied. A 75-g OGTT was performed to determine glucose tolerance and insulin response. Insulin sensitivity and ß-cell function were studied using a modified frequently sampled IV glucose tolerance test (FISGTT) to determine the acute insulin response (AIRG), as well as Si by minimal model analysis. Si was decreased in PCOS women (2.49 0.18 vs. 3.41 ± 0.36, p < 0.05), but no difference in AIRG existed between the PCOS and control group (75.1 ± 4.6 vs. 63.4 ± 4.6, p < 0.05). BMI and WHR correlated negatively with Si (r = −0.43; r = −0.289, p < 0.001, respectively), but not with AIRG (r = 0.116; r = −0.02, p > 0.05, respectively). Increasing age correlated negatively with AIRG (r = −0.285, p < 0.001). There was a significant interaction between disease (PCOS), BMI, and WHR on Si as well as between age and PCOS on AIRG. Thus, patients below the age of 25 with PCOS showed enhanced AIRG (89.5 ± 7.1 vs. 65.1 ± 6.7, p < 0.05) and decreased Si (2.43 ± 0.25 vs. 4.52 ± 0.62, p < 0.05) compared to age-matched controls. In conclusion, these data suggest that not all patients with PCOS have basal and stimulated hyperinsulinemia, insulin resistance, and impaired glucose tolerance. Based on these data in young PCOS subjects, the development of insulin resistance and T2DM may be prevented with appropriate treatment strategies.

Impaired insulin secretion without changes in insulin sensitivity explains hyperglycemia in patients with acromegaly treated by pasireotide LAR

Impaired insulin secretion without changes in insulin sensitivity explains hyperglycemia in patients with acromegaly treated by pasireotide LAR

Partial Clinical Remission of Type 1 Diabetes: The Need for an Integrated Functional Definition Based on Insulin-Dose Adjusted A1c and Insulin Sensitivity Score.

Despite advances in the characterization of partial clinical remission (PR) of type 1 diabetes, an accurate definition of PR remains problematic. Two recent studies in children with new-onset T1D demonstrated serious limitations of the present gold standard definition of PR, a stimulated C-peptide (SCP) concentration of >300 pmol/L. The first study employed the concept of insulin sensitivity score (ISS) to show that 55% of subjects with new-onset T1D and a detectable SCP level of >300 pmol/L had low insulin sensitivity (IS) and thus might not be in remission when assessed by insulin-dose adjusted A1c (IDAA1c), an acceptable clinical marker of PR. The second study, a randomized controlled trial of vitamin D (ergocalciferol) administration in children and adolescents with new-onset T1D, demonstrated no significant difference in SCP between the ergocalciferol and placebo groups, but showed a significant blunting of the temporal trend in both A1c and IDAA1c in the ergocalciferol group. These two recent studies indicate the poor specificity and sensitivity of SCP to adequately characterize PR and thus call for a re-examination of current approaches to the definition of PR. They demonstrate the limited sensitivity of SCP, a static biochemical test, to detect the complex physiological changes that occur during PR such as changes in insulin sensitivity, insulin requirements, body weight, and physical activity. These shortcomings call for a broader definition of PR using a combination of functional markers such as IDAA1c and ISS to provide a valid assessment of PR that reaches beyond the static changes in SCP alone.

Deletion of the Vitamin D Receptor in Skeletal Muscle is Associated with Improved Glucose Tolerance and Reduced Muscle Function

Skeletal muscle insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus. Epidemiological studies have demonstrated that vitamin D deficiency is associated with the presence of type 2 diabetes in humans. To probe the role of the vitamin D receptor (VDR), an intracellular and nuclear protein that mediates the bioactivity of the active vitamin D ligand, 1,25‐dihydroxyvitamin D, in skeletal muscle mediated glucose disposal, we deleted the skeletal muscle VDR in adult mice. We assessed glucose disposal, insulin concentrations and sensitivity, and skeletal muscle gene expression in Vdr knockout and wild‐type Vdr mice. Following the induction of a skeletal muscle‐specific Crerecombinase with tamoxifen in adult male Vdrfl/flmice, efficient deletion of the Vdrwas demonstrated. In skeletal muscle‐specific Vdrknockout mice, basal glucose concentrations were similar to those in wild‐type Vdrmice. In Vdrknockout mice, blood glucose concentrations decreased more rapidly following the administration of intraperitoneal glucose than in control mice expressing wild‐type Vdr (Figure 1A and Figure 1B). The AUC for glucose concentrations in Vdrfl/fl.actin iCre mice treated with tamoxifen was reduced by 20% (p=0.015) compared to the AUC of blood glucose concentrations prior to tamoxifen treatment. Pre‐and post‐treatment AUC’s for blood glucose in Vdrfl/fl.actin iCre mice treated with vehicle and in Vdrfl/flmice treated with tamoxifen were unchanged (p=0.97,0.23). Plasma insulin concentrations were identical in knockout and wild‐type Vdr mice following a bolus of glucose, demonstrating that deletion of the Vdr in skeletal muscle did not influence the release of insulin in response to glucose (one‐way ANOVA, p=0.45). Insulin sensitivity was similar in Vdrknockout and wild‐type Vdrmice. Gene expression analysis of skeletal muscle mRNA derived from Vdrknockout mice and wild‐type mice demonstrated an increase in the expression of genes associated with oxidative phosphorylation, fatty acid oxidation and adipogenesis pathways that could potentially alter glucose utilization. We conclude that selective deletion of the Vdr in the skeletal muscle of adult mice results in more efficient glucose disposal than in wild‐type Vdrmice; basal and glucose‐stimulated insulin serum concentrations are identical in knock‐out and wild type VDR mice with no changes in insulin sensitivity. The data suggest that modulation of the vitamin‐D endocrine system is unlikely to improve glucose utilization.

Investigation into the Role of the Skeletal Muscle BBSome in Insulin Sensitivity

The BBSome is a protein complex composed of eight Bardet‐Biedl syndrome (BBS) proteins including BBS1. Humans and mice lacking a functional BBSome display impaired insulin sensitivity, hyperglycemia, and type 2 diabetes, highlighting the importance of this protein complex in the control of insulin action and glucose homeostasis. However, the contribution of the BBSome in insulin sensitive tissues such as the skeletal muscle to the control of insulin sensitivity is not clear. We hypothesized that BBSome deficiency in the skeletal muscle will lead to insulin resistance and diabetes. To test this, we generated a novel conditional knockout mouse model lacking the Bbs1 gene specifically in the skeletal muscle. This was achieved by crossing mice expressing floxed alleles of the Bbs1 gene (Bbs1fl/fl) with mice expressing Cre‐recombinase in the skeletal muscle (MCKCre). These mice were further bred with tdTomato reporter mice to validate Cre‐recombinase using red tdTomato protein fluorescence. Body weight, glucose handling (measured using glucose tolerance test, GTT) and insulin sensitivity (measured using insulin tolerance test, ITT) of Bbs1fl/fl/MCKCre mice were compared to littermate controls. Furthermore, we used Western blot to test the ability of insulin to activate Akt, a key signaling pathway associated with the insulin receptor. We found that both male and female Bbs1fl/fl/MCKCre mice have no significant alteration in body weight relative to wild type controls (31.4±1.5 vs 31.1±1.0 g in males and 24.1±2.2 vs 23.0±1.7 g in females at 16 weeks of age). There was also no significant change in glucose handling (GTT AUC: 30608±2106 vs 30741±3480 in males and 28836±4466 vs 26530±3334 AUC in females) and insulin sensitivity (ITT AUC: 11017±1285 vs 9935±1080 in males and 8223±792 vs 5803±978 AUC in females) between Bbs1fl/fl/MCKCre mice and controls. This was further confirmed by the lack of difference in insulin‐induced Akt activation in skeletal muscle, liver, and adipose tissue. These findings suggest that BBS1 protein in skeletal muscle is not required for insulin sensitivity. Next, we assessed whether challenging the mice with high fat/high sucrose diet (HFHSD), starting at weaning, could reveal a role for the skeletal muscle BBSome in insulin sensitivity. The weight gain evoked by HFHSD was comparable between Bbs1fl/fl/MCKCre mice and controls (32.3±3.1 vs 33.3±1.0 g in males at 10 weeks of age). Once they reach 16 weeks of age, the HFHSD mice will be subject to glucose tolerance and insulin sensitivity tests to determine if obesity exaggerates hyperglycemia and insulin resistance in Bbs1fl/fl/MCKCre mice.

Central deficiency of IL-6Ra in mice impairs glucose-stimulated insulin secretion

ObjectiveIL-6 is an important contributor to glucose and energy homeostasis through changes in whole-body glucose disposal, insulin sensitivity, food intake and energy expenditure. However, the relative contributions of peripheral versus central IL-6 signaling to these metabolic actions are presently unclear. A conditional mouse model with reduced brain IL-6Ra expression was used to explore how blunted central IL-6 signaling alters metabolic status in lean and obese mice. MethodsTransgenic mice with reduced levels of central IL-6 receptor alpha (IL-6Ra) (IL-6Ra KD mice) and Nestin Cre controls (Cre+/- mice) were fed standard chow or high-fat diet for 20 weeks. Obese and lean mouse cohorts underwent metabolic phenotyping with various measures of energy and glucose homeostasis determined. Glucose-stimulated insulin secretion was assessed in vivo and ex vivo in both mouse groups. ResultsIL-6Ra KD mice exhibited altered body fat mass, liver steatosis, plasma insulin, IL-6 and NEFA levels versus Cre+/- mice in a diet-dependent manner. IL-6Ra KD mice had increased food intake, higher RER, decreased energy expenditure with diminished cold tolerance compared to Cre+/- controls. Standard chow-fed IL-6Ra KD mice displayed reduced plasma insulin and glucose-stimulated insulin secretion with impaired glucose disposal and unchanged insulin sensitivity. Isolated pancreatic islets from standard chow-fed IL-6Ra KD mice showed comparable morphology and glucose-stimulated insulin secretion to Cre+/- controls. The diminished in vivo insulin secretion exhibited by IL-6Ra KD mice was recovered by blockade of autonomic ganglia. ConclusionsThis study shows that central IL-6Ra signaling contributes to glucose and energy control mechanisms by regulating food intake, energy expenditure, fuel flexibility and insulin secretion. A plausible mechanism linking central IL-6Ra signaling and pancreatic insulin secretion is through the modulation of autonomic output activity. Thus, brain IL-6 signaling may contribute to the central adaptive mechanisms engaged in response to metabolic stress.

Changes in Food and Nutrient Intake and Diet Quality on a Low-Fat Vegan Diet Are Associated with Changes in Body Weight, Body Composition, and Insulin Sensitivity in Overweight Adults: A Randomized Clinical Trial

BackgroundConsuming different food groups and nutrients can have differential effects on body weight, body composition, and insulin sensitivity. ObjectiveThe aim was to identify how food group, nutrient intake, and diet quality change relative to usual-diet controls after 16 weeks on a low-fat vegan diet and what associations those changes have with changes in body weight, body composition, and measures of metabolic health. DesignSecondary analysis of a randomized clinical trial conducted between October 2016 and December 2018 in four replications. Participants/settingParticipants included in this analysis were 219 healthy, community-based adults in the Washington, DC, area, with a body mass index (BMI) between 28 and 40, who were randomly assigned to either follow a low-fat vegan diet or make no diet changes. InterventionA low-fat, vegan diet deriving approximately 10% of energy from fat, with weekly classes including dietary instruction, group discussion, and education on the health effects of plant-based nutrition. Control group participants continued their usual diets. Main outcome measuresChanges in food group intake, macronutrient and micronutrient intake, and dietary quality as measured by Alternate Healthy Eating Index-2010 (AHEI-2010), analyzed from 3-day diet records, and associations with changes in body weight, body composition, and insulin sensitivity were assessed. Statistical analyses performedA repeated-measure analysis of variance model that included the factors group, subject, and time was used to test the between-group differences throughout the 16-week study. Interaction between group and time was calculated for each variable. Within each diet group, paired comparison t tests were calculated to identify significant changes from baseline to 16 weeks. Spearman correlations were calculated for the relationship between changes in food group intake, nutrient intake, AHEI-2010 score, and changes in body weight, body composition, and insulin sensitivity. The relative contribution of food groups and nutrients to weight loss was evaluated using linear regression. ResultsFruit, vegetable, legume, meat alternative, and whole grain intake significantly increased in the vegan group. Intake of meat, fish, and poultry; dairy products; eggs; nuts and seeds; and added fats decreased. Decreased weight was most associated with increased intake of legumes (r = −0.38; P < 0.0001) and decreased intake of total meat, fish, and poultry (r = +0.43; P < 0.0001). Those consuming a low-fat vegan diet also increased their intake of carbohydrates, fiber, and several micronutrients and decreased fat intake. Reduced fat intake was associated with reduced body weight (r = +0.15; P = 0.02) and, after adjustment for changes in BMI and energy intake, with reduced fat mass (r = +0.14; P = 0.04). The intervention group’s AHEI-2010 increased by 6.0 points on average, in contrast to no significant change in the control group (treatment effect, +7.2 [95% CI +3.7 to +10.7]; P < 0.001). Increase in AHEI-2010 correlated with reduction in body weight (r = 0.14; P = 0.04), fat mass (r = −0.14; P = 0.03), and insulin resistance as measured by the Homeostasis Model Assessment (HOMA-IR; r = −0.17; P = 0.02), after adjustment for changes in energy intake. ConclusionsWhen compared with participants’ usual diets, intake of plant foods increased, and consumption of animal foods, nuts and seeds, and added fats decreased on a low-fat vegan diet. Increased legume intake was the best single food group predictor of weight loss. Diet quality as measured by AHEI-2010 improved on the low-fat vegan diet, which was associated with improvements in weight and metabolic outcomes. These data suggest that increasing low-fat plant foods and minimizing high-fat and animal foods is associated with decreased body weight and fat loss, and that a low-fat vegan diet can improve measures of diet quality and metabolic health.

Early supplementation of folate and vitamin B12 improves insulin resistance in intrauterine growth retardation rats.

Insulin sensitivity is changed during the neonatal period in small for gestational age (SGA) infants. Yet, the interventional strategies are still limited. We aimed to investigate the effects of supplementation with high folate and vitamin B12 diets in the early postnatal period on the changes in insulin sensitivity in an intrauterine growth retardation (IUGR) rat model. IUGR rat model was established by both low-protein diet feeding and daily diet restriction. High folate and vitamin B12 diet was supplied in IUGR as nutritional interventional group (IUGR-I), otherwise, the non-intervened IUGR group (IUGR-NI). In this study, male rats were studied in order to avoid hormonal and gender influence. At 21, 60 and 120 days, fasting plasma glucose, insulin, triglyceride, cholesterol, and homocysteine levels were measured among the control, IUGR-I, and IUGR-NI groups. Pearson analysis was used to evaluate the correlation between homocysteine and fasting blood glucose, insulin, HOMA-IR, triglyceride, and cholesterol levels. We established IUGR rat model by both low protein and restricted diet feeding during pregnancy and the incidence of IUGR pups was 93.33%. There was no difference in fasting glucose, insulin, HOMA-IR, triglyceride and cholesterol levels between the control, the IUGR-NI and the IUGR-I group at day 21. At day 60, insulin, HOMA-IR and triglyceride levels in the IUGR-I group were remarkably lower than those in the IUGR-NI group, but still higher than those in the control group (F=38.34, P=0.02; F=49.48, P=0.02; F=17.93, P<0.001, respectively). At day 120, glucose, insulin, HOMA-IR and Hcy levels in the IUGR-I group were obviously lower than those in the IUGR-NI group, although still higher than those in the control group (F=21.60, P<0.001; F=164.46, P<0.001; F=75.15, P<0.001; F=35.46, P<0.001, respectively). There were no significant differences in triglyceride and cholesterol levels between the IUGR-I group and the control group at day 120. At 120-day, homocysteine in IUGR-I group was highly positively correlated with fasting glucose and HOMA-IR (r=0.863, P=0.006; r=0.725, P=0.042, respectively); Only homocysteine was positively correlated with fasting glucose in IUGR-NI group (r=0.721, P=0.044). Early supplementation of folate and vitamin B12 improved insulin resistance and lipid levels in IUGR rats to some extent, along with decreasing homocysteine levels, but not enough to completely repair glucose and lipid metabolism.

Acute effect of passive heat exposure on markers of cardiometabolic function in adults with type 2 diabetes mellitus.

Heat therapy is a promising strategy to improve cardiometabolic health. This study evaluated the acute physiological responses to hot water immersion in adults with type 2 diabetes mellitus (T2DM). On separate days in randomized order, 13 adults with T2DM [8 males/5 females, 62 ± 12 yr, body mass index (BMI): 30.1 ± 4.6 kg/m2] were immersed in thermoneutral (34°C, 90 min) or hot (41°C, core temperature ≥38.5°C for 60 min) water. Insulin sensitivity was quantified via the minimal oral model during an oral glucose tolerance test (OGTT) performed 60 min after immersion. Brachial artery flow-mediated dilation (FMD) and reactive hyperemia were evaluated before and 40 min after immersion. Blood samples were drawn to quantify protein concentrations and mRNA levels of HSP70 and HSP90, and circulating concentrations of cytokines. Relative to thermoneutral water immersion, hot water immersion increased core temperature (+1.66°C [+1.47, +1.87], P < 0.01), heart rate (+34 beats/min [+24, +44], P < 0.01), antegrade shear rate (+96 s-1 [+57, +134], P < 0.01), and IL-6 (+1.38 pg/mL [+0.31, +2.45], P = 0.01). Hot water immersion did not exert an acute change in insulin sensitivity (-0.3 dL/kg/min/μU/mL [-0.9, +0.2], P = 0.18), FMD (-1.0% [-3.6, +1.6], P = 0.56), peak (+0.36 mL/min/mmHg [-0.71, +1.43], P = 0.64), and total (+0.11 mL/min/mmHg × min [-0.46, +0.68], P = 0.87) reactive hyperemia. There was also no change in eHSP70 (P = 0.64), iHSP70 (P = 0.06), eHSP90 (P = 0.80), iHSP90 (P = 0.51), IL1-RA (P = 0.11), GLP-1 (P = 0.59), and NF-κB (P = 0.56) after hot water immersion. The physiological responses elicited by hot water immersion do not acutely improve markers of cardiometabolic function in adults with T2DM.NEW & NOTEWORTHY Heat therapy has been shown to improve markers of cardiometabolic health in preclinical and clinical studies. However, the effects of heat therapy in individuals with type 2 diabetes mellitus (T2DM) remain understudied. We examined the acute effect of hot water immersion on glucose tolerance, flow-mediated dilation, reactive hyperemia, inflammatory markers, and heat shock proteins in adults with T2DM. Hot water immersion did not acutely improve the markers studied.

Light exposure during sleep impairs cardiometabolic function

SignificanceAmbient nighttime light exposure is implicated as a risk factor for adverse health outcomes, including cardiometabolic disease. However, the effects of nighttime light exposure during sleep on cardiometabolic outcomes and the related mechanisms are unclear. This laboratory study shows that, in healthy adults, one night of moderate (100 lx) light exposure during sleep increases nighttime heart rate, decreases heart rate variability (higher sympathovagal balance), and increases next-morning insulin resistance when compared to sleep in a dimly lit (<3 lx) environment. Moreover, a positive relationship between higher sympathovagal balance and insulin levels suggests that sympathetic activation may play a role in the observed light-induced changes in insulin sensitivity.

Abstract P100: Changes In Adiponectin But Not Tnfα Predict Changes In Insulin Sensitivity Following Health Behavior Intervention Among Latino Youth

Background: Pediatric obesity is characterized by an imbalance in pro- and anti-inflammatory markers that are associated with cardiometabolic diseases. Adiponectin (Adpn), an anti-inflammatory marker, is associated with insulin sensitivity, while tumor necrosis factor-alpha (TNFα) has been associated with insulin resistance among youth with obesity. However, it is unknown whether longitudinal changes in Adpn or TNFα predict changes in insulin sensitivity among high-risk youth. Methods: A total of 73 Latino youth with obesity (age 13.3±1.4 y, Female 40.3%, BMIz 2.2±0.3) were enrolled in either a lifestyle intervention or usual care. Given that there were no between-group differences in changes in insulin sensitivity at 6-months, groups were combined for the present analysis. Fasting serum samples were used to measure high-molecular weight Adpn and TNFα before and after intervention. Insulin sensitivity was estimated by the whole-body insulin sensitivity index (WBISI) using insulin and glucose concentrations from a 75-g, 2-h oral glucose tolerance test. Baseline associations were analyzed using Pearson correlations. Linear regression was used to analyze whether changes in Adpn or TNFα predict changes in WBISI, adjusting for age, sex, and intervention assignment. Data from linear regressions are presented as betas (β) and standard errors (SE). Results: At baseline, WBISI was positively and significantly associated with Adpn (r=0.296, p=0.015) but not with TNFα (r=-0.171, p=0.168), adjusting for age and sex. Increases in Adpn were associated with increases in WBISI, whereby for every 1 μg/dL increase in Adpn, there was a 0.7 unit increase in WBISI (SE=0.3, p=0.027). Changes in TNFα did not significantly predict changes in WBISI (β=0.1, SE=0.5, p=0.915). Conclusion: Changes in Adpn but not TNFα were associated with changes in insulin sensitivity following intervention among Latino youth with obesity. Whether Adpn is the mechanism by which health behavior changes increase insulin sensitivity warrants further investigation among high-risk youth populations.

Abstract MP30: Circulating MicroRNA-128-1 And Changes In Energy Metabolism And Insulin Sensitivity In Response To Weight Loss Diet Interventions: The Pounds Lost Trial

Background: MicroRNA (miRNAs) are short non-coding RNAs that play important roles in regulating gene expression. Recently, miR-128-1 was identified as a potential thrifty miRNA that controls energy expenditure, contributing to obesity and metabolic diseases. miR-128-1 is located at the locus harboring the lactase ( LCT ) gene, a hallmark gene of the positive selection and evolutionary adaptation to famine by promoting energy storage. Hypothesis: We investigated whether circulating thrifty miR-128-1 was associated with insulin resistance, adiposity, and energy expenditure among adults with overweight and obesity and tested whether miR-128-1 was associated with changes in these metabolic conditions after low-calorie weight-loss diet interventions. Methods: We included 495 participants from the POUNDS Lost trial with available data on circulating miR-128-1-5p measured at baseline and 6 months after the intervention. The LCT genotype rs4988235, which is responsible for lactase persistence in Europeans, was assessed to analyze the relationship between miR-128-1 and the positive selection at this locus. Outcome measurements included adiposity (weight, waist circumference [WC], and body composition), insulin resistance (HOMA-IR), and energy metabolism. Habitual physical activity was assessed by the Baecke questionnaires; total, leisure time, sport, work index were calculated. Results: The LCT rs4988235 (A) allele was associated with higher levels of miR-128-1 ( p =0.04). Pre-intervention miR-128-1 was significantly and positively associated with HOMA-IR ( p =0.009), insulin ( p =0.008), BMI ( p =0.0002), WC ( p =0.036), and whole-body total % fat mass ( p =0.013), and energy metabolism (resting energy expenditure, oxygen consumption, and carbon dioxide production; p &lt;0.05 for all). Also, we found that higher miR-128-1 was related to lower total physical activity index ( p =0.001) and subscales (leisure index ( p =0.007) and sport index ( p =0.02)). We found significant interactions between miR-128-1 and physical activity on changes in adiposity and insulin resistance at 6 months after the interventions ( P interaction =0.03 for weight; P interaction =0.004 for WC; and P interaction =0.01 for HOMA-IR). Participants with lower levels of physical activity and higher miR-128-1 at baseline responded better to the intervention to improve HOMA-IR at 6 months. There were also significant interactions between changes in miR-128-1 and changes in physical activity on changes in HOMA-IR and energy expenditure. Conclusions: Elevated levels of circulating miR-128-1 were associated with greater adiposity and insulin resistance in adults with overweight and obesity. The thrifty miR-128-1 interacted with physical activity on changes in energy metabolism and insulin sensitivity in response to weight-loss diet interventions.

Is Methylprednisolone Acetate-Related Insulin Resistance Preventable in Cats?

Methylprednisolone acetate (MPA) is often prescribed to cats despite being recognized eventually as diabetogenic. To assess MPA-related insulin resistance and evaluate the efficacy of metformin or an obesity and diabetes mellitus (O&D) adjuvant diet as protective factors, a randomized clinical trial was conducted with 28 owned cats undergoing glucocorticoid therapy. A single MPA dose of 20 mg intramuscularly was administered to each cat. Controls (n = 10) received only MPA. In the diet group (n = 9), replacement of their habitual diet by ad-libitum feeding of a feline commercial O&D diet (Equilíbrio O&D, Total Alimentos ADM) was made. In the metformin group (n = 9), metformin chlorhydrate 25mg/cat PO/q24h was administered for 30 days. All patients were clinically evaluated at baseline (T0), day 15 (T15), and day 30 (T30) and blood draw for complete blood count, serum biochemistry, and determination of insulin concentrations. Fasting Insulin Sensitivity Index (SI), Amended Insulin to Glucose Ratio (AIGR), Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and Homeostatic Model Assessment of beta-cell function (HOMA-B) were calculated based on fasting glycemia and insulinemia. All groups showed significantly higher levels (P < .05) of neutrophils, albumin, glucose, cholesterol, triglycerides, and serum insulin at T15. Patients in the metformin group showed also higher SI, AIGR, and HOMA-IR results at T15. Also, at T15, reduced levels (P < .05) of eosinophils, lymphocytes, and creatinine were documented in all groups. An MPA single dose induced changes in insulin sensitivity in cats; however, neither metformin nor O&D feeding used in this study was effective as protective factors against MPA-related insulin resistance.

MST1 deletion protects \u03b2-cells in a mouse model of diabetes

The pro-apoptotic kinase Mammalian Sterile 20-like kinase 1 (MST1), an integral component of the Hippo pathway, is a key regulator of organ size, stress response, and tissue homeostasis; its aberrant hyperactivation is linked to multiple pathological disorders including diabetes. Here we show that MST1 deletion in mice resulted in improved glucose tolerance and insulin secretion, and restored pancreatic β-cell mass as a result of improved β-cell survival and proliferation in the combined high fat/high sucrose and streptozotocin (HFS/STZ) model of β-cell destruction and diabetes. Importantly, the glucose-lowering effects in the MST1-knockout (KO) mice could be accounted to the enhanced β-cell mass and improved insulin secretion without changes in insulin sensitivity. Metabolic and morphological data suggest that normalization of blood glucose and insulin secretion, islet architecture, and β-cell mass by MST1 deletion in response to diabetes-induced injury occurs as a result of improved β-cell survival and proliferation establishing MST1 as potent regulator of physiological β-cell turnover.

Central Nervous System Control of Glucose Homeostasis: A Therapeutic Target for Type 2 Diabetes?

Historically, pancreatic islet beta cells have been viewed as principal regulators of glycemia, with type 2 diabetes (T2D) resulting when insulin secretion fails to compensate for peripheral tissue insulin resistance. However, glycemia is also regulated by insulin-independent mechanisms that are dysregulated in T2D. Based on evidence supporting its role both in adaptive coupling of insulin secretion to changes in insulin sensitivity and in the regulation of insulin-independent glucose disposal, the central nervous system (CNS) has emerged as a fundamental player in glucose homeostasis. Here, we review and expand upon an integrative model wherein the CNS, together with the islet, establishes and maintains the defended level of glycemia. We discuss the implications of this model for understanding both normal glucose homeostasis and T2D pathogenesis and highlight centrally targeted therapeutic approaches with the potential to restore normoglycemia to patients with T2D.

Fructose consumption induces molecular adaptations involving thyroid function and thyroid-related genes in brown adipose tissue in rats.

The increasing incidence of metabolic diseases is in part due to the high fructose consumption, a carbohydrate vastly used in industry, with a potent lipogenic capacity. Thyroid hormones (TH) are essential for metabolism regulation and are associated with changes in body weight, energy expenditure, insulin sensitivity, and dyslipidemia. This study aimed to investigate the influence of fructose intake on thyroid function and thyroid-related genes. Male Wistar rats were divided into Control (CT, n=8) and Fructose (FT - 10% in drinking water, n=8) groups for three weeks. The FT group showed higher glycemia and serum triacylglycerol, indicating metabolic disturbances, and increased thyroid mass, accompanied by higher expression of Srebf1c and Lpl, suggesting increased lipid synthesis. The FT group also presented higher expression of Tpo and Dio1 in the thyroid, suggesting activation of the thyroid gland, but with no alterations in serum TH concentrations. Brown adipose tissue (BAT) of the FT group exhibited higher expression of Dio2, Thra, and Thrb, indicating increased T3 intra-tissue bioavailability and signaling. These responses were accompanied by increased BAT mass and higher expression of Adrb3, Pparg, Srebf1c, Fasn, Ppara, and Ucp1, suggesting increased BAT adrenergic sensitivity, lipid synthesis, oxidation, and thermogenesis. Therefore, short-term fructose consumption induced thyroid molecular alterations and increased BAT expression of thyroid hormone-related signaling genes that potentially contributed to higher BAT activity.