Insulin Sensitivity In Type Research Articles

Down-regulation of betatrophin enhances insulin sensitivity in type 2 diabetes mellitus through activation of the GSK-3β/PGC-1α signaling pathway.

The incidence of type 2 diabetes mellitus (T2DM) among children and adolescents has been rising. Accumulating evidences have noted the significant role of betatrophin in the regulation of lipid metabolism and glucose homeostasis. In our study, we tried to figure out the underlying mechanism of betatrophin in insulin resistance (IR) in type 2 diabetes mellitus (T2DM). First, fasting serum betatrophin, fasting blood glucose (FBG), insulin, total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) were detected in T2DM children. The homeostasis model assessment of insulin resistance (HOMA-IR), Gutt insulin sensitivity index (ISIG) and Matsuda insulin sensitivity index (ISIM) were calculated. A T2DM-IR mouse model was induced by high-fat diet, with the expression of GSK-3β and PGC-1α detected. Besides, HepG2 cells were induced by a high concentration of insulin to establish an IR cell model (HepG2-IR). The cell viability, glucose consumption, liver glycogen content, inflammation, and fluorescence level of GSK-3β and PGC-1α were analyzed. Betatrophin was highly expressed in serum of T2DM children and was positively correlated with FBG, insulin, TC, TG, LDL-C and HOMA-IR, while negatively correlated with ISIG and ISIM. Betatrophin and GSK-3β in the liver tissues of T2DM-IR mice were increased, while the PGC-1α expression was decreased. Betatrophin expression was negatively correlated with PGC-1α and positively correlated with GSK-3β. Silencing of betatrophin enhanced insulin sensitivity through the activation of GSK-3β/PGC-1α signaling pathway. In vitro experiments also found that silencing of betatrophin promoted glucose consumption and glycogen synthesis while inhibited inflammation. Our findings concluded that silencing of betatrophin could enhance insulin sensitivity and improve histopathological morphology through the activation of GSK-3β/PGC-1α signaling pathway.

Resveratrol attenuates dapagliflozin-induced renal gluconeogenesis via activating the PI3K/Akt pathway and suppressing the FoxO1 pathway in type 2 diabetes.

Dapagliflozin alleviates hyperglycemia by increasing glycosuria, but it induces renal gluconeogenesis, thus neutralizing its efficacy. Resveratrol (Rsv), a natural polyphenolic chemical, improves insulin sensitivity in type 2 diabetes (T2D). Here, we investigated the regulatory effects and underlying mechanisms of Rsv on dapagliflozin-induced renal gluconeogenesis. Male ob/ob mice were given the vehicle (HF), dapagliflozin (1 mg kg-1), Rsv (10 mg kg-1), or dapagliflozin and Rsv combination for 10 weeks. Glucose metabolism was evaluated by glucose and pyruvate tolerance tests. HK-2 cells (human renal proximal tubule cells) were treated with dapagliflozin (1 μmol L-1) for 2 h and further incubated with Rsv (10 μmol L-1) for 12 h. The effects of Rsv on gluconeogenesis and insulin signaling were assessed. Dapagliflozin treatment increased glucose production in HK-2 cells and lowered blood glucose and induced gluconeogenesis in ob/ob mice. After Rsv treatment, the enhanced glucose production and gluconeogenesis were alleviated. The upregulated mRNA and protein expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) and the activation of the forkhead transcription factor O1 (FoxO1) protein in the dapagliflozin group were attenuated by Rsv administration. Rsv also improved renal insulin signaling by increasing PI3K and Akt phosphorylation. The PI3K inhibitor LY294002 dramatically decreased the p-Akt expression and activated FoxO1 by dephosphorylation, thus diminishing the inhibitory effects of Rsv on dapagliflozin-induced PEPCK and G6Pase expression. The data showed the mechanisms of Rsv in attenuating dapagliflozin-induced renal gluconeogenesis via activating the PI3K/Akt pathway and further suppressing FoxO1 activation, suggesting a potential intervention to achieve better glucose-lowering effects for SGLT2 inhibitors in T2D therapy.

Correlation Between Adiponectin Receptor with Indices of Glucose Homeostasis and Mediators Of Insulin Sensitivity in Type 2 Diabetic Rats Treated With Puguntano (Curanga felterrae Lour.) Leaf Extract

ABSTRACT
 Objective: Adiponectin receptors (AdipoR) regulates metabolism and has anti-inflammatory and insulin-sensitizing effects. We aimed to determine the relationships between AdipoR with parameters of glucose homeostasis (FPG, insulin, and HOMA-IR), and insulin sensitivity (PPAR-γ and p38MAPK) in T2DM rats treated with puguntano (Curanga felterrae Lour.) leaf extract.
 Methods: T2DM was induced in Wistar rats aged 8–10 weeks and weighing 180–200 g by high-fat diet (HFD) feeding and low-dose streptozotocin (30mg/kg.bw) administration. The rats were then allocated randomly to a treatment group and a control group (n=24 each). The treatment group was orally administered puguntano leaf extract (200 mg/kg.bb) once daily for 10 days. Subsequently, FPG and plasma insulin were measured, and HOMA-IR was calculated.
 Results: There was significantly difference between treatment group and control group on AdipoR and parameter of glucose homeostasis (FPG, Insulin, HOMA-IR) and insulin sensitivity (PPAR-γ, p38MAPK (all, p<0.01). In both groups, there were no significantly correlations between of AdipoR with all parameter of glucose homeostasis and insulin sensitivity except PPAR-ϒ (p <0.003) across the entire cohort of rats.
 Conclusion: Our data suggest that puguntano could improve glucose homeostasis, insulin sensitivity and molecular mediators of insulin sensitivity. There were no significantly correlated between improvement of AdipoR with glucose homeostasis and molecular mediators of insulin sensitivity in T2DM.

Human clinical trial to assess the effect ofconsumption ofmultigrain Indian bread on glycemic regulation intype 2 diabetic participants.

The efficacy of multigrain flatbread in regulating the lipid profile and carbohydrate homeostasis among type 2 diabetic patients was studied in 100 type 2 diabetic participants. The results revealed that the anthropometric parameters remained unaltered in both test and control groups. The fasting blood glucose levels (140.70±8.43 versus 132.89±5.63mg/dl) did not significantly decrease. In contrast, the insulin levels (12.96±1.06 versus 10.83±1.03 μIU/ml) and HbA1c levels (8.01±0.27 versus 7.40±0.21%) in the test group decreased significantly, and it was associated with a decrease in insulin resistance. The LDL levels in the test group decreased after the intervention (116.0±5.67 versus 98.7±5.68mg/dl), while triglycerides and VLDL increased significantly and HDL levels remained unaltered. A significant decrease in average blood pressure (systolic/diastolic) was noticed among the test group participants. The human RBP4 and hs-CRP remained unaltered. PRACTICAL APPLICATIONS: Millets are rich in fibers, has complex carbohydrate, protein, and is lower in fat content. Millets provide a wide range of nutrients, phytochemicals, and are gluten-free with low glycemic nature. Their intake can reduce factors such as insulin resistance and oxidative stress responsible for the pathogenesis of type 2 diabetes and cardiovascular diseases. Our study indicated the use of multigrain flatbreads prepared from millets helped reduce serum insulin, LDL cholesterol, HbA1c levels, and incidentally blood pressure levels with a significant increase in insulin sensitivity in type 2 diabetes participants. The results suggest using the multigrain flatbread meal as a food supplement or meal replacer in diabetic participants in terms of glucose control and insulin sensitivity.

GLP-1 improves adipose tissue glyoxalase activity and capillarization improving insulin sensitivity in type 2 diabetes

Methylglyoxal was shown to impair adipose tissue capillarization and insulin sensitivity in obese models. We hypothesized that glyoxalase-1 (GLO-1) activity could be diminished in the adipose tissue of type 2 diabetic obese patients. Moreover, we assessed whether such activity could be increased by GLP-1-based therapies in order to improve adipose tissue capillarization and insulin sensitivity. GLO-1 activity was assessed in visceral adipose tissue of a cohort of obese patients. The role of GLP-1 in modulating GLO-1 was assessed in type 2 diabetic GK rats submitted to sleeve gastrectomy or Liraglutide treatment, in the adipose tissue angiogenesis assay and in the HUVEC cell line. Glyoxalase-1 activity was decreased in visceral adipose tissue of pre-diabetic and diabetic obese patients, together with other markers of adipose tissue dysfunction and correlated with increased HbA1c levels. Decreased adipose tissue GLO-1 levels in GK rats were increased by sleeve gastrectomy and Liraglutide, being associated with overexpression of angiogenic and vasoactive factors, as well as insulin receptor phosphorylation (Tyr1161). Moreover, GLP-1 increased adipose tissue capillarization and HUVEC proliferation in a glyoxalase-dependent manner. Lower adipose tissue GLO-1 activity was observed in dysmetabolic patients, being a target for GLP-1 in improving adipose tissue capillarization and insulin sensitivity.

Magnesium supplementation enhances insulin sensitivity and decreases insulin resistance in diabetic rats.

Objective(s):Diabetes mellitus has been suggested to be the most common metabolic disorder associated with magnesium deficiency. This study aimed to investigate the effects and mechanisms of magnesium supplementation on insulin receptor activity in elderly type 2 diabetes using a rat model and to provide experimental evidence for insulin resistance improvement by magnesium supplementation. Materials and Methods:Rat model of type 2 diabetes was developed using a high-fat diet along with low dose streptozotocin (STZ) treatment. Magnesium supplement was given orally by mixing with the high-fat diet. Serum insulin level, insulin sensitivity, and insulin receptor affinity were assessed using radioimmunoassay (RIA). Insulin receptor, insulin receptor substrate (IRS-2), and β-Arrestin-2 gene and protein expression levels were measured using immunohistochemistry and RT-PCR. Xanthine oxidase assay, thiobarbituric acid reactive substance assay (TCA method), colorimetric assay, and ELISA were used to determine the serum SOD, MDA, T-AOC, and ox-LDL levels, respectively. Results:Magnesium supplementation enhanced insulin sensitivity and decreased insulin resistance in diabetic rats mainly through increasing insulin receptor expression, affinity, and augmenting insulin receptor signaling. Magnesium supplementation also inhibited lipid peroxidation in diabetic rats and protected against pancreatic cell injury in diabetic rats. In addition, we found that β-arrestin-2 gene expression was suppressed in diabetes, which was possibly attributed to gene methylation modification, as β-arrestin 2 promotor was rich in methylation-regulating sites. Magnesium supplementation could affect β-arrestin-2 gene expression and methylation.Conclusion:Magnesium supplementation has a positive effect on insulin receptor activity and insulin sensitivity in type 2 diabetes.

Estimated insulin sensitivity in Type 1 diabetes adults using clinical and research biomarkers

AimsInsulin resistance in people with type 1 diabetes (T1D) is associated with increased risk of chronic complications and death. The gold standard to quantify insulin sensitivity, a euglycaemic hyperinsulinaemic clamp, is not applicable to clinical practice. We have employed clamp studies to develop a panel of formulae to estimate insulin sensitivity in adults with T1D for use in clinical practice and trials. MethodsClamps were conducted in 28 adults with T1D, who were also characterised with 38 clinical and research biomarkers. Exhaustive search analysis was used to derive equations correlating with clamp-quantified glucose disposal rate (GDR), GDR/plasma insulin (M/I) and log10M/I. ResultsMeasured insulin sensitivity correlated with BMI, WHR, HDL-C, adipokines and inflammation markers on univariate analysis. Exhaustive search analysis derived three formulae correlating with clamp-derived GDR and logM/I (p < 0.0001), accounting for ≈62% of their variability. A formula using gender, age, HDL-C, pulse pressure and WHR performed as well as those containing inflammation and adipokine measures. ConclusionsThe performance of formulae using routinely available parameters with/without research biomarkers in clinical studies and trials, particularly related to future complications, relevant lifestyle interventions, insulin delivery modes and insulin sensitisers is merited.

Skeletal muscle microvascular insulin resistance in type 2 diabetes is not improved by eight weeks of regular walking.

We aimed to examine whether individuals with type 2 diabetes (T2D) exhibit suppressed leg vascular conductance and skeletal muscle capillary perfusion in response to a hyperinsulinemic-euglycemic clamp and to test whether these two variables are positively correlated. Subsequently, we examined whether T2D-associated skeletal muscle microvascular insulin resistance, as well as overall vascular dysfunction, would be ameliorated by an 8-wk walking intervention (45 min at 60% of heart rate reserve, 5 sessions/week). We report that, relative to healthy subjects, overweight and obese individuals with T2D exhibit depressed insulin-stimulated increases in leg vascular conductance, skeletal muscle capillary perfusion, and Akt phosphorylation. Notably, we found that within individuals with T2D, those with lesser increases in leg vascular conductance in response to insulin exhibited the lowest increases in muscle capillary perfusion, suggesting that limited muscle capillary perfusion may be, in part, linked to the impaired ability of the upstream resistance vessels to dilate in response to insulin. Furthermore, we show that the 8-wk walking intervention, which did not evoke weight loss, was insufficient to ameliorate skeletal muscle microvascular insulin resistance in previously sedentary, overweight/obese subjects with T2D, despite high adherence and tolerance. However, the walking intervention did improve (P < 0.05) popliteal artery flow-mediated dilation (+4.52%) and reduced HbA1c (-0.75%). It is possible that physical activity interventions that are longer in duration, engage large muscle groups with recruitment of the maximum number of muscle fibers, and lead to a robust reduction in metabolic risk factors may be required to overhaul microvascular insulin resistance in T2D.NEW & NOTEWORTHY This report provides evidence that in sedentary subjects with type 2 diabetes diminished insulin-stimulated increases in leg vascular conductance and ensuing blunted capillary perfusion in skeletal muscle are not restorable by increased walking alone. More innovative physical activity interventions that ultimately result in a robust mitigation of metabolic risk factors may be vital for reestablishing skeletal muscle microvascular insulin sensitivity in type 2 diabetes.

Activation of central galanin receptor 2 mitigated insulin resistance in adipocytes of diabetic rats.

Our and other's studies showed that administration of neuropeptide galanin may mitigate insulin resistance via promoting glucose transporter 4 (GLUT4) expression and translocation in rats. The objective of this study is to investigate whether galanin receptor 2 (GAL2-R) in brain mediates the ameliorative effect of galanin on insulin resistance in adipose tissues of type 2 diabetic rats. In this study galanin, GAL2-R agonist M1145 and GAL2-R antagonist M871 were respectively or cooperatively injected into intracerebroventricles of type 2 diabetic rats once a day for successive fifteen days. Then the plasma and fat tissues of rats were used to estimate the alterations of insulin resistance indexes. The central administration of galanin enhanced 2-deoxy-[3H]-D-glucose, peroxisome proliferator-activated receptor γ and adiponectin levels, food intake and body weight, GLUT4 mRNA expression and GLUT4 concentration in plasma membranes, as well as homeostasis model assessment-insulin resistance index. Those effects of galanin may be blocked by M817, and imitated by M1145 except for food intake and body weight. Those results suggest that central GAL2-R mediates the beneficial effects of galanin on insulin sensitivity in type 2 diabetic rats. GAL2-R agonist may be taken as a potential antidiabetic agent to treat insulin resistance and type 2 diabetes.

Metformin, Microbiome and Protection Against Colorectal Cancer.

Metformin is widely used as a firstline therapy to improve insulin sensitivity in type 2 diabetes mellitus (T2DM) patients. This is achieved primarily through regulating AMP-activated protein kinase (AMPK)-dependent pathways leading to reduced hepatic gluconeogenesis and improved muscular uptake of glucose. Epidemiological studies first recognized a relationship with metformin use in T2DM patients and reduced colorectal cancer (CRC) risk. Thereafter, metformin has gained wide attention as a candidate CRC chemopreventative agent; however, the molecular mechanisms underlying its gastrointestinal anti-cancer properties appear multi-faceted and are not well understood. An intriguing area of research is the growing evidence of metformin's metabolic juncture with gut microbiota at the intestinal mucosal interface. This review examines the mechanistic evidence which may account for metformin's protection against CRC through interactions between the drug, gut microbiota and the colonic epithelial mucosa.

2267-PUB: 1,5-Anhydroglucitol X Glycated Hemoglobin A1c/100: A Potential Biomarker for Islet ß-Cell Function in Type 2 Diabetes Mellitus

Aims: The goals of the current study were to explore the level of and changes in the AH index (AHI, defined as 1,5-anhydroglucitol × glycated hemoglobin A1c/100) associated with different glucose metabolism statuses, and to evaluate the islet function and insulin sensitivity of type 2 diabetes mellitus (T2DM) patients with different AHI levels. Methods: A total of 3562 individuals were enrolled in the study. According to the 2010 American Diabetes Association (ADA) diagnostic criteria, 1697 subjects were diagnosed as T2DM. The disposition index (DI) was defined as the product of insulin sensitivity-related indexes and islet secretion function. Results: The overall AHI level was 1.0 (0.7-1.3), while the AHI level of the T2DM group was 0.8 (0.5-1.2), which was significantly lower than that of the normal glucose tolerance group and the impaired glucose regulation group [both AHI 1.2 (0.9-1.5), and P &amp;lt; 0.01]. The T2DM group was further divided into four subgroups according to the quartile of AHI level. The results demonstrated that the homeostasis model assessment of insulin resistance (HOMA-IR) decreased with the increase of AHI level (P for trend &amp;lt; 0.01). However, other parameters [i.e., HOMA of β-cell function (HOMA-β), insulin generation index, insulin sensitivity index, and DI] increased while AHI level increased (all P for trend &amp;lt; 0.01). Multivariate logistic regression illustrated that the odds ratios for a low DI for increasing levels of AHI were 1.00, 0.22 (0.16-0.29), 0.16 (0.11-0.22), and 0.09 (0.06-0.13), respectively, showing a decreasing trend (P for trend &amp;lt; 0.01). Conclusion: AHI could reflect the changes in the trend of glucose metabolism disorder and the function of islet β cells to some extent. The lower AHI was associated with worsening of the glucose metabolism disorder in recent years, and the islet β-cell function was correspondingly poor. Disclosure X. Ma: None. H. Su: None. Y. Shen: None. X. He: None. L. Ying: None. W. Zhu: None. Y. Wang: None. Y. Bao: None. J. Zhou: None.

Effect of Whey Protein on Insulin Sensitivity and Glucose Metabolism in Women with and Without Polycystic Ovary Syndrome (PCOS)

Abstract Objectives This study focuses on the metabolic effects of whey protein isolate (WPI) supplementation glucose and insulin metabolism in women with and without Polycystic Ovary Syndrome (PCOS). Affecting up to 20% of post-puberty aged females around the world, PCOS is identified by three main symptoms: increased levels of androgens, irregular cycles, and the presence of ovarian cysts. Women with PCOS tend to be insulin resistant and have faulty insulin signaling. We hypothesize that because WPI has been seen to increase insulin sensitivity in type 2 diabetic populations, it will attenuate blood glucose and insulin levels and in women with PCOS. Methods 15 women with PCOS and 14 women without PCOS (CON) underwent four 150-min oral glucose tolerance tests (OGTT): (i) baseline (no protein), (ii) Day 20 (iii) and Day 40 of WPI preload. Daily, participants consumed 35 g WPI 30 min before glucose load on test days. Plasma levels of glucose and insulin were assessed using a Biolis 24i chemistry analyzer. Additionally, variations in gene expression levels of glucose metabolism regulators, e.g., GLUT-4, were analyzed in 3T3-L1 cells under normal and PCOS-simulated conditions using qt-PCR before and after WPI supplementation. Results At baseline, both PCOS and CON women had similar fasting glucose levels (107.2 ± 19.54 and 101.14 ± 11.03 respectively). After 20 days of WPI supplementation, fasting glucose increased (103.75 ± 0.5 and 117.25 ± 9.60) but was attenuated by Day 40 (91.5 ± 0.71 and 94.5 ± 0.71). Furthermore, the baseline levels of GLUT-4 expression between women with PCOS (2.698 ± 0.145) and CON (2.188, ± 0.062) were not statistically different. Levels of gene expression post-supplementation with WPI are in the process of being measured. And lastly, plasma insulin levels are in the progress of being measured for both populations before and after supplementation. Conclusions Preliminary analysis indicates that upon WPI supplementation, both groups glucose levels increased after 20 days, but was then attenuated by Day 40, with a slightly greater effect in the PCOS group compared to CON. Overall, our data indicates that WPI may be a potential dietary approach to better managing the symptoms of PCOS. Funding Sources Glanbia Nutritionals, Human Nutrition Research Funds, and Texas Woman's University.

Relationship between sleep disturbances, lipid profile and insulin sensitivity in type 1 diabetic patients: a cross-sectional study.

Objective The consequences of sleep deprivation in type 1 diabetes (T1D) patients are poorly understood. Our aim was to determine how sleep disorders influence lipid profile and insulin sensitivity in T1D patients. Materials and methods This was a cross-sectional study at a public university hospital. Demographic information and medical histories were obtained during regular scheduled visit of T1D patients to the outpatient clinic. Insulin sensitivity was obtained using the estimated glucose disposal rate (eGDR) formula. Sleep quality was assessed using the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Berlin Questionnaire. Results The adult participants (n = 66, 62% women) had a median age of 28.0 years (interquartile range 21.8-33.0). Six patients (9%) had metabolic syndrome according to the International Diabetes Federation criteria. Thirty patients (46%) were considered poor sleepers according to the Pittsburgh Sleep Quality Index. The LDL-c and total cholesterol levels of poor sleepers were higher than those of good sleepers (103 v. 81; p = 0.003 and 178.0 v. 159.5 mg/dL; p = 0.009, respectively). Three patients (4%) were at high risk of obstructive sleep apnea syndrome (OSAS) according to the Berlin Questionnaire. The eGDR was lower in the group of patients with high probability of having OSAS (6.0 v. 9.1 mg.kg-1.min-1;p = .03). Conclusions Poor subjective quality of sleep and higher risk of OSAS were correlated with a worsened lipid profile and decreased insulin sensitivity, respectively. Therefore, T1D patients with sleep disturbances might have an increased cardiovascular risk in the future.

N1-Methylnicotinamide Improves Hepatic Insulin Sensitivity via Activation of SIRT1 and Inhibition of FOXO1 Acetylation.

Objective To explore the effects of N1-methylnicotinamide (MNAM) on insulin resistance and glucose metabolism in obese type 2 diabetes mellitus (T2DM) mice and regulatory mechanisms of the NAD-dependent deacetylase sirtuin-1 (SIRT1)/forkhead box protein O1 (FOXO1) pathway. Methods Blood glucose and insulin levels were examined in mice. HE and oil red O staining were used to observe the effects of MNAM on liver lipid deposition in ob/ob mice. Real-time PCR and Western blotting were used to detect expression of gluconeogenesis, insulin signaling-related proteins, and SIRT1/FOXO1 pathway-related proteins. L-O2 cells were cultured as a model of insulin resistance, and MNAM and SIRT1 inhibitors were administered in vivo. Residual glucose and insulin signaling-related proteins were detected and the mechanisms associated with the SIRT1/FOXO1 signaling pathway in insulin resistance explored. Results MNAM can effectively reduce levels of fasting blood glucose and insulin, improve liver morphology, and reduce lipid accumulation in obese type 2 diabetes mellitus mice. MNAM also downregulates the key proteins in the gluconeogenesis pathway in the liver, upregulates Sirt1 expression, and reduces acetylation of the FOXO1 protein. In vitro, MNAM could promote the glucose uptake capacity of L-O2 cells induced by palmitic acid (PA), a saturated fatty acid that induces IR in various scenarios, including hepatocytes, improving insulin resistance. As Sirt1 expression was inhibited, the reduction of hepatocyte gluconeogenesis and the regulation of the insulin signaling pathway by MNAM were reversed. Conclusion MNAM activates SIRT1 and inhibits acetylation of FOXO1, which in turn regulates insulin sensitivity in type 2 diabetic mice, leading to a reduction of hepatic glucose output and improvement of insulin resistance.

Anti-diabetic effects of Bifidobacterium animalis 01 through improving hepatic insulin sensitivity in type 2 diabetic rat model

Abstract The anti-diabetic effects of Bifidobacterium animalis 01 and its potential mechanisms were investigated. Male SD rats were given a high-fat chow diet with low-dose streptozotocin (30 mg/kg BW) to induce T2DM. The supplements with B. animalis 01 were given in a pre- and post-treatment method. Oral administration of B. animalis 01 decreased food and water intake, blood glucose concentration, and glycosylated hemoglobin level. Treatment with B. animalis 01 improved OGTT, HOMA-IR, lipid profiles, representative cytokines, and liver injury markers in the serum. B. animalis 01 also exhibited hepatoprotective effects by reducing hepatic tissues injuries, increasing the glycogen levels, and improving the antioxidant indexes. Furthermore, B. animalis 01 treatment showed beneficial influence on the gene expressions of hepatic glucose metabolism and IRS/PI3K/AKT pathway. Moreover, B. animalis 01 administration positively regulated hepatic Keap1/Nrf2 pathway. The results suggested that the hepatic protective effect of B. animalis 01 against diabetes attributed to IRS/PI3K/AKT and Keap1/Nrf2 signaling activation.

Indirubin promotes adipocyte differentiation and reduces lipid accumulation in 3T3‑L1 cells via peroxisome proliferator‑activated receptor γ activation.

The peroxisome proliferator-activated receptor γ (PPARγ) plays an important role in insulin sensitivity and adipocyte differentiation. It is known as ligand-receptor that improves insulin sensitivity in type 2 diabetes mellitus. Several kinds of indigo plant have been already used to treat diabetes in oriental traditional medicine, but its mechanism has not been clarified yet. To investigate the effect of indirubin, which is a component of Polygonum tinctorium on the cell differentiation and adipprocess in 3T3-L1 cells, 3T3-L1 cells were cultured to determine the effect of cell differentiation and glucose uptake with indirubin. As a result, Indirubin compound enhanced adipocyte differentiation in 3T3-L1 cells similar to rosiglitazone. This effect was terminated by cotreatment with GW9662, a PPARγ antagonist. In mature 3T3-L1 adipocytes, the lipid droplet size and accumulation were reduced by this compound. The basal and insulin-stimulated glucose uptakes were also significantly increased. In addition, indirubin treatment significantly enhanced estrogen level by 1.64-fold with mature adipocytes which can be attributed to its aromatase activity. Conclutionaly, this finding suggested that indirubin is a potential anti-diabetic compound for type 2 diabetes mellitus by promoting adipocyte differentiation and glucose uptake via PPARγ.

RESIST! Blood-flow Restriction Resistance Training for Improving Insulin Sensitivity in Type 2 Diabetes

RESIST! Blood-flow Restriction Resistance Training for Improving Insulin Sensitivity in Type 2 Diabetes

275-OR: Higher Liver Fat and Whole-Body Insulin Sensitivity in Newly Diagnosed Type 2 Diabetes Patients with a Variant in Transmembrane 6 Superfamily Member 2 Protein

Knockdown of the gene encoding transmembrane 6 superfamily member 2 protein (TM6SF2) in mice increases hepatocellular lipid content (HCL) and decreases very low-density lipoprotein secretion. Humans with TM6SF2 mutations are at higher risk of nonalcoholic fatty liver disease, but lower risk of cardiovascular disease. The relevance of TM6SF2 mutations for HCL and insulin sensitivity in type 2 diabetes is less clear. This study aimed at elucidating the relevance of the E167K (SNP rs58542926) mutation in the gene encoding TM6SF2 for HCL, hepatic insulin sensitivity and whole-body insulin sensitivity in type 2 diabetes. We compared male patients with recently diagnosed type 2 diabetes with (n=16) or without (n=16) E167K mutation, matched for age and BMI (50±1 vs. 48±3 years; 32±1 vs. 32±2 kg/m2) from the German Diabetes Study. Whole-body and hepatic insulin sensitivity were assessed by Botnia-clamp tests with [6,6-2H2]glucose, HCL by 1H magnetic resonance spectroscopy and hepatic fibrosis by the fibrosis-4 index (FIB4). Patients with and without TM6SF2 mutation had comparable levels of HbA1c (6.2±0.2 vs. 5.9±0.1%) and serum triglycerides (136±14 vs. 149±14 mg/dl). Carriers of TM6SF2 mutation had higher HCL (9.0±1.9 vs. 4.6±0.4%, p&amp;lt;0.05) and whole-body insulin sensitivity (7.1±0.6 vs. 5.4±0.2 mg/(kg*min), p&amp;lt;0.05), but similar hepatic insulin sensitivity (1.6±0.1 vs. 1.6±0.1 mg/(kg*min)) and fibrosis score (1.2±0.1 vs. 1.0±0.1). In conclusion, the E167K mutation of the TM6SF2 gene dissociates liver steatosis from whole-body insulin sensitivity. This may result from favored trapping of triglycerides within the liver, which would in turn protect peripheral tissues from insulin resistance induced by liver-derived lipids. Disclosure K. Bodis: None. J. Szendroedi: None. J.M. Ahlers: None. Y. Karusheva: None. O.P. Zaharia: None. S. Antoniou: None. B. Knebel: None. Y. Kupriyanova: None. J. Hwang: None. V. Burkart: None. K. Muessig: None. H. Al-Hasani: None. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. D.F. Markgraf: Research Support; Self; Sanofi.

1928-P: GDF15 Protects against Insulin Resistance in Individuals with Type 2 Diabetes

Reduced insulin sensitivity is the putative defect in the onset of type 2 diabetes (T2D). Roux-en-Y gastric bypass (RYGB) can restore euglycemia and improve insulin sensitivity in individuals with T2D. However, the mechanisms contributing to surgical remission of T2D are not fully understood. Growth Differentiating Factor 15 (GDF15) is a circulating stress-responsive cytokine with appetite suppressive properties and therapeutic potential for treating obesity and T2D. However, the effect of GDF15 on insulin sensitivity is not known. The purpose of this investigation was to assess the role of GDF15 in insulin sensitivity in type 2 diabetic populations and to evaluate the effect of exogenous GDF15 treatment in obese diabetic mice. Twelve human volunteers with T2D (age: 40±2, BMI: 46.2±1.7) underwent RYGB surgery. Glucose tolerance and fasting plasma GDF15 levels were assessed prior to and 3-month post-surgery. Additionally, 8-week-old db/db mice were injected every other day for 4 weeks with saline or rhGDF15. After 4 weeks of treatment, body composition, insulin tolerance, and blood metabolites were assessed. Plasma GDF15 significantly increased after RYGB (PRE: 581.6±93.0 POST: 910.1±137.4 pg/ml, P&amp;lt;0.001). Change in GDF15 in humans with T2D correlated with improvements in insulin sensitivity based on the Matsuda index (R=0.6, P=0.05). Supporting our human data, 4 weeks of GDF15 treatment in db/db mice increased insulin sensitivity (P&amp;lt;0.05) while body weight (P&amp;lt;0.01), fasting blood glucose (P&amp;lt;0.05) and plasma insulin (P&amp;lt;0.05) were reduced. In conclusion, GDF15 is associated with improved insulin sensitivity in humans with T2D, and increases insulin sensitivity in db/db mice. These data support a role for GDF15 as a therapeutic target for type 2 diabetes. Disclosure H. Zhang: None. W. Dantas: None. W.T. King: None. C.L. Axelrod: None. S. Gil: None. I. Murai: None. H. Roschel: None. B. Gualano: None. J.P. Kirwan: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; Louisiana Clinical &amp; Translational Science Center

Sleep quality and sleep duration, but not circadian parameters are associated with decreased insulin sensitivity in Type 1 diabetes

ABSTRACTThe objective of this cross-sectional analysis was to investigate in 109 adults with type 1 diabetes the relationship between sleep, circadian parameters and insulin sensitivity, as assessed by estimated glucose disposal rate (eGDR). In multiple regression analysis only poor sleep quality and sleep duration were negatively associated with eGDR (β = −0.219 [95%CI:-1.977; −0.445], p = .002 for poor sleep quality; β = −0.183 [95%CI: −0.645; −0.111], p = .006 for sleep duration) independent of age, gender, smoking status and body mass index. In conclusion, poor sleep quality and longer sleep duration were significant predictors of decreased insulin sensitivity. Social jetlag, chronotype, and sleep debt had no effect on insulin sensitivity.