Decreased Fasting Plasma Glucose Research Articles

MTNR1B Gene Polymorphisms Are Associated With the Therapeutic Responses to Repaglinide in Chinese Patients With Type 2 Diabetes Mellitus.

The objective of this study was to investigate whether MTNR1B gene variants influence repaglinide response in Chinese patients with newly diagnosed type 2 diabetes mellitus (T2DM). A total of 300 patients with T2DM and 200 control subjects were enrolled to identify MTNR1B rs10830963 and rs1387153 genotypes by real-time polymerase chain reaction (PCR), with subsequent high-resolution melting (HRM) analysis. Ninety-five patients with newly diagnosed T2DM were randomly selected to undergo 8 weeks of repaglinide treatment (3 mg/day). After 8-week repaglinide monotherapy, patients with at least one G allele of MTNR1B rs10830963 showed a smaller decrease in fasting plasma glucose (FPG) (P = 0.031) and a smaller increase in homeostasis model assessment for beta cell function (HOMA-B) (P = 0.002) levels than those with the CC genotype did. The T allele carriers at rs1387153 exhibited a smaller decrease in FPG (P = 0.007) and smaller increases in postprandial serum insulin (PINS) (P = 0.016) and HOMA-B (P < 0.001) levels compared to individuals with the CC genotype. These data suggest that the MTNR1B rs10830963 and rs1387153 polymorphisms are associated with repaglinide monotherapy efficacy in Chinese patients with T2DM.

Attenuation of diabetic cardiomyopathy by relying on kirenol to suppress inflammation in a diabetic rat model.

Diabetic cardiomyopathy is characterized by diabetes‐induced myocardial abnormalities, accompanied by inflammatory response and alterations in inflammation‐related signalling pathways. Kirenol, isolated from Herba Siegesbeckiae, has potent anti‐inflammatory properties. In this study, we aimed to investigate the cardioprotective effect of kirenol against DCM and underlying the potential mechanisms in a type 2 diabetes mellitus model. Kirenol treatment significantly decreased high glucose‐induced cardiofibroblasts proliferation and increased the cardiomyocytes viability, prevented the loss of mitochondrial membrane potential and further attenuated cardiomyocytes apoptosis, accompanied by a reduction in apoptosis‐related protein expression. Kirenol gavage could affect the expression of pro‐inflammatory cytokines in a dose‐dependent manner but not lower lipid profiles, and only decrease fasting plasma glucose, fasting plasma insulin and mean HbA1c levels in high‐dose kirenol‐treated group at some time‐points. Left ventricular dysfunction, hypertrophy, fibrosis and cell apoptosis, as structural and functional abnormalities, were ameliorated by kirenol administration. Moreover, in diabetic hearts, oral kirenol significantly attenuated activation of mitogen‐activated protein kinase subfamily and nuclear translocation of NF‐κB and Smad2/3 and decreased phosphorylation of IκBα and both fibrosis‐related and apoptosis‐related proteins. In an Electrophoretic mobility shift assay, the binding activities of NF‐κB, Smad3/4, SP1 and AP‐1 in the nucleus of diabetic myocardium were significantly down‐regulated by kirenol treatment. Additionally, high dose significantly enhanced myocardial Akt phosphorylation without intraperitoneal injection of insulin. Kirenol may have potent cardioprotective effects on treating for the established diabetic cardiomyopathy, which involves the inhibition of inflammation and fibrosis‐related signalling pathways and is independent of lowering hyperglycaemia, hyperinsulinemia and lipid profiles.

Triple therapy with low-dose dapagliflozin plus saxagliptin versus dual therapy with each monocomponent, all added to metformin, in uncontrolled type 2 diabetes.

AimTo evaluate the efficacy and safety of triple therapy with low‐dose dapagliflozin plus saxagliptin added to metformin in uncontrolled type 2 diabetes.Materials and methodsThis 24‐week, double‐blind trial (NCT02681094) randomized 883 patients (glycated haemoglobin [HbA1c] 7.5‐10.0%) on metformin ≥1500 mg/d to add‐on dapagliflozin 5 mg/d plus saxagliptin 5 mg/d or to add‐on of either monocomponent. The primary endpoint was change in HbA1c from baseline.ResultsBaseline mean ± SD patient characteristics were: age 56.7 ± 10.5 years; HbA1c 8.2 ± 0.9%; and diabetes duration 7.6 ± 6.1 years. Triple therapy significantly decreased HbA1c versus dual therapy (−1.03% vs. −0.63% [dapagliflozin] vs. −0.69% [saxagliptin]; P < .0001). More patients achieved HbA1c <7.0% with triple versus dual therapy (41.6% vs. 21.8% [dapagliflozin; P < .0001] vs. 29.8% [saxagliptin; P = .0018]). Triple therapy significantly decreased fasting plasma glucose (−1.5 mmol/L vs. −1.1 mmol/L [dapagliflozin; P = .0135] vs. −0.7 mmol/L [saxagliptin; P < .0001]) and body weight (−2.0 kg vs. −0.4 kg [saxagliptin; P < .0001]), and β‐hydroxybutyrate levels were lower than with dapagliflozin plus metformin (mean difference −0.51; P = .0009). Urinary tract/genital infections and hypoglycaemia occurred in <5.0% and 5.8% of patients, respectively, with triple therapy.ConclusionsTriple therapy with once‐daily dapagliflozin 5 mg, saxagliptin 5 mg and metformin significantly improved glycaemic control versus dual therapy with either agent added to metformin in uncontrolled type 2 diabetes, and was generally well tolerated.

1845-P: Divergent Effects on T2D of Alleles Associated with Increased Liver Fat Reflect Differential Impact on Hepatic Glucose and Lipid Output: An IMI DIRECT Study

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) often coincide but the physiological relationship is unclear. Important clues are provided by human genetics: variants associated with NAFLD-risk have divergent effects on T2D. At TM6SF2 the NAFLD-risk allele (rs58542926:T) predisposes to T2D whilst at GCKR (rs1260326:T), it protects. We hypothesize that these divergent effects result from the impact of NAFLD-raising alleles on hepatic lipid output (HLO) and hepatic glucose output (HGO) respectively. To test this hypothesis, we applied structural equation modeling (SEM) to data from the IMI-DIRECT study, including 1350 European participants, 923 nondiabetic (C1) and 427 with recently-diagnosed T2D (C2). Insulin sensitivity (IS) was modeled from frequently sampled OGTT (C1) and mixed-meal tolerance tests (C2), and liver fat (LF) measured by MRI. SEM fit was assessed by comparing model χ2s with comparable null models: variables randomized to nodes in identical SEM definition giving comparable degrees of freedom and structure, 10,000 iterations. The hypothesized model provided a better fit than null models (C1: χ2=242, P=0.005; C2: χ2=63, P=0.01). Decreasing HLO (via TM6SF2) was associated with an increase in LF (C1: ß=0.28 [SE 0.09], P=0.001; C2: ß=0.28 [0.12], P=0.02) and fasting plasma glucose (FG): these were mediated by LF and IS (C1: ß=0.09 [0.03], P=0.001; C2: ß=0.07 [0.03], P=0.027). Decreasing HGO (via GCKR) was not associated with LF in either cohort but was associated with a direct (non-mediated) decrease in FG (C1 only: ß=-0.08 [0.04], P=0.04). The results support a model whereby increased genetic risk of NAFLD, arising from defects in two processes (HLO and HGO) results in opposing glycemic effects. This has important consequences for therapeutic strategies for combatting NAFLD: approaches to reduce NAFLD through targeting of HLO (as opposed to HGO) may also reduce risk of hyperglycaemia and T2D. Disclosure R.W. Koivula: None. P.W. Franks: Board Member; Self; Zoe Ltd. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk A/S, Novo Nordisk Foundation, Sanofi, Servier. T.H. Hansen: None. M. Laakso: None. E. Pearson: None. F. Rutters: None. F. Karpe: None. J.W. Tomlinson: Advisory Panel; Self; Novo Nordisk Inc., Pfizer Inc., Poxel SA. A. Mahajan: None. M. McCarthy: Advisory Panel; Self; European Association for the Study of Diabetes, Pfizer Inc. Consultant; Self; Eli Lilly and Company, Merck &amp; Co., Inc. Consultant; Spouse/Partner; Merck &amp; Co., Inc. Research Support; Self; AbbVie Inc., Boehringer Ingelheim International GmbH. Research Support; Spouse/Partner; Diabetes UK. Research Support; Self; Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., National Institutes of Health. Research Support; Spouse/Partner; National Institutes of Health. Research Support; Self; Novo Nordisk A/S. Research Support; Spouse/Partner; Novo Nordisk A/S. Research Support; Self; Novo Nordisk Foundation, Roche Pharma, Sanofi-Aventis, Servier, Takeda Pharmaceutical Company Limited. Funding Novo Nordisk Foundation (NNF18OC0031650); Innovative Medicines Initiative Joint Undertaking (115317)

2011-P: Totum-63 Lowers Adipose Tissue Inflammation and Reverses Both Hepatic Steatosis and Insulin Resistance in High-Fat Diet-Induced Obese Mice

The worldwide prevalence of obesity, metabolic syndrome and type 2 diabetes (T2D) is reaching epidemic proportions that urge the development of new therapeutic strategies. Obesity-associated meta-inflammation contributes to nonalcoholic fatty liver disease (NAFLD) and plays a central role in the development of insulin resistance and T2D. Totum-63 has recently been developed for the management of prediabetes and shown to prevent high-fat diet (HFD)-induced metabolic disorders in mice. In the present study, we investigated whether Totum-63 could also improve metabolic homeostasis in insulin-resistant obese mice. For this purpose, C57Bl6/J male mice were fed a low- (LFD) or HFD for 12 weeks followed by supplementation with or without Totum-63 (2.7% w/w) for 4 additional weeks. Although no metabolic phenotype was observed in LFD-fed mice, Totum-63 decreased body weight in HFD-fed mice, an effect exclusively due to reduced fat mass and associated with a transient reduction in food intake confined to the first days of supplementation. The liver and brown adipose tissue weights were significantly reduced, whereas adipose tissue (AT) mass and adipocyte size distribution were not affected. Totum-63 markedly reduced hepatic macrovesicular steatosis and liver triglyceride content. Furthermore, potent decreases in fasting plasma glucose, insulin and leptin levels, and improvements in systemic insulin sensitivity and glucose tolerance were observed. Remarkably, a significant reduction in AT M1-like pro-inflammatory macrophages was found, indicating that Totum-63 can modulate macrophage recruitment/polarization and lower HFD-induced AT inflammation. Altogether, our results strongly suggest that Totum-63 reverses hepatic steatosis and insulin resistance in obese mice at least partly by dampening meta-inflammation, constituting a promising new approach for alleviating NAFLD and metabolic dysfunctions in established T2D. Disclosure H.J. van der Zande: None. A. Zawistowska-Deniziak: None. F. Otto: None. V. Chavanelle: Employee; Self; Valbiotis. S. Peltier: Board Member; Self; Valbiotis. P. Sirvent: Board Member; Self; Valbiotis. B. Guigas: Advisory Panel; Self; Valbiotis. Research Support; Self; Valbiotis.

Impact of exenatide on mitochondrial lipid metabolism in mice with nonalcoholic steatohepatitis.

Exenatide (Exe) is a glucagon-like peptide (GLP)-1 receptor agonist that enhances insulin secretion and is associated with induction of satiety with weight loss. As mitochondrial dysfunction and lipotoxicity are central features of nonalcoholic steatohepatitis (NASH), we tested whether Exe improved mitochondrial function in this setting. We studied C57BL/6J mice fed for 24 weeks either a control- or high-fructose, high-trans-fat (TFD)-diet (i.e., a NASH model previously validated by our laboratory). For the final 8 weeks, mice were treated with Exe (30 µg/kg/day) or vehicle. Mitochondrial metabolism was assessed by infusion of [13C3]propionate, [3,4-13C2]glucose and NMR-based 13C-isotopomer analysis. Exenatide significantly decreased fasting plasma glucose, free fatty acids and triglycerides, as well as adipose tissue insulin resistance. Moreover, Exe reduced 23% hepatic glucose production, 15% tri-carboxylic acid (TCA) cycle flux, 20% anaplerosis and 17% pyruvate cycling resulting in a significant 31% decrease in intrahepatic triglyceride content (P = 0.02). Exenatide improved the lipidomic profile and decreased hepatic lipid byproducts associated with insulin resistance and lipotoxicity, such as diacylglycerols (TFD: 111 ± 13 vs Exe: 64 ± 13 µmol/g protein, P = 0.03) and ceramides (TFD: 1.6 ± 0.1 vs Exe: 1.3 ± 0.1 µmol/g protein, P = 0.03). Exenatide lowered expression of hepatic lipogenic genes (Srebp1C, Cd36) and genes involved in inflammation and fibrosis (Tnfa, Timp1). In conclusion, in a diet-induced mouse model of NASH, Exe ameliorates mitochondrial TCA cycle flux and significantly decreases insulin resistance, steatosis and hepatocyte lipotoxicity. This may have significant clinical implications to the potential mechanism of action of GLP-1 receptor agonists in patients with NASH. Future studies should elucidate the relative contribution of direct vs indirect mechanisms at play.

East Asian Genome-wide association study derived loci in relation to type 2 diabetes in the Han Chinese population

Meta-analysis of GWAS in East Asian populations had established 10 loci that were associated withtype2diabetes. Eight of them were with genome-wide significance and two with a border line association. Since these data have not been studied in an independent Han Chinese population, we aimed to investigate the association of these susceptibility loci with type 2 diabetes in an independent Han Chinese population. We executed a case-control study in 2 000 Chinese by the SNPscan method. Firstly, the repetitive sequences of 10 loci were assessed. Next, we investigated the association of 8 SNPs out of 10 with type 2 diabetes and constructed the GRS of those 8 SNPs. Finally, the relationship of the 8 loci and diabetes-related traits was analyzed. Based on the fact, that highly repetitive sequences were detected in 2 SNPs, we investigated the remaining 8 SNPs. With the exception of four SNPs (CMIP rs16955379, PEPD rs3786897, PSMD6 rs831571, ZFAND3 rs9470794), the other SNPs had the same direction of effect (odds ratio [OR]>1.0) as in the original reports, especially GLIS3 rs7041847 and KCNK16 rs1535500 were significantly associated with type 2 diabetes (rs1535500: p=0.005, OR=1.224, 95% CI 1.062-1.409; rs7041847: p=0.035, OR=1.118, 95% CI 1.070-1.388). The GRS constructed from the 8 SNPs was significantly associated with type 2 diabetes in the Chinese population (p=0.004, OR=1.065, 95% CI: 1.021-1.111). Among the participants with 24≤BMI<28 kg/m2 the 8 SNPs were significantly associated with type 2 diabetes (p=0.040, OR=1.079, 95% CI: 1.003-1.160). In quantitative trait analyses, WWOX rs17797882 was associated with decreased HOMA-β and increased level of TG and HDL-Ch, while PEPD rs3786897 and MAEA rs6815464 were associated with decreased fasting plasma glucose, and KCNK16 rs1535500 has shown a significant association with increased T-Ch and PSMD6 rs831571 had a significant association with decreased HDL-Ch. In Conclusion, with high probability the 8 loci identified in the East Asian GWAS meta-analysis are associated with type 2 diabetes in the Han Chinese population.

Effects of sodium-glucose cotransporter (SGLT) inhibitors in addition to insulin therapy on glucose control and safety outcomes in adults with type 1 diabetes: A meta-analysis of randomized controlled trials.

Sodium-glucose cotransporter (SGLT) inhibitors added to insulin therapy have been proposed as treatment strategy for type 1 diabetes (T1D). We thus conducted a meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and adverse effects of this combination in T1D. We searched the PubMed, EMBASE, and Cochrane Library databases and ClinicalTrials.gov for RCTs. Statistical analyses were performed using STATA 15. Ten eligible placebo-controlled trials involving 5961 patients were included. Compared with placebo, SGLT inhibitors were associated with a reduction in HbA1c of -0.39% (95% CI, -0.43 to -0.36), an improved mean amplitude of glucose excursion (MAGE) of -14.81mg/dL (95% CI, -19.08 to -10.54), and a reduction in body weight of -3.47% (95% CI, -3.78 to -3.16), as well as no increased relative risk of hypoglycaemia (1.01; 95% CI, 0.99-1.02) or severe hypoglycaemia (0.91; 95% CI, 0.77-1.07). SGLT inhibitors decreased fasting plasma glucose and insulin requirement but increased the risk of genital infection (3.57; 95% CI, 2.97-4.29) and diabetic ketoacidosis (3.11; 95% CI, 2.11-4.58). However, the very low dose empagliflozin (2.5mg) did not increase the risk of diabetic ketoacidosis (risk ratio [RR] 0.67; 95% CI, 0.11-3.95). SGLT inhibitors had no effect on overall adverse events, urinary tract infection, or bone fracture but slightly increased the risk of serious adverse events (1.35; 95% CI, 1.16-1.58), severe adverse events (1.84; 95% CI, 1.20-2.84), adverse events leading to discontinuation (1.50; 95% CI, 1.22-1.84), drug-related adverse events (1.78; 95% CI, 1.44-2.19), and diarrhoea (1.54; 95% CI, 1.15-2.05). Although adverse events exist, the available data provide evidence that the combination of SGLT inhibitors with basal insulin treatment is beneficial in patients with T1D.

SAT-136 Investigation of Glycemic State among Responders to Hepatitis C Treatment

Recently, Human Immunodeficiency Virus (HIV)/Hepatitis C (HCV) co-infected persons were reported to have an increased incidence of insulin resistance and lipodystrophy when compared to mono-infected persons. There are multiple randomized multi centered clinical trials that have found that HIV/HCV co-infected persons had a higher risk for diabetes compared to HIV mono-infected subjects even when adjusted for BMI and family history of diabetes. Our aim was to do retrospective analysis to evaluate the changes in the glycemic state following HCV based treatment regimens in patients co-infected with HIV/HCV. Several well published studies show improvement in glycemic control after treatment of HCV. However, after a thorough review of the literature, we did not find any publication examining the effects on glycemic control after treating HCV in those co-infected with HCV/HIV. The purpose of this study is to see if treating HCV in co-infected patients will yield comparable results in improving glycemic control and decreased insulin resistance as other studies have in in treating HCV mono-infection. We observed and analyzed changes in fasting plasma glucose (FPG) and HbA1c levels in 57 patients co-infected with HIV/HCV after achievement of sustained viral response at 12 weeks (SVR 12) that met our inclusion and exclusion criteria. We used FPG and HbA1c levels as our primary end points. We considered improvement of the glycemic state as a decrease of FPG by at least 20 mg/dL (1.1mmol/L) and HbA1c 0.5% when compared to baseline values or reduction of hypoglycemic drugs dosing after HCV had been treated.We found there was no significant difference of FPG and HbA1c from baseline to follow up. There were significant improvements in AST and ALT levels. These findings were not dependent on BMI levels or baseline fibrosure scores. Our patients were all on protease inhibitors which are known to be associated with peripheral insulin resistance and impaired glucose tolerance which could have contributed to the fact that our patients did not have statistically significant improvement of glycemic control after achieving SVR 12. We plan to complete a prospective trial of those mono-infected with HCV in the future.

SAT-388 The Influence of Dietary Sodium Intake on Cortisol and Glucose Homeostasis

Background: Glucose homeostasis is regulated by a range of physiological processes, including cortisol. Hypercortisolism and dietary sodium intake can influence glycemia and cardiovascular risk. Herein, we investigated the influence of dietary sodium intake on cortisol and glucose homeostasis. Methods: 630 participants free of cardiovascular disease were evaluated following one week of liberal dietary sodium intake (200 mmol/day) and again after one week of restricted dietary sodium intake (10 mmol/day). Following each diet, laboratory investigations included 24-hour urinary free cortisol (24hUFC), fasting morning serum cortisol, plasma glucose and insulin concentration. The effects of sodium intake on cortisol and glucose parameters were evaluated using paired t-tests. The association between cortisol and fasting plasma glucose was evaluated using linear regression with adjustment for sex, race, body mass index, blood pressure, diabetes status, urinary sodium excretion, serum aldosterone and plasma renin activity. Results: Participants ranged from 18 to 66 years old (mean 46.1 ± 10.6 years). Mean 24h urinary sodium excretion was 243.9 ± 68.1 mmol/day on the liberal sodium diet and 13.9 ± 9.8 mmol/day on the restricted sodium diet. When compared to restricted sodium intake, the liberal sodium intake decreased fasting plasma glucose (91.3 ± 15.4 vs. 95.0 ± 17.8 mg/dl, p <0.001) and insulin (10.4 ± 8.4 vs. 11.8 ± 8.3 μU/ml, p<0.001), but increased 24hUFC (64.5 ± 32.5 vs. 44.0 ± 23.8 μg/day, p<0.001). When participants consumed a liberal sodium diet, 24hUFC was positively associated with fasting plasma glucose (adjusted β = 0.05852 mcg per mg/dL, 95% CI: 0.02472 - 0.09233, p<0.001). In contrast, when participants consumed a restricted sodium diet, there was no association between 24hUFC and fasting plasma glucose. There was no association between serum cortisol and fasting plasma glucose on either dietary condition. Conclusions: Liberal dietary sodium intake increased 24hUFC and decreased fasting plasma glucose, when compared to restricted dietary sodium intake. Further, higher 24hUFC levels were associated with higher fasting plasma glucose values when participants consumed a liberal sodium, but not restricted sodium diet. Dietary sodium intake appears to modulate levels of 24hUFC, fasting glucose, and the relationship between cortisol and glucose in a manner that may have clinical and prognostic implications for the evaluation of glycemia and cardiovascular risk in the general population.

Drowsiness associated with a generic fixed‐dose glibenclamide/metformin combination tablet

AbstractBackgroundCurrently, there is limited documentation on adverse reactions associated with generic fixed‐dose combination antidiabetic drugs.AimThe aim of this study was to report the incidental finding of drowsiness associated with brand substitution of a fixed‐dose glibenclamide/metformin combination tablet.MethodsA prospective cross‐over study was conducted among 84 patients previously treated with a stable dose of 320 mg gliclazide coadministered with 2000 mg metformin. Patients were switched to two tablets twice daily of originator or generic fixed‐dose glibenclamide 2.5 mg/metformin 500 mg for 12 weeks. After 12 weeks, patients who received originator fixed‐dose glibenclamide/metformin were switched to generic tablets, whereas patients who had received generic tablets were switched to originator tablets. Both groups were subsequently followed‐up for another 12 weeks.ResultsSix patients (7.14%) experienced drowsiness with generic fixed‐dose glibenclamide/metformin but not with the originator tablets. The patients complained of being unable to perform normal activities unless they had a nap. Blood glucose levels during these symptoms in four of the patients were between 8.3 and 9.4 mmol/L. There were no significant changes in fasting plasma glucose (FPG) or HbA1c levels in any of the affected patients. One patient had a 9.3‐mmol/L decrease in FPG, but the HbA1c was still within the normal range.ConclusionThe cases of drowsiness with generic fixed‐dose glibenclamide/metformin were unlikely to be associated with hypoglycaemia.

Effects of Flaxseed Oil Omega-3 Fatty Acids Supplementation on Regression and Metabolic Status in Endometrial Hyperplasia: A randomized, Double-Blind, Placebo-Controlled Trial.

Background:Data on the effects of omega-3 fatty acid supplementation on clinical symptoms and metabolic profiles in patients with endometrial hyperplasia (EH) are limited. This intervention was performed to assess the effects of omega-3 fatty acid supplementation on clinical symptoms and metabolic profiles in patients with endometrial hyperplasia (EH).Methods:This randomized, double-blind, placebo-controlled trial was conducted among 40 women diagnosed with simple endometrial hyperplasia (EH). EH diagnosis was performed based on specific diagnostic procedures of biopsy. Participants were randomised into two groups to intake 1,000 mg omega-3 fatty acid supplements from flaxseed oil (n = 20) or placebo (n = 20), twice a day for 12 weeks. Fasting blood samples were taken at baseline and after the 12-week intervention to determine related markers.Results:Compared with the placebo, omega-3 fatty acid supplementation significantly decreased fasting plasma glucose (FPG) (-7.1 ± 9.6 vs. +2.0 ± 4.9 mg/dL, P = 0.001), serum insulin levels (-1.5 ± 4.6 vs. +1.6 ± 3.9 μIU/mL, P = 0.02) and homeostasis model of assessment-insulin resistance (HOMA-IR) (-0.4 ± 1.1 vs. +0.4 ± 1.0, P = 0.02). In addition, a significant increase in plasma total antioxidant capacity (TAC) (+102.6 ± 69.6 vs. +5.0 ± 37.1 mmol/L, P < 0.001) and total glutathione (GSH) levels (+63.6 ± 84.9 vs. -3.0 ± 69.4 μmol/L, P = 0.01) were seen following the supplementation of omega-3 fatty acid compared with the placebo. Omega-3 fatty acid supplementation had no significant effect on regression, lipid profiles, and other biomarkers of inflammation and oxidative.Conclusions:In conclusion, we found that omega-3 fatty acid administration for 12 weeks to subjects with EH significantly improved FPG, insulin, HOMA-IR, TAC and GSH levels, but did not influence regression, lipid profiles, and other biomarkers of inflammatory and oxidative stress.

The Effects of Synbiotic Supplementation on Metabolic Status in Diabetic Patients Undergoing Hemodialysis: a Randomized, Double-Blinded, Placebo-Controlled Trial.

This study was conducted to evaluate the effects of synbiotic supplementation on metabolic profiles in diabetic patients undergoing hemodialysis (HD). This randomized, double-blinded, placebo-controlled clinical trial was performed in 60 diabetic HD patients. Participants were randomly assigned into two groups to receive either synbiotic capsule, containing Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum (2 × 109CFU/g each), plus 0.8g/day of inulin (n = 30) or placebo (n = 30) for 12weeks. Synbiotic supplementation significantly decreased fasting plasma glucose (β - 13.56mg/dL; 95% CI, - 23.82, - 3.30; P = 0.01), insulin levels (β - 5.49μIU/mL; 95% CI, - 6.92, - 4.05; P < 0.001), and insulin resistance (β - 2.25; 95% CI, - 3.02, - 1.48; P < 0.001), while increased the quantitative insulin sensitivity check index (β 0.02; 95% CI, 0.01, 0.02; P < 0.001) compared with the placebo. Additionally, synbiotic intake resulted in a significant reduction in high-sensitivity C-reactive protein (β - 2930.48ng/mL; 95% CI, - 3741.15, - 2119.80; P < 0.001) and malondialdehyde levels (β - 0.60μmol/L; 95% CI, - 0.99, - 0.20; P = 0.003). Moreover, we found a significant increase in total antioxidant capacity (β 142.99mmol/L; 95% CI, 61.72, 224.25; P = 0.001) and total glutathione levels (β 131.11μmol/L; 95% CI, 89.35, 172.87; P < 0.001) in the synbiotic group compared with the placebo group. Overall, synbiotic supplementation for 12weeks had beneficial effects on glycemic control, biomarkers of inflammation, and oxidative stress in diabetic patients under HD. This study was registered in the Iranian website (www.irct.ir) for registration of clinical trials (http://www.irct.ir: IRCT2017090133941N17). http://www.irct.ir: IRCT2017090133941N17.

The Effects of Probiotic Supplementation on Genetic and Metabolic Profiles in Patients with Gestational Diabetes Mellitus: a Randomized, Double-Blind, Placebo-Controlled Trial.

This study was carried out to evaluate the effects of probiotic supplementation on genetic and metabolic profiles in patients with gestational diabetes mellitus (GDM) who were not on oral hypoglycemic agents. This randomized, double-blind, placebo-controlled clinical trial was conducted in 48 patients with GDM. Participants were randomly divided into two groups to intake either probiotic capsule containing Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, Lactobacillus fermentum (2 × 109CFU/g each) (n = 24) or placebo (n = 24) for 6weeks. Probiotic intake upregulated peroxisome proliferator-activated receptor gamma (P = 0.01), transforming growth factor beta (P = 0.002) and vascular endothelial growth factor (P = 0.006), and downregulated gene expression of tumor necrosis factor alpha (P = 0.03) in peripheral blood mononuclear cells of subjects with GDM. In addition, probiotic supplementation significantly decreased fasting plasma glucose (β, - 3.43mg/dL; 95% CI, - 6.48, - 0.38; P = 0.02), serum insulin levels (β, - 2.29μIU/mL; 95% CI, - 3.60, - 0.99; P = 0.001), and insulin resistance (β, - 0.67; 95% CI, - 1.05, - 0.29; P = 0.001) and significantly increased insulin sensitivity (β, 0.009; 95% CI, 0.004, 0.01; P = 0.001) compared with the placebo. Additionally, consuming probiotic significantly decreased triglycerides (P = 0.02), VLDL-cholesterol (P = 0.02), and total-/HDL-cholesterol ratio (P = 0.006) and significantly increased HDL-cholesterol levels (P = 0.03) compared with the placebo. Finally, probiotic administration led to a significant reduction in plasma malondialdehyde (P < 0.001), and a significant elevation in plasma nitric oxide (P = 0.01) and total antioxidant capacity (P = 0.01) was observed compared with the placebo. Overall, probiotic supplementation for 6weeks to patients with GDM had beneficial effects on gene expression related to insulin and inflammation, glycemic control, few lipid profiles, inflammatory markers, and oxidative stress.

Changes in metabolic parameters and cardiovascular risk factors after therapeutic control of acromegaly vary with the treatment modality. Data from the Bicêtre cohort, and review of the literature.

Untreated acromegaly is associated with increased morbidity and mortality due to malignant, cardiovascular, and cerebrovascular disorders. Effective treatment of acromegaly reduces excess mortality, but its impact on cardiovascular risk factors and metabolic parameters are poorly documented. We analyzed changes in cardiovascular risk factors and metabolic parameters in patients receiving various treatment modalities. We retrospectively studied 96 patients with acromegaly, both at diagnosis and after IGF-I normalization following surgery alone (n = 51) or medical therapy with first generation somatostatin analogues (SSA, n = 23), or pegvisomant (n = 22). Duration of follow-up was 77 (42-161) months, 75 (42-112) months, and 62 (31-93) months, in patients treated with surgery alone, SSA, and pegvisomant, respectively. In all the cases except four, patients treated medically had underwent previous unsuccessful surgery. IGF-I normalization was associated with increased body weight, decreased systolic blood pressure (SBP) in hypertensive patients, decreased fasting plasma glucose (FPG) and HOMA-IR and HOMA-B levels, increased HDL cholesterol (HDLc); whereas, LDL cholesterol (LDLc) was not significantly different. Plasma PCSK9 levels were unchanged in patients with available values. Cardiovascular and metabolic changes varied with the treatment modality: surgery, but not pegvisomant, had a beneficial effect on SBP; FPG decreased after surgery but increased after SSA; the decline in HOMA-IR was only significant after surgery; pegvisomant significantly increased LDLc and total cholesterol; whereas SA increased HDLc and had no effect on LDLc levels. Treatments used to normalize IGF-I levels in patients with acromegaly could have differential effects on cardiovascular risk factors and metabolic parameters.

Effect of imatinib on plasma glucose concentration in subjects with chronic myeloid leukemia and gastrointestinal stromal tumor

BackgroundType 2 diabetes mellitus has become one of the most important public health concerns worldwide. Due to its high prevalence and morbidity, there is an avid necessity to find new therapies that slow the progression and promote the regression of the disease. Imatinib mesylate is a tyrosine kinase inhibitor that binds to the Abelson tyrosine kinase and related proteins. It enhances β-cell survival in response to toxins and pro-inflammatory cytokine. The aim of this study is to evaluate the effect of imatinib on fasting plasma glucose in subjects with normal fasting glucose, subjects with impaired fasting glucose and in subjects with type 2 diabetes mellitus.MethodsWe identified 284 subjects diagnosed with chronic myeloid leukemia or gastrointestinal stromal tumors from the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran database. 106/284 subjects were treated with imatinib. We compared the effect of imatinib on fasting plasma glucose after 1 and 6 months of treatment. We used ANOVA test of repeated samples to determine statistical significance in fasting plasma glucose before imatinib treatment and the follow-up. Statistical analysis was performed with Statistical Package for the Social Sciences v22.ResultsWe included a total of 106 subjects: 76 with fasting plasma glucose concentrations < 100 mg/dL (normal FG), 19 subjects with fasting plasma glucose concentrations ≥100 mg/dL (impaired fasting glucose), and 11 subjects with ≥126 mg/dL (type 2 diabetes mellitus). We found a significant increase in fasting plasma glucose concentration in the normal fasting glucose group (p = 0.048), and a significant decrease in fasting plasma glucose concentration in the type 2 diabetes mellitus group (p = 0.042). In the impaired fasting glucose group, we also found a tendency towards a decrease in fasting plasma glucose (p = 0.076). We identified 11 subjects with type 2 diabetes mellitus, of whom, 7 (64%) had a reduction in their fasting plasma glucose concentrations after 6 months. A significant glycosylated hemoglobin reduction (p = 0.04) was observed.ConclusionSubjects with chronic myeloid leukemia or gastrointestinal stromal tumor with type 2 diabetes mellitus had a significant reduction in fasting plasma glucose and glycosylated hemoglobin at 1 and 6 months while using imatinib.

A randomized, double-blind clinical trial of canrenone vs hydrochlorothiazide in addition to angiotensin II receptor blockers in hypertensive type 2 diabetic patients.

AimThe aim of this study was to evaluate the effects of canrenone compared to hydrochlorothiazide (HCTZ) added to angiotensin II receptor blockers (ARBs) on glycemia, lipid profile, potassium, aldosterone and renal function in patients with hypertension and type 2 diabetes mellitus.Patients and methodsThe study enrolled 182 Caucasian patients with hypertension and type 2 diabetes mellitus. Patients were already taking ARBs and were randomized to canrenone, 50 mg once a day, or HCTZ, 12.5 mg once a day for 1 month. After the first month, patients not reaching an adequate blood pressure (BP) were up-titrated to canrenone 100 mg or HCTZ 25 mg once a day for 12 months. The following parameters were considered at 6 and 12 months: BP, body weight, body mass index (BMI), fasting plasma glucose (FPG), post-prandial glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin (HOMA-IR), lipid profile, potassium, plasma aldosterone, urine albumin excretion rate and estimated glomerular filtration rate (eGFR).ResultsWe observed a similar decrease in BP with both treatments. Canrenone led to a significant decrease in FPG, PPG and HOMA index compared to baseline, while there was a significant increase in the same parameters with HCTZ. HCTZ also worsened glycated hemoglobin (HbA1c), while canrenone did not change it. No variations in lipid profile were recorded with canrenone, while there was a worsening of total cholesterol (TC) and triglycerides (Tg) with HCTZ. Potassium levels were decreased and uric acid levels were increased by HCTZ, but not by canrenone that had a neutral effect on these parameters. We recorded a slight decrease in eGFR with HCTZ and an improvement with canrenone; creatinine and eGFR were improved by canrenone compared to HCTZ. Plasma aldosterone levels were decreased by canrenone and increased by HCTZ.ConclusionCanrenone and HCTZ have a similar effect on BP; however, canrenone seems to improve metabolic parameters, while HCTZ worsens them.

Treatment Effects of Once-Weekly Dulaglutide vs. Insulin Glargine in Patients with Different Baseline Glycemic Patterns (Based on High/Low Fasting or High/Low Postprandial Glucose)—A Post-Hoc Analysis of the AWARD-2 Clinical Trial

Insulin glargine (Glar) exerts its action primarily through a decrease in fasting plasma glucose (FPG), whereas dulaglutide (DU), a once-weekly GLP-1RA, targets both fasting and postprandial glucose (PPG). This post-hoc analysis of the AWARD-2 study assessed the efficacy of DU vs. Glar in patients with type 2 diabetes with different glycemic patterns at baseline determined by self-monitoring of blood glucose (fasting glucose [FG] vs. PPG). Patients were categorized into 4 groups based on combinations of low and high FG and PPG, with median baseline values of FG (151 mg/dL) and PPG (182 mg/dL) being used as threshold for low and high, respectively. Analyses were conducted using analysis of covariance. DU showed a statistically significantly greater reduction in A1c compared with Glar for all of the subgroups, except for low FG/high PPG, where the numerical difference was in favor of DU but did not reach statistical significance (Table). Total hypoglycemia was numerically lower for DU vs. Glar in all subgroups. DU showed efficacy on A1c reductions across different baseline glycemic patterns vs. Glar (with the exception of low FG/high PPG), indicating a clinical benefit of targeting both FG and PPG, irrespective of the baseline glycemic phenotype. Disclosure F. Giorgino: Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim GmbH. Research Support; Self; Eli Lilly and Company, Johnson &amp; Johnson Services, Inc.. Consultant; Self; MedImmune, Merck Sharp &amp; Dohme Corp., Roche Diabetes Care Health and Digital Solutions, Sanofi. Research Support; Self; Takeda Development Centre Europe Ltd. M. Yu: Employee; Self; Eli Lilly and Company. A. Haupt: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Z. Milicevic: Employee; Self; Eli Lilly and Company. L. Garcia-Perez: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.

Regulation of Systemic Energy Metabolism by a Human-Specific Long Noncoding RNA In Vivo

Long non-coding RNAs (lncRNAs) are widely expressed in mammals and play critical roles in a broad array of physiological processes. We have recently demonstrated that lncRNAs sense and regulate lipid and glucose metabolism in mice. However, it remains to be determined whether human lncRNAs regulate metabolism in vivo and whether they play a role in the pathogenesis of human metabolic disorders. The lack of knowledge of lncRNA’s functions in human metabolism is partly caused by the extremely low sequence conservation between human and mouse lncRNAs, which makes it difficult to apply the functional information of mouse lncRNAs to human physiology. To overcome this limitation, we have produced liver-specific humanized mice in which over 80% of mouse hepatocytes in the liver can be replaced by human ones and have confirmed that human metabolic genes in these mice maintain proper responses to metabolic cues. Using the liver-specific humanized mice, we identify a Fasting induced, Human-specific, and Liver-enriched lncRNA (lncFHL). Knocking down of lncFHL in humanized mice results in decreased expression of genes in Peroxisome Proliferator Activated Receptor Alpha (PPARalpha) pathway, which leads to decreased fasting plasma glucose and ketone levels. We further find that lncFHL interacts with and affects the mRNA interactions of HuR, a RNA binding protein that suppresses hepatic PPARalpha pathway in human. Finally, by analyzing published genome-wide association studies (GWAS) and expression quantitative trait loci (eQTLs) data, we find the hepatic expressions of lncFHL are associated with human metabolic diseases including diabetes and coronary artery disease. These studies not only provide a proof of principle that the humanized mice could sever as a suitable model to study the metabolic function of human lncRNAs but also demonstrate that regulatory mechanism mediated by human-specific lncRNAs contributes significantly to physiological and pathophysiological metabolic homeostasis. Disclosure X. Ruan: None. P. Li: None. H. Cao: None.

Targeting Ketohexokinase (KHK) with a Novel Antisense Oligonucleotide (ASO) Decreases De Novo Lipogenesis and Improves Insulin-Mediated Whole Body Glucose Metabolism

Increased sucrose consumption is associated with rising rates of obesity and related conditions [e.g., insulin resistance, type 2 diabetes and nonalcoholic fatty liver disease (NAFLD)]. Ketohexokinase (KHK) catalyzes the first step of fructose metabolism and is highly expressed in liver, kidney and brain, though found in many tissues. Essential fructosuria (hepatic KHK deficiency) is a benign condition, suggesting that KHK is a viable drug target. Inhibition of hepatic KHK would block metabolism of fructose (50% of dietary sucrose) and improve numerous facets of metabolism. ASO’s potently decrease target expression in liver and WAT and we hypothesized that a novel KHK ASO would prevent NAFLD and insulin resistance in normal rats fed a low fat (12% calories from fat), sucrose containing diet (17% calories from fructose). KHK ASO decreased hepatic KHK mRNA and protein expression by 96 and 90%, respectively. KHK ASO decreased WAT mRNA expression by 65%. KHK ASO did not alter body mass. KHK ASO decreased fasting plasma glucose (102±2 vs. 94±2 mg/dL, P=0.01), fasting plasma triglyceride 60% (52±7 vs. 21±2 mg/dL P&amp;lt;0.01) and liver triglyceride by 30% (8.2±0.4 vs. 5.6±0.3 mg TG/g liver, P&amp;lt;0.001) but not plasma insulin or non-esterified fatty acids. Insulin sensitivity was assessed by a 4 mU kg-1 min-1 hyperinsulinemic-euglycemic clamp. Surprisingly, there were no differences in rates of EGP or suppression of EGP. Instead there was a 25% improvement in insulin stimulated whole body glucose metabolism (36.6±0.8 vs. 45.6±2.2, P&amp;lt;0.01). We attribute this to a 40% decrease in hepatic DNL (53±4 vs. 32±4%, P&amp;lt;0.01) and VLDL secretion rate (11.0± 0.8 vs. 5.5± 0.5 mg/dL-min P&amp;lt;0.01) independent of changes in SREBP1 or ChREBP mRNA expression. Thus, decreased DNL and VLDL export prevents fructose induced peripheral insulin resistance. Conclusion: KHK ASO prevents NAFLD, decreases plasma triglyceride and improves insulin sensitivity. Disclosure D. Liu: None. J.A. Sterpka: None. D.F. Vatner: None. M. Bell: Employee; Self; Ionis Pharmaceuticals, Inc.. Employee; Spouse/Partner; Ionis Pharmaceuticals, Inc. S. Murray: Employee; Self; Ionis Pharmaceuticals, Inc. S. Bhanot: Employee; Self; Ionis Pharmaceuticals, Inc.. G. Cline: None. V. Samuel: None.