Aim: To examine the mechanisms responsible for the increase in glucose and ketone production caused by SGLT2 inhibition with empagliflozin in T2DM patients. Research Design and Methods: 12 T2DM subjects (Age = 53; BMI = 31.7; HbA1c = 7.4%) participated in two studies performed in random order. At 0700h following an overnight fast subjects received an 8-hour infusion of 6,6D2-glucose to measure endogenous (hepatic) glucose production. At 0900 h an infusion of 3H-norepinephrine was started. At 1000h subjects ingested 25 mg of empagliflozin (n=8) or matching placebo (n=4) and were followed for 5 hours (1500 h) . Within 1 week subjects returned for a repeat study with pancreatic clamp to maintain plasma insulin and glucagon concentrations constant at the basal level. As per study one, subjects ingested empagliflozin 25 mg or placebo prior to the pancreatic clamp. Results: When empagliflozin was ingested under fasting conditions, EGP increased by 31% in association with a decrease in plasma glucose (-34 mg/dl) and insulin (-52%) concentrations and increases in plasma glucagon (+19%) , FFA (+29%) and β-hydroxybutyrate (β-HB) (+48%) concentrations. When empagliflozin was ingested under pancreatic clamp conditions, plasma insulin and glucagon concentrations remained unchanged, and the increase in plasma FFA and ketone concentrations was completely blocked, while the increase in EGP persisted. Total-body NE turnover rate increased significantly in subjects receiving empagliflozin (+67%) compared to placebo under both fasting and pancreatic clamp conditions. No difference in plasma norepinephrine concentration was observed in either study. Conclusion: The decrease in plasma insulin and increase in plasma glucagon concentration caused by empagliflozin is responsible for the increase in plasma FFA concentration and ketone production. The increase in EGP caused by empagliflozin is independent of the change in plasma insulin or glucagon concentrations and is explained by the increase in total-body NE turnover. Disclosure S. Abdelgani: None. J. M. Adams: None. G. Daniele: n/a. F. Almulla: None. R. A. Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker’s Bureau; AstraZeneca. M. Abdul-ghani: None. M. Abu-farha: None. S. Del prato: Advisory Panel; Applied Therapeutics, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Consultant; Menarini Group, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker’s Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Sanofi, Stock/Shareholder; Novo Nordisk A/S. Funding National Institute of Health, Boehringer Ingelheim provided empagliflozin and placebo
ANGPTL8 (A8), expressed mainly in the liver and adipocytes, regulates lipoprotein lipase (LPL) and lipid metabolism. Hepatic A8 and ANGPTL3 form a complex that inhibits LPL. However, the precise intracellular role of A8 in adipocytes is yet to be explored. We observed that RNAi-knockdown of A8 in mouse primary subcutaneous (SC) pre-adipocytes reduces adipocyte differentiation, glycerol, and fatty acid release at day 7 post-differentiation. RNAseq analysis of A8 siRNA or control siRNA transfected SC pre-adipocytes on days 0, 2, 4 and 7 of differentiation showed that A8 silencing impeded adipogenic and oxidative phosphorylation pathways and reduced expression of insulin signaling pathway genes IRS1, IRS2, PPARG, mTOR, early during differentiation, suggesting a role for A8 in the regulation of insulin sensitivity. Next, we investigated the functional role of adipose A8 by generating conditional adipocyte-specific A8 Knockout (AT-A8-KO) mice. AT-A8-KO mice on 45% high fat diet (HFD) with 30% fructose for 20 weeks showed a decrease in body weight gain, glycemia, brown fat mass, plasma TG and smaller cell size of SC adipocytes, while increased rectal temperature compared to controls. Interestingly, OGTT revealed AT-A8-KO mice in control diet or in HFD have significantly lower insulinemia. ITT results confirmed significant improvement of insulin sensitivity of AT-A8-KO mice on HFD. In addition, upon exposure to 6°C for 24h, AT-A8-KO mice exhibited elevated body temperature and energy expenditure compared to control mice, indicating that adipose tissue A8 negatively modulates cold-induced thermogenesis. Our results reveal that A8 regulates in vitro adipocyte differentiation, probably by modulating insulin signaling and mitochondrial respiration, and that deletion of adipocyte A8 in mice enhances insulin sensitivity, cold induced body temperature and energy expenditure. Therefore, targeting adipose specific A8 may be beneficial in promoting insulin sensitivity and preventing obesity. Disclosure A.Ghosh: None. I.Al-khairi: None. J.Abubaker: None. F.Al-mulla: None. M.Abu-farha: None. M.Prentki: None. Y.H.Leung: None. J.C.Y.Yu: None. R.M.Sladek: None. I.Chenier: None. A.Oppong: None. M.Peyot: None. M.Madiraju: None. Funding Dasman Diabetes Institute (731)
Background: ANGPTL8 has been recently identified as lipid metabolism and inflammation regulator. It interacts with ANGPTL3 and, more recently, ANGPTL4 to regulate LPL activity. It was also shown to modulate NF-κB activity through its interaction with ikkα/β. A genetic variant rs2278426 (R59W) in ANGPTL8 has been associated with reduced LDL and HDL in Hispanics and increased FBG in Arabs. The objective of the study was to investigate the impact of the R59W variant on LPL and the inflammatory activity of ANGPTL8. Methods: ANGPTL8 was genotyped in a discovery cohort of 738 Kuwaiti individuals. ANGPTL8 level, as well as inflammatory markers and LPL, were measured in plasma. Additionally, metabolite analysis, overexpression, luciferase binding assay, confocal microscopy, and cellular fractionation analyses were conducted in the HepG2 cell line to assess differences between the ANGPTL8 and its variant. Results: The ANGPTL8 rs2278426 variant was associated with an increase in circulatory levels of TNF-α and IL7 in our cohort. Carrier versus reference genotype of the studied variant showed differences in the following metabolites: Acylcarnitines, Phosphatidylcholine, and Cholesteryl Ester. These metabolites are implicated in modulating NF-κB and TNF-α levels. Our in vitro analyses showed that the activity levels of NF-κB p65 was higher in the R59W than the wild type, and it was further elevated with TNFα stimulations. The data was validated by the luciferase activity, confocal microscopy, and cellular fractionation. Conclusion: This study showed that ANGPTL8 variant R59W is associated with increased circulatory TNF-α and IL7 levels but not the LPL plasma levels. We have also demonstrated the pro-inflammatory role of the R59W variant in regulating the NF-κB pathway as reflected by genotyping, in vitro, metabolomics, and structural analyses. Further studies are needed to expand our understanding of other signaling pathways and possible crosstalk in the context of inflammation. Disclosure A.Mohammad: None. A.T.Thangavel: None. F.Almulla: None. J.Abubaker: None. M.Abu-farha: None. D.Madhu: None. P.T.Cherian: None. I.Al khairi: None. P.Hebbar: None. S.A.Kavalakatt: None. H.Arefanian: None. N.Alam-eldin: None. Funding Kuwait Foundation for the Advancement of Sciences
Studies have implicated CAV1 in the pathophysiology of diabetes and obesity. Previously, we demonstrated a potential association between the CAV1 rs1997623 C/A variant and metabolic syndrome (MetS) in Kuwaiti children. In the present study, we substantiate the association of CAV1 with MetS in adult Arab individuals. Method: The CAV1 rs1997623 was genotyped in three cohorts of Arabs (n=479) , South Asians (n=660) and South East Asians (n=362) . MetS status of the individuals was diagnosed using the IDF criteria (i.e., presence of central obesity and of at least two abnormalities of high TG, low HDL, hypertension, or type 2 diabetes) . The quantitative measure of MetS was calculated as siMS=2*WC/Height + FBG/5.6 + TG/1.7 + SBP/130 - HDL/1.02 for males or HDL/1.28 for females. Allelic associations with quantitative and dichotomous traits were assessed using linear and logistic regression, respectively, with and adjustment for age and sex. CAV1 transcripts were quantified in adipose tissues from a cohort of 50 Arab individuals differing in siMS score. Results: The CAV1 variant was significantly associated with MetS status (OR=1.8[1.25-2.61]; P-value=0.0015; Pemp=0.0013) and with siMS (Effect size = 0.206; P-value=0.0035; Pemp=0.0028) in the cohort of Arab individuals. The variant was weakly and insignificantly associated in the cohorts of South Asian and South East Asian individuals (OR= 1.and 1.11; P-values= 0.25 and 0.67, respectively) . siMS scores correlated positively with mRNA levels of CAV1 in adipose tissue. Conclusion: The association of CAV1 rs1997623 C/A with MetS in Arab pediatric is now demonstrated in adults as well. Higher expression levels were seen in individuals poses increasing MetS rates further validates the implication of CAV1 rs1997623 C/A variant in MetS phenotype. Only a weak association signal was seen in the South Asian and South East Asian populations leading us to propose that the CAV1 rs1997623 association with MetS is probably specific to Arab ethnicity. Disclosure A.Al madhoun: None. P.Hebbar: None. R.Nizam: None. D.Haddad: None. M.H.Dashti: None. M.Abu-farha: None. R.Ahmad: None. A.T.Thangavel: None. F.Almulla: None. Funding Kuwait Foundation for the Advancement of Sciences (KFAS) and Dasman Diabetes Institute, Project RA CB-2021-007
Background: Polypeptide N-Acetylgalactosaminyltransferase 2 (GALNT2) gene has been associated with serum lipid levels, insulin resistance, and adipogenesis. One of its variants, rs4846914 has been shown to associate with Triglycerides and HDL levels in global genome-wide association studies. ANGPTL proteins have emerged as important regulators of lipid metabolism through its regulation of lipoprotein lipase activity. In this study we aimed to evaluate the association between GALNT2 variant with plasma level of ANGPTL3, 8 and apolipoproteins in individuals of Arab ethnicity. Methods: GALNT2 rs4846914 variant was genotyped in a cohort of 278 Arab individuals from Kuwait. Plasma levels of ANGPTL3 and 8 were measured by ELISA. Apolipoproteins were measured by Luminex multiplexing assay. Significance of association signals was assessed using Bonferroni-corrected P-values. Results: The GALNT2 rs4846914_G allele was associated with increased ANGPTL3 but not ANGPTL8 plasma levels. It was associated with obesity status with an odds ratio of 1.45 (CI:1.024-2.055) (P-value =0.036) . It also associated with increased levels of ApoC1 (P-values ≤0.006) and lower levels of HDL (P-values ≤0.05) . Levels of HDL were found to be mediated by interactions between genotypes (AG+GG) at rs4846914 and measures of percentage body fat (PBF) , apolipoproteins A1a, C1 and B48. Conclusions: Association between GALNT2 variant and lipid metabolism could be mediated through the increased ANGPTL3 protein level. Disclosure A.T.Thangavel: None. M.Abu-farha: None. P.Hebbar: None. M.G.Qaddoumi: None. F.Almulla: None. J.Abubaker: None.
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