bluuebunny/crossref_metadata_2025 huggingface dataset:
15-LB: Safety and Efficacy of Tetramethylpyrazine Nitrone in Treating Patients with Type 2 Diabetes and Microalbuminuria—A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase II Clinical Trial
Authors: YANG JINKUI
Published: May 2022

Background and purpose: Tetramethylpyrazine nitrone (TBN) is a multi-functional agent that has shown kidney protective effects in preclinical studies. TBN has a unique mechanism of action, i.e., scavenging free radicals and activating AMPK/PGC-1α/NRF2 pathway. This phase II clinical trial investigated the safety and efficacy of TBN in patients with early diabetic kidney disease (DKD) .

Methods: This multicenter, randomized, double-blind, placebo-controlled trial enrolled 143 Chinese type 2 diabetic patients (T2DM) with microalbuminuria (urinary albumin-to-creatinine ratio ≥ 30 to <300 mg/g creatinine) treated with or without renin-angiotensin system inhibitor who had eGFR ≥60 ml/min per 1.73 m2. Participants were randomized (1:1:1:1) to receive 300 mg, 600 mg or 1200 mg TBN bid or placebo for 180 days. The primary outcome was change in urinary albumin-to-creatinine ratio (UACR) from baseline to day 180. The safety outcome included any adverse events during 180 days.

Results: TBN was safe and well-tolerated. There were no statistical differences among the incidences of drug-related adverse event among the TBN and the placebo groups. TBN (600 mg, bid) decreased UACR by -46.56% [90% CI,-61.15, -1.74, p>0.99] from baseline to day 180 versus -14.33% [90% CI, -38.26, 19.39] in the placebo group. The proportion of patients with ≥ 30% reduction in UACR was 54.8% [95% CI, -9.10, 38.26, p=0.216] in the TBN (600 mg) group versus 39.4% in the placebo group. The change in eGFR from baseline to day 180 was 0 [95% CI, -6.66, 5.00, p>0.99] in the TBN (600 mg) group versus a decline of -2.12% [95% CI, -11.90, -0.63] in the placebo group.

Conclusions: TBN is a promising new treatment for early DKD and its safety and efficacy will be further investigated in clinical trials.

Disclosure

J. Yang: None.

Funding

Guangzhou Magpie Pharmaceutical Co. Ltd (CTR20220455)
181-LB: Fracture Risk of Antidiabetic Agents in Type 2 Diabetes—A Network Meta-analysis
Authors: HSUAN TSAI WEN , KE KONG SIANG , TSAI MING-CHIEH
Published: May 2022

Background: Diabetes is associated with greater risk of fracture. Our aim is to evaluate the correlation of different antidiabetic agents with the risk of fracture among subjects with type 2 diabetes.

Methods: The literature search was conducted in PubMed, Embase, and ClinicalTrials.gov on 22 October 2020. Keywords included “type 2 diabetes,” “fracture,” “randomized controlled trial,” “metformin,” “insulin,” “thiazolinedione,” “sodium-glucose co-transporter-2 inhibitor,” “glucagon-like peptide-1 receptor agonists,” “dipeptidyl peptidase 4 inhibitors” and “sulfonylurea.” Two authors (W-H. T and M-C.T) conducted study selection and data extraction independently. The primary main outcome was the fracture events during the followed-up period pooled by random-effected models.

Results: A total of 214686 patients with diabetes in 188 studies were included and 2850 patients had fracture events. Patients taking sodium-glucose co-transporter-2 inhibitor had higher risk of fracture when compared with glucagon-like peptide-1 receptor agonists (risk ratio [RR] 1.43 [95% confidence interval (CI) 1.08–1.91]) and sulfonylurea (RR 1.45 [95% CI 1.07–1.98]) . Patients taking dipeptidyl peptidase 4 inhibitors also had higher risk of fracture when compared with glucagon-like peptide-1 receptor agonists (risk ratio [RR] 1.4 [95% confidence interval (CI) 1.03–1.91]) and sulfonylurea (RR 1.42 [95% CI 1.03–1.95]) . Metformin, glucagon-like peptide-1 receptor agonists and sulfonylurea had protective effect on fracture when compared with thiazolinedione.

Conclusions: Patients with diabetes taking sodium-glucose co-transporter-2 inhibitor or dipeptidyl peptidase 4 inhibitors had higher risk of fracture when compared with glucagon-like peptide-1 receptor agonists and sulfonylurea. Metformin, glucagon-like peptide-1 receptor agonists and sulfonylurea had protective effect on fracture when compared with thiazolinedione.

Disclosure

W. Tsai: None. S. Kong: None. M. Tsai: None.
191-OR: Hepatic Expression of the Branched-Chain Keto Acid Dehydrogenase Kinase Is Sufficient to Cause Glucose Intolerance in Lean Mice
Authors: WALEJKO JACQUELYN , MCGARRAH, III ROBERT W. , WHITE PHILLIP J.
Published: May 2022

Perturbed branched-chain amino acid homeostasis is a feature of obesity, insulin-resistance and type 2 diabetes. Induction of the branched-chain keto acid dehydrogenase kinase (BDK) in liver is one mechanism that is thought to contribute to elevated BCAA levels in these conditions. Whether higher levels of BDK in liver are sufficient to disturb systemic BCAA homeostasis and promote glucose intolerance in the absence of obesity or insulin resistance has never been directly tested. We treated 12 week-old C57BL6/J mice with adeno-associated virus, serotype 8 (AAV8) -BDK or control AAV8-GFP to promote long term expression of BDK specifically in liver of lean mice. Mice were then maintained on a standard low-fat chow diet for 8 weeks (n= 9 AAV8-GFP and n=AAV8-BDK) . AAV8-BDK significantly raised BDK protein and mRNA expression in liver but not adipose, skeletal muscle, or cardiac tissue compared to AAV8-GFP control mice. The higher expression of BDK in liver was associated with robust inhibitory phosphorylation of the branched-chain keto acid dehydrogenase (BCKDH) on ser293. AAV8-mediated induction of BDK expression in liver in our study was sufficient to promote significant elevations in circulating levels of the direct substrate of BCKDH, the branched chain α-keto acids as well as their cognate BCAA. There was no effect of AAV8-BDK to alter food intake, weight gain or adiposity. However, glucose tolerance measured by a 1g/kg intraperitoneal glucose tolerance test at week 7 was significantly impaired in mice receiving AAV8-BDK compared to AAV8-GFP control. These data demonstrate for the first time that induction of BDK in liver, as occurs with obesity, is sufficient to disturb systemic BCAA and glucose homeostasis in lean mice.

Disclosure

J.Walejko: None. R.W.Mcgarrah: None. P.J.White: None.

Funding

American Diabetes Association (1-16-INI-17)
193-OR: Chronotherapy with the Glucokinase Activator AZD1656 Greatly Affects Its Ability to Improve Metabolism in Obese Zucker Rats
Authors: KROON TOBIAS , HAGSTEDT THERESE , ALEXANDERSSON IDA , FERM ANNETT , PETERSSON MARIE , MAURER STEFANIE , ZARROUKI BADER , WALLENIUS KRISTINA , OAKES NICHOLAS D. , BOUCHER JEREMIE
Published: May 2022

Circadian rhythms play critical roles in regulating metabolism, including daily feeding/fasting periods and oscillating expressions of certain genes. Glucokinase (Gck) , expressed in the liver and pancreas, is central for whole-body glucose homeostasis by acting as a glucose sensor and regulating metabolism according to prevailing glucose levels. Gck expression has also been shown to follow a circadian rhythm. Gck activators (GKAs) effectively reduce hyperglycemia, however, adverse events have also involved hypoglycemia, hyperlipidemia, and hepatic steatosis. Given the circadian rhythmicity and natural postprandial activation of Gck, we hypothesized that GKA treatment would benefit from being timed specifically during feeding periods. We compared the metabolic effects following differentially timed administrations of the GKA AZD1656 in the obese, insulin resistant Zucker rat. Four weeks of continuous treatment significantly improved glycemic control; however, hepatic steatosis and inflammation manifested. In contrast, a robust reduction in hepatic steatosis and inflammation on top of improved glycemia, was observed when AZD1656 administration was timed to feeding periods only. When AZD1656 was timed to fasting periods, detrimental metabolic effects were observed, including impaired glycemic control, severe liver steatosis and elevated inflammation. Mechanistically, timing AZD1656 administration to feeding periods was found to divert de novo lipogenesis-derived lipids away from hepatic storage towards VLDL synthesis and secretion, without affecting plasma triglyceride levels. In conclusion, intermittent AZD1656 dosing timed to feeding periods promotes glucose disposal when needed the most, while the daily drug holiday allows for maintained metabolic flexibility and avoids hepatic steatosis. Chronotherapeutic approaches should be considered for the development of GKAs and other drugs acting on metabolic targets.

Disclosure

T. Kroon: Employee; AstraZeneca. I. Alexandersson: Employee; AstraZeneca. A. Ferm: Employee; AstraZeneca. M. Petersson: Employee; AstraZeneca. S. Maurer: Employee; AstraZeneca, Merck Sharp & Dohme Corp. B. Zarrouki: Employee; AstraZeneca. K. Wallenius: Employee; AstraZeneca. N.D. Oakes: Employee; AstraZeneca. J. Boucher: Employee; AstraZeneca, Evotec International GmbH.
195-OR: A Novel 13C5 Glutamine Tracer Method (Q Flux) Reveals a Key Role of Succinyl CoA Anaplerosis in Promoting Increased Rates of Hepatic Gluconeogenesis during Hyperglucagonemia
Authors: HUBBARD BRANDON T. , SHULMAN GERALD I.
Published: May 2022

Hyperglucagonemia is a hallmark of type 2 diabetes mellitus (T2DM) and contributes to increased rates of endogenous glucose production (EGP) , mostly through increased rates of hepatic gluconeogenesis (GNG) , but the anaplerotic pathways and respective substrates that support this process are unclear. To address this question, we developed a novel and extensively validated 13C5 glutamine-based in vivo metabolic flux analysis method (Q Flux) , which allows for quantitation of both the relative and absolute rates of hepatic gluconeogenesis from pyruvate (via pyruvate carboxylase [PC]) , succinyl CoA (via methylmalonyl CoA mutase [MUT]) , glutamine (via glutaminase [GLS2]) , and glycerol. Male Sprague-Dawley rats (∼300 g) were infused for 90 minutes with either low-dose (LD) glucagon (1.25 ng/[kg-min]) or high-dose (HD) glucagon (ng/[kg-min]) , plus insulin (0.5 mU/[kg-min]) , somatostatin (4 μg/[kg-min]) , and 13C5 glutamine (3 μmol/[kg-min]) after a 16-hour fast to deplete hepatic glycogen. HD animals displayed significantly increased plasma glucose concentrations and EGP relative to LD controls. Analyses of liver tissues collected at sacrifice revealed that in LD animals, 70% of mitochondrial GNG was from pyruvate, 15% from succinyl CoA, and 15% from glutamine. In HD animals, 59% of mitochondrial GNG was derived from pyruvate (p=0.vs. LD) , 26% from succinyl CoA (p=0.0vs. LD) , and 15% from glutamine (p=0.99 vs. LD) .

Conclusion: We find an unexpected role for succinyl CoA anaplerosis and methylmalonyl CoA mutase flux in supporting increased rates of mitochondrial GNG during hyperglucagonemia. Furthermore, relative contributions of glutamine to hepatic gluconeogenesis were unchanged, contrary to previous reports. Taken together, these results identify novel targets to reduce hyperglucagonemia-induced increases in rates of gluconeogenesis and hyperglycemia in T2DM.

Disclosure

B.T.Hubbard: None. G.I.Shulman: Advisory Panel; 89bio, Inc., AstraZeneca, Equator Therapeutics, Inc., Janssen Research & Development, LLC, Merck & Co., Inc., Consultant; DiCerna Pharmaceuticals, Inc. , Novo Nordisk, Other Relationship; Generian Pharmaceuticals, iMetabolic Biopharma Corporation, Maze Therapeutics, The Liver Company, Stock/Shareholder; Levels Health, Inc. .
196-OR: (Pro) renin Receptor Signaling in Tyrosine Hydroxylase Neurons in the Hypothalamic Paraventricular Nucleus Is Required for Obesity-Associated Glucose Metabolic Impairment
Authors: SOUZA LUCAS AC. , WORKER CALEB J. , GAYBAN ARIANA JULIA , SCHWARTZ MICHAEL W. , EARLEY YUMEI FENG
Published: May 2022

We recently reported that neuron-specific (pro) renin receptor (PRR) deletion reduces fasting blood glucose (BG) levels and improves glucose tolerance in high fat diet (HFD) -treated mice. To investigate underlying mechanisms, we focused on tyrosine hydroxylase (TH) neurons in the hypothalamic paraventricular nucleus (THPVN neurons) , a largely GABAergic population that expresses PRR and projects to autonomic centers important for BG regulation. To delete PRR from THPVN neurons, we injected into the PVN of PRR-loxp mice either an adeno-associated virus expressing cre recombinase under the control of the rat TH promoter (AAV2-TH-Cre) or AAV2-TH-eGFP as a control. After placing animals on a HFD for 6 wk, we found that the obesity-induced increase of fasting BG levels was blocked by PRR deletion from THPVN neurons (118.0 ± 3.7 vs. 139.3 ± 6.6 mg/dL, n=6/group, p= 0.04) , accompanied by a trend towards improved i.p. glucose tolerance (AUC: 12990 ± 1136 vs. 9467 ± 1298, n=6, p=0.07) . To further investigate the role of THPVN neurons in glucose homeostasis, we employed a Designer Receptors Exclusively Activated by Designer Drugs (DREADD) approach whereby AAV2-TH-Cre was injected bilaterally into the PVN of either hM3Dq-loxp (excitatory) or hM4Di-loxp (inhibitory) mice, and continuous glucose monitoring was performed in conscious, freely moving mice. Following i.p. injection of clozapine-N-oxide (CNO, 1 mg/Kg) or vehicle, we found that whereas basal BG levels were not altered by THPVN neuron activation, THPVN neuron inhibition significantly increased basal BG levels compared to vehicle in male (ΔBG: 31.6 ± 8.6 mg/dL vs. 11.0 ± 6.7 mg/dL, n=4, p=0.03) but not female mice. These findings establish a role for THPVN neuron PRR signaling in the pathogenesis of obesity-associated glucose metabolic impairment, and show that in male mice, basal THPVN neuron activity is required for normal glucose homeostasis.

Disclosure

L.Ac. souza: None. C.J.Worker: None. A.Gayban: None. M.W.Schwartz: None. Y.Feng earley: None.

Funding

National Institutes of Health (R01HL122770, R35HL155008, RDK83042, RDK124238)
199-LB: Artemisia scoparia Attenuates Glucocorticoid-Induced Lipolysis in Adipocytes
Authors: HARVEY INNOCENCE , STEPHENS JACQUELINE M.
Published: May 2022

Prescription glucocorticoid use is widespread across developed countries for the treatment of several inflammatory conditions. Elevated glucocorticoids are known to promote lipolysis and often result in metabolic disorders such as insulin resistance and hepatic lipid accumulation. An extract of Artemisia scoparia (SCO) has been shown to reduce lipolysis and promote metabolic health but has not been investigated in the context of glucocorticoid-mediated metabolic disease. We assessed the ability of SCO to modulate glucocorticoid-induced lipolysis in 3T3-L1 adipocytes. Mature adipocytes were pretreated with vehicle (DMSO) , SCO (50 ug/mL) , or rosiglitazone for three days. Cells from each condition were then exposed to either vehicle (ethanol/BSA) , Dexamethasone (synthetic glucocorticoid; 500 nM) , or TNFa (0.75 nM) , in the presence or absence of RU486 (glucocorticoid receptor (GR) antagonist; 250 nM) for 20 hours. Separate experiments were performed to determine the involvement of the GR in SCO’s effects using an siRNA approach. Glycerol and free fatty acids (FFA’s) were measured from the media to evaluate changes in lipolysis. The expression and phosphorylation status of several lipolytic genes and proteins were also assessed via qPCR and western blot, respectively. SCO significantly attenuated dexamethasone-induced glycerol and FFA release, with the combination of SCO and RU486 resulting in the greatest effects. SCO led to significant reductions in the monomeric forms of PDE3B and PDE4D, but greater expression of multimeric complexes were observed. Reduction in GR expression did not interfere with the effects of SCO, suggesting the GR is not required for SCO-mediated attenuation of lipolysis. These observations shed some light on the protective effects of SCO under conditions of elevated glucocorticoids, but additional studies are needed to identify the underlying mechanisms that confer beneficial effects of SCO to combat both diet- and glucocorticoid-induced metabolic dysfunction.

Disclosure

I. Harvey: None. J. M. Stephens: None.

Funding

National Center for Complementary and Integrative Health T32 (AT004094)
207-LB: Aldose Reductase Inhibition by AT-001 Limits Diastolic Dysfunction and Adverse Remodelling in Diabetic Cardiomyopathy
Authors: KARWI QUTUBA G. , GOPAL KESHAV , AMIRHOSSEIN TABATABAEI DAKHILI SEYED , WAGG CORY S. , ZHANG LIYAN , SUN QIUYU , SAED CHRISTINA T. , PANIDARAPU SAI , PERFETTI RICCARDO , RAMASAMY RAVICHANDRAN , USSHER JOHN R. , LOPASCHUK GARY
Published: May 2022

Diabetic cardiomyopathy (DbCM) increases mortality and morbidity in type 2 diabetes (T2D) subjects. Increased cardiac aldose reductase (AR) activity has been correlated with impaired cardiac function and less effective energy metabolism in DbCM subjects. The aim of the present study was to evaluate the effect AT-001, a potent and selective AR inhibitor, on cardiac function, structure, and energy metabolism in diabetic cardiomyopathic mice that overexpress the human AR (hAR-Tg) . The effects of AT-001 were compared to those of dapagliflozin, a sodium-glucose cotransporter inhibitor that decreases the risk of cardiovascular death. DbCM was induced in human AR overexpressing transgenic (hAR-Tg) mice by subjecting them to a high-fat diet (60% kcal from lard) for 10-wk with a single intraperitoneal streptozotocin injection (75 mg/kg) at 4-wk. Male mice were randomized to receive either vehicle, AT-001 (40 mg/kg/day) ,or dapagliflozin (1 mg/kg/day) for the final 3-wk. AT-001 treatment improved diastolic function in vivo (a decrease in the E/e’ ratio and an increase in the E’/A’) and reduced left ventricular mass (LV) mass in DbCM mice compared to vehicle-treated DbCM mice. Cardioprotection by AT-001 was associated with reduced cardiac AR activity, decreased circulating blood sorbitol levels, and a reduction in cardiac fatty acid oxidation rates in the DbCM mice. Treatment with dapagliflozin did not significantly affect either diastolic function or LV mass in DbCM mice. In addition, dapagliflozin did not have a significant effect on cardiac fatty acid oxidation rates.

In summary, the present study demonstrates that AT-001 attenuates diastolic dysfunction and cardiac hypertrophy in DbCM. AT-001-induced cardioprotection is accompanied by reduced cardiac fatty oxidation rates in DbCM.

Disclosure

Q. G. Karwi: None. R. Ramasamy: Consultant; Applied Therapeutics. J. R. Ussher: None. G. Lopaschuk: None. K. Gopal: None. S. Tabatabaei dakhili: None. C. S. Wagg: None. L. Zhang: None. Q. Sun: None. C. T. Saed: None. S. Panidarapu: None. R. Perfetti: Employee; Applied Therapeutics.
208-OR: Posttranslational Truncation of Apolipoproteins C1 and C2 and Plasma Lipids in Multiethnic Study of Atherosclerosis (MESA)
Authors: KOSKA JURAJ , FURTADO JEREMY , SINARI SHRIPAD , MCCLELLAND ROBYN , BILLHEIMER DEAN , REAVEN PETER
Published: May 2022

Apolipoproteins (apo) C1 and C2 are small interchangeable molecules that regulate lipoprotein metabolism. ApoC1 inhibits lipoprotein lipase (LPL) and stimulates reverse cholesterol transport while apoC2 activates LPL. Both exist as full-size native and minor truncated proteoforms; however, whether distribution of these apoC1 and C2 proteoforms may influence plasma lipids is largely unknown. Baseline plasma from 5,791 MESA participants was tested for truncated to native apoC1 and apoC2 ratios (apoC1’/C1; apoC2’/C2) . Total apoC1 and C2 concentrations were measured in a subset of 3,851 participants. Plasma lipids were measured for up to 6 times over 15 years. In adjusted models (Table) , higher apoC1’/C1 was associated with lower triglycerides (TG) and higher total (TC) and LDL cholesterol both at baseline and follow-up, and higher HDL at follow-up. Higher apoC2’/C2 was associated with lower TG and higher LDL at baseline, and higher baseline and follow-up TC and HDL. In contrast, the associations of total apoC1 and apoC2 concentrations with TG and HDL were largely in opposite directions of their proteoform ratios. For example, plasma TG were inversely associated with apoC1 and apoC2 truncation but positively associated with total apoC1 and apoC2 concentrations. Our data indicate a possible role of posttranslational apoC1 and apoC2 modification in regulating lipid metabolism.

Disclosure

J.Koska: None. J.Furtado: Research Support; Eli Lilly and Company, Pfizer Inc. S.Sinari: None. R.Mcclelland: None. D.Billheimer: None. P.Reaven: Research Support; AstraZeneca, Dexcom, Inc.

Funding

National Institutes of Health (R01-HL138969
210-OR: Presence of Type 2 Diabetes (T2D) Affects HDL Particle Proteomic Composition Independently of Obesity or Fatty Liver
Authors: BRIL FERNANDO , PEARCE RYAN , COLLIER TIMOTHY S. , KALAVALAPALLI SRILAXMI , MCPHAUL MICHAEL J. , CUSI KENNETH
Published: May 2022

Patients with T2D remain at high risk of cardiovascular (CV) events despite adequate glycemic and LDL-C control. Changes in HDL particle composition and function may explain part of this increased CV risk. The aim of this study was to determine the proteomic composition of isolated HDL particles in T2D patients, and establish which factors contribute to these abnormalities. Patients (n=213) with and without T2D were included in the study and underwent an OGTT, liver MRS, and routine blood chemistries. Advanced lipid testing and lipoprotein subfractions were measured by ion mobility. ApoA-I containing particles (i.e., HDL) were isolated and a novel targeted proteomic approach using multiple reaction monitoring (MRM) by liquid chromatography and tandem mass spectrometry (LC-MS/MS) was undertaken to measure HDL-bound proteins. Patients with (n=146) vs. without (n=67) T2D were older (56±9 vs. 47±12) , more obese (34.2±4.7 vs. 32.6±5.3 kg/m2) , but had no significant differences in other important clinical characteristics, such as gender or race. Patients with T2D had lower HDL-C (38±9 vs. 43±13 mg/dl, p<0.001) , but no difference in the number of HDL particles. A panel of 28 HDL-bound proteins were targeted and quantified by MRM LC-MS/MS. After correction for multiple comparisons (false discovery rate set at 5%) and adjustment for obesity and NAFLD, 4 proteins were found to be decreased in T2D patients (ApoA-I, ApoC-I, ApoM, and PON3; all p<0.0015) . The pCAD index (well-validated score for coronary artery disease and CV mortality based on HDL-bound proteins) was increased in patients with T2D, irrespectively of obesity or NAFLD (93±15 vs. 61±38, p<0.0001) .

In conclusion, patients with T2D showed significant differences in the apolipoproteomic composition of HDL particles, and this translated into increased CV risk based on pCAD index. Different HDL composition and function may explain the residual CV risk of patients with T2D optimally treated for hyperglycemia and LDL-C.

Disclosure

F.Bril: None. R.Pearce: Employee; Quest Diagnostics. T.S.Collier: Employee; Quest Diagnostics, Stock/Shareholder; Quest Diagnostics. S.Kalavalapalli: None. M.J.Mcphaul: Employee; Quest Diagnostics. 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.

Funding

American Diabetes Association (1-08-CR-08) ; The Obesity Society (Early-Career Research Grant) Veterans Affairs (1 I01 CX000167-01) . UF CTSI (UL1TR001427)
211-OR: Plasma Insulin Is Required for the Increase in Plasma ANGPTL8 Concentration following Glucose Ingestion
Authors: ABU-FARHA MOHAMED , ABUBAKER JEHAD , KHAIRI IRINA AL , CHERIAN PREETHI T. , AGYIN CHRISTINA , ABDELGANI SIHAM , ALOZAIRI EBAA S. , ADAMS JOHN M. , ALMULLA FAHD , DEFRONZO RALPH A. , ABDUL-GHANI MUHAMMAD
Published: May 2022

Aim: ANGPTL8 plays an important role in regulating lipoprotein lipase activity. Its plasma level is increased following nutrient ingestion. Its not well characterized whether insulin or glucose drive the increased ANGPTL8 after food uptake. To address this, we examined the dynamic relationship between plasma insulin level, ANGPTL8 concentration and glucose following glucose ingestion.

Methods: 30 healthy subjects with impaired fasting glucose (IFG) (n=14) and normal glucose tolerance (NGT) (n=16) received 75-glucose OGTT, multistep euglycemic hyperinsulinemic clamp and pancreatic clamp. ANGPTL8 level was measured during the fasting state, OGTT and the clamp studies.

Results: Subjects with IFG had significantly higher ANGPTL8 during the fasting state (80±5.6 pmol/L VS 68±4.9 pmol/L respectively, p<0.05) . During the OGTT, plasma ANGPTL8 level increased by 62% above the fasting level (from 81±8 pmol/L to 131±pmol/L, p<0.0001) . During the insulin clamp, insulin infusion caused a dose-dependent increase in ANGPTL8 level (figure 1) . Conversely, during the pancreatic clamp and in the absence of an increase in plasma insulin, the increase in plasma glucose concentration failed to cause a significant increase in plasma ANGPTL8 concentration.

Conclusion: The increased ANGPTL8 expression in circulation after glucose ingestion was driven by increased insulin and not glucose.

Disclosure

M.Abu-farha: 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. J.Abubaker: None. I.Al khairi: None. P.T.Cherian: None. C.Agyin: None. S.Abdelgani: None. E.S.Alozairi: None. J.M.Adams: None. F.Almulla: None.

Funding

Kuwait Foundation for the Advancement of Sciences
216-LB: Hepatocyte N6-Methyladenosine mRNA Modification in Hepatic Gluconeogenesis and Diabetes
Authors: ZHENG QIANTAO , ZHONG XIAO , REN DECHENG , RUI LIANGYOU
Published: May 2022

The liver produces endogenous glucose to support life during fasting. Counterregulatory hormones, including glucagon, catecholamines, and glucocorticoids, stimulate the expression of gluconeogenic enzymes in the liver, thus driving liver glucose production. In contrast, insulin suppresses hepatic gluconeogenesis, thereby restraining postprandial glucose levels. Hepatic gluconeogenesis aberrantly increases in type 2 diabetes due to an imbalance between insulin and counterregulatory hormone actions, contributing to hyperglycemia and glucose intolerance. N6-methyladenosine (m6A) RNA methylation has emerged as a critical paradigm shaping cell identities and functions. The Mettl3/Mettl14 complex catalyzes m6A on RNA and RNA-binding proteins bind to the m6A motifs and determine the fate of client mRNAs (splicing, trafficking, stability, and/or translation) . However, m6A RNA modification has not been explored in liver gluconeogenesis. Here, we identified Mettl14 as an important positive regulator of hepatic gluconeogenesis. Liver Mettl14 levels were increased in db/db mice and mice with high fat diet (HFD) -induced obesity. Hepatocyte-specific deletion of Mettl14 decreased hepatic glucose production and ameliorated HFD-induced glucose intolerance; conversely, liver-specific overexpression of Mettl14 increased liver glucose production and HFD-induced glucose intolerance. Of note, Mettl14 did not alter liver insulin actions under our experimental conditions. Remarkably, hepatic deficiency of Mettl14 profoundly blunted the ability of glucagon to stimulate gluconeogenesis in mice. Consistently, deletion of Mettl14 largely blocked glucagon-stimulated gluconeogenesis ex vivo in liver slices as well as in primary hepatocyte cultures. In contrast, overexpression of Mettl14 had the opposite effects. Collectively, these data unravel a previously unrecognized glucagon/Mettl14/gluconeogenesis axis that is involved in hyperglycemia and glucose intolerance in diabetes.

Disclosure

Q. Zheng: None. X. Zhong: None. D. Ren: None. L. Rui: None.

Funding

National Institutes of Health (RO1DK127568) , American Heart Association (831585)
225-LB: Impaired Microvascular Responses May Explain Health Disparities and Impaired Metabolic Flexibility in Hispanic Residents of the Rio Grande Valley
Authors: RUSSELL RYAN D. , LUN TAI YU , MARUPUDI SMARAN
Published: May 2022

Purpose: Impaired skeletal muscle microvascular blood flow (MBF) is one of the earliest pathophysiologies of type 2 diabetes (T2D) . People with a family history of T2D (FH+ are at greater risk for developing T2D than those with no family history (FH-) . Further, we have shown that normoglycemic Caucasian FH+ individuals have impaired skeletal muscle microvascular responses and metabolic flexibility (MF - ability to switch substrate oxidation upon stimulation) to a mixed meal challenge (MMC) when compared with matched FH- (p<0.01) , suggesting early vascular insulin resistance. Mexican Hispanic individuals have the highest prevalence of T2D in the US and make up ∼95% of Hispanic residents of the Rio Grande Valley (HRGV) where T2D diagnosis rates are ∼3x the national average. Therefore, we sought to determine if impaired MBF responses are present in healthy HRGV.

Methods: 15 FH- and 13 FH+ HRGV were recruited to assess MF and MBF responses to a MMC. MF was measured via indirect calorimetry and MBF via contrast-enhanced ultrasound while fasting and again 60-min post MMC.

Results: No changes in skeletal MBF were noted in FH- (1.21 ± 0.53 SEM and 0.86 ± 0.23 SEM fasting and postprandial MBF respectively) or FH+ (2.17 ± 0.98 SEM and 1.49 ± 0.66 SEM fasting and postprandial MBF respectively) groups. Abdominal adipose MBF responses increased in FH+ (-2.3 ± 0.71 SEM, p=0.004) , but not in FH- (-0.49 ± 0.39 SEM p=0.39) . FH+ display impaired postprandial metabolic flexibility (MF) responses during 60-min of testing post-MMC. Neither blood glucose responses (99.3 ± 1.3 SEM and 102.27 ± 2.1 SEM fasting and post-prandial respectively, p=0.2) nor body composition differed between FH groups.

Conclusions: HRGV display impaired skeletal muscle MBF responses, indicating early vascular insulin resistance. Further, the impairment in MF in FH+ may be partially explained by increased adipose MBF responses, as adipose is less metabolically active than skeletal muscle.

Disclosure

R. D. Russell: None. Y. Tai: None. S. Marupudi: None.
229-OR: Role of Insulin Signaling in the Regulation of Proteostasis in Astrocytes
Authors: GEFFKEN SHAWN , SMITH CATHERINE , LEE HIU HAM , CAI WEIKANG
Published: May 2022

Insulin is a principal metabolic hormone. It regulates a plethora of metabolic pathways in sensitive peripheral tissues. Recent studies show insulin signaling plays fundamental roles in the brain. Loss of insulin action in different neuronal and glial cells contributes to a variety of metabolic and behavioral abnormalities in mice. In particular, loss of astrocytic insulin signaling leads to impaired brain glucose sensing and increased depressive-like behavior in mice. How insulin signaling modulates astrocytic cellular functions and neural circuits is not completely known. Using next-generation RNA sequencing, we show that insulin triggers a robust transcriptional regulation on multiple metabolic pathways in primary astrocytes. As expected, insulin increased expression of genes involved in cholesterol biosynthesis, important for supporting synaptic integrity and remodeling. Further, autophagy is a quintessential pathway subjected to insulin regulation, indicating the role of insulin action on proteostasis in astrocytes. Thus, insulin suppresses the expression of most critical genes involved in autophagy, including p62, Ulk1/2, several Atg genes. The inhibitory effect is potent, as 1 nM is sufficient to suppress gene expression. To determine whether insulin receptors (IR) are required for such regulation, we examined the insulin response in astrocytes without endogenous IR. IR loss only partially reverses insulin-dependent suppression of autophagic genes, indicating that insulin may act through closely related IGF-1 receptors in astrocytes.

In summary, insulin potently suppresses autophagy in astrocytes through transcriptional regulation, indicating a potential important role of astrocytic insulin signaling on regulating proteostasis in accordance with systemic nutritional status. Impairment of this regulation in insulin resistance and diabetes may affect the modulation of neural circuits by astrocytes and contribute to neurological complications linked to diabetes.

Disclosure

S.Geffken: None. C.Smith: None. H.Lee: None. W.Cai: None.

Funding

KDK120740
232-OR: Alterations in Decision-Making Neurocircuits during Hypoglycemia in Patients with T1DM
Authors: DEAJON-JACKSON JELANI , RANGEL ELIZABETH SANCHEZ , LACADIE CHERYL , GREENE ABIGAIL S. , BELFORT-DEAGUIAR RENATA , CONSTABLE TODD , ROTHMAN DOUGLAS L. , HWANG JANICE J.
Published: May 2022

Prior work by our group and others have shown that, in response to hypoglycemia, individuals with T1DM have altered regional brain activity and resting state functional connectivity (FC) in reward and decision-making regions such as the orbitofrontal cortex (OFC) and insula. Recently, fMRI studies have found that performing trait-relevant tasks while measuring FC can provide a more accurate representation of cognitive function. Thus, we tested whether individuals with T1DM have different patterns of “task-amplified” FC in response to hypoglycemia compared to non-diabetic control subjects. Twenty-five individuals (17 T1DM, 7F/10M, age 36±3 years, BMI 26±1 kg/m2, HbA1c 7.2±0.2%, duration of DM 19±2 years and 8 healthy controls (HC) , 5F/3M, age 31±2 years, BMI 25±1 kg/m2, HbA1c 5.3±0.1%) underwent BOLD fMRI scanning for FC at rest and during the performance of a Card-Guessing Task to assess reward-based decision making. During scanning, glucose levels were controlled using a 2-step hyperinsulinemic euglycemic (90 mg/dl) -hypoglycemic (60 mg/dl) clamp. Seed-based analysis using a predefined region of interest in the OFC was performed. During resting state, there were no significant Group (HC, T1DM) X Session (euglycemia, hypoglycemia) interactions. In contrast, during the Card Guess task, there was a significant Group X Session interaction (P<0.001) in the dorsal anterior cingulate cortex (dACC) . Specifically, during the task, hypoglycemia elicited connectivity changes between the OFC and the dACC in healthy control subjects but not T1DM subjects. These findings suggest that task-amplified FC may be a more sensitive method to assess neurological differences in T1DM patients that are not apparent at rest. Moreover, because the OFC and dACC have direct neuronal connections and encode a variety of decision-making processes, these data highlight the need for better understanding of not only neurocognitive changes in patients with T1DM but also the factors contributing to these changes.

Disclosure

J.Deajon-jackson: None. E.Sanchez rangel: None. C.Lacadie: None. A.S.Greene: None. R.Belfort-deaguiar: Research Support; Fractyl Health, Inc. T.Constable: None. D.L.Rothman: None. J.J.Hwang: None.

Funding

National Institute of Health (DK020495)
241-OR: Increased Time in Range on Days with Structured Aerobic, Interval, or Resistance Exercise as Compared with Sedentary Days, in Adults with Type 1 Diabetes (T1D)
Authors: LI ZOEY , RIDDELL MICHAEL , RICKELS MICHAEL R. , BECK ROY , CASTLE JESSICA R. , CLEMENTS MARK A. , DOYLE FRANCIS J. , GAL ROBIN L. , GILLINGHAM MELANIE B. , JACOBS PETER G. , MARTIN CORBY K. , PATTON SUSANA R. , CALHOUN PETER
Published: May 2022

Different types of exercise (i.e., aerobic vs. interval vs. resistance) may have different immediate glycemic effects in adults with T1D, but the impact of exercise type on percent time in range 70-180 mg/dL (TIR) on physically active and inactive days is unknown. The Type 1 Diabetes Exercise Initiative (T1DEXI) study examined CGM data on active vs. sedentary days to assess the effect of exercise type on TIR. Adults (N=497) with T1D ([mean ± SD] age= 37 ± 14 years; HbA1C= 6.6 ± 0.8%) , completed six aerobic, interval, or resistance study-designed exercise videos at home over a 4-week period. TIR was higher and mean glucose concentration lower on days when the study-designed exercise video was completed, as compared with sedentary days (Table) . Time below range was low in general in this cohort, although slightly higher on exercise days. Results were remarkably similar for each exercise type, with marginally less increase in hypoglycemia with resistance exercise.

In summary, adults with type 1 diabetes have clinically significant improvements in TIR on active days as compared to inactive days, regardless of the exercise type.

Disclosure

Z.Li: None. P.G.Jacobs: Other Relationship; Pacific Diabetes Technologies, Research Support; Dexcom, Inc. C.K.Martin: Advisory Panel; Wondr Health, Board Member; EHE Health, Other Relationship; ABGIL, ABGIL, Academy of Nutrition and Dietetics. S.R.Patton: None. P.Calhoun: None. M.Riddell: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Consultant; Eli Lilly and Company, Jaeb Center for Health Research, Speaker's Bureau; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk. M.R.Rickels: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Consultant; L-Nutra Inc. R.Beck: Consultant; Diasome, Eli Lilly and Company, Insulet Corporation, Novo Nordisk, Research Support; Ascensia Diabetes Care, Beta Bionics, Inc., Bigfoot Biomedical, Inc., Dexcom, Inc., Eli Lilly and Company, Medtronic, Novo Nordisk, Roche Diabetes Care, Tandem Diabetes Care, Inc. J.R.Castle: Advisory Panel; Insulet Corporation, Novo Nordisk, Zealand Pharma A/S, Stock/Shareholder; Pacific Diabetes Technologies. M.A.Clements: Consultant; Glooko, Inc., Research Support; Abbott Diabetes, Dexcom, Inc. F.J.Doyle: Other Relationship; Dexcom, Inc., Insulet Corporation, Roche Diabetes Care, Stock/Shareholder; Mode AGC. R.L.Gal: None. M.B.Gillingham: None.
256-OR: Five-Year Simulation of Diabetes-Related Complications in Individuals Treated with Once-Weekly Tirzepatide and Semaglutide vs. Once-Daily Insulin Glargine
Authors: NIU SHU , JIAO TIANZE , GUO YI , BIAN JIANG , SHI LIZHENG , FONSECA VIVIAN , SHAO HUI
Published: May 2022

This study compared the 5-year risk of diabetes complications of tirzepatide (TZP) and semaglutide with insulin glargine in individuals with type 2 diabetes (T2Ds) , using the BRAVO diabetes model, which has been validated to have a high degree of accuracy. We used the BRAVO model to predict 5-year complications among users of TZP (5 mg, mg, or 15 mg) , semaglutide (1 mg) , and insulin glargine, based on short-tern efficacy data from the SURPASS-2 trial and SUSTAIN-4 trial, under two scenarios: the short-term drug efficacy lasted for 5 years (optimistic) , and the drug efficacy diminished in 5 years (conservative) . We found a 5-year risk reduction in major adverse cardiovascular events (MACE) (relative risk [RR] 63.7%, 95% CI: 61.4%-66.2%) with 15 mg TZP under an optimistic scenario, and MACE (RR 87.6%, 95% CI: 86.8%-88.6%) risk reduction with 15 mg TZP under a conservative scenario, when compared with insulin glargine (Figure) . Lower doses of TZP also had similar, albeit slightly smaller, benefits. The long-term use of TZP and semaglutide may lead to a substantial reduction in diabetes-related complications among individuals with T2Ds, compared to insulin. A high dose of TZP was also superior to semaglutide in this respect.

Disclosure

S.Niu: None. T.Jiao: None. Y.Guo: None. J.Bian: None. L.Shi: None. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. H.Shao: Board Member; BRAVO4HEALTH, LLC.
259-OR: Stem Cell–Derived, Fully Differentiated Islet Cells for Type 1 Diabetes
Authors: MARKMANN JAMES F. , NAJI ALI , RICKELS MICHAEL R. , ALBA MARIA , MARIGOWDA GAUTHAM , ROSS LEORAH , WANG CHENKUN , PAGLIUCA FELICIA , SANNA BASTIANO , KEAN LESLIE S. , PETERS ANNE L. , WITKOWSKI PIOTR , RICORDI CAMILLO
Published: May 2022

Cadaveric islet transplantation can achieve glycemic control in T1D, but cadaveric islet quantity and quality are limiting. We report the first patient-administered VX-880, an investigational allogeneic stem cell–derived, fully differentiated, pancreatic islet cell replacement therapy.

A 64-year-old male with a 40-year history of T1D complicated by impaired awareness of hypoglycemia with 5 severe hypoglycemic events (SHEs) the year before VX-880 was receiving 34U insulin/day at baseline (HbA1c 8.6%; undetectable fasting and stimulated C-peptide) . After a single VX-880 infusion at half target dose, fasting C-peptide was detected by Day 29 and increased rapidly; HbA1c and daily insulin decreased in parallel. At Day 90, robust increases in fasting and stimulated C-peptide, improved glycemic control, and a substantial reduction in exogenous insulin administration were observed and continued to improve through last time point assessed (Table) .

VX-880 was generally safe and well tolerated; most AEs were mild or moderate and consistent with immunosuppression. The most common AEs were SHEs (not serious or related to VX-880) , which occurred in the perioperative period. There was 1 serious AE of rash (mild, unrelated to VX-880) , which resolved.

These unprecedented results are the first evidence that stem cell–derived islets can restore insulin production and glucose control in T1D. The study continues to enroll and dose patients.

Disclosure

J.F.Markmann: Consultant; Vertex Pharmaceuticals Incorporated. L.S.Kean: Advisory Panel; HiFiBio, Mammoth Biosciences, Other Relationship; Bristol-Myers Squibb Company, Research Support; Bluebird Bio, Gilead Sciences, Inc., Magenta Therapeutics, Merck & Co., Inc., Novartis AG, Regeneron Therapeutics. A.L.Peters: Advisory Panel; Abbott Diabetes, AstraZeneca, Eli Lilly and Company, Novo Nordisk, Shouti, Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Other Relationship; Omada Health, Inc., Research Support; Abbott Diabetes, Dexcom, Inc., Insulet Corporation, Leona M. and Harry B. Helmsley Charitable Trust, Stock/Shareholder; Teladoc Health. P.Witkowski: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated. C.Ricordi: Advisory Panel; Vertex Pharmaceuticals Incorporated. A.Naji: None. M.R.Rickels: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Consultant; L-Nutra Inc. M.Alba: None. G.Marigowda: None. L.Ross: Employee; Vertex Pharmaceuticals Incorporated. C.Wang: Employee; Vertex Pharmaceuticals Incorporated. F.Pagliuca: Employee; Vertex Pharmaceuticals Incorporated, Other Relationship; Vertex Pharmaceuticals Incorporated, Stock/Shareholder; Vertex Pharmaceuticals Incorporated. B.Sanna: Employee; Vertex Pharmaceuticals Incorporated.
26-OR: Metabolic Benefits beyond Glycemic Control with Artificial Intelligence, Internet of Things, and Whole-Body Digital Twin: Initial Six Months Results of a Randomized Control Trial
Authors: JOSHI SHASHANK R. , SHAH LISA , MOHAMED MALUK , MOHAMMED JAHANGIR , POON TERRENCE , DHARMALINGAM MALA , VADAVI ARUN , SABOO BANSHI , DAMODHARAN SURESH , KESHAVAMURTHY ASHOK , THAJUDEEN MOHAMED , BHONSLEY SUCHITRA , SHAMANNA PARAMESH
Published: May 2022

We analyzed the efficacy of Twin Precision Treatment (TPT) : a novel whole-body digital twin enabled precision nutrition that utilises 174 health markers and 3000 daily data points from blood tests and connected devices that measure weight, physical activity, sleep and sensor glucose values, for achieving remission, at six months among 199 people with T2D enrolled in RCT in India. Mean age was 43 years (±8.7) ; diabetes duration was 3.7 years (±2.7) .Mean baseline A1C (%) of 9 (±1.8) reduced to 5.7 (±0.5) . 189 people (94.9%) achieved AIC < 6.5%, of which 167 (83.9%) achieved remission (return of HbA1c to less than 6.5%, with absence of glucose-lowering pharmacotherapy, for at least 3 months) . There was a significant improvement in the A1C, metabolic markers (HDL-C, TGs, sdLDL, TG/HDL, VAI, NAFLD scores, hsCRP, ferritin, WBC, ESR, MICR) and SBP, DBP, body weight, BMI, waist circumference and ASCVD risk score. (Figure) . The initial analysis of the ongoing trial demonstrates the efficacy of the proprietary digital twin technology, to achieve remission of T2D. These initial findings need corroboration with long term follow-up, to assess if this remission is durable.

Disclosure

S.R.Joshi: Advisory Panel; AstraZeneca, Consultant; Biocon, Franco India, Glenmark Pharmaceuticals, Marico, Sanofi, Twinhealth , Zydus Cadila, Speaker's Bureau; Abbott, Serdia Pharmaceuticals (India) Pvt. Ltd. A.Keshavamurthy: None. M.Thajudeen: None. S.Bhonsley: None. P.Shamanna: None. L.Shah: None. M.Mohamed: None. J.Mohammed: None. T.Poon: None. M.Dharmalingam: None. A.Vadavi: None. B.Saboo: None. S.Damodharan: None.
261-OR: Dorzagliatin, a Dual-Acting Glucokinase Activator. Improves Insulin Secretion and Glucose Sensitivity in Glucokinase-Maturity-Onset Diabetes of the Young (GCK-MODY)
Authors: CHOW ELAINE , WANG KE , LIM CADMON K.P. , TSOI SANDRA , FAN BAOQI , LUK ANDREA , MA RONALD C. , FERRANNINI ELE , MARI ANDREA , CHEN LI , CHAN JULIANA C.
Published: May 2022

Glucokinase maturity onset diabetes of the young (GCK-MODY) is caused by heterozygous inactivating mutations in GCK that is not responsive to conventional glucose lowering drugs. We investigated the effects of dorzagliatin, a novel allosteric activator of hepatic and beta-cell GCK on insulin secretion rates (ISR) and glucose sensitivity (GS) in GCK-MODY and recent onset type 2 diabetes (T2D) . In a double-blind, randomized cross-over study, 8 GCK-MODY (mean±SD age 36.1­±6.4years) and T2D subjects (mean age 50.2±6.9 years, median T2D duration 0.90 [0.60-1.42] years) underwent 2-hour 12 mmol/L hyperglycemic clamps following a single oral dose of dorzagliatin 75mg or matched placebo. Insulin and C-peptide were measured. GCK-MODY group showed significantly higher absolute (mean±SD 432±85 versus 272±91 pmol/min/m2, p=0.002) and incremental (342­±91 vs. 241±74 pmol/min/m2, p=0.004) second-phase ISR following dorzagliatin versus placebo. Dorzagliatin significantly improved GS in GCK-MODY (51±21 vs. 33­±13 pmol/min/m2 per mmol/L p=0.028) with an upward and leftward shift in ISR-glucose response. In T2D, basal ISR was significantly improved following dorzagliatin (102±57 vs. 60±42, p=0.018) with smaller increases in second phase ISR and GS. Dorzagliatin improves second phase ISR and GS, with larger effects in GCK-MODY than T2D.

Disclosure

E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. L.Chen: Employee; Hua Medicine. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. K.Wang: None. C.K.P.Lim: None. S.Tsoi: None. B.Fan: None. A.Luk: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. E.Ferrannini: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Oramed Pharmaceuticals, Consultant; Elgia Therapeutics, Research Support; Janssen Research & Development, LLC, Oramed Pharmaceuticals, Sanofi-Aventis U.S., Speaker's Bureau; Boehringer Ingelheim International GmbH. A.Mari: Consultant; Lilly, Research Support; Lilly.

Funding

Hua Medicine Investigator Initiated Clinical Research