bluuebunny/crossref_metadata_2025 huggingface dataset:
1735-P: Effect of TLR4 Inhibition in Fat-Induced Insulin Resistance in Human Subjects
Authors: LIANG HANYU , SATHAVARODOM NATTAPOL , COLMENARES CLAUDIA V. , GANAPATHY VINUTHA , MUSI NICOLAS
Published: June 2020

Obese subjects have increased levels of free fatty acids (FFA) in plasma that may mediate the inflammation and insulin resistance seen in these individuals. Data generated mostly in cells and rodents suggest that toll like receptor 4 (TLR4) mediates the inflammatory and insulin resistant states induced by FFA. In the present study, we tested the hypothesis that pharmacologic blockade of TLR4 with eritoran would prevent lipid-induced insulin resistance. We recruited 10 lean, healthy subjects (Age: 51 ± 1 y, Sex: 6M/4F, BMI: 23.8 ± 0.7 kg/m2, Fasting plasma glucose (FPG): 5.5 ± 0.1 mmol/l). They were randomized to receive the following 72 h long i.v. treatments on separate occasions: saline (30 ml/h)+vehicle (12 mg every 12 h); Intralipid (30 ml/h)+vehicle; Intralipid (30 ml/h)+eritoran (12 mg every 12 h). After these infusions, insulin sensitivity was measured with an hyperinsulinemic clamp. Infusion of Intralipid significantly decreased insulin sensitivity (M value) by 14%. FPG and fasting plasma insulin concentrations increased with Intralipid infusion by 7% and 22%, respectively. Intralipid also caused a low-grade inflammatory state, evidenced by increases in plasma levels of TNFa (32%), lipopolysaccharide (14%), LPS binding protein (21%), and blood monocytes counts (15%). However, metabolic and inflammatory outcomes were not different between the Intralipid+vehicle and the Intralipid+eritoran groups. We conclude that short-term TLR4 inhibition with eritoran fails to prevent lipid-induced inflammation and insulin resistance. Studies with longer acting TLR4 inhibitors may be needed to clarify the role of TLR4 on the pro-inflammatory and insulin resistant states seen obesity and type 2 diabetes.

Disclosure

H. Liang: None. N. Sathavarodom: None. C.V. Colmenares: None. V. Ganapathy: None. N. Musi: None.

Funding

American Diabetes Association (7-13-GSK-01 to N.M.); National Institutes of Health (R01DK080157)
1745-P: High Prevalence of Thyroid Abnormalities in Patients with Congenital Generalized Lipodystrophy
Authors: FERNANDES VIRGINIA O. , LIMA GRAYCE ELLEN D. , MONTENEGRO ANA PAULA D. , CARVALHO ANNELISE B. , RODRIGUES GRETNA M. , MELO IVANA P. , MARTINS LIVIA V. , BATISTA LIVIA A. , AGUIAR LINDENBERG , MONTENEGRO RENAN M. ,   UIRED LIPODYSTROPHIES (BRAZLIPO) BRAZILIAN GROUP FOR THE STUDY OF INHERITED AND ACQ
Published: June 2020

Background: It is related that thyroid appears can be affected by insulin resistance (IR). Early and severe IR is a characteristic of Congenital Generalized Lipodystrophy (CGL), characterized by near to total absence of subcutaneous adipose tissue. There are few studies about thyroid abnormalities in CGL.

Aim: To describe thyroid structure and function in patients with CGL and correlate with HOMA-IR. Methods: The patients were submitted to a medical interview, physical examination, thyroid ultrasonography and biochemical, lipid profile and thyroid hormones evaluation.

Results: Twenty-three patients with a CGL were included, median age was 13.3 years (3.6 to 38.7), 15 (65%) were younger than 19 years, 14/23 (60.8%) were women and 14 (60.8%) patients had diabetes. All patients had low leptin levels, low HDL cholesterol and 18/23 (78,2%) had hypertriglyceridemia (316.55-1052mg/dL). The prevalence of thyroid hormonal dysfunction was 17.4% (4/23): subclinical (1/23) and clinical hypothyroidism (1/23), subclinical (1/23) and clinical hyperthyroidism (1/23). TSH level was 1.27 uUI/mL (0.48 - 6.71), fT4, 1.06 ng/dL (0.82 - 1.92) and T3, 1.27 ng/dL (0, 69 - 1.76). Antithyroperoxidase (ATPO) and anti-titreoglobulin (ATG) antibodies were positive in 4% (1/23) and in 17.3% (4/23). There was a negative correlation between HOMA-IR and fT4 (r= 0.036). The thyroid volume was 4.3 cm³ (1.04 - 60.4), it was altered in 19% of the patients: 33% had nodules and another 33%, parenchyma heterogenicity. There was a positive correlation between HOMA-IR and volume (r= 0.035). A case of thyroid carcinoma was diagnosed in an 8 years-old girl.

Conclusion: The prevalence of thyroid abnormalities was higher than in population data, especially in a young population. IR correlated positively with thyroid volume and negatively with T4l levels. This study did not show correlation between IR and autoimmunity. These data support that thyroid may be directly influenced by the high levels of insulin present in CGL.

Disclosure

V.O. Fernandes: None. G.D. Lima: None. A.D. Montenegro: None. A.B. Carvalho: None. G.M. Rodrigues: None. I.P. Melo: None. L.V. Martins: None. L.A. Batista: None. L. Aguiar: None. R.M. Montenegro: None.
1812-P: Glucagon Resistance and Decreased Susceptibility to Diabetes in a Model of Chronic Hyperglucagonemia
Authors: LUBACZEUSKI CAMILA , BOZADJIEVA NADEJDA , BLANDINO-ROSANO MANUEL , BERNAL-MIZRACHI ERNESTO
Published: June 2020

Elevation of glucagon levels and increase in α-cell mass are associated to states of hyperglycemia in diabetes. However, little is known about the mechanisms that control glucagon secretion and α-cell mass expansion in normal or diabetogenic conditions. The current studies investigated the effects of activation of nutrient signaling by conditional deletion of the mTORC1 inhibitor, TSC2, in α-cells (αTSC2KO), we showed that activation of mTORC1 signaling is sufficient to induce chronic hyperglucagonemia as a result of α-cell proliferation, cell size and mass expansion. Hyperglucagonemia in αTSC2KO was associated to increase in glucagon content, enhanced glucagon secretion and defective adaptation to fasting. This model allowed us to identify the beneficial effects of chronic hyperglucagonemia in glucose homeostasis by inducing insulin secretion and resistance to glucagon in the liver. Liver glucagon resistance in αTSC2KO mice was characterized by reduced expression of the glucagon receptor (GCGR), phosphoenolpyruvate carboxykinase (PEPCK) and genes involved in amino acid metabolism and urea production. Surprisingly, hyperglucagonemia in αTSC2KO mice was associated to improved glucose levels in models of Streptozotocin (STZ)-induced β-cell destruction and high fat diet-induced glucose intolerance. Contrary to our current understanding of glucagon action, these studies demonstrate that endogenous chronic hyperglucagonemia improve glucose homeostasis by augmenting insulin secretion and by inducing glucagon resistance in the liver. These novel in vivo findings support the concept that enhancing glucagon action could be used as an alternative strategy to treat hyperglycemia in diabetes.

Disclosure

C. Lubaczeuski: None. N. Bozadjieva: None. M. Blandino-Rosano: None. E. Bernal-Mizrachi: None.

Funding

U.S. Department of Veterans Affairs (IBX002728A); Diabetes Research Connection
1830-P: Therapeutic Effect of a Novel Long-Acting GLP-1/GIP/Glucagon Triple Agonist (HM15211) in CDHFD-Induced NASH and Fibrosis Mice
Authors: CHOI JAEHYUK , KIM JUNG KUK , LEE SEON MYEONG , KWON HYUNJOO , LEE JONGSOO , BAE SUNGMIN , KIM DAEJIN , CHOI IN YOUNG
Published: June 2020

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease characterized by steatosis and inflammation, which results in fibrosis. In particular, advanced fibrosis due to NASH is associated with a high risk of liver-related mortality, becoming one main cause for liver transplant. To date, there are, however, no pharmacological therapy approved. One major hurdle for the drug development is limited pathologic features of current animal models, in terms of clinical relevance. The choline-deficient and high fat diet (CDHFD) mice have known to develop multiple aspects of NASH and fibrosis similarly with those in human, being increasingly recognized as a feasible disease model. HM15211 is a novel long-acting GLP-1/GIP/Glucagon triple agonist. Previously, HM15211 treatment improved liver fat and fibrosis in various animal models of NASH and fibrosis. Here, we further explored its efficacy in CDHFD mice. In CDHFD mice (8 wks induction), HM15211 significantly reduced hepatic TG and TBARS (oxidative stress marker). Histological analysis indicated a significant reduction both in hepatic inflammatory marker expression and NAFLD activity score. Of note, when compared to FXR agonist or ACC (acetyl CoA carboxylase) inhibitor, HM15211 treatment was associated with greater efficacy improvement. To further confirm, CDHFD mice with an extended induction period (up to 16 wks) was used. Despite the severe disease progression featured by advanced liver fibrosis, HM15211 reduced hepatic hydroxyproline (-42% vs. vehicle) and sirius red positive area (11.9% vs. 4.1% for vehicle and HM15211) markedly in addition to significant liver TG reduction (66.2% vs. vehicle). Therefore, consistent efficacy in various animal models including CDHFD mice suggests the beneficial effect of HM15211 on NASH and fibrosis. Efficacy studies in biopsy proven NASH patients are ongoing to assess the clinical relevance of these findings.

Disclosure

J. Choi: Employee; Self; Hanmi Pharmaceutical. J. Kim: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. H. Kwon: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Bae: Employee; Self; Hanmi Pharmaceutical. D. Kim: Board Member; Self; Hanmi Pharmaceutical. I. Choi: Board Member; Self; Hanmi Pharmaceutical.
1831-P: Activating AMPK Mediates FGF1 Protection from NAFLD in Diabetic Mice
Authors: LIN QIAN , CAI GENXIANG , LIU ZHENGSHUAI , LI JINGYA , LI JIA , WINTERGERST KUPPER A. , EPSTEIN PAUL N. , CAI LU , LI YU , TAN YI
Published: June 2020

Fibroblast growth factor 1 (FGF1) demonstrated protection against nonalcoholic fatty liver disease (NAFLD) in type 2 diabetic (T2D) and obese mice by uncertain mechanism. This study investigated the therapeutic activity and mechanism of a non-mitagenic FGF1 variant (FGF1ΔHBS) against NAFLD. FGF1ΔHBS administration was effective in 9-month old db/db mice with established NAFLD; liver weight, lipid deposition and inflammation declined and liver function improved. FGF1ΔHBS reduced oxidative stress by nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and elevation of antioxidant protein expression. FGF1ΔHBS also inhibited activity and/or expression of lipogenic genes, coincident with phosphorylation of AMP-activated protein kinase (AMPK) and its substrates. Mechanistic studies on palmitate exposed hepatic cells demonstrated that NAFLD-like oxidative damage and lipid accumulation could be reversed by FGF1ΔHBS. In palmitate treated hepatic cells, siRNA knockdown of Nrf2 abolished only FGF1ΔHBS anti-oxidative actions but not lipid metabolism improvement. In contrast, AMPK inhibition by pharmacological agents or siRNA abolished both FGF1ΔHBS benefits on oxidative stress and lipid metabolism that was FGF receptor 4 (FGFR4) dependent. Further support of these in vitro findings is that liver specific AMPK knockout abolished therapeutic effects of FGF1ΔHBS against high-fat-high-sugar diet-induced hepatic steatosis. These findings indicate that FGF1ΔHBS is effective in late stage NAFLD and acts by activation of AMPK via hepatocyte FGFR4.

Disclosure

Q. Lin: None. G. Cai: None. Z. Liu: None. J. Li: None. J. Li: None. K.A. Wintergerst: None. P.N. Epstein: None. L. Cai: None. Y. Li: None. Y. Tan: None.

Funding

American Diabetes Association (1-13-JF-53 to Y.T.), (1-18-IBS-082 to L.C.)
1856-P: Hepatic Insulin Clearance Is Not Driven by Liver Fat but by Systemic Inflammation: A Mendelian Randomization Study
Authors: LAMPRINOU APOSTOLIA , MACHANN JÜRGEN , SCHICK FRITZ , ECKSTEIN SABINE S. , MAN CHIARA DALLA , VISENTIN ROBERTO , STEFAN NORBERT , BIRKENFELD ANDREAS L. , PETER ANDREAS , HAERING HANS-ULRICH , FRITSCHE ANDREAS , HENI MARTIN , WAGNER ROBERT
Published: June 2020

Introduction: Type 2 diabetes is not only associated with insulin resistance but also with decreased insulin clearance. Insulin is mostly eliminated from portal blood during the first pass through the liver. The magnitude of this effect is closely related to systemic insulin sensitivity. As insulin resistance is often accompanied by fatty liver, we here investigated whether there is a causal link between liver fat and hepatic insulin clearance (IC).

Methods: We computed IC using data from oral glucose tolerance tests in 3391 non diabetic individuals and the oral C-peptide and Insulin Minimal Models. Liver fat was quantified by 1H-MR-spectroscopy in 1211 participants. We performed Mendelian randomization analyses to test for causal determination of IC by liver fat and potentially related traits using established single nucleotide polymorphisms (liver fat: 115 SNPs, alanine-aminotransferase: 155 SNPs, insulin sensitivity: 37 SNPs, C-reactive protein: 193 SNPs).

Results: IC associated inversely with liver fat content (β=-0.1±0.03, p<0.003) and insulin sensitivity (β=0.6±0.03, p < 0.0001). Both liver fat content and IC were independently associated with insulin sensitivity (β=-0.2±0.03 and β=0.1±0.02 respectively, both p < 0.0001). Neither liver fat content nor alanine-aminotransferase were causally linked to IC (p=0.6 and 0.2, respectively), as indicated by the Mendelian randomization. On the other hand, both genetically determined insulin sensitivity and C-reactive protein levels influenced IC (β=0.3±0.1, p=0.04 and β=0.1±0.07, p=0.03, respectively).

Conclusion: This study supports the hypothesis that systemic effects such as inflammatory activity and/or genetic factors determining insulin resistance might modulate insulin extraction in the liver.

Disclosure

A. Lamprinou: None. J. Machann: None. F. Schick: None. S.S. Eckstein: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. R. Visentin: None. N. Stefan: None. A.L. Birkenfeld: None. A. Peter: None. H. Haering: None. A. Fritsche: None. M. Heni: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S. R. Wagner: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Eli Lilly and Company.

Funding

German Center of Diabetes Research (01GI0925)
1866-P: Adipocyte Hypertrophy Is Associated with Increased Dietary Fatty Acid Storage in Adipose Tissue and Reduced Postprandial Hepatic Fatty Acid Uptake and Esterification in Humans
Authors: YE RUN ZHOU , PHOENIX SERGE , NOLL CHRISTOPHE , MONTASTIER EMILIE , FRISCH FRÉDÉRIQUE , BOUFFARD LUCIE , AMRANI MEHDI , TURCOTTE ERIC E. , CARPENTIER ANDRÉ C.
Published: June 2020

Introduction: Excessive exposure of lean tissues to nonesterified fatty acids (NEFA) leads to insulin resistance (IR). Adipocyte hypertrophy is associated with IR and increase in adipose tissue intracellular triglyceride lipolysis and in NEFA levels, that may contribute to hepatic steatosis and IR. The effect of adipocyte hypertrophy on postprandial hepatic NEFA flux and metabolism and dietary fatty acids (DFA) storage in adipose tissues has not been studied, however.

Methods: In 28 healthy adult subjects, fat cell size (FCS) was determined via histomorphologic analysis of abdominal subcutaneous fat tissue. Adipose tissue DFA storage was measured using oral administration of 18FTHA with positron emission tomography (PET). Postprandial hepatic NEFA uptake, oxidation, and esterification were determined using intravenous 11C-palmitate with dynamic PET acquisition.

Results: As expected, FCS was correlated positively with fasting glycemia (ρ=0.44, P-value=0.029), homeostasis model assessment-estimated insulin resistance (HOMA-IR) (ρ=0.43, P-value=0.049), and hepatic fat content from CT radiodensity (ρ=0.32, P-value=0.10). FCS was correlated positively with DFA storage in intra-abdominal adipose tissues (ρ=0.48, P-value=0.022) and negatively with postprandial hepatic NEFA uptake (ρ=-0.42, P-value=0.027) and esterification (ρ=-0.58, P-value=0.0080).

Conclusion: Adipocyte hypertrophy is associated with increased DFA storage in intra-abdominal adipose tissues and reduced postprandial hepatic NEFA uptake and esterification, despite being associated with greater hepatic fat content, fasting glycemia and HOMA-IR. Adipocyte hypertrophy is thus associated with adipose tissue metabolic adaptation that limits the exposure of the liver to fatty acids in the postprandial period.

Disclosure

R. Ye: None. S. Phoenix: None. C. Noll: None. E. Montastier: None. F. Frisch: None. L. Bouffard: None. M. Amrani: None. E.E. Turcotte: None. A.C. Carpentier: Advisory Panel; Self; HLS Therapeutics, Inc.

Funding

Canadian Institutes of Health Research (MOP53094); Centre de recherche du CHUS; Centre d’imagerie moléculaire de Sherbrooke; Faculté de médecine et des sciences de la santé de l’Université de Sherbrooke
1888-P: Activation of Myocardial Mitochondrial Akt1 Remotely Modulated Body Composition and Adiposity through LXR/RXR Signaling
Authors: CHEN YU-HAN , TA ALBERT , TOM EMILY , CHEN YUMAY , WANG PING H.
Published: June 2020

Insulin resistance contributed to the development of type 2 diabetes (T2D) and is a major risk factor for diabetic cardiomyopathy (DCM). We have previously reported that insulin resistance led to impaired Akt1 translocation into myocardial mitochondria in DCM. To study the role of mitochondrial Akt1 in DCM, we have generated two cardiac-specific inducible Cre-lox transgenic mice models that expresses (1) a mitochondria-targeting dominant negative Akt (CAMDAKT) or (2) a mitochondria-targeting constitutively active Akt (CAMCAKT) upon Tamoxifen induction (T). T-CAMDAKT mice showed LV dysfunction with increased heart failure markers, while T-CAMCAKT mice restored LV dysfunction to normal in the T2D model. In a T2D model induced by high fat/high fructose diet with relative insulin deficiency, T-CAMCAKT mice showed lower body fat mass (16.6% vs. 26.5%, p<0.001) and higher body lean mass (77.1% vs. 68.1%, p<0.001). To study the mechanism underlying the changes of body composition, we performed transcriptomic profiling and analysis in gonadal white adipose tissues (WAT) by bulk RNA sequencing. When compared to the control T2D mice, 544 genes were upregulated and 1077 genes were downregulated in the WAT of T-CAMCAKT T2D mice. The result indicated enhanced lipid catabolism, triglyceride catabolism, HDL assembly, and downregulated critical nuclear transcription. Pathway analysis revealed the Liver X receptor/Retinoid X receptor signaling was activated in WAT of T-CAMCAKT mice as compared to the controls. This was accompanied by increased fatty acid oxidation and apolipoproteins expression. These findings suggest that impaired mitochondrial Akt signaling in DCM could remotely increase adiposity by reducing lipid catabolism in WAT through modulating LXR/RXR signaling.

Disclosure

Y. Chen: None. A. Ta: None. E. Tom: None. Y. Chen: None. P.H. Wang: Board Member; Self; Dianavi.

Funding

National Institutes of Health (R01HL096987)
1900-P: HNF1A Deficiency Leads to Perturbed Glucagon Secretion in Humans
Authors: SAPONARO CHIARA , ACOSTA-MONTALVO ANA , ANGUELOVA LIA , THEVENET JULIEN , CHIRAL MAGALI , PASQUETTI GIANNI , PIRON ANTHONY , CNOP MIRIAM , GMYR VALERY , PREHN JOCHEN , KERR-CONTE JULIE A. , PATTOU FRANCOIS , PONTOGLIO MARCO , OWEN KATHARINE R. , SPILIOTIS IOANNIS , BONNER CAROLINE
Published: June 2020

Mutations in HNF1A cause Maturity Onset Diabetes of the Young (HNF1A-MODY). Carriers are normoglycemic in childhood, but with age, they develop hyperglycemia associated with insulin secretory defects and beta cell dysfunction. Although endogenous glucose production has been reported, glucagon in HNF1A-MODY has been less explored. Patients respond well to low dose sulfonylureas such as gliclazide, which increases insulin secretion independent of glucose but may predispose to hypoglycemia. We aimed to investigate whether low dose gliclazide had an effect on glucagon secretion in HNF1A-MODY. Additionally, we explored the potential of GLP-1 to normalize hormone secretion using in vivo and in vitro models of HNF1A deficiency. A 75g oral glucose tolerance test was performed in 7 MODY patients before and 72h after stopping gliclazide. Glucose rise was greater off gliclazide (p=0.003), while c-peptide and glucagon levels were similar between the groups. When adjusting for glucose levels during the OGTT, the change from baseline glucagon levels (Δ glucagon/glucose ratio) showed a significant decrease in those taking gliclazide (p=0.048), while there was no difference in Δ c-peptide/glucose ratio. Hnf1a-/- mice compared to WT mice are hyperglycemic, have decreased plasma insulin levels and hyperglucagonemia that was not suppressed after a glucose challenge (p=0.008). Furthermore, induction of the HNF1A variant Pro291fsInsC in rat INS1 cells reduced insulin and increased glucagon secretion, both of which were improved by GLP-1 treatment. Using the TIGER database we found HNF1A to be heterogeneously expressed in human islets, and siHNF1A reduced insulin secretion at high glucose. Collectively, these findings indicate that HNF1A is also essential for the regulation of glucagon secretion and glucose homeostasis. The mechanism by which GLP-1 normalizes insulin and glucagon secretion needs further investigation but could contribute to a better understanding of treatment response in HNF1A-MODY.

Disclosure

C. Saponaro: None. A. Acosta-Montalvo: None. L. Anguelova: None. J. Thevenet: None. M. Chiral: None. G. Pasquetti: None. A. Piron: None. M. Cnop: None. V. Gmyr: None. J. Prehn: None. J.A. Kerr-Conte: None. F. Pattou: None. M. Pontoglio: None. K.R. Owen: None. I. Spiliotis: None. C. Bonner: None.

Funding

European Foundation for the Study of Diabetes/Lilly European Diabetes Research Programme; Oxford Health Sciences Research Committee (1233)
1901-P: Individual and Longitudinal Effects of Gastric Bypass Surgery on the Circulating Proteome
Authors: THOMAS CECILIA E. , HÄUSSLER RAGNA S. , HONG MUN-GWAN , RAVERDY VIOLETA , DALE MATILDA , CANOUIL MICKAËL , MAZZONI GIANLUCA , VIÑUELA ANA , FROGUEL PHILIPPE , BRUNAK SØREN , SCHWENK JOCHEN M. ,   THE IMI DIRECT CONSORTIUM
Published: June 2020

Roux-en-Y gastric bypass surgery (RYGB) has been effective for inducing weight-loss and remission of diabetes in obese persons. Nonetheless, the response to RYGB and resulting improvements in glycemic control are heterogeneous and not well understood. To gain molecular insights into how individuals respond to RYGB, we monitored the longitudinal effects of RYGB surgery via circulating proteins. We quantified 368 proteins using multiplexed and sensitive immunoassays (Olink) in sera collected from 146 obese persons with T2D (BMI > 35 kg/m2) prior to, and at one and three months after surgery. We observed an overall longitudinal change in circulating levels for ∼50% of the proteins (FDR < 0.01). This included a post-RYGB increase in levels of GH, IGFBP-2, NT-proBNP, REGA1 and MMP-3, as well as a decrease in levels of SSC4D, SERPINA12, GIF, FBP1, CES1. To deconvolute the inter-individual heterogeneity of the circulating proteomes and protein-related longitudinal dynamics, we clustered the total of ∼44,000 protein profiles into 10 response patterns. Just 8% (28/368) of the proteins’ levels changed in a common manner across the majority of individuals, as these were grouped into 3 or fewer clusters. Among these were proteins related to adipogenesis (LEP, DLK1, GH), white adipocyte differentiation (LEP, FABP4), as well as innate immunity (CHIT1, PTX3, CSTB). However, out of these 28 proteins, only levels of VSIG2 were significantly associated (FDR < 0.01) with diabetes remission at 12 months (HbA1c < 6.5%, no diabetes medication). Overall, our results suggest a wide-reaching, individual-specific, but predominantly short-term impact of RYGB surgery on the circulating proteome. Current investigations examine how genetic variance and mRNA expression in adipose and liver tissue influence the donors’ circulating proteomes in order to explain the observed heterogeneity and its impact on a person’s molecular homeostasis.

Disclosure

C.E. Thomas: None. R.S. Häussler: None. M. Hong: None. V. Raverdy: None. M. Dale: None. M. Canouil: None. G. Mazzoni: None. A. Viñuela: None. P. Froguel: None. S. Brunak: Board Member; Self; Intomics A/S, Proscion A/S. Research Support; Self; Novo Nordisk Foundation. Stock/Shareholder; Self; Lundbeck, Novo Nordisk A/S. J.M. Schwenk: None.

Funding

Innovative Medicines Initiative Joint Undertaking (115317); European Union’s Seventh Framework Programme (FP7/2007-2013); Conseil Regional Nord-Pas-de-Calais; European Commission (FEDER 12003944); European Genomic Institute for Diabetes (ANR-10-LABX-46); Foundation Coeur et Arteres (R15112EE); Fonds hospitalier d’aide a l’emergence et a la structuration des activities et des equipes de recherche 2015 (CHRU Lille, France)
1912-P: Bariatric Surgery Downregulates Glucocorticoid Signaling in Mice
Authors: AKALESTOU ELINA , NORIEGA LIVIA LOPEZ , CHRISTAKIS IOANNIS , LECLERC ISABELLE , RUTTER GUY A.
Published: June 2020

Background: Glucocorticoids (GC) produced by the adrenal cortex are essential for the maintenance of metabolic homeostasis. GC activation is catalyzed by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and signalling is achieved through the glucocorticoid receptor (GR), a ligand-dependent transcription factor. Excess glucocorticoids are associated with insulin resistance and hyperglycaemia. A small number of studies have investigated the effects of bariatric surgery, a gastrointestinal procedure known to improve insulin sensitivity, on glucocorticoid metabolism, but the hypothesised mechanism is assumed to be via weight loss.

Aim: To investigate the effect of bariatric surgery on glucocorticoid metabolism in lean and obese mice.

Methods: Fourteen lean mice and twelve HFD mice underwent Vertical Sleeve Gastrectomy (VSG) (n=7-8) or sham (n=5-6) surgery. Glucose and insulin tolerance tests were performed four weeks post operatively. Liver, gut and adipose tissue were harvested from fed mice and analysed using Quantitative real-time PCR (qRT-PCR) and Western Blot (WB).

Results: VSG did not cause excess weight loss in lean mice when compared to sham operated mice (p=0.37). However, both lean and HFD VSG mice displayed significantly improved glucose and insulin tolerance (p<0.001). Of note, qPCR and Western blotting analysis on mouse liver demonstrated a significant lowering of 11β-HSD1 levels 4 and 12 weeks after VSG (p<0.01). Additionally, in lean mice, 11β-HSD1 expression was also lowered in omental adipose tissue (p=0.01) and GR expression was inhibited in liver and ileum at the transcript level (p<0.05).

Conclusions: Bariatric surgery improves insulin sensitivity and reduces glucocorticoid activation physiologically and in the obese state, irrespective of weight loss. The reduction in glucocorticoid signalling may represent an additional contribution to the health benefits of bariatric surgery. These findings point towards a physiologically-relevant gut-adrenal axis.

Disclosure

E. Akalestou: None. L. Lopez Noriega: None. I. Christakis: None. I. Leclerc: Consultant; Spouse/Partner; Sun Pharmaceutical Industries Ltd. Research Support; Spouse/Partner; Servier. G.A. Rutter: Consultant; Self; Sun Pharmaceutical Industries Ltd. Research Support; Self; Servier, Sun Pharmaceutical Industries Ltd.

Funding

Rosetrees Foundation (M825); British Society for Neuroendocrinology; Society for Endocrinology (19ES001); UK Wellcome Trust (212625/Z/18/Z); Medical Research Council UK (MR/R022259/1); European Union (115881)
1922-P: Type 2 Adipocyte Subpopulation Mediates Obesity-Associated Inflammation in a PPARγ Dependent Pathway
Authors: HUANG JUN , SHARMA RITA , LEE KEVIN Y.
Published: June 2020

Recent studies have shown that heterogeneity among adipocytes exists within a single WAT depot. Our lab has uncovered three developmentally distinct subpopulations of WAT adipocytes distinguished by the expression of these genes: Wilms’ Tumor 1 (Wt1) (Type 1), Transgelin (Tagln) (Type 2), and Myxovirus 1 (Mx1) (Type 3). Utilizing Cre transgenic mice, transcription of which is directed by the promoters of these marker genes, lineage tracing analysis showed that these three preadipocyte subpopulations independently gave rise to adipocytes in vivo, and differentially contribute to the adipose tissue depots. This study extends these findings to investigate the role of Type 2 adipocytes during obesity. The number of Type 2 preadipocytes and adipocytes was not significantly altered by high fat diet induced obesity. However, greater than 80% of recruited macrophages, organized into crown-like structures were found in direct contact with Type 2 adipocytes, suggesting increased apoptosis of this adipocyte subpopulation. Furthermore, treatment of Type 2 adipocytes with the inflammatory cytokine TNFα promoted a 15% increase apoptosis specifically in Type 2 adipocytes, with no effects on other adipocytes. RNA-seq analysis of Type 2 adipocytes revealed a global downregulation of 102 of 298 known PPARγ regulated genes in Type 2 adipocytes. Although PPARγ mRNA was not altered, the protein level of PPARγ was reduced by 60% in Type 2 vs. control adipocytes. Pre-treatment of Type 2 adipocytes with the PPARγ agonist, rosiglitazone reduces TNFα-induced apoptosis in this subpopulation to similar levels found in control adipocytes, suggesting that reduced PPARγ activity in Type 2 adipocytes may, at least in part, regulates obesity-associated inflammation. Thus, further investigation of the physiological role of these adipocyte subpopulations are promising avenues of study to develop novel treatment strategies to combat diabetes and other disorders associated with the obesity epidemic.

Disclosure

J. Huang: None. R. Sharma: None. K.Y. Lee: None.

Funding

Ohio University
1927-P: Protective Role of DNAJB3 Cochaperone against Obesity-Induced Insulin Resistance and Diabetes
Authors: DEHBI MOHAMMED , DIANE ABDOULAYE , SCOGGIN SHANE , BENSMAIL ILHAM , KHATTAB NAMAT , RAMALINGAM LATHA , EFOTTE ALIYAH , MOUSTAID-MOUSSA NAIMA
Published: June 2020

The last decade has witnessed a dramatic increase in the prevalence of obesity and type 2 diabetes (T2D) in some Middle Eastern countries. In the GCC countries, over 35% and 20% develop obesity and T2D, respectively. Of extreme concern, the disease starts affecting the population at a relatively younger age (∼40 years), and vulnerable individuals manifest severe insulin resistance (IR). We previously showed that subjects with obesity and T2D among the Kuwaiti population have reduced expression of DNAJB3 that was associated with increased metabolic stress and poor clinical outcomes. Furthermore, physical exercise was effective in restoring the normal expression of DNAJB3 with the concomitant metabolic improvements. These observations suggest a therapeutic value of DNAJB3 against obesity-associated metabolic diseases. To gain further insights into this protective role, we generated mice lacking DNAJB3 using CRISPR/Cas9 approach, and challenged them with high fat diet (HFD). We also determined the in vitro effects of DNAJB3 overexpression/knockdown in modulating metabolic stress, mitochondrial and glucose homeostasis in C2C12 cells. Accordingly, DNAJB3 KO mice showed increased body weight and fat mass in response to HFD, compared to wild type. In addition, DNAJB3 KO mice on HFD exhibited increased glucose intolerance. Moreover, overexpression of DNAJB3 prevented the activation of both JNK and IKK in response to palmitate and inflammatory cytokines, respectively; while it promoted the PI3K/AKT pathway and both basal and insulin-stimulated glucose uptake. These observations were consistent with DNAJB3 knockdown experiments. Mechanistically, we showed a significant effect of DNAJB3 on enhancing Glut4 translocation and stimulating expression of key mitochondrial markers including PPARγ, PGC1α and OXPHOS. Together, these data indicate an important physiological role of DNAJB3 in obesity-induced IR and T2D and warrant further in vivo animal and clinical investigations.

Disclosure

M. Dehbi: None. A. Diane: None. S. Scoggin: None. I. Bensmail: None. N. Khattab: None. L. Ramalingam: None. A. Efotte: None. N. Moustaid-Moussa: None.

Funding

Qatar Biomedical Research Institute (IGP 2014-001)
193-OR: Physiology-Informed Type 2 Diabetes Genetic Clusters and Gestational Diabetes
Authors: POWE CAMILLE E. , UDLER MIRIAM , HSU SARAH , KUANG ALAN , ALLARD CATHERINE , MANNING ALISA , BOUCHARD LUIGI , PERRON PATRICE , FLOREZ JOSE C. , LOWE WILLIAM , SCHOLTENS DENISE , HIVERT MARIE-FRANCE
Published: June 2020

Background: We previously described physiology-informed genetically-anchored type 2 diabetes (T2D) clusters based on associations between glycemic traits and T2D-associated variants discovered in prior GWAS. Cluster polygenic scores (PSs) delineate T2D subtypes with distinct features (e.g., reduced beta-cell function, obesity, lipodystrophy-like). These PSs have not been tested for association with gestational diabetes (GDM).

Methods: We tested for associations between PSs (beta-cell, proinsulin, lipodystrophy, obesity, liver/lipid) and traits at 24-30 weeks gestation in the Gen3G cohort (N=582, 97% white non-Hispanic) with linear regression (β=change per 1 SD increase in PS). In 3 cohorts [Gen3G, HAPO (N=1369, 100% white non-Hispanic) MGH2(N=621, 62% white non-Hispanic)], we tested for associations between PSs and GDM using logistic regression and conducted fixed effects meta-analyses.

Results: The beta-cell PS was associated with higher 1-hr OGTT glucose (β=4.5 mg/dl, P<0.001) and lower insulin secretory response (β=-45.7 Stumvoll 1st phase index, P=0.02). The obesity PS was associated with higher BMI (β=0.5 kg/m2, P=0.03) and HbA1c (β=0.03%, P=0.02). The lipodystrophy PS was associated with higher 1-hr OGTT glucose (β=2.6 mg/dl, P=0.03), higher fasting triglycerides (TGs) (β=6 mg/dl, P=0.01), and lower insulin sensitivity (β=-0.6 Matsuda index, P=0.005). The liver/lipid PS was associated with lower fasting TGs (β=-11 mg/dl, P<0.001). In 3-cohort meta-analyses (297 cases), only the beta-cell PS was associated with GDM (OR 1.19, P=0.009). There was heterogeneity across cohorts for the liver/lipid PS-GDM association. No PS was associated with birth weight. Adjustment for maternal age and genetic principal components did not alter results.

Conclusion: Clusters of T2D-associated genetic variants derived based on physiology outside of pregnancy are associated with expected traits in pregnancy. A cluster representing reduced beta-cell function is associated with GDM.

Disclosure

C.E. Powe: None. M. Udler: None. S. Hsu: None. A. Kuang: None. C. Allard: None. A. Manning: None. L. Bouchard: None. P. Perron: None. J.C. Florez: Advisory Panel; Self; Doris Duke Charitable Foundation. Other Relationship; Self; Novo Nordisk Inc., Park Street School. W. Lowe: None. D. Scholtens: None. M. Hivert: None.

Funding

American Diabetes Association (1-15-ACE-26 to M-F.H.); National Institutes of Health (K23DK113218); Robert Wood Johnson Foundation; Harold Amos Medical Faculty Development Award (72456)
1930-P: The Knockdown of TRIL in POMC-Expressing Neurons Reduces Body Adiposity and Ameliorates Leptin Responsiveness
Authors: MOURA-ASSIS ALEXANDRE , JUNIOR JOSÉ , GASPAR JOANA M. , VELLOSO LICIO , NOGUEIRA PEDRO AUGUSTO S.
Published: June 2020

Chronic HFD intake induces low-grade inflammation in the hypothalamus, which is characterized by proinflammatory cytokine overproduction. This process occurs, at least in part, via TLR4 activation by circulant saturated fatty acids. The TLR4 signaling in the brain is mediated by the TLR4 interactor with leucine-rich repeats (TRIL), an upstream accessory protein. Our main purpose was to determine the putative involvement of TRIL in diet-induced hypothalamic inflammation. We employed male, 8-12 week-old C57BL and POMCCRE mice fed on chow or HFD. The mRNA levels in the hypothalamus were measured by RT-PCR, western blot analyses was used for determination of protein content and immunofluorescence microscopy for evaluate the distribution of TRIL in arcuate nucleus (ARC) of hypothalamus and leptin signaling in POMC-expressing neurons. Finally, bilateral viral injections were performed to non-specific knockdown of TRIL in ARC using shRNA-based lentivirus and Cre-dependent AAV to knockdown TRIL specifically in POMC neurons. The non-specific knockdown of TRIL in the ARC of mice fed on HFD attenuated body weight gain despite no alterations in food intake, improved glucose homeostasis and increased energy expenditure. Moreover, nlrp3, il1β and hspa5 mRNA expression were decreased upon knockdown of TRIL. POMC-specific knockdown of TRIL reduced body fat with no changes in food intake or body weight gain in mice fed on HFD for 8 weeks. The inhibition of TRIL in POMC neurons resulted in a trend of improved leptin signaling in those neurons. We also found increased expression of thermogenic genes in the iBAT and improved fasting glucose. POMC-specific inhibition of TRIL in mice fed on HFD for long-term (24 weeks) did not prevent POMC loss or diminishes cleaved-caspase 3 in ARC. Collectively our results suggest that TRIL is involved in the TLR4-mediated early response to dietary fats and TRIL targeting counteract hypothalamic inflammation and partially restores metabolic homeostasis.

Disclosure

A. Moura-Assis: None. J. Junior: None. J.M. Gaspar: None. L. Velloso: None. P.S. Nogueira: None.

Funding

São Paulo Research Foundation (2016/01245-5)
1987-P: Inflammation and Insulin Resistance in Adipose Tissue
Authors: SØNDERGAARD ESBEN , ESPINOSA DE YCAZA ANA E. , MORGAN-BATHKE MARIA , LYTLE KELLI , DELIVANIS DANAE A. , CARRANZA LEON BARBARA G. , JENSEN MICHAEL D.
Published: June 2020

Background: Adipose tissue inflammation is linked to adipose tissue insulin resistance. However, whether this is a causal relationship remains controversial. Therefore, we aimed to explore the relationship between measures of adipose tissue inflammation and adipose tissue insulin sensitivity over a wide range of body fat distribution and adipose tissue insulin sensitivity.

Methods: We recruited a total of 87 volunteers (30 men and 57 women). Adipose tissue insulin sensitivity was quantified as the insulin concentration required for a 50% suppression of lipolysis (IC50). Lipolysis was measured as steady-state palmitate flux before and during a hyperinsulinemic-euglycemic clamp. Adipose tissue macrophage (ATM) was quantified by immunohistochemistry with antibodies against CD68 (total ATM), CD14 (pro-inflammatory ATM) and CD206 (anti-inflammatory ATM) and senescent preadipocyte content was quantified by β-galactosidase positivity using fluorescent microscopy in abdominal and femoral fat biopsies.

Results: Total ATM content was only weakly associated with IC50 in abdominal fat (r=0.26, p=0.01) and no association was observed for femoral fat. No association was observed between IC50 and pro-inflammatory ATM content. Anti-inflammatory ATM content was associated with IC50 in abdominal (r=0.46, p<0.001) and femoral (r=0.33, p=0.02) fat. Senescent preadipocyte content was weakly associated with IC50 in femoral fat (r=0.36, p=0.01), but no association was observed in abdominal fat. Fat cell size was strongly associated with IC50 in both abdominal (r=0.6 p<0.001) and femoral (r=0.48, p<0.01) fat.

Conclusions: ATM content is only weakly associated to adipose tissue insulin sensitivity. Only the content of anti-inflammatory, not pro-inflammatory macrophages, was associated with adipose tissue insulin sensitivity. This argues against pro-inflammatory macrophages as mediators of insulin resistance in adipose tissue.

Disclosure

E. Søndergaard: None. A.E. Espinosa De Ycaza: None. M. Morgan-Bathke: None. K. Lytle: None. D.A. Delivanis: None. B.G. Carranza Leon: None. M.D. Jensen: None.

Funding

National Institutes of Health (DK40404, DK45343)
200-LB: Ceramide Kinase CERK Regulates Inflammatory Responses in Monocytes/Macrophages Induced by TNF-a
Authors: ALRASHED FATEMA , AHMAD RASHEED
Published: June 2020

Obesity is associated with elevated levels of TNF-α and proinflammatory CD11c monocytes/macrophages. TNF-α mediated dysregulation in the plasticity of monocytes/macrophages is concomitant with pathogenesis of several inflammatory diseases, including metabolic syndrome, but the underlying mechanisms are incompletely understood. Since Ceramide kinase (CERK; a critical mediator of eicosanoid synthesis, and its product, ceramide-1-phosphate (C1P)) is a key enzyme for ceramide production involved in inflammation, we investigated whether the CERK contributed to the inflammatory changes in the monocytes/macrophages induced by TNF-α. In this study, we demonstrate that the disruption of CERK activity in monocytes/macrophages either by chemical inhibitor NVP- 231 or small interfering RNA (siRNA)against CERK gene results in defects in the TNF-α mediated expression of CD11c and CD11b and HLA-Dr. Furthermore, blockage of CERK in monocytes/macrophages inhibited the secretion of IL-1b and MCP-1. Phosphorylation of JNK, p38 and NF-κB resulting from TNF-α stimulation was also attenuated by the inhibition of CERK. Moreover, NF-kB/AP-1 activity was blocked by the inhibition of CERK. Our human data show that CERK was elevated in PBMCs from obese individuals and positively corelated with TNF-α. These findings indicate that CERK acts, in a part, as a master switch in the TNF-α mediated inflammatory responses in monocytes/macrophages.

Disclosure

F. Alrashed: None. R. Ahmad: None.

Funding

Kuwait Foundation for the Advancement of Sciences (RA-AM 2016007)
2021-P: Comparing BMI and Physical Activity with Diabetes Risk in College Freshman: The HERD Study
Authors: POWELL ROBERT , CYPHERT HOLLY
Published: June 2020

Obesity and Physical Inactivity are leading risk factors for insulin resistance and type 2 diabetes. West Virginia leads the U.S. in obesity rates and ranks 11th for no leisure time physical activity. Data is scarce examining modifiable risk factors in young adults transitioning from high school to college. The purpose of this analysis was to examine the relationship between BMI and Physical Activity on insulin levels in college-aged freshman enrolled in the HERD (Higher Education Reducing Diabetes) Study at Marshall University in Huntington, West Virginia. The HERD Study is a 4 year, randomized study examining the effects of a freshman healthy lifestyle intervention on type 2 diabetes risk. One hundred eighty three freshman enrolled into the study [age= 18.3±1.5 years; female=59.4%(n=107); 85.5% Caucasian(n=153); BMI= 27.3±8.1 kg/m2; VO2max=35.6 ±8.59 ml/kg/min]. Diabetes risk values were A1c= 5.09±.43%; fasting glucose= 85.9±9.66 mg/dl; insulin= 0.76±.60ng/ml. Fifty four percent (n=92) of students were deemed overweight or obese (BMI ≥ 25 kg/m2) while 67% (n= 122) did not meet current physical activity guidelines. No significant differences were found between BMI and A1c (p=.48) or fasting glucose (p=.82). However, students with a BMI ≥25 kg/m2 showed fasting insulin levels twice as high as students with a BMI <25 kg/m2 (.50 vs. .98 ng/ml, p=.003). With physical activity, there was a significant, inverse correlation between VO2max and insulin levels (r=-.23, p=.048). However, no differences were found between students whom aerobic train vs. not aerobic train (p=.60). A trend was shown where resistance trained students had lower insulin levels compared to non-resistance trained (.52+.61 vs. .77+.37 ng/ml, p=.06). BMI and fitness measures appear to impact insulin levels in college-aged freshman thereby increasing their risk for diabetes. Future analysis will examine the effects of lifestyle intervention on improvements in BMI and cardiometabolic markers.

Disclosure

R. Powell: None. H. Cyphert: None.
2030-P: The Efficacy of Laparoscopic Sleeve Gastrectomy in Severely Obese Patients with Varying Serum Triglyceride Levels
Authors: LI GUIFANG , HUANG YUEYE , ZHANG JUNYI , WANG XINGCHUN , QIAN CHUNHUA , CHENG XIAOYUN , QU SHEN
Published: June 2020

Purpose: To investigate the metabolic improvements in obese patients with different serum triglyceride (TG) levels after laparoscopic sleeve gastrectomy (LSG).

Methods: 118 severely obese patients [body mass index (BMI)>35kg/m2] underwent LSG with complete information of follow-up for 3 and 6 months were analyzed. Patients were divided into two groups based on their different baseline serum levels of TG.

Results: The metabolic parameters (BMI, NC, WC, HC, WHR, blood pressure, liver function, blood glucose, blood lipids, insulin resistance, HbA1c, and UA) of the normal and higher TG groups were significantly improved after surgery. Patients with normal TG had better improvement in BMI and WC compared with higher TG patients in both 3 and 6 months. After adjustment for age and gender, ΔWC positively correlated with ΔBMI (r=0.446, P<0.001), creatinine level (ΔCr, r=0.365, P=0.005) in the normal group in 3 months follow-up. In 6 months after LSG, ΔWC positively correlated with ΔBMI (r=0.657, P<0.001) and ΔCr (r=0.442, P=0.009) while ΔWC negatively correlated with the change in eGFR level (ΔeGFR, r=-0.374, P=0.009) in the normal group. In addition, multivariate linear regression analysis showed that decreased ΔWC levels significantly correlated with ΔBMI (β=1.333, R2 =0.259, P<0.001) and ΔCr (β=0.336, R2 =0.160, P=0.005) both in 3 months and 6 months after LSG.

Conclusion: LSG can effectively improve metabolic disorders. Moreover, there were differences in weight loss between the normal and high TG groups after LSG, indicating that the baseline TG level can be used to predict short-term weight loss after LSG.

Disclosure

G. Li: None. Y. Huang: None. J. Zhang: None. X. Wang: None. C. Qian: None. X. Cheng: None. S. Qu: None.

Funding

National Key Research and Development Program of China (2018YFC1314100); National Natural Science Foundation of China (81970677); Shanghai Pujiang Program (2019PJD040); Shanghai Committee of Science and Technology (18411951803, 17DZ1910603)
2043-P: Hyaluronan Produced by Inflamed Islet Endothelial Cells Contributes to HIAPP Aggregation
Authors: CASTILLO JOSEPH J. , HOGAN MEGHAN F. , APLIN ALFRED , ESSER NATHALIE , TEMPLIN ANDREW T. , HULL REBECCA L.
Published: June 2020

In type 2 diabetes (T2D), aggregation of human islet amyloid polypeptide (hIAPP) occurs within the islet extracellular matrix (ECM) and is toxic to β cells. We recently showed that hIAPP aggregation also induces a pro-inflammatory response in islet endothelial cells (ECs). In most tissues, this inflammatory response in ECs is mediated by upregulating production of ECM components, such as hyaluronan (HA). Indeed, we find that HA accumulates in the islet ECM of hIAPP transgenic mice, where it was colocalized with amyloid deposits, while no HA accumulation occurred in non-transgenic littermate controls (which do not develop islet amyloid). Therefore, we hypothesized that hIAPP aggregation results in HA production from islet ECs, and that this HA production exacerbates hIAPP deposition/toxicity. To test this hypothesis, we utilized immortalized murine islet ECs (MS-1 cells), which under normal conditions express low levels of HA synthase (Has isoforms 2 and 3). Treatment of these cells for 48 h with hIAPP (20 µM) increased Has2 and Has3 mRNA levels (23±4 and 8±1 fold over vehicle; n=4, p<0.05 for both), which was abrogated upon co-incubation with Congo red, an inhibitor of hIAPP aggregation (1.4±0.3 and 1.4±0.2 for Has2 and Has3, respectively; n=4). Next, we used a thioflavin T assay, wherein fluorescence is proportional to fibril formation from amyloidogenic peptides, to determine the kinetics of hIAPP aggregation ± HA. We found co-incubation of HA with synthetic hIAPP peptide resulted in a marked acceleration (log time of 1 vs. 40 hours) and increase in maximal (greater than 2-fold) hIAPP accretion. In sum, exposure of islet ECs to aggregated hIAPP increases HA synthesis by these cells, which in turn further exacerbates aggregation of hIAPP to form amyloid. Thus, interventions targeting endothelial cell inflammation and/or HA production may be useful in blocking amyloid formation and its toxic effects in T2D.

Disclosure

J.J. Castillo: None. M.F. Hogan: None. A. Aplin: None. N. Esser: None. A.T. Templin: None. R.L. Hull: None.

Funding

National Institutes of Health (T32HL007028)