196-OR: Pharmacological Modulation of Prostaglandin E2 Receptor Activity Enhances ß-Cell Mass in a Mouse Model of Type 2 Diabetes and Human Islets

The transition from β-cell compensation to β-cell failure is not well understood. Previous works by our group and others have demonstrated a role for Prostaglandin EP3 receptor (EP3), encoded by the Ptger3 gene, in the loss of functional β-cell mass in Type 2 diabetes (T2D). The primary endogenous EP3 ligand is the arachidonic acid metabolite prostaglandin E2 (PGE2). Expression of the pancreatic islet EP3 and PGE2 synthetic enzymes and/or PGE2 excretion itself have all been shown to be upregulated in primary mouse and human islets isolated from animals or human organ donors with established T2D compared to nondiabetic controls. In this study, we took advantage of a rare and fleeting phenotype in which a subset of Black and Tan BRachyury (BTBR) mice homozygous for the Leptinob/ob mutation—a strong genetic model of T2D—were entirely protected from fasting hyperglycemia even with equal obesity and insulin resistance as their hyperglycemic littermates. Utilizing this model, we found numerous alterations in full-body metabolic parameters in T2D-protected mice (e.g., gut microbiome composition, circulating pancreatic and incretin hormones, and markers of systemic inflammation) that correlate with improvements in EP3-mediated β-cell dysfunction.

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Development of a Nongenetic Mouse Model of Type 2 Diabetes

Experimental Diabetes Research ◽

10.1155/2011/416254 ◽

2011 ◽

Vol 2011 ◽

pp. 1-12 ◽

Cited By ~ 64

Author(s):

Elizabeth R. Gilbert ◽

Zhuo Fu ◽

Dongmin Liu

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Mouse Model ◽

Serum Insulin ◽

Cell Mass ◽

Low Fat ◽

Β Cell ◽

Islet Mass ◽

Metabolic Characteristics

Insulin resistance and loss of β-cell mass cause Type 2 diabetes (T2D). The objective of this study was to generate a nongenetic mouse model of T2D. Ninety-six 6-month-old C57BL/6N males were assigned to 1 of 12 groups including (1) low-fat diet (LFD; low-fat control; LFC), (2) LFD with 1 i.p. 40 mg/kg BW streptozotocin (STZ) injection, (3), (4), (5), (6) LFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively, (7) high-fat diet (HFD), (8) HFD with 1 STZ injection, (9), (10), (11), (12) HFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively. After 4 weeks, serum insulin levels were reduced in HFD mice administered at least 2 STZ injections as compared with HFC. Glucose tolerance was impaired in mice that consumed HFD and received 2, 3, or 4 injections of STZ. Insulin sensitivity in HFD mice was lower than that of LFD mice, regardless of STZ treatment. Islet mass was not affected by diet but was reduced by 50% in mice that received 3 STZ injections. The combination of HFD and three 40 mg/kg STZ injections induced a model with metabolic characteristics of T2D, including peripheral insulin resistance and reduced β-cell mass.

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A Novel Mouse Model for Type 2 Diabetes and Non-alcoholic Fatty Liver Disease: Spontaneous Amelioration of Diabetes by Augmented Beta Cell Mass

Endocrine Journal ◽

10.1507/endocrj.k08e-315 ◽

2009 ◽

Vol 56 (2) ◽

pp. 227-234 ◽

Cited By ~ 7

Author(s):

Aya OZE-FUKAI ◽

Tomomi FUJISAWA ◽

Ken SUGIMOTO ◽

Koji NOJIMA ◽

Nobuyasu SHINDO ◽

...

Keyword(s):

Type 2 Diabetes ◽

Liver Disease ◽

Mouse Model ◽

Beta Cell ◽

Fatty Liver Disease ◽

Cell Mass ◽

Beta Cell Mass ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

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Elevated Neuropeptide Y1 Receptor Signaling Contributes to β-cell Dysfunction and Failure in Type 2 Diabetes

10.1101/2021.05.14.444149 ◽

2021 ◽

Author(s):

Chieh-Hsin Yang ◽

Danise Ann-Onda ◽

Xuzhu Lin ◽

Stacey Fynch ◽

Shaktypreya Nadarajah ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glycaemic Control ◽

Neuropeptide Y ◽

Cell Mass ◽

Human Islets ◽

Receptor Signaling ◽

Β Cell ◽

Cell Dysfunction ◽

Y1 Receptor

Loss of functional β-cell mass is a key factor contributing to the poor glycaemic control in type 2 diabetes. However, therapies that directly target these underlying processes remains lacking. Here we demonstrate that gene expression of neuropeptide Y1 receptor and its ligand, neuropeptide Y, was significantly upregulated in human islets from subjects with type 2 diabetes. Importantly, the reduced insulin secretion in type 2 diabetes was associated with increased neuropeptide Y and Y1 receptor expression in human islets. Consistently, pharmacological inhibition of Y1 receptors by BIBO3304 significantly protected β-cells from dysfunction and death under multiple diabetogenic conditions in islets. In a preclinical study, Y1 receptor antagonist BIBO3304 treatment improved β-cell function and preserved functional β-cell mass, thereby resulting in better glycaemic control in both high-fat-diet/multiple low dose streptozotocin- and db/db type 2 diabetic mice. Collectively, our results uncovered a novel causal link of increased islet NPY-Y1 receptor signaling to β-cell dysfunction and failure in human type 2 diabetes. These results further demonstrate that inhibition of Y1 receptor by BIBO3304 represents a novel and effective β-cell protective therapy for improving functional β-cell mass and glycaemic control in type 2 diabetes.

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