Effects of saxagliptin and sitagliptin on glycaemic control and pancreatic β-cell mass in a streptozotocin-induced mouse model of type 2 diabetes

The incretins are peptide hormones secreted from the gut in response to food. They increase the secretion of insulin. The incretin response is reduced in patients with type 2 diabetes so drugs acting on incretins may improve glycaemic control. Incretins are metabolised by dipeptidyl peptidase, so selectively inhibiting this enzyme increases the concentration of circulating incretins. A similar effect results from giving an incretin analogue that cannot be cleaved by dipeptidyl peptidase. Studies have identified other actions including improvement in pancreatic β cell glucose sensitivity and, in animal studies, promotion of pancreatic β cell proliferation and reduction in β cell apoptosis.

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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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Islet Inflammation Impairs the Pancreatic β-Cell in Type 2 Diabetes

Physiology ◽

10.1152/physiol.00032.2009 ◽

2009 ◽

Vol 24 (6) ◽

pp. 325-331 ◽

Cited By ~ 171

Author(s):

Marc Y. Donath ◽

Marianne Böni-Schnetzler ◽

Helga Ellingsgaard ◽

Jan A. Ehses

Keyword(s):

Type 2 Diabetes ◽

Cell Mass ◽

Metabolic Stress ◽

Innate Immune ◽

Pancreatic Β Cell ◽

Β Cell ◽

Amyloid Deposits ◽

Impaired Insulin ◽

Islet Inflammation

Onset of Type 2 diabetes occurs when the pancreatic β-cell fails to adapt to the increased insulin demand caused by insulin resistance. Morphological and therapeutic intervention studies have uncovered an inflammatory process in islets of patients with Type 2 diabetes characterized by the presence of cytokines, immune cells, β-cell apoptosis, amyloid deposits, and fibrosis. This insulitis is due to a pathological activation of the innate immune system by metabolic stress and governed by IL-1 signaling. We propose that this insulitis contributes to the decrease in β-cell mass and the impaired insulin secretion observed in patients with Type 2 diabetes.

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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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Pancreatic β-Cell Proliferation in Obesity1,2

Advances in Nutrition ◽

10.3945/an.113.005488 ◽

2014 ◽

Vol 5 (3) ◽

pp. 278-288 ◽

Cited By ~ 46

Author(s):

Amelia K. Linnemann ◽

Mieke Baan ◽

Dawn Belt Davis

Keyword(s):

Type 2 Diabetes ◽

Cell Proliferation ◽

Cell Mass ◽

Pancreatic Β Cell ◽

Β Cell ◽

Extracellular Signals ◽

Secreted Factors ◽

And Function ◽

Hepatocyte Growth

Abstract Because obesity rates have increased dramatically over the past 3 decades, type 2 diabetes has become increasingly prevalent as well. Type 2 diabetes is associated with decreased pancreatic β-cell mass and function, resulting in inadequate insulin production. Conversely, in nondiabetic obesity, an expansion in β-cell mass occurs to provide sufficient insulin and to prevent hyperglycemia. This expansion is at least in part due to β-cell proliferation. This review focuses on the mechanisms regulating obesity-induced β-cell proliferation in humans and mice. Many factors have potential roles in the regulation of obesity-driven β-cell proliferation, including nutrients, insulin, incretins, hepatocyte growth factor, and recently identified liver-derived secreted factors. Much is still unknown about the regulation of β-cell replication, especially in humans. The extracellular signals that activate proliferative pathways in obesity, the relative importance of each of these pathways, and the extent of cross-talk between these pathways are important areas of future study.

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Clinical Potential of Extracellular Vesicles in Type 2 Diabetes

Frontiers in Endocrinology ◽

10.3389/fendo.2020.596811 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jie Liu ◽

Xin Sun ◽

Fu-Liang Zhang ◽

Hang Jin ◽

Xiu-Li Yan ◽

...

Keyword(s):

Type 2 Diabetes ◽

Extracellular Vesicles ◽

Sedentary Lifestyle ◽

Cell Mass ◽

Pancreatic Β Cell ◽

Β Cell ◽

Peripheral Tissues ◽

And Function ◽

Clinical Potential

Type 2 diabetes (T2D) is a major public health disease which is increased in incidence and prevalence throughout the whole world. Insulin resistance (IR) in peripheral tissues and insufficient pancreatic β-cell mass and function have been recognized as primary mechanisms in the pathogenesis of T2D, while recently, systemic chronic inflammation resulting from obesity and a sedentary lifestyle has also gained considerable attention in T2D progression. Nowadays, accumulating evidence has revealed extracellular vesicles (EVs) as critical mediators promoting the pathogenesis of T2D. They can also be used in the diagnosis and treatment of T2D and its complications. In this review, we briefly introduce the basic concepts of EVs and their potential roles in the pathogenesis of T2D. Then, we discuss their diagnostic and therapeutic potentials in T2D and its complications, hoping to open new prospects for the management of T2D.

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