Glucagon Receptor Knockout Prevents Insulin-Deficient Type 1 Diabetes in Mice

Lee, Young Ah; Wang, May-Yun; Du, Xiaoqing; Charron, Maureen J.; Unger, Roger H

doi:10.2337/db10-0426

Cited by 300 publications

(311 citation statements)

References 41 publications

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“…Loss of this paracrine inhibition in diabetes promotes hypersecretion of glucagon, and the hyperglycemia and hyperketonemia of diabetes classically thought to be a consequence of blunted insulin signaling are mediated, in part, by excess glucagon (Brand et al 1996, Lee et al 2011, Unger & Cherrington 2012. Therefore, abnormal alphacell function and an increased glucagon:insulin ratio are central to the pathology of fatty liver disease.…”

Section: Introductionmentioning

confidence: 99%

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Geisler

Renquist

2017

Journal of Endocrinology

153

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Fatty liver can be diet, endocrine, drug, virus or genetically induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator-activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic and ketogenic genes, promoting hyperglycemia, hyperlipidemia and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency and elevated sympathetic tone. These endocrine and metabolic changes further encourage hepatic steatosis by regulating adipose tissue lipolysis, liver lipid uptake, de novo lipogenesis (DNL), beta-oxidation, ketogenesis and lipid export. Hepatic lipid accumulation may be induced by 4 separate mechanisms: (1) increased hepatic uptake of circulating fatty acids, (2) increased hepatic de novo fatty acid synthesis, (3) decreased hepatic beta-oxidation and (4) decreased hepatic lipid export. This review will discuss the hormonal regulation of each mechanism comparing multiple physiological models of hepatic lipid accumulation. Nonalcoholic fatty liver disease (NAFLD) is typified by increased hepatic lipid uptake, synthesis, oxidation and export. Chronic hepatic lipid signaling through PPARgamma results in gene expression changes that allow concurrent activity of DNL and beta-oxidation. The importance of hepatic steatosis in driving systemic metabolic dysfunction is highlighted by the common endocrine and metabolic disturbances across many conditions that result in fatty liver. Understanding the mechanisms underlying the metabolic dysfunction that develops as a consequence of hepatic lipid accumulation is critical to identifying points of intervention in this increasingly prevalent disease state.

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Section: Introductionmentioning

confidence: 99%

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Geisler

Renquist

2017

Journal of Endocrinology

153

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“…In the absence of the opposing action of insulin, this results in unrestricted hepatic gluconeogenesis and glycogenolysis, resulting in high blood glucose levels and contributing to diabetic ketoacidosis. Recently, a study reported that deleting the glucagon receptor, and therefore eliminating glucagon action, after streptozotocin-induced β-cell destruction in mice normalized fasting blood glucose concentrations and lowered free fatty acid levels [7]. Thus, blocking glucagon action might also be helpful in preventing and treating diabetic ketoacidosis.…”

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confidence: 99%

Transcriptional regulation of α‐cell differentiation

Bramswig

Kaestner

2011

Diabetes Obesity Metabolism

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The development of the endocrine pancreas and the differentiation of its five cell types, α, β, δ, ε and pancreatic polypeptide (PP) cells, are a highly complex and tightly regulated process. Proper differentiation and function of α-and β-cells are critical for blood glucose homeostasis. These processes are governed by multiple transcription factors and other signalling systems, and its dysregulation results in diabetes. The differentiation of α-cells and the maintenance of α-cell function can be influenced at several stages during development and in the maturing islet. Many transcription factors, such as neurogenin 3 (Ngn3), pancreatic duodenal homeobox 1 (Pdx1) and regulatory factor x6 (Rfx6), play a crucial role in the determination of the endocrine cell fate, while other transcription factors, such as aristaless-related homeobox (Arx) and forkhead box A2 (Foxa2), are implicated in the initial or terminal differentiation of α-cells. In vivo and in vitro studies have shown that preproglucagon transcription, and therefore the maintenance of α-cell function, is regulated by several factors, including forkhead box A1 (Foxa1), paired box 6 (Pax6), brain4 (Brn4) and islet-1 (Isl-1). Detailed information about the regulation of normal and abnormal α-cell differentiation gives insight into the pathogenesis of diabetes, identifies further targets for diabetes treatment and provides clues for the reprogramming of α-to β-cells for replacement therapy. Keywords: α-cells, diabetes, pancreatogenesis, transcriptional regulation, transdifferentiation Date submitted 1 April 2011; date of final acceptance 19 April 2011 IntroductionThe pancreas is a complex organ made up of exocrine and endocrine cells, and is crucial for nutrient digestion and blood glucose homeostasis. In the embryo, the entire pancreas originates as two buds from the foregut endoderm, and initially all pancreatic epithelial precursors express the transcriptional regulator pancreatic duodenal homeobox 1 (Pdx1) [1,2]. Acinar cells, as part of the exocrine compartment, secrete digestive enzymes into the ductal lumen system, which is connected to the duodenum. The five endocrine cell types are α, β, δ, ε and pancreatic polypeptide (PP) cells, which collectively constitute less than 2% of the mass of the pancreas, and are organized into the islets of Langerhans. The islets of Langerhans belong to the neuroendocrine system (NES), which also includes the neuronal cells of the central and peripheral nervous systems and disseminated cells in the gut mucosa [3]. During evolution, islet hormone-producing cells first appeared in the nervous system, were next seen as disseminated cells in the mucosa of the alimentary tract, and did not evolve as a separate functional unit (in the form of the islet) until the appearance of the first vertebrates.Pancreatic α-cells produce glucagon from preproglucagon via prohormone convertase 2 (PC2). Glucagon, a hormone critical for blood glucose homeostasis, stimulates hepatic gluconeogenesis and glycogenolysis. It mobilizes glucose from...

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“…The discovery that hyperglycemia could result from increased glucagon production in pancreatic a-cells and other tissues renewed interest in this hormone (21)(22)(23), particularly when glucagon suppression restored normoglycemia (24). Accordingly, mice with genetic ablation of glucagon signaling have improved peripheral insulin sensitivity (25,26) and are protected against both type 1 and type 2 models of diabetes (27,28). In both settings, hyperglycemia is prevented primarily by reduced glucagon-mediated hepatic glucose production.…”

Section: Discussionmentioning

confidence: 99%

PTEN Deletion in Pancreatic α-Cells Protects Against High-Fat Diet–Induced Hyperglucagonemia and Insulin Resistance

et al. 2014

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An aberrant increase in circulating catabolic hormone glucagon contributes to type 2 diabetes pathogenesis. However, mechanisms regulating glucagon secretion and α-cell mass are not well understood. In this study, we aimed to demonstrate that phosphatidylinositol 3-kinase (PI3K) signaling is an important regulator of α-cell function. Mice with deletion of PTEN, a negative regulator of this pathway, in α-cells show reduced circulating glucagon levels and attenuated l-arginine–stimulated glucagon secretion both in vivo and in vitro. This hypoglucagonemic state is maintained after high-fat–diet feeding, leading to reduced expression of hepatic glycogenolytic and gluconeogenic genes. These beneficial effects protected high-fat diet–fed mice against hyperglycemia and insulin resistance. The data demonstrate an inhibitory role of PI3K signaling on α-cell function and provide experimental evidence for enhancing α-cell PI3K signaling for diabetes treatment.

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Glucagon Receptor Knockout Prevents Insulin-Deficient Type 1 Diabetes in Mice

Cited by 300 publications

References 41 publications

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Transcriptional regulation of α‐cell differentiation

PTEN Deletion in Pancreatic α-Cells Protects Against High-Fat Diet–Induced Hyperglucagonemia and Insulin Resistance

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