Metabolic manifestations of insulin deficiency do not occur without glucagon action

Lee, Young Ho; Berglund, Eric D.; Wang, May-Yun; Fu, Xiaorong; Yu, Xinxin; Charron, Maureen J.; Burgess, Shawn C.; Unger, Roger H

doi:10.1073/pnas.1205983109

Cited by 137 publications

(130 citation statements)

References 36 publications

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“…Following restoration of glucagon function by administration of Ad-Gcgr, diabetes reappeared. These studies suggest that glucagon is essential for hyperglycaemia in type 1 diabetes and that blocking glucagon action prevents deadly metabolic and clinical derangements [5,6] (Table 1). Without glucagon action, the liver does not produce enough glucose to exceed the native glucose consumption by the brain [7].…”

Section: Glucagon Is Essential For Hyperglycaemia In Type 1 Diabetesmentioning

confidence: 99%

Glucagon is the key factor in the development of diabetes

et al. 2016

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Glucagon plays important roles in normal glucose homeostasis and in metabolic abnormalities, particularly diabetes. Glucagon excess, rather than insulin deficiency, is essential for the development of diabetes for several reasons. Glucagon increases hepatic glucose and ketone production, the catabolic features of insulin deficiency. Hyperglucagonaemia is present in every form of diabetes. Beta cell destruction in glucagon receptor null mice does not cause diabetes unless mice are administered adenovirus encoding the glucagon receptor. In rodent studies the glucagon suppressors leptin and glucagon receptor antibody suppressed all catabolic manifestations of diabetes during insulin deficiency. Insulin prevents hyperglycaemia; however, insulin monotherapy cannot cure diabetes such that non-diabetic glucose homeostasis is achieved. Glucoseresponsive beta cells normally regulate alpha cells, and diminished insulin action on alpha cells will favour hypersecretion of glucagon by the alpha cells, thus altering the insulin:glucagon ratio. Treating diabetes by suppression of glucagon, with leptin or antibody against the glucagon receptor, normalised glucose level (without glycaemic volatility) and HbA 1c . Glucagon suppression also improved insulin sensitivity and glucose tolerance. If these results can be translated to humans, suppression of glucagon action will represent a step forward in the treatment of diabetes. This review summarises a presentation given at the 'Novel data on glucagon' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by

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Section: Glucagon Is Essential For Hyperglycaemia In Type 1 Diabetesmentioning

confidence: 99%

Glucagon is the key factor in the development of diabetes

et al. 2016

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“…Similarly, lower hepatic glucose production and improved glucose tolerance are observed in mice that are deficient in the a-cell transcription factor ARX (aristaless-related homeobox), leading to the loss of glucagon-producing a-cells (189) . More recently, it has been shown that the metabolic and clinical alterations caused by type 1 diabetes are absent in glucagon receptor KO mice treated with streptozotocin and that the restoration of the hepatic glucagon receptor in this model leads to the reappearance of hyperglycaemia (104,190) . However, a limited glucagon action could interfere with the role of glucagon in hepatic lipid metabolism and lead to an increased susceptibility to hepatosteatosis after a high-fat diet (13) , or it could also interfere with the hepatic survival function of glucagon (191) .…”

Section: Therapeutic Potential Of Modulating Glucagon Secretion and Amentioning

confidence: 99%

Nutrient regulation of glucagon secretion: involvement in metabolism and diabetes

et al. 2014

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Glucose homeostasis is precisely regulated by glucagon and insulin, which are released by pancreatic a-and b-cells, respectively. While b-cells have been the focus of intense research, less is known about a-cell function and the actions of glucagon. In recent years, the study of this endocrine cell type has experienced a renewed drive. The present review contains a summary of established concepts as well as new information about the regulation of a-cells by glucose, amino acids, fatty acids and other nutrients, focusing especially on glucagon release, glucagon synthesis and a-cell survival. We have also discussed the role of glucagon in glucose homeostasis and in energy and lipid metabolism as well as its potential as a modulator of food intake and body weight. In addition to the well-established action on the liver, we discuss the effects of glucagon in other organs, where the glucagon receptor is expressed. These tissues include the heart, kidneys, adipose tissue, brain, small intestine and the gustatory epithelium. Alterations in a-cell function and abnormal glucagon concentrations are present in diabetes and are thought to aggravate the hyperglycaemic state of diabetic patients. In this respect, several experimental approaches in diabetic models have shown important beneficial results in improving hyperglycaemia after the modulation of glucagon secretion or action. Moreover, glucagon receptor agonism has also been used as a therapeutic strategy to treat obesity.

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“…Moreover, recent reports showed that glucagon suppression induced by glucagon-like peptide -1 (GLP-1) and GLP-1 receptor agonist administration ameliorates blood glucose levels in type 1 diabetic patients without residual insulin secretion (5). Thus, glucagon suppression might play a key role in glucose homeostasis and the "glucagonocentric hypothesis" was proposed, which states that antecedent α-cell failure and inhibition of glucagon secretion are responsible for diabetes progression (6,7). This hypothesis was further supported by many studies using glucagon receptor gene knockout mice and anti-glucagon receptor antibody (8,9).…”

Section: Introductionmentioning

confidence: 99%

Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets

et al. 2017

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: Accumulating evidence supports the "glucagonocentric hypothesis", in which antecedent α-cell failure and inhibition of glucagon secretion are responsible for diabetes progression. Protein kinase C (PKC) is involved in glucagon secretion from α-cells, although which PKC isozyme is involved and the mechanism underlying this PKC-regulated glucagon secretion remains unknown. Here, the involvement of PKCδ in the onset and progression of diabetes was elucidated. Immunofluorescence studies revealed that PKCδ was expressed and activated in α-cells of STZ-induced diabetic model mice. Phorbol 12-myristate 13-acetate (PMA) stimulation significantly augmented glucagon secretion from isolated islets. Pre-treatment with quercetin and rottlerin, PKCδ signaling inhibitors, significantly suppressed the PMA-induced elevation of glucagon secretion. While Go6976, a Ca 2+ -dependent PKC selective inhibitor did not suppress glucagon secretion. Quercetin suppressed PMA-induced phosphorylation of Tyr 311 of PKCδ in isolated islets. However, quercetin itself had no effect on either glucagon secretion or glucagon mRNA expression. Our data suggest that PKCδ signaling inhibitors suppressed glucagon secretion. Elucidation of detailed signaling pathways causing PKCδ activation in the onset and progression of diabetes followed by the augmentation of glucagon secretion could lead to the identification of novel therapeutic target molecules and the development of novel therapeutic drugs for diabetes.

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Metabolic manifestations of insulin deficiency do not occur without glucagon action

Cited by 137 publications

References 36 publications

Glucagon is the key factor in the development of diabetes

Glucagon is the key factor in the development of diabetes

Nutrient regulation of glucagon secretion: involvement in metabolism and diabetes

Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets

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