Human islets contain a subpopulation of glucagon-like peptide-1 secreting α cells that is increased in type 2 diabetes

Campbell, S.; Golec, Dominic P.; Hubert, Matt; Johnson, Janyne; Salamon, Nicole; Barr, Amy; MacDonald, Patrick E.; Philippaert, Koenraad; Light, Peter E.

doi:10.1016/j.molmet.2020.101014

Cited by 62 publications

(58 citation statements)

References 36 publications

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“…Whereas the GLP-1 receptor agonist targets the islet cells directly, the DPP-4 inhibitor is likely to rely on the endogenous production of the incretin by islet α-cells, via a hypothetical switch from PC2 to PC1/3. A highly contested finding for non-diabetic native mouse islets, GLP-1 expression in α-cells is likely to be induced by the diabetic conditions ( Figure 5), in line with recent human data [47]. At the same time, the ex vivo (non-diabetic) effect of sitagliptin on the α-cell transdifferentiation ( Figure 4B) is at odds with this mechanism and is therefore likely to be linked to an induction of islet GLP-1 expression in response to the chronic (72 h) culture conditions.…”

Section: Consensus Modelsupporting

confidence: 85%

Antidiabetic drug therapy alleviates type 1 diabetes in mice by promoting pancreatic α-cell transdifferentiation

Sarnobat

Moffett

Tanday

et al. 2020

Biochemical Pharmacology

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Gut incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), enhance secretion of insulin in a glucose-dependent manner, predominantly by elevating cytosolic levels of cAMP in pancreatic β-cells. Successful targeting of the incretin pathway by several drugs, however, suggests the antidiabetic mechanism is likely to span beyond the acute effect on hormone secretion and include, for instance, stimulation of β-cell growth and/or proliferation. Likewise, the antidiabetic action of kidney sodium-glucose linked transporter-2 (SGLT-2) inhibitors exceeds simple increase glucose excretion. Potential reasons for these 'added benefits' may lie in the long-term effects of these signals on developmental aspects of pancreatic islet cells. In this work, we explored if the incretin mimetics or SGLT-2 inhibitors can affect the size of the islet αor β-cell compartments, under the condition of β-cell stress. To that end, we utilised mice expressing YFP specifically in pancreatic α-cells, in which we modelled type 1 diabetes by injecting streptozotocin, followed by a 10-day administration of liraglutide, sitagliptin or dapagliflozin. We observed an onset of diabetic phenotype, which was partially reversed by the administration of the antidiabetic drugs. The mechanism for the reversal included induction of β-cell proliferation, due to a decrease in β-cell apoptosis and, for the incretin mimetics, transdifferentiation of α-cells into β-cells. Our data therefore emphasize the role of chronic incretin signalling in induction of α-/β-cell transdifferentiation. We conclude that incretin peptides may act directly on islet cells, making use of the endogenous local sites of 'ectopic' expression, whereas SGLT-2 inhibitors work via protecting β-cells from chronic hyperglycaemia.

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Section: Consensus Modelsupporting

confidence: 85%

Antidiabetic drug therapy alleviates type 1 diabetes in mice by promoting pancreatic α-cell transdifferentiation

Sarnobat

Moffett

Tanday

et al. 2020

Biochemical Pharmacology

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“…To assess the effect of liraglutide treatment and the role of β cell GLP-1R signaling on α cell GLP-1 expression, pancreatic sections from these mice were costained for GLP-1 and glucagon, using an antibody that has been rigorously validated to be specific for GLP-1 ( 29 ). Liraglutide treatment increased islet GLP-1 staining compared with saline in WT mice but not in KO mice ( Figure 1, B and C ; P < 0.01).…”

Section: Resultsmentioning

confidence: 99%

GLP-1 receptor signaling increases PCSK1 and β cell features in human α cells

Saikia¹,

Holter²,

Donahue³

et al. 2021

JCI Insight

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“…It is a matter of debate whether this only occurs as a consequence of metabolic alterations, such as pancreatectomy [ 9 , 10 ] and bariatric surgery [ 11 ], resulting in gut-derived glucagon, or glucagon receptor inhibition [ 12 ] and streptozotocin treatment [ 13 ], resulting in pancreatic-derived GLP-1. Pancreatic GLP-1 has been suggested to be part of heathy physiology by contributing to a local incretin axis [ 14 , 15 , 16 ]. In the measurement of glucagon, analytical challenges due to cross-reactivity with other GCG-derived peptides have been an issue [ 17 , 18 ], and using liquid chromatography–mass spectrometry, glucagon secretion was not found to be increased after bypass surgery [ 19 ].…”

Section: Processing and Secretion Of Glucagonmentioning

confidence: 99%

The Vicious Circle of Hepatic Glucagon Resistance in Non-Alcoholic Fatty Liver Disease

Galsgaard

2020

JCM

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A key criterion for the most common chronic liver disease—non-alcoholic fatty liver disease (NAFLD)—is an intrahepatic fat content above 5% in individuals who are not using steatogenic agents or having significant alcohol intake. Subjects with NAFLD have increased plasma concentrations of glucagon, and emerging evidence indicates that subjects with NAFLD may show hepatic glucagon resistance. For many years, glucagon has been thought of as the counterregulatory hormone to insulin with a primary function of increasing blood glucose concentrations and protecting against hypoglycemia. However, in recent years, glucagon has re-emerged as an important regulator of other metabolic processes including lipid and amino acid/protein metabolism. This review discusses the evidence that in NAFLD, hepatic glucagon resistance may result in a dysregulated lipid and amino acid/protein metabolism, leading to excess accumulation of fat, hyperglucagonemia, and increased oxidative stress contributing to the worsening/progression of NAFLD.

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Human islets contain a subpopulation of glucagon-like peptide-1 secreting α cells that is increased in type 2 diabetes

Cited by 62 publications

References 36 publications

Antidiabetic drug therapy alleviates type 1 diabetes in mice by promoting pancreatic α-cell transdifferentiation

Antidiabetic drug therapy alleviates type 1 diabetes in mice by promoting pancreatic α-cell transdifferentiation

GLP-1 receptor signaling increases PCSK1 and β cell features in human α cells

The Vicious Circle of Hepatic Glucagon Resistance in Non-Alcoholic Fatty Liver Disease

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