The Role of Glucagon in the Endogenous Hyperglycemia of Diabetes Mellitus

Unger, Roger H; Orci, Lelio

doi:10.1146/annurev.me.28.020177.001003

Cited by 46 publications

(34 citation statements)

References 22 publications

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“…Accordingly, a proper ratio of beta and alpha cells is crucial to meet the challenges of metabolic stress. Reduced number and function of beta cells with alpha cell excess is a pathological hallmark in diabetes [4][5][6]. Beta cell regeneration, in principle, could be achieved by neogenesis of islet stem/progenitor cells [7] or self-replication of pre-existing beta cells [8].…”

Section: Introductionmentioning

confidence: 99%

Rb and p107 are required for alpha cell survival, beta cell cycle control and glucagon-like peptide-1 action

Cai

Luk

et al. 2014

Diabetologia

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Aims/hypothesis Diabetes mellitus is characterised by beta cell loss and alpha cell expansion. Analogues of glucagonlike peptide-1 (GLP-1) are used therapeutically to antagonise these processes; thus, we hypothesised that the related cell cycle regulators retinoblastoma protein (Rb) and p107 were involved in GLP-1 action. Methods We used small interfering RNA and adenoviruses to manipulate Rb and p107 expression in insulinoma and alpha-TC cell lines. In vivo we examined pancreas-specific Rb knockout, whole-body p107 knockout and Rb/p107 doubleknockout mice.Results Rb, but not p107, was downregulated in response to the GLP-1 analogue, exendin-4, in both alpha and beta cells. Intriguingly, this resulted in opposite outcomes of cell cycle arrest in alpha cells but proliferation in beta cells. Overexpression of Rb in alpha and beta cells abolished or attenuated the effects of exendin-4 supporting the important role of Rb in GLP-1 modulation of cell cycling. Similarly, in vivo, Rb, but not p107, deficiency was required for the beta cell proliferative response to exendin-4. Consistent with this finding, Rb, but not p107, was suppressed in islets from humans with diabetes, suggesting the importance of Rb regulation for the compensatory proliferation that occurs under insulin resistant conditions. Finally, while p107 alone did not have an essential role in islet homeostasis, when combined with Rb deletion, its absence potentiated apoptosis of both alpha and beta cells resulting in glucose intolerance and diminished islet mass with ageing. Conclusions/interpretation We found a central role of Rb in the dual effects of GLP-1 in alpha and beta cells. Our findings highlight unique contributions of individual Rb family members to islet cell proliferation and survival.

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Section: Introductionmentioning

confidence: 99%

Rb and p107 are required for alpha cell survival, beta cell cycle control and glucagon-like peptide-1 action

Cai

Luk

et al. 2014

Diabetologia

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“…In physiological states, glucagon is released into the bloodstream in response to hypoglycemia to oppose the action of insulin in peripheral tissues, and works as a counter-regulatory hormone to restore normoglycemia. Secreted glucagon works predominantly on the liver, and promotes hepatic gluconeogenesis, glycogenolysis, and simultaneously inhibits glycolysis and glycogenesis (Exton et al, 1966;Unger and Orci, 1977), thus contributing to restoring glucose homeostasis by counteracting the action of insulin. In contrast, insulin suppresses hepatic glucose output while enhancing hepatic glucose uptake and glycogenesis, indicating that a balance between these two hormones ath the hepatocyte determines hepatic glucose metabolism, thus systemic glycemic homeostasis.…”

Section: Functions Of Glucagon 21 Functions Of Glucagonmentioning

confidence: 99%

Molecular Mechanism Underlying the Intra-Islet Regulation of Glucagon Secretion

Kawamori¹,

Kulkarni²

2011

Diabetes - Damages and Treatments

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“…This inappropriate secretion of glucagon leads to excess hepatic glucose production and is an important contributor to postprandial hyperglycemia. 19,20 Pramlintide administered before a meal significantly reduced postprandial glucagon secretion compared to placebo in clinical studies of patients with type 1 or type 2 diabetes. 14,15 The efficacy of pramlintide as an adjunct to mealtime insulin has been demonstrated in both type 1 and type 2 diabetic patients in several long-term, double-blind, placebo-controlled trials.…”

Section: Pharmacy and Therapeuticsmentioning

confidence: 99%

“…14,15 The efficacy of pramlintide as an adjunct to mealtime insulin has been demonstrated in both type 1 and type 2 diabetic patients in several long-term, double-blind, placebo-controlled trials. [17][18][19][20][21][22][23][24] In the type 1 diabetic population, after 6 months of treatment with pramlintide (30 or 60 μg, three to four times daily), the mean reduction in A1C from a baseline of ~8.9% was 0.4% (P < 0.05) compared to a reduction of 0.1% in the placebo group. On average, pramlintide patients lost 1.1 kg (P < 0.05) in body weight, as opposed to a 0.6 kg weight gain in the placebo group.…”

Section: Pharmacy and Therapeuticsmentioning

confidence: 99%