Dataset Information

A glucagon variant, glucagon 1-61, identified in man, controls blood glucose through regulation of insulin secretion and hepatic glucose production

ABSTRACT: Glucagon is secreted from pancreatic α-cells, and hypersecretion (hyperglucagonemia) contributes to diabetic hyperglycemia. Molecular heterogeneity in hyperglucagonemia is poorly investigated. By screening human plasma by high-resolution-proteomics, we identified several glucagon variants among which proglucagon 1-61 (PG 1-61) appears to be the most abundant form. PG 1-61 was secreted in obese subjects before and as well after gastric bypass surgery with protein and fat as the main drivers for secretion before surgery, but glucose after. Studies in hepatocytes and in β-cells demonstrated that PG 1-61 dose-dependently increased levels of cAMP, through the glucagon receptor, and increased insulin secretion and protein levels of enzymes regulating glycogenolysis and gluconeogenesis. As a consequence, PG 1-61 increased blood glucose and plasma insulin and decreased plasma levels of amino acids in vivo. Glucagon variants, such as PG 1-61, may contribute to glucose regulation by stimulating hepatic glucose production and insulin secretion.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: Mario Oroshi

LAB HEAD: Felix Meissner

PROVIDER: PXD005677 | Pride | 2017-10-20

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20151211_Orbi6_DaHo_SA_Nicolai_KidneyCO_Chemotrypsin.raw	Raw
	20151211_Orbi6_DaHo_SA_Nicolai_KidneyCO_GluC.raw	Raw
	20151211_Orbi6_DaHo_SA_Nicolai_KidneyCO_LysC.raw	Raw
	20151211_Orbi6_DaHo_SA_Nicolai_KidneyCO_empty.raw	Raw
	20151211_Orbi6_DaHo_SA_Nicolai_KidneyCO_noEnzyme.raw	Raw

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Project description:Appropriate glucagon secretion from pancreatic alpha cells in response to hypoglycemia is an important component of maintaining glucose homeostasis. Dysregulated glucagon secretion leads to the delayed recovery from a hypoglycemic attack in type 1 diabetes patients which can be lethal. Although elucidating the precise mechanism of glucagon secretion in hypoglycemia is warranted, the underlying mechanism remains poorly understood.The present study provides evidence of the role of autophagy in glucagon secretion in hypoglycemia by demonstrating that autophagy regulates adrenergic stimulation of glucagon secretion downstream of beta2 adrenergic receptor. First, from the analyses of T1D human islets and the published database of scRNA-seq of T1D human alpha cells, we described autophagy pathways altered in T1D alpha cells. Second, we generated alpha cell-specific Atg7KO mice (alphaAtg7KO) and clarified that the lack of autophagy in alpha cells impairs the reactive glucagon secretion in acute hypoglycemia. Third, to interrogate the molecular mechanism of autophagy-mediated glucagon regulation, we analyzed top genes downregulated inT1D and T2D alpha cells and found the expression of beta2 adrenergic receptor showed significant down-regulation in T1D alpha cells. We confirmed the decreased expression of beta2 adrenergic receptor in alpha cells of the T1D pancreas section, the islets of alphaAtg7KO mice, and a murine alpha cell line with stable knockdown of Atg7. Furthermore, in vivo and ex vivo studies of alphaAtg7KO mice exhibited that lack of autophagy led to the loss of stimulatory effect of beta2-adrenergic signaling on glucagon secretion. Finally, we established the Atg7 knockdown model in sorted human alpha cells and confirmed the effect of autophagy on the expression of the beta2 adrenergic receptor. Together, our study provides novel insights into the regulatory role of autophagy in glucagon secretion in response to hypoglycemia and provides therapeutic options to achieve stable glycemic control in T1D patients.

Dataset Information

A glucagon variant, glucagon 1-61, identified in man, controls blood glucose through regulation of insulin secretion and hepatic glucose production

Dataset's files

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