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Mahvash Disease
Published in Dongyou Liu, Tumors and Cancers, 2017
Mahvash disease (named after the first name of the index patient and also known as nesidioblastosis, alpha cell hyperplasia, microglucagonoma, or nonfunctioning islet cell tumor) was initially noted in 2007 in a 60-year-old female patient who presented with abdominal pain, mild hypoglycemia (735 pg/mL vs. normal, <311 pg/mL) and elevated glucagon levels (59,284 pg/mL vs. normal, <150 pg/mL) without symptoms of glucagonoma syndrome (e.g., skin rash, hyperglycemia, weight loss, thromboembolism, or stomatitis). Normal levels of insulin, gastrin, vasoactive intestinal peptide, and calcitonin were observed. This patient had a past history of gastroesophageal reflux, duodenal ulcer, diverticulosis, anemia, β thalassemia minor, anxiety, depression, and meningioma. An abdominal CT showed a hypertrophic pancreas and a 3-cm mass in the uncinate process. Histological examination of the surgically resected pancreas revealed a nonfunctioning neuroendocrine tumor composed of an apparently normal pancreas and numerous glucagon-positive, insulin-negative hyperplastic islets in the walls of the pancreatic ducts, along with two microadenomas, suggesting α cell neogenesis and high lifetime recurrence risk. Sequencing analysis of the 13 coding exons and intronexon borders of the glucagon receptor gene (GCGR) identified a homozygous, missense C-to-T mutation in exon 4, resulting in replacement of proline with serine at amino acid residue 86 (P86S) in the GCGR protein. Although the index patient is homozygous for P86S mutation, her brother has two wild-type GCGR alleles, suggesting that their parents are heterozygous for P86S mutation [3,4].
Evidence for the existence and potential roles of intra-islet glucagon-like peptide-1
Published in Islets, 2021
Scott A. Campbell, Janyne Johnson, Peter E. Light
Amino acids are also a potent stimulant of glucagon secretion from alpha cells, and are candidates for triggering alpha cell hyperplasia.57 Another rhodopsin-like GPCR, GPR142, functions as an L-tryptophan sensor. GPR142 signaling increases Akt activation, ultimately increasing PC1/3 expression in both alpha and L-cells (Figure 1).22 GPR142 agonism augments insulin secretion in a GLP-1R dependent manner,22,58,59 but it is not required for basal GLP-1 secretion. Indeed, GPR142 KO and control littermates have no apparent differences in glucose tolerance and exhibit similar insulin secretion profiles in response to intraperitoneal and oral glucose.59 This latter finding argues against a major physiological role for GPR142 alone, although this receptor may act in concert with other GPCRs to fine-tune islet cell function. While it is not explicitly shown to regulate PC1/3 expression, GPR119, a monoacylglycerol sensing GPCR, can potentiate glucagon granule release from alpha cells in hypoglycemia,60 and its activation elevates intracellular cAMP.61 When considering the co-packaging of glucagon and GLP-1 in secretory granules, it is plausible that GPR119 activation may regulate GLP-1 secretion.
What is on the horizon for type 2 diabetes pharmacotherapy? – An overview of the antidiabetic drug development pipeline
Published in Expert Opinion on Drug Discovery, 2020
Karl Sebastian Johansson, David Peick Sonne, Filip Krag Knop, Mikkel Bring Christensen
Due to the mode of action, there is an apparent risk of hypoglycemia. Clinical studies have shown increases in bodyweight, blood pressure, and circulating levels of lipids and liver transaminases [85–87]. There is also an increased risk of pancreatic alpha cell hyperplasia [87]. Some drugs have been abandoned due to the risk of hepatotoxicity [87–89].