Pancreatic α-cell hyperplasia and hyperglucagonemia due to a glucagon receptor splice mutation

Abstract

SummaryGlucagon stimulates hepatic glucose production by activating specific glucagon receptors in the liver, which in turn increase hepatic glycogenolysis as well as gluconeogenesis and ureagenesis from amino acids. Conversely, glucagon secretion is regulated by concentrations of glucose and amino acids. Disruption of glucagon signaling in rodents results in grossly elevated circulating glucagon levels but no hypoglycemia. Here, we describe a patient carrying a homozygous G to A substitution in the invariant AG dinucleotide found in a 3′ mRNA splice junction of the glucagon receptor gene. Loss of the splice site acceptor consensus sequence results in the deletion of 70 nucleotides encoded by exon 9, which introduces a frame shift and an early termination signal in the receptor mRNA sequence. The mutated receptor neither bound 125I-labeled glucagon nor induced cAMP production upon stimulation with up to 1 µM glucagon. Despite the mutation, the only obvious pathophysiological trait was hyperglucagonemia, hyperaminoacidemia and massive hyperplasia of the pancreatic α-cells assessed by histology. Our case supports the notion of a hepato–pancreatic feedback system, which upon disruption leads to hyperglucagonemia and α-cell hyperplasia, as well as elevated plasma amino acid levels. Together with the glucagon-induced hypoaminoacidemia in glucagonoma patients, our case supports recent suggestions that amino acids may provide the feedback link between the liver and the pancreatic α-cells.Learning points:Loss of function of the glucagon receptor may not necessarily lead to the dysregulation of glucose homeostasis.Loss of function of the glucagon receptor causes hyperaminoacidemia, hyperglucagonemia and α-cell hyperplasia and sometimes other pancreatic abnormalities.A hepato–pancreatic feedback regulation of the α-cells, possibly involving amino acids, may exist in humans.

Effect of a glucagon receptor antibody (REMD‐477) in type 1 diabetes: A randomized controlled trial

“…While not measured with other compounds, a recent publication showed an increase in hepatic fat content with LY2409021, which was the first to correlate the transaminase increase with potential, underlying pathophysiology . An additional concern is that chronic glucagon receptor blockade will cause pancreatic α‐cell hyperplasia, which has been shown in animal models and in case reports demonstrating α‐cell hypertrophy and severe hyperglucagonaemia, without evidence of glucagonoma syndrome, in individuals with loss‐of‐function glucagon receptor mutations . Our study is the only one published, that we are aware of, that assesses the use of glucagon receptor blockade in individuals with type 1 diabetes, and it is possible that adverse effects with glucagon antagonism will differ between type 1 and type 2 diabetes.…”

Evidence of a liver–alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids

“…These observations have led to the proposal of the existence of a hitherto neglected feedback loop between the pancreatic alpha cells and the liver [8,30]. Consistent with this proposed feedback loop, individuals with glucagon-producing tumours have decreased levels of plasma amino acids [11,31], and, conversely, individuals with glucagon receptor mutations [10,32,33] and mice with glucagon receptor deficiency [30,34] exhibit increased levels of plasma amino acids. Hyperglucagonaemia has also been reported in individuals with fatty liver disease independent of their glycaemic status [35], and this has recently been linked to an increased plasma pool of amino acids including alanine, but excluding the BCAAs isoleucine, leucine and valine [36].…”

“…This glucagon-amino acid feedback loop may be as important for metabolism as the glucagon-glucose loop [9]. In line with this, individuals with complete disruption of glucagon signalling develop not hypoglycaemia but increasing amino acid levels, leading to severe alpha cell hypersecretion and hyperplasia [7,10]. In addition, hyperglucagonaemia (as in individuals with glucagon-producing tumours) does not always cause diabetes, but it severely decreases amino acid levels, resulting in muscular wasting and decreased cellular proliferation in the skin [11,12].…”

A Hepatocyte FOXN3-α Cell Glucagon Axis Regulates Fasting Glucose

“…In both animal models of absolute glucagon resistance, α cell mass is expanded to compensate for the lack of glucagon signaling, which is marked by improved glucose tolerance. Somewhat surprisingly, a single homozygous human carrier of a loss-of-function GCGR mutation developed massive α cell hyperplasia and hyperglucagonemia, but he did not have decreased fasting blood glucose or show improved glucose tolerance (Larger et al, 2016). Characterization of additional human carriers of GCGR mutations will give us a more complete understanding of the life-long role of this signaling pathway in regulating glucose and nitrogen metabolism (Holst et al, 2017).…”