The Liver–α-Cell Axis and Type 2 Diabetes

Abstract

Both type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD) strongly associate with increasing body mass index, and together these metabolic diseases affect millions of individuals. In patients with T2D, increased secretion of glucagon (hyperglucagonemia) contributes to diabetic hyperglycemia as proven by the significant lowering of fasting plasma glucose levels following glucagon receptor antagonist administration. Emerging data now indicate that the elevated plasma concentrations of glucagon may also be associated with hepatic steatosis and not necessarily with the presence or absence of T2D. Thus, fatty liver disease, most often secondary to overeating, may result in impaired amino acid turnover, leading to increased plasma concentrations of certain glucagonotropic amino acids (e.g., alanine). This, in turn, causes increased glucagon secretion that may help to restore amino acid turnover and ureagenesis, but it may eventually also lead to increased hepatic glucose production, a hallmark of T2D. Early experimental findings support the hypothesis that hepatic steatosis impairs glucagon’s actions on amino acid turnover and ureagenesis. Hepatic steatosis also impairs hepatic insulin sensitivity and clearance that, together with hyperglycemia and hyperaminoacidemia, lead to peripheral hyperinsulinemia; systemic hyperinsulinemia may itself contribute to worsen peripheral insulin resistance. Additionally, obesity is accompanied by an impaired incretin effect, causing meal-related glucose intolerance. Lipid-induced impairment of hepatic sensitivity, not only to insulin but potentially also to glucagon, resulting in both hyperinsulinemia and hyperglucagonemia, may therefore contribute to the development of T2D at least in a subset of individuals with NAFLD.

Nonalcoholic Fatty Liver Disease Impairs the Liver–Alpha Cell Axis Independent of Hepatic Inflammation and Fibrosis

“…Our study therefore expands the understanding of how NAFLD may induce a vicious cycle of diabetogenic hyperglucagonemia. (25,26) Given that NAFLD is a disease with a wide histologic spectrum of disease and with worsening metabolic consequences (27)(28)(29) as the disease progresses from hepatic steatosis to the fibroinflammatory state, as seen in NASH, it would seem fair to assume that ureagenesis is affected in line with any escalation of the disease. Interestingly, we found no such support for this assumption as all NAFLD groups presented with comparable hyperaminoacidemia and hyperglucagonemia at baseline.…”

“…Intrahepatocyte build-up of triglycerides is known to interfere with several metabolic functions of the liver. (30) Hepatic steatosis has been hypothesized to impact the development of glucagon resistance to ureagenesis, (25) analogous to hepatic steatosis being a key feature in hepatic insulin resistance. (3,31,32) Glucagon's impact on ureagenesis includes transcriptional changes in genes (such as carbamoylphosphate synthase 1 [CPS1], glutamic-oxaloacetic transaminase 1 [GOT1], and solute carrier family 25 member 18 [SLC25A18]) that regulate hepatic nitrogen conversion in NAFLD, as has been shown in HOMA-IR Glucagon-alanine index R 2 = 0.165 P < 0.05 several studies.…”

NAFLD as a continuum: from obesity to metabolic syndrome and diabetes

“…We highlight that hepatic IR and glucagon resistance at the AAs metabolism can putatively contribute to T2D development in NAFLD patients [53], and it might have clinical and therapeutic implications. Treatments targeting weight loss and/or reducing liver fat content may restore the physiology of the liver-pancreas axis, so decreasing IR and glucagon levels, and possibly mitigating the increase in hepatic glucose production.…”

Metabolic Functions of G Protein-Coupled Receptors in Hepatocytes—Potential Applications for Diabetes and NAFLD

“…The glucagon receptor (GCGR) is abundantly expressed by hepatocytes and is the most extensively studied Gs-coupled GPCR in the liver [ 25 ]. GCGR is activated by the 29 amino acid polypeptide glucagon, which is secreted by α cells of the endocrine pancreas, in particular during the fasted state or exercise [ 26 ]. The primary function of glucagon is to prevent hypoglycemia during fasting by increasing hepatic glucose production (HGP) from hepatocytes by stimulating both glycogenolysis and gluconeogenesis [ 27 , 28 ].…”