The liver–alpha cell axis associates with liver fat and insulin resistance: a validation study in women with non-steatotic liver fat levels

Abstract

Aims/hypothesis Many individuals who develop type 2 diabetes also display increased glucagon levels (hyperglucagonaemia), which we have previously found to be associated with the metabolic syndrome. The concept of a liver–alpha cell axis provides a possible link between hyperglucagonaemia and elevated liver fat content, a typical finding in the metabolic syndrome. However, this association has only been studied in individuals with non-alcoholic fatty liver disease. Hence, we searched for a link between the liver and the alpha cells in individuals with non-steatotic levels of liver fat content. We hypothesised that the glucagon–alanine index, an indicator of the functional integrity of the liver–alpha cell axis, would associate with liver fat and insulin resistance in our cohort of women with low levels of liver fat. Methods We analysed data from 79 individuals participating in the Prediction, Prevention and Subclassification of Type 2 Diabetes (PPSDiab) study, a prospective observational study of young women at low to high risk for the development of type 2 diabetes. Liver fat content was determined by MRI. Insulin resistance was calculated as HOMA-IR. We conducted Spearman correlation analyses of liver fat content and HOMA-IR with the glucagon–alanine index (the product of fasting plasma levels of glucagon and alanine). The prediction of the glucagon–alanine index by liver fat or HOMA-IR was tested in multivariate linear regression analyses in the whole cohort as well as after stratification for liver fat content ≤0.5% (n = 39) or >0.5% (n = 40). Results The glucagon–alanine index significantly correlated with liver fat and HOMA-IR in the entire cohort (ρ = 0.484, p < 0.001 and ρ = 0.417, p < 0.001, respectively). These associations resulted from significant correlations in participants with a liver fat content >0.5% (liver fat, ρ = 0.550, p < 0.001; HOMA-IR, ρ = 0.429, p = 0.006). In linear regression analyses, the association of the glucagon–alanine index with liver fat remained significant after adjustment for age and HOMA-IR in all participants and in those with liver fat >0.5% (β = 0.246, p = 0.0.23 and β = 0.430, p = 0.007, respectively) but not in participants with liver fat ≤0.5% (β = −0.184, p = 0.286). Conclusions/interpretation We reproduced the previously reported association of liver fat content and HOMA-IR with the glucagon–alanine index in an independent study cohort of young women with low to high risk for type 2 diabetes. Furthermore, our data indicates an insulin-resistance-independent association of liver fat content with the glucagon–alanine index. In summary, our study supports the concept that even lower levels of liver fat (from 0.5%) are connected to relative hyperglucagonaemia, reflecting an imminent impairment of the liver–alpha cell axis.

Hepatocyte cholesterol content modulates glucagon receptor signalling

“…Our data also potentially reconcile the observations that NAFLD is associated with both an increase in hepatic cholesterol (Min et al, 2012;Puri et al, 2007) and glucagon resistance (Albrechtsen et al, 2018;Gar et al, 2021). Contrasting with the possibility discussed above, i.e.…”

“…To date, the mechanism behind this phenomenon is incompletely understood (Janah et al, 2019). Hepatic cholesterol accumulation is a feature of NAFLD and, interestingly, the degree of both glucagon resistance (Gar et al, 2021) and hepatic cholesterol accumulation (Min et al, 2012;Puri et al, 2007) are correlated with histological severity of the disease.…”

Hyperglucagonemia in Pediatric Adiposity Associates With Cardiometabolic Risk Factors but Not Hyperglycemia

“…Support for this theory comes from the ADDITION-PRO study, as circulating levels of amino acids (alanine, glutamine, and tyrosine) associated with fasting glucagon in 1408 adults with normal and impaired glucose tolerance ( 38 ). These findings were replicated in an independent cohort of women with low to high risk for type 2 diabetes, where even lower levels of liver fat % were associated with hyperglucagonemia, reflecting impairments of the liver–alpha cell axis ( 39 ). It is hypothesized that a similar relationship may exist in youth, since the present study found a positive association between fasting glucagon, liver fat %, and ALT.…”

High Protein Diets Improve Liver Fat and Insulin Sensitivity by Prandial but Not Fasting Glucagon Secretion in Type 2 Diabetes

“…The role of GCGN in the dysregulation of glucose and lipid metabolism is debated at present ( 5 , 10 , 15 ). GCGN is consistently elevated in people with fatty liver and T2DM and contributes to hyperglycemia as shown with GCGN antagonists ( 27 , 28 ). However, GCGN antagonists increased dyslipidemia, IHL and liver enzymes ( 13 ).…”