Abstract
Aims/hypothesisMany 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.MethodsWe 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).ResultsThe 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/interpretationWe 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.
Highlights
IntroductionIncreased plasma glucagon concentration (hyperglucagonaemia) has been suggested to play a crucial role in the development of type 2 diabetes
Increased plasma glucagon concentration has been suggested to play a crucial role in the development of type 2 diabetes
We examined the association of liver fat, at lower concentrations than those observed in nonalcoholic fatty liver disease (NAFLD), and insulin resistance with the glucagon–alanine index
Summary
Increased plasma glucagon concentration (hyperglucagonaemia) has been suggested to play a crucial role in the development of type 2 diabetes. Inhibition of glucagon signalling by treatment with a glucagon receptor antagonist has shown favourable effects on glucose metabolism in individuals with type 2 diabetes [1, 2]. The concept of a liver–alpha cell axis provides a potential causal link between the metabolic syndrome and hyperglucagonaemia [4, 5]. According to this concept, fat deposition in the liver, a hallmark of the metabolic syndrome [6], might impair hepatic glucagon signalling. Hyperglucagonaemia may compensate for the increasing glucagon resistance and thereby restore amino acid metabolism. A vicious cycle develops in which the steadily rising hepatic glucose production eventually evolves into type 2 diabetes [5]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have