Determinants of plasma levels of gcg and metabolic impact of glucagon receptor signalling - a UK Biobank study

Aims/hypothesesGlucagon and Glucagon-like peptide-1 (GLP-1) are derived from the same precursor; proglucagon (gcg), and dual agonists of their receptors are currently explored for the treatment of obesity and steatotic liver disease. Elevated levels of endogenous glucagon (hyperglucagonaemia) have been linked with hyperglycaemia in individuals with type 2 diabetes but are also observed in individuals with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). It is unknown whether type 2 diabetes, obesity or MASLD causes hyperglucagonaemia or vice versa. We investigated potential determinants of plasma gcg and associations of glucagon receptor signalling with metabolic diseases based on data from the UK Biobank. MethodsWe used exome sequencing data from the UK Biobank for [~]410,000 Caucasians to identify glucagon receptor variants and grouped them based on their known or predicted signalling. Plasma levels of gcg estimated using Olink technology was available for a subset of the cohort ([~]40,000). We determined associations between glucagon receptor variants and gcg with BMI, type 2 diabetes, and liver fat (quantified by liver MRI) and performed survival analyses to investigate if elevated gcg predicts type 2 diabetes development. ResultsObesity, MASLD, and type 2 diabetes independently associated with elevated plasma levels of gcg. Baseline gcg levels were statistically significantly associated with the risk of type 2 diabetes development over a 14-year follow-up period (hazard ratio = 1.13; 95% confidence interval (CI) = 1.09, 1.17, p < 0.0001). This association was of the same magnitude across strata of BMI. Carriers of glucagon receptor variants with reduced cAMP signalling had elevated levels of gcg ({beta} = 0.847; CI = 0.04, 1.66; p = 0.04), and carriers of variants with a predicted frameshift mutation had significantly higher levels of liver fat compared to wild-type controls ({beta} = 0.504; CI = 0.03, 0.98; p = 0.04). Conclusions/interpretationOur findings support that glucagon receptor signalling is involved in MASLD and type 2 diabetes, and that plasma levels of gcg are determined by genetic variation in the glucagon receptor, obesity, type 2 diabetes, and MASLD. Determining the molecular signalling pathways downstream of glucagon receptor activation may guide the development of biased GLP-1/glucagon co-agonist with improved metabolic benefits. Research in contextWhat is already known about this subject? O_LIGlucagon contributes to fasting hyperglycaemia in type 2 diabetes C_LIO_LIHyperglucagonemia is often observed in metabolic dysfunction-associated steatotic liver disease (MASLD), obesity and type 2 diabetes C_LIO_LIGlucagon/GLP-1 co-agonists have superior metabolic benefits compared to monoagonists C_LI What is the key question? What are key determinants of plasma proglucagon (gcg) and is elevated plasma gcg a cause or consequence (or both) of type 2 diabetes? What are the new findings? O_LIPlasma levels of gcg are increased in type 2 diabetes, MASLD and obesity independently of each other C_LIO_LIIncreased plasma gcg associates with higher risk of type 2 diabetes development C_LIO_LIGlucagon signalling associates with hepatic fat C_LI How might this impact on clinical practice in the foreseeable future? O_LIBiased glucagon receptor-regulating agents may be beneficial in the treatment of obesity and MASLD. C_LI