Glucagon (GCGN) plays a key role in
glucose and
amino acid (AA) metabolism by increasing hepatic
glucose output. AA strongly stimulate GCGN secretion which regulates hepatic AA degradation by ureagenesis. Although increased fasting GCGN levels cause
hyperglycemia GCGN has beneficial actions by stimulating hepatic lipolysis and improving
insulin sensitivity through
alanine induced activation of AMPK. Indeed, stimulating prandial GCGN secretion by isocaloric
high protein diets (HPDs) strongly reduces intrahepatic
lipids (IHLs) and improves
glucose metabolism in
type 2 diabetes mellitus (T2DM). Therefore, the role of GCGN and circulating AAs in metabolic improvements in 31 patients with T2DM consuming HPD was investigated. Six weeks HPD strongly coordinated GCGN and AA levels with IHL and
insulin sensitivity as shown by significant correlations compared to baseline. Reduction of IHL during the intervention by 42% significantly improved
insulin sensitivity [homeostatic model assessment for
insulin resistance (HOMA-IR) or hyperinsulinemic euglycemic clamps] but not fasting GCGN or AA levels. By contrast, GCGN secretion in mixed meal tolerance tests (MMTTs) decreased depending on IHL reduction together with a selective reduction of GCGN-regulated
alanine levels indicating greater GCGN sensitivity. HPD aligned
glucose metabolism with GCGN actions. Meal stimulated, but not fasting GCGN, was related to reduced liver fat and improved
insulin sensitivity. This supports the concept of GCGN-induced hepatic lipolysis and
alanine- and ureagenesis-induced activation of AMPK by HPD.