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

Abstract

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.

Markers of Glucagon Resistance Improve With Reductions in Hepatic Steatosis and Body Weight in Type 2 Diabetes

“…We assessed parameters of glucagon metabolism only during fasting, overlooking postprandial excursions, which may contribute substantially to disease, as shown for glucose metabolism [ 40 ]. In a similar study [ 23 ] closely resembling the isocaloric study presented here, individuals with type 2 diabetes followed a 6-week isocaloric high-protein diet that yielded no changes in fasting levels of glucagon, mirroring our findings. Nevertheless, the authors [ 23 ] also assessed the effect of a mixed-meal tolerance test following 6 weeks’ high-protein feeding and showed a noteworthy reduction in postprandial alanine levels, while postprandial glucagon levels remained unchanged, indicative of improved glucagon signaling.…”

“…In a similar study [ 23 ] closely resembling the isocaloric study presented here, individuals with type 2 diabetes followed a 6-week isocaloric high-protein diet that yielded no changes in fasting levels of glucagon, mirroring our findings. Nevertheless, the authors [ 23 ] also assessed the effect of a mixed-meal tolerance test following 6 weeks’ high-protein feeding and showed a noteworthy reduction in postprandial alanine levels, while postprandial glucagon levels remained unchanged, indicative of improved glucagon signaling. Indeed, glucagon is also important for the postprandial regulation of glucose and amino acid metabolism [ 9 ] and perhaps also lipid metabolism [ 41 ].…”

“…However, the independent contribution to the evidenced improvements in glucagon resistance following reduction in hepatic steatosis from that of weight loss is not clear. Additionally, changes in systemic amino acid availability by altered macronutrient composition may also affect glucagon resistance by altering pancreatic glucagon secretion [ 7 , 22 , 23 ] since increased protein intake affects hepatic amino acid metabolism via effects on the alpha cells [ 24 , 25 ].…”

A High Protein Diet Is Associated with Improved Glycemic Control Following Exercise among Adolescents with Type 1 Diabetes

“…Studies in people with type 2 diabetes (T2D) have observed similar increases in the gut hormone GLP-1 as well as a pancreatic polypeptide (PYY)with high protein diets, which have been shown to suppress the rate of gastric emptying and, therefore, the rate at which blood glucose concentrations increase following a meal [46,47]. Additionally, high protein diets have been shown to improve insulin sensitivity via reductions in intra-hepatic liver triglycerides and increases in post-meal glucagon secretion among people with T2D [48][49][50][51]. It is possible that improvements in insulin sensitivity and reductions in gastric emptying rate associated with elevated protein intakes may contribute to the improvements in post-exercise glycemia observed in this study.…”

The Regulation and Secretion of Glucagon in Response to Nutrient Composition: Unraveling Their Intricate Mechanisms

“…However, the relative contributions of alpha- to beta-cell cross talk and diminished inhibition of glucagon secretion by insulin resistance or deficiency and increased AA stimulation is presently unclear. Both fatty liver and insulin resistance correlate well with glucagon levels in plasma [ 105 ].…”