Glucagon was initially regarded as a hyperglycemic substance; however, recent research has revealed its broader role in metabolism, encompassing effects on glucose, amino acids (AAs), and lipid metabolism. Notably, the interplay of glucagon with nutrient intake, particularly of AAs, and non-nutrient components is central to its secretion. Fasting and postprandial hyperglucagonemia have long been linked to the development and progression of type 2 diabetes (T2DM). However, recent studies have brought to light the positive impact of glucagon agonists on lipid metabolism and energy homeostasis. This review explores the multifaceted actions of glucagon, focusing on its regulation, signaling pathways, and effects on glucose, AAs, and lipid metabolism. The interplay between glucagon and other hormones, including insulin and incretins, is examined to provide a mechanistic understanding of its functions. Notably, the liver–α-cell axis, which involves glucagon and amino acids, emerges as a critical aspect of metabolic regulation. The dysregulation of glucagon secretion and its impact on conditions such as T2DM are discussed. The review highlights the potential therapeutic applications of targeting the glucagon pathway in the treatment of metabolic disorders.

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.

Scope: Secretion of the gut hormones glucagon‐like peptide (GLP‐1) and peptide YY (PYY) are induced by nutrients reaching the lower small intestine which regulate insulin and glucagon release, inhibit appetite, and may improve β‐cell regeneration. The aim is to test the effect of a slowly digested isomaltulose (ISO) compared to the rapidly digested saccharose (SAC) as a snack given 1 h before a standardized mixed meal test (MMT) on GLP‐1, PYY, glucose‐dependent insulinotropic peptide (GIP), and metabolic responses in participants with or without type 2 diabetes (T2DM).Methods and results: Fifteen healthy volunteers and 15 patients with T2DM consumed either 50 g ISO or SAC 1 h preload of MMT on nonconsecutive days. Clinical parameters and incretin hormones are measured throughout the whole course of MMT. Administration of 50 g ISO as compared to SAC induced a significant increase in GLP‐1, GIP, and PYY responses over 2 h after intake of a typical lunch in healthy controls. Patients with T2DM showed reduced overall responses of GLP‐1 and delayed insulin release compared to controls while ISO significantly enhanced the GIP and almost tripled the PYY response compared to SAC.Conclusion: A snack containing ISO markedly enhances the release of the metabolically advantageous gut hormones PYY and GLP‐1 and enhances GIP release in response to a subsequent complex meal.

To investigate the impact of diabetes duration and different nutrient profiles on type 2 diabetes remission (T2DR) in response to very low-calorie diets (VLCDs). Participants with a BMI > 27 kg/m² and diabetes duration of ≤ 4 years or ≥ 8 years were studied before and after a VLCD (600-800 kcal/day) for three months, including discontinuation of antidiabetic medication. Individuals were randomly assigned to one of two VLCDs with slightly different macronutrient composition. T2DR, defined as plasma fasting glucose < 126 mg/dl, was achieved in 34 of 47 participants (72%). Despite similar weight loss of subjects with short and long diabetes duration (-15.2 ± 5.8 kg vs. -13.9 ± 4.8 kg; p = 0.473), subjects with long diabetes duration had a 32% lower remission rate (82% vs. 50%; p = 0.027).T2DR was found to be higher with the high-fiber, high-protein, and low-carb, low-fat formula diet (91% vs. 56%; p = 0.008). Individuals that achieved T2DR had significantly lower fasting plasma glucose and higher C-peptide levels at baseline. Fasting plasma glucose, C-peptide levels, diabetes duration, and used macronutrient profile emerged as important factors for the achievement of T2DR, although a considerable remission is still possible after long duration of type 2 diabetes.

In the context of type 2 diabetes (T2DM), fasting and postprandial hyperglucagonemia have long been linked to the disease's development and progression. However, recent studies have brought to light the positive impact of glucagon-agonists on lipid metabolism and energy homeostasis. This review delves into the intricate relationship and underlying mechanisms between glucagon and nutrient composition, which may hold promise in devising novel therapeutic approaches for T2DM management.