The Liver Alpha Cell Axis and Type 2 Diabetes
Nicolai J. Wewer Albrechtsen
Glucagon is a fascinating peptide hormone. Since the discovery of a ‘glucose stimulatory factor’ from the pancreas (2), the physiological role of glucagon continues to be investigated and highly debated (1, 3-5). This is exemplified by glucagon’s role in glucose control (5). From randomized clinical trials with glucagon receptor antagonists, we know that glucagon is a powerful regulator of fasting glucose in humans. Glucagon mediates its effect on glycemia in the fasted state by downstream signaling pathways of cAMP, whereas nutrients, in particular proteins, together with glucagon constitute a physiological interplay (the liver-alpha cell axis) that fine tunes amino acid metabolism in both fasted and postprandial state by signaling independent to that of glucose production/cAMP thereby evoking the possibility of biased signaling pathways of glucagon explaining the emerging terminology of glucagon receptor resistance towards amino acid metabolism but not glucose(6). In this talk, I will discuss what I believe to be glucagon physiological role: amino acid metabolism and put it in the context of liver diseases and diabetes. Finally, I am exited to share out preliminary data on a potential glucagon sensitivity test in humans.
- Albrechtsen NJW, Kuhre RE, Pedersen J, Knop FK, and Holst JJ. The biology of glucagon and the consequences of hyperglucagonemia. Biomarkers in Medicine 10: 1141-1151, 2016.
- Kimball CP, and Murlin JR. AQUEOUS EXTRACTS OF PANCREAS: III. SOME PRECIPITATION REACTIONS OF INSULIN. Journal of Biological Chemistry 58: 337-346, 1923.
- Müller TD, Finan B, Clemmensen C, DiMarchi RD, and Tschöp MH. The New Biology and Pharmacology of Glucagon. Physiological Reviews 97: 721-766, 2017.
- Pearson MJ, Unger RH, and Holland WL. Clinical Trials, Triumphs, and Tribulations of Glucagon Receptor Antagonists. Diabetes Care 39: 1075-1077, 2016.
- Unger RH, and Cherrington AD. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. The Journal of Clinical Investigation 122: 4-12, 2012.
- Wewer Albrechtsen NJ, Pedersen J, Galsgaard KD, Winther-Sorensen M, Suppli MP, Janah L, Gromada J, Vilstrup H, Knop FK, and Holst JJ. The liver-alpha cell axis and type 2 diabetes. Endocrine reviews 2019.
Nicolai have for the last 10 years dedicated his life to understand and explore how the gastrointestinal tract contribute to a healthy metabolism, and to the development and the pathophysiology of metabolic diseases. During medical school, Nicolai spearheaded the development of a new antibody and mass-spectrometry based measurement of these hormones hereof in particular the accurate measurement of glucagon later commercialized by a Swedish biotechnology company. Subsequently, Nicolai applied these methodologies to identify a putative novel hormone (GCG1-61) and characterized its metabolic functions, generated proteomic based biomarker panels of dysmetabolic conditions (evaluated clinically at Rigshospitalet) and a phosphoproteomic ‘atlas’ of insulin signaling in diabetes, and contributed to the identification and characterization of a physiological feedback system between the liver and the glucagon producing alpha-cells (the liver-alpha cell axis). Nicolai currently focus on glucagon biology and to explore the inter-organ cross talk between the liver and the pancreas.