Signal recognition of metabolic stimuli in the pancreatic alpha cell: experimental and numerical investigations

• Applicants: Professor Dr.-Ing. Michael Müller; Professor Dr. Ingo Rustenbeck
• Subject Area: Endocrinology, Diabetology, Metabolism ; Pharmacology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 559811548

The physiological role of glucagon is primarily considered to consist in the prevention of hypoglycemias. Thus it appears logical that the reaction of the glucagon-secreting alpha cell to changes in the glucose concentration is the opposite of the one of the insulin-secreting beta cell. The situation is more complex, however, since the increase of certain amino acids, e.g. alanine, is related to elevated glucagon levels in the bloodstream. It has remained unclear so far to which degree the secretion of glucagon is influenced by the autonomous nervous system or the neighboring beta cells and to which degree the alpha cell disposes of an endogenous signal recognition. Since the alpha cell expresses glucokinase and ATP-sensitive potassium channels, as does the beta cell, it is currently assumed that like in the beta cell the oxidative phosphorylation, the increase in the cytosolic ATP/ADP ratio and the closure of the KATP channels are necessary components of the stimulus secretion coupling. Our recent investigations, however, revealed substantial differences in the response to depolarization and in the mitochondrial metabolism. Therefore, we want to broaden the scope of our investigations into the mitochondrial metabolism of the alpha cell to clarify the mechanisms underlying the changes of the cytosolic ATP/ADP ratio. In addition to glucose selected amino-, keto-, and fatty acids will be used to characterize their effects on mitochondrial function. A close comparison of alpha- and beta cells is intended to separate what is similar and what is different between these endocrine cell types. The additional measurements of the electrical activity, the cytosolic Ca2+ concentration and finally, of the hormone secretion will give an encompassing view on stimulus-secretion coupling. The measurement of glucagon secretion requires the use of perifused intact islets, where the activity of the beta cells exerts an inhibitory paracrine effect. This potentially obscuring influence can be assessed by the simultaneous measurement of insulin secretion and by repeating the perifusion with selective inhibition of the exocytosis of the beta cells. These observations can be linked with the mitochondrial function via the simultaneous measurement of oxygen consumption and glucagon secretion of perifused clonal Alpha TC1 cells. The question whether the measured parameters are sufficient to correctly describe the stimulus-secretion coupling of alpha cells will be addressed by further evolution of modeling procedures which have been developed over the last 20 years to describe the sequence of stimulus-secretion coupling in beta cells. Emphasis will be placed on the modeling of the substrate flux of the citric acid cycle, since major differences between alpha- and beta cells can be expected to exist at this site, which has a crucial role for nutrient stimulation of the beta cell. The results of the modeling will serve to generate hypotheses for experimental verification.

• DFG Programme: Research Grants