The thermodynamic basis of glucose-stimulated insulin release: a model of the core mechanism

Abstract

A model for glucose sensing by pancreatic β‐cells is developed and compared with the available experimental data. The model brings together mathematical representations for the activities of the glucose sensor, glucokinase, and oxidative phosphorylation. Glucokinase produces glucose 6‐phosphate (G‐6‐P) in an irreversible reaction that determines glycolytic flux. The primary products of glycolysis are NADH and pyruvate. The NADH is reoxidized and the reducing equivalents transferred to oxidative phosphorylation by the glycerol phosphate shuttle, and some of the pyruvate is oxidized by pyruvate dehydrogenase and enters the citric acid cycle. These reactions are irreversible and result in a glucose concentration–dependent reduction of the intramitochondrial NAD pool. This increases the electrochemical energy coupled to ATP synthesis and thereby the cellular energy state ([ATP]/[ADP][Pi]). ATP and Pi are 10–100 times greater than ADP, so the increase in energy state is primarily through decrease in ADP. The decrease in ADP is considered responsible for altering ion channel conductance and releasing insulin. Applied to the reported glucose concentration–dependent release of insulin by perifused islet preparations (Doliba et al. 2012), the model predicts that the dependence of insulin release on ADP is strongly cooperative with a threshold of about 30 μmol/L and a negative Hill coefficient near −5.5. The predicted cellular energy state, ADP, creatine phosphate/creatine ratio, and cytochrome c reduction, including their dependence on glucose concentration, are consistent with experimental data. The ability of the model to predict behavior consistent with experiment is an invaluable resource for understanding glucose sensing and planning experiments.

Glutamate dehydrogenase: role in regulating metabolism and insulin release in pancreatic β-cells

“…When channel conductance reaches a critically low value, the cell depolarizes, Ca 2ϩ enters the cells and induces exocytosis of insulin containing vesicles (1, 2, 6 -8, 19, 33, 36 -39, 44, 45, 47, 64). Our GK-core model does not include any source of reducing equivalents other than glucose, however, and as glucose concentration falls progressively below normal the predicted intramitochondrial [NADH]/[NAD ϩ ] and energy state continue to fall, reaching metabolically disruptive levels (63,64). This progressive decrease in energy state is predicted because the rate of consumption of reducing equivalents by oxidative phosphorylation is determined by the rate of ATP consumption and that is not directly affected by glucose concentration.…”

“…This includes the changes in concentrations of creatine phosphate and Pi that occur in muscle during the rest-to-work (60) and work-to-rest (62) transitions. To better understand regulation of insulin release and glucose homeostasis the next step was to model the activity of glucokinase (GK), the glucose sensor of ␤-cells (16, 18, 36, 40, 41, 54 -56), and graft it onto that for oxidative phosphorylation (63,64). GK translates change in glucose concentration into a change in cellular energy state by altering the intramitochondrial [NADH]/ [NAD ϩ ].…”

“…Predictions of the model are consistent with available experimental data on the activity of GDH-1 in vivo. This GDH-1 model is then grafted onto our model (64) for glucose-dependent release of insulin (GK-core model). The combined model shows that GDH-1 acts as a dynamic redox buffer, preventing intramitochondrial [NADH]/[NAD ϩ ], and thereby the energy state ([ATP]/[ADP][Pi]), from falling to levels that seriously disrupt cell metabolism during periods of hypoglycemia.…”

Counter-regulatory responses to Telfairia occidentalis-induced hypoglycaemia

“…What led to the simultaneous insulin-glucagon surge after 7-day treatment with TO? Just like β-cell secretion, pancreatic α-cell secretion is also regulated by glucose and insulin through GCK as a sensor [ [24] , [25] , [26] ]. Glucagon suppression as insulin increases appears to relate to insulin sensitivity in normal individuals [ 27 , 28 ] while hyperglucagonaemia in the presence of hyperinsulinaemia and hyperglycaemia is due to insulin resistance/reduced insulin sensitivity in α-cells [ 29 ].…”

“…The GCK, present in the liver and pancreatic β- and α–cells, plays a critical role in hepatic glucose metabolism [ 43 , 44 ], especially by regulating insulin and glucagon secretion [ 24 , 26 ]. After being facilitated into the liver cells [ 45 , 46 ], the free glucose is phosphorylated by GCK to form G6P whose production increases as blood glucose increases and then used in glycogenesis, the pentose phosphate pathway, or glycolysis.…”