Abstract
A major problem in the insulin therapy of patients with diabetes type 2 (T2DM) is the increased occurrence of hypoglycemic events which, if left untreated, may cause confusion or fainting and in severe cases seizures, coma, and even death. To elucidate the potential contribution of the liver to hypoglycemia in T2DM we applied a detailed kinetic model of human hepatic glucose metabolism to simulate changes in glycolysis, gluconeogenesis, and glycogen metabolism induced by deviations of the hormones insulin, glucagon, and epinephrine from their normal plasma profiles. Our simulations reveal in line with experimental and clinical data from a multitude of studies in T2DM, (i) significant changes in the relative contribution of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization; (ii) decreased postprandial glycogen storage as well as increased glycogen depletion in overnight fasting and short term fasting; and (iii) a shift of the set point defining the switch between hepatic glucose production and hepatic glucose utilization to elevated plasma glucose levels, respectively, in T2DM relative to normal, healthy subjects. Intriguingly, our model simulations predict a restricted gluconeogenic response of the liver under impaired hormonal signals observed in T2DM, resulting in an increased risk of hypoglycemia. The inability of hepatic glucose metabolism to effectively counterbalance a decline of the blood glucose level becomes even more pronounced in case of tightly controlled insulin treatment. Given this Janus face mode of action of insulin, our model simulations underline the great potential that normalization of the plasma glucagon profile may have for the treatment of T2DM.
Highlights
Hepatic glucose metabolism is altered in type 2 diabetes mellitus (T2DM)
To this end we carried out a series of simulations, where we used the model with identical parameterization as it was initially developed for normal subjects and only altered the glucose-hormone response profiles to those observed in T2DM
After having validated the applicability of our model to the hepatic glucose metabolism in T2DM, we performed another series of model simulations to reveal the impact of the altered hormone plasma profiles in T2DM on (i) the set point defining the plasma glucose level at which the liver switches between the glucose producing (HGP) and glucose consuming mode (HGU); (ii) the contributions of glycogenolysis/gluconeogenesis and gluconeogenesis/glycolysis to the diabetes phenotype; (iii) the capability of the liver to respond to changes in blood glucose in untreated T2DM (Fig. 4) and in different modes of insulin treatment of T2DM (Figs. 5, 6, and supplemental Fig. S2–S4)
Summary
Hepatic glucose metabolism is altered in type 2 diabetes mellitus (T2DM). Results: Detailed kinetic modeling of hepatic glucose metabolism including its hormonal regulation predicts the hepatic T2DM phenotype and hypoglycemia in insulin treatment. To elucidate the potential contribution of the liver to hypoglycemia in T2DM we applied a detailed kinetic model of human hepatic glucose metabolism to simulate changes in glycolysis, gluconeogenesis, and glycogen metabolism induced by deviations of the hormones insulin, glucagon, and epinephrine from their normal plasma profiles. The inability of hepatic glucose metabolism to effectively counterbalance a decline of the blood glucose level becomes even more pronounced in case of tightly controlled insulin treatment. Given this Janus face mode of action of insulin, our model simulations underline the great potential that normalization of the plasma glucagon profile may have for the treatment of T2DM
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