Abnormal glucose homeostasis and fasting intolerance in patients with congenital porto-systemic shunts

Abstract

In physiological glucose homeostasis, the liver plays a crucial role in the extraction of glucose from the portal circulation and storage as glycogen to enable release through glycogenolysis upon fasting. In addition, insulin secreted by the pancreas is partly eliminated from the systemic circulation by hepatic first-pass. Therefore, patients with a congenital porto-systemic shunt present a unique combination of (a) postabsorptive hyperinsulinemic hypoglycaemia (HH) because of decreased insulin elimination and (b) fasting (ketotic) hypoglycaemia because of decreased glycogenolysis. Patients with porto-systemic shunts therefore provide important insight into the role of the portal circulation and hepatic function in different phases of glucose homeostasis.

Keywords: congenital hyperinsulinism; congenital porto-systemic shunt; glucose metabolism; hyperinsulinism; hypoglycaemia; insulin; portal circulation.

Figure 1

Normal situation (glucose = white dot, insulin = purple dot, glycogen = yellow coin): (A) Post prandial. 1) Glucose is absorbed from the intestines into the mesenteric veins. 2) Glucose is converted and stored as glycogen in the liver during the first pass effect. 3) Pancreatic beta cells detect the increased glucose levels. 4) Pancreatic beta cells secrete insulin according to glucose levels. 5) Hepatic insulin metabolism reduces systemic insulin levels. (B) During fasting. 1) Stored glycogen is converted to glucose and enters the bloodstream. 2) This mechanism prevents hypoglycemia during fasting. CPSS (A) Post prandial glucose. 1) Glucose is absorbed from the intestines into the mesenteric veins. 2) Due to the porto-systemic shunt the glucose partly bypasses the liver, 3) causing less glucose to be stored as glycogen in the liver 4) and a systemic hyperglycemia (purple warning sign). 5) Pancreatic beta cells detect the increased glucose levels. 6) Pancreatic beta cells excrete more insulin. 7) The insulin bypasses the hepatic metabolism directly flowing into the systemic circulation 8) leading to systemic hyperinsulinemia. 9) Hyperinsulinemia results in a late hypoglycemia in end-organs (yellow warning sign). (B) During fasting. 1) Due to reduced glycogen storage in the liver, significantly less glycogen can be converted to glucose to enter the bloodstream 2) resulting in a hypoglycemia in end-organs (yellow warning sign).