F. Sprangers

Subnormal response of plasma glucose concentration to glucagon despite adequate glycogenolysis: the importance of kinetic measurements.

Abstract The plasma glucose concentration response to a glucagon bolus is considered an important diagnostic tool in hypoglycemia of unknown origin. The response of plasma glucose concentration to glucagon can however also be misleading in the differential diagnosis. In a 3-week-old male infant suffering recurrent severe preprandial hypoglycemia and dependent on continuous i.v. glucose infusion, extensive diagnostic screening including a liver biopsy did not lead to a diagnosis. Based on an insufficient glycemic response (twice) to a glucagon bolus, a disorder of glycogenolysis was suspected. Glucose production and gluconeogenesis were measured (glycogenolysis calculated) during diminishing i.v. glucose infusion and after a glucagon bolus. Reducing glucose infusion resulted in a steep increase in glycogenolysis and gluconeogenesis, maintaining total glucose turnover (production plus infusion) constant at ±9 mg · kg−1 · min−1 (±60% gluconeogenesis, ±40% glycogenolysis). Plasma glucose concentration however decreased from 4.9 mmol/l to 3.4 mmol/l. Glucagon increased glucose production by 50% but resulted in only a minor increase in glucose concentration. Conclusion As glucose concentration depends on the balance between glucose production and utilization (uptake), facilitated glucose uptake rather than impaired glycogenolysis explains the hypoglycemic episodes in this patient. A subnormal response of plasma glucose to glucagon therefore does not necessarily imply a disturbance in glycogenolysis. In cases of hypoglycemia of unknown origin, measurement of glucose kinetics with stable isotopes is indicated.

Regulators of hepatic glucose and glycogen metabolism

SamenvattingDit proefschrift beschrijft aspecten van de fysiologische en pathofysiologische regulatie van het intrahepatische glucosemetabolisme tijdens vasten, om beter inzicht te krijgen in de gestoorde regulatie die type-II-diabetes mellitus kenmerkt. De rol van potentiële mediatoren in de regulatie van de glucoseproductie door de lever werd onderzocht met behulp van geavanceerde stabiele isotooptechnieken. Bekend is dat paracriene interactie tussen Kupffer-cellen (levermacrofagen) en hepatocyten bij de regulatie een rol speelt. Verschillende paden van glucoseproductie werden onderzocht in de aanwezigheid of afwezigheid van verschillende mediatoren (stikstofoxide, NO; gamma-interferon, ifn-γ; en vrije vetzuren, ffa), zowel in vitro bij hepatocyten, als in vivo bij gezonde honden en mensen.