Glucose production rates in type 1 glycogen storage disease

Abstract

Glucose production rates were measured in six patients with glycogen storage disease type 1 (five type 1A, one type 1B) using a primed continuous infusion of either [3-3H]glucose or [6,6-2H2]glucose. In four patients exogenous glucose was needed to maintain normoglycaemia. At blood glucose concentrations of 2.3-4.7 mmol/L, the endogenous glucose production rates were between 34 and 100% of that predicted for healthy subjects. No relationship was found between the blood glucose concentration and glucose production rates but there was a positive correlation between that of blood lactate and glucose production rate. The initial steady state was perturbed either by reducing the exogenous glucose infusion rate or by giving intravenous glucagon (20 micrograms/kg) or alanine (0.1-0.2 g/kg). Reducing the exogenous glucose infusion rate had little short term effect on glucose production rate. Intravenous glucagon increased the glucose production rate as well as blood glucose and lactate concentrations. A bolus of alanine (0.2 g/kg) given intravenously increased the glucose production rate and blood glucose concentrations but blood lactate concentrations fell. In four of the patients the studies were repeated under similar conditions and the glucose production rate was higher in all patients. We conclude that the glucose production rate is not fixed but varies with the prevailing metabolic status, a finding that has implications for the treatment of type 1 glycogen storage disease.

A Potential New Role for Muscle in Blood Glucose Homeostasis

“…Deficiencies in the Glc-6-Pase-␣ complex result in the metabolic disorder GSD-I, which is characterized by hypoglycemia, growth retardation, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic acidemia (1, 2). Despite the absence of the Glc-6-Pase-␣ complex, GSD-I patients are capable of endogenous glucose production (17)(18)(19). We now show that muscle may be able to contribute to interprandial blood glucose homeostasis through the activity of Glc-6-Pase-␤/Glc-6-PT and Glc-6-Pase-␤/vGlc-6-PT.…”

“…Currently the best indication of the extent of the endogenous non-hepatic blood glucose production comes from studies of GSD-Ia patients, who lack a functional Glc-6-Pase-␣. These studies show that the endogenous glucose production rate improves with age, ranging from 50% normal in young GSD-Ia patients, to 67-100% normal in adult GSD-Ia patients (17)(18)(19). Because the muscle mass is only ϳ 20% of the body weight of a newborn but improves through adolescence (36% muscle mass) to adulthood (40 -45%) (31), it is reasonable to suggest that the improvement in the susceptibility of patients to hypoglycemia is attributable to endogenous glucose production by the muscle Glc-6-Pase-␤/Glc-6-PT or Glc-6-Pase-␤/vGlc-6-PT complex.…”

“…Despite disruption of the Glc-6-Pase-␣ complex in GSD-I patients, several studies (17)(18)(19) indicate that GSD-Ia patients are still capable of producing glucose. In light of the discovery of Glc-6-Pase-␤, this implies that non-gluconeogenic tissues may be contributing to interprandial glucose homeostasis through the activity of a Glc-6-Pase-␤/Glc-6-PT or a Glc-6-Pase-␤/vGlc-6-PT complex.…”

A Glucose-6-phosphate Hydrolase, Widely Expressed Outside the Liver, Can Explain Age-dependent Resolution of Hypoglycemia in Glycogen Storage Disease Type Ia

“…The results are given as mean Ϯ S.E. 100% of normal in adult GSD-Ia patients (5)(6)(7). Because the muscle mass is only ϳ20% of the body weight of a newborn but improves through adolescence (36% muscle mass) to adulthood (40 -45%) (27), it is reasonable to suggest that the muscle G6Pase-␤/G6PT complex may be the source of some or all of the extra blood glucose.…”

“…Despite disruption of the G6Pase complex in GSD-I patients, several studies (5)(6)(7) indicate that these patients are still capable of producing glucose, implying there are alternative pathways for endogenous glucose production. G6PT is expressed ubiquitously (8), but G6Pase expression is considered to be restricted to the liver, kidney, and intestine (9,10).…”