Effect of Insulin on Oxidation of Intracellularly and Extracellularly Derived Glucose in Patients With NIDDM: Evidence for Primary Defect in Glucose Transport and/or Phosphorylation but Not Oxidation

Abstract

Insulin-stimulated glucose oxidation is decreased in patients with non-insulin-dependent diabetes mellitus (NIDDM). It is not known whether this decrease is due to a primary defect in the oxidative pathway or is secondary to impaired glucose transport and/or phosphorylation. To address this issue, glucose oxidation was measured under steady-state conditions at low (approximately 270 pmol) and high (approximately 17 mumol) insulin concentrations in seven patients with NIDDM and seven healthy nondiabetic subjects matched for sex, age, and obesity. Glucose oxidation was measured simultaneously by indirect calorimetry and the isotopedilution technique. Although glucose oxidation and nonoxidative storage were lower (P less than 0.05) in diabetic than nondiabetic subjects during the low- and high-dose insulin infusions, oxidation of intracellularly derived glucose, estimated by subtracting the rate of oxidation measured isotopically (i.e., glucose oxidation derived from the extracellular space) from that measured by indirect calorimetry (i.e., total glucose oxidation), did not differ in diabetic and nondiabetic subjects during the low-dose insulin infusion (3.3 +/- 0.1 vs. 3.0 +/- 0.1 mumol.kg-1.min-1). Both techniques provided identical estimates of glucose oxidation during the high-dose insulin infusion. Impaired oxidation of extracellularly but not intracellularly derived glucose strongly suggests that the cause of decreased glucose oxidation in patients with NIDDM is secondary to impaired glucose transport and/or phosphorylation rather than a primary abnormality in the oxidative pathway.

Assessment of insulin action and glucose effectiveness in diabetic and nondiabetic humans.

“…However, an alteration in intracellular glucose metabolism presumably would not influence glucose uptake if glucose transport/phosphorylation remained rate limiting. Data have been presented arguing both for (41,42) and against (43) transport/phosphorylation as the rate-limiting step for glucose uptake in NIDDM during insulin infusion. Third, although transport may remain rate limiting, hyperglycemia and hyperinsulinemia may facilitate glucose uptake via different transporters.…”

Association study of genetic polymorphisms of SLC2A10 gene and type 2 diabetes in the Taiwanese population

“…Defects in facilitative glucose transport have been implicated in the pathogenesis of type 2 diabetes [20][21][22]. The gene encoding the glucose transporter protein solute carrier family 2, facilitated glucose transporter, member 10 (SLC2A10, previously known as glucose transporter 10 [GLUT10]), lies within the NIDDM3 susceptibility region, and is a novel facilitative glucose transporter that is highly expressed in the liver and pancreas, the two major organs involved in maintaining blood glucose homeostasis [23].…”

Evidence for defects in the trafficking and translocation of GLUT4 glucose transporters in skeletal muscle as a cause of human insulin resistance.

“…In fact, Bonnadonna et al, using a novel isotope tracer and limb balance approach (5), and Kelley et al (6), analyzing rate constants for [ 18 F]2-deoxyglucose uptake during positron emission scanning, have provided evidence for separate defects in both transport and glucose phosphorylation in type 2 diabetes. However, under conditions of stimulated glucose flux, investigators have found that free glucose and glucose-6-phosphate do not accumulate in skeletal muscle (4,(7)(8)(9) and that metabolism within intracellular pathways can be normalized (10)(11)(12). These latter data indicate that transport system defects likely predominate in mediating insulin resistance.…”