Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals

Abstract

Our objectives were to quantitate insulin-stimulated inward glucose transport and glucose phosphorylation in forearm muscle in lean and obese nondiabetic subjects, in lean and obese type 2 diabetic (T2DM) subjects, and in normal glucose-tolerant, insulin-resistant offspring of two T2DM parents. Subjects received a euglycemic insulin (40 mU ⅐ m Ϫ2 ⅐ min Ϫ1 ) clamp with brachial artery/deep forearm vein catheterization. After 120 min of hyperinsulinemia, a bolus of3 H]glucose (tripletracer technique) was given into brachial artery and deep vein samples obtained every 12-30 s for 15 min. Insulin-stimulated forearm glucose uptake (FGU) and whole body glucose metabolism (M) were reduced by 40 -50% in obese nondiabetic, lean T2DM, and obese T2DM subjects (all P Ͻ 0.01); in offspring, the reduction in FGU and M was ϳ30% (P Ͻ 0.05). Inward glucose transport and glucose phosphorylation were decreased by ϳ40 -50% (P Ͻ 0.01) in obese nondiabetic and T2DM groups and closely paralleled the decrease in FGU. The intracellular glucose concentration in the space accessible to glucose was significantly greater in obese nondiabetic, lean T2DM, obese T2DM, and offspring compared with lean controls. We conclude that 1) obese nondiabetic, lean T2DM, and offspring manifest moderate-tosevere muscle insulin resistance (FGU and M) and decreased insulin-stimulated glucose transport and glucose phosphorylation in forearm muscle; these defects in insulin action are not further reduced by the combination of obesity plus T2DM; and 2) the increase in intracelullar glucose concentration under hyperinsulinemic euglycemic conditions in obese and T2DM groups suggests that the defect in glucose phosphorylation exceeds the defect in glucose transport. insulin resistance; muscle; glucose phosphorylation; type 2 diabetes; obesity INSULIN RESISTANCE IN MUSCLE, the primary tissue responsible for glucose disposal (18), is a characteristic feature of type 2 diabetes mellitus (T2DM) (19,20,31) and obesity (4,5,19,20,31,33). In T2DM, impaired insulin action is an inherited trait (41, 65), whereas in obesity insulin resistance is acquired (58) secondarily to disturbances in free fatty acid (FFA) metabolism (27, 53), altered fat topography (13), and deranged secretion of adipocytokines (3). Skeletal muscle insulin resistance in T2DM and obesity affects both the glycogen synthetic and glucose oxidative pathways (22), suggesting a proximal defect in insulin action. Recent studies have demonstrated multiple disturbances in insulin signaling in T2DM subjects (15,35,36). However, there has been considerable debate about the contributions of impaired glucose transport vs. reduced glucose phosphorylation to the defect in insulin action in T2DM (6, 7, 12, 36, 56, 66 -68).Only one previous study (7) has examined the contributions of impaired muscle glucose transport vs. reduced glucose phosphorylation to the defect in insulin action in lean T2DM subjects. Inward transmembrane glucose transport was markedly impaired in lean T2DM subjects under conditions of euglycemic...

The Effect of Type 2 Diabetes on Body Composition of Older Adults

“…Type 2 diabetes is characterized by insulin resistance and impaired insulin secretion by the pancreas. Insulin resistance causes a reduced insulin-mediated glucose uptake in skeletal muscle, 46 resulting in reduced energy production and weaker contraction of the muscle, especially of type I fibers, 47 which are more common in the muscle of older persons than type II fibers. 48 Furthermore, insulin resistance may lead to muscle protein breakdown.…”

Nuclear Imaging of Glucose Transport/Metabolism – An Interesting Tool to Screen Insulin Resistance, Refine Diagnosis of Type 2 Diabetes, Understand Disease Mechanisms, and/or Evaluate New Therapies

“…The same group studied high fat diet rats showing a defect in skeletal muscle glucose transport under insulin conditions (Halseth et al, 2000), and the influence of muscle www.intechopen.com Nuclear Imaging of Glucose Transport/Metabolism -An Interesting Tool to Screen Insulin Resistance, Refine Diagnosis of Type 2 Diabetes, Understand Disease Mechanisms... 297 fiber types on the rate of insulin-stimulated muscle glucose uptake, with glucose delivery and transport being the primary limiting factors in type II muscle (Halseth et al, 2001;Petersen et al, 2003). Recently, in vivo rates of transmembrane glucose transport and intracellular glucose phosphorylation were determined by analyzing the dilution curves of D-mannitol, [ 14 C]3OMG, and D-[3-3 H]glucose, using a multicompartmental model of glucose kinetics in forearm tissues (Pendergrass et al, 2007). The authors concluded that 1) obese non diabetic, lean type 2 diabetic, and offspring manifest moderate-to severe muscle insulin resistance and decreased insulinstimulated glucose transport and glucose phosphorylation in forearm muscle; these defects in insulin action are not further reduced by the combination of obesity plus diabetes; and 2) the increase in intracelullar glucose concentration under hyperinsulinaemic euglycaemic conditions in obese and type 2 diabetic groups suggests that the defect in glucose phosphorylation exceeds the defect in glucose transport (Pendergrass et al, 2007).…”

“…Recently, in vivo rates of transmembrane glucose transport and intracellular glucose phosphorylation were determined by analyzing the dilution curves of D-mannitol, [ 14 C]3OMG, and D-[3-3 H]glucose, using a multicompartmental model of glucose kinetics in forearm tissues (Pendergrass et al, 2007). The authors concluded that 1) obese non diabetic, lean type 2 diabetic, and offspring manifest moderate-to severe muscle insulin resistance and decreased insulinstimulated glucose transport and glucose phosphorylation in forearm muscle; these defects in insulin action are not further reduced by the combination of obesity plus diabetes; and 2) the increase in intracelullar glucose concentration under hyperinsulinaemic euglycaemic conditions in obese and type 2 diabetic groups suggests that the defect in glucose phosphorylation exceeds the defect in glucose transport (Pendergrass et al, 2007). Concerning imaging studies, the fact that emission from 18 F can occur at either [ 18 F]FDG or [ 18 F]FDG-6-P, creates implicit uncertainty as to whether compartmental modeling achieves separate estimations of glucose transport and phosphorylation.…”

Normal muscle glucose uptake in mice deficient in muscle GLUT4

“…This state of hyperglycaemia is contributed by three main defects: increased glucose production from the liver, a diminished capacity of the pancreas to secrete insulin and impaired insulin action on muscle and fat , Stumvoll et al 2005. Studies have shown that the primary defect in insulin action in individuals with type 2 diabetes resides predominantly within the skeletal muscle (DeFronzo et al 1981, Utriainen et al 1998, Pendergrass et al 2007. Skeletal muscle insulin resistance is apparent long before the hyperglycaemia becomes evident (Warram et al 1990), as demonstrated in lean, normal glucose-tolerant offspring of parents with type 2 diabetes who have a similar degree of reduced glucose uptake to that of their parents (Gulli et al 1992, Perseghin et al 1997, Ferrannini et al 2003, Tripathy et al 2003.…”