Carbohydrate Oxidation and Storage in Obese Non-insulin-dependent Diabetic Patients: Effects of Improving Glycemic Control

Boden, Guenther; Ray, Tarun K; Smith, Robert H.; Owen, Oliver E.

doi:10.2337/diab.32.11.982

Cited by 47 publications

(21 citation statements)

References 12 publications

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“…The decrease in GRd of -3 mg/kg per min which occurred when FFA concentrations rose from -50 to -500 gM was accounted for equally by decreases in CHO oxidation and glycogen synthesis, while the decline in GRd which occurred when plasma FFA concentrations rose further (from -550 to -750 ,gM) was caused exclusively by a decrease in glycogen synthesis. These findings expanded earlier observations (13,43) that the effect of fat on CHO oxidation was relatively small and that the main problem in obese diabetic and nondiabetic subjects, whose FFA concentrations are commonly > 500 OM, was a defect in nonoxidative glucose disposal (1)(2)(3)(4)(5)(6)(7)(8)(9) and muscle biopsy samples revealed, however, that glycogen synthesis was already inhibited before inhibition of muscle GS activity. This indicated the presence of an additional, earlier fatty acid-induced block ofglycogen synthesis which was unrelated to an impairment of GS.…”

Section: Discussionsupporting

confidence: 73%

“…While its cause remains uncertain, insulin resistance is known to be commonly associated with an inability of insulin to normally promote nonoxidative glucose disposal (glucose storage) and to activate skeletal muscle glycogen synthase (GS) (2)(3)(4)(5)(6)(7)(8)(9). There is evidence to suggest that in many instances the defects in glucose uptake and storage may be related to abnormal fat metabolism (10,11).…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of fatty acid-induced inhibition of glucose uptake.

Boden

Chen²,

Ruiz³

et al. 1994

J. Clin. Invest.

2,889

654

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Increased plasma FFA reduce insulin-stimulated glucose uptake. The mechanisms responsible for this inhibition, however, remain uncertain. It was the aim of this study to determine whether the FFA effect was dose dependent and to investigate its mechanism. We have examined in healthy volunteers (13 male/1 female) the effects of three steady state plasma FFA levels ( -50, -550, -750 MuM) on rates of glucose uptake, glycolysis (both with 3-3H-glucose), glycogen synthesis (determined with two independent methods), carbohydrate (CHO) oxidation (by indirect calorimetry), hepatic glucose output, and nonoxidative glycolysis (glycolysis minus CHO oxidation) during euglycemic-hyperinsulinemic clamping. Increasing FFA concentration (from -50 to -750 gM) decreased glucose uptake in a dose-dependent fashion (from -9 to -4 mg/kg per min). The decrease was caused mainly (-2/3) by a reduction in glycogen synthesis and to a lesser extent ( 1/3) by a reduction in CHO oxidation. We have identified two independent defects in glycogen synthesis. The first consisted of an impairment of muscle glycogen synthase activity. It required high FFA concentration ( -750MM), was associated with an increase in glucose-6-phosphate, and developed after 4-6 h of fat infusion. The second defect, which preceded the glycogen synthase defect, was seen at medium ( -550MM) FFA concentration, was associated with a decrease in muscle glucose-6-phosphate concentration, and was probably due to a reduction in glucose transport/phosphorylation. In addition, FFA and/or glycerol increased insulin-suppressed hepatic glucose output by -50%. We concluded that fatty acids caused a dose-dependent inhibition of insulin-stimulated glucose uptake (by decreasing glycogen synthesis and CHO oxidation) and that FFA and/or glycerol increased insulin-suppressed hepatic glucose output and thus caused insulin resistance at the peripheral and the hepatic level. (J. Clin. Invest. 1994. 93:2438-2446

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Mechanisms of fatty acid-induced inhibition of glucose uptake.

Boden

Chen²,

Ruiz³

et al. 1994

J. Clin. Invest.

2,889

654

View full text Add to dashboard Cite

show abstract

“…The data of the present and previous studies (16,17,(53)(54)(55) indicate that 30-40% ofan oral glucose load is immediately oxidized; specifically, in the present studies 24.9 g (37%) of a 67.6-g oral load was oxidized. About 35% of this (8.9 g) could be accounted for by muscle.…”

Section: Discussionsupporting

confidence: 55%

Skeletal muscle glycolysis, oxidation, and storage of an oral glucose load.

Kelley¹,

Mitrakou²,

Marsh³

et al. 1988

J. Clin. Invest.

287

181

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Although muscle is considered to be the most important site for postprandial glucose disposal, the metabolic fate of oral glucose taken up by muscle remains unclear. We, therefore, employed the dual isotope technique (intravenous, [6-3HJ-glucose; oral, l1-'4Clglucose), indirect calorimetry, and forearm balance measurements of glucose, lactate, alanine, pyruvate, 02, and CO2 in nine normal volunteers to determine the relative importance of muscle glycogenic, glycolytic, and oxidative pathways in disposal of an oral glucose load. During the 5 h after glucose ingestion (1 g/kg), 37±3% (24.9±2.3 g) of the load was oxidized and 63±3% (42.8±2.7 g) was stored. At least 29% (19.4±1.3 g) was taken up by splanchnic tissues. Muscle took up 26% (17.9±2.9 g) of the oral glucose coincident with a 50% reduction in its oxidation of fat. 15% of the oral glucose taken up by muscle (2.5±0.9 g) was released as lactate, alanine, or pyruvate; 50% (8.9±1.4 g) was oxidized, and 35% (6.4±2.3 g) was available for storage. We conclude that muscle and splanchnic tissues take up a comparable percentage of an oral glucose load and that oxidation is the predominant fate of glucose taken up by muscle, with storage in muscle accounting for < 10% of the oral load. Thus, contrary to the prevailing view, muscle is neither the major site of storage nor the predominant site of disposal of an oral glucose load.

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“…Thereafter, a number of studies have confirmed that elevated rates oflipid oxidation are associated with impaired oxidative glucose disposal in nondiabetic and NIDD subjects (18)(19)(20)(21)(22)(23)(24). However, it remains unproven whether enhanced lipid oxidation also inhibits the nonoxidative pathways of glucose metabolism (21)(22)(23)(24)(25)(26). An association between elevated plasma FFA/lipid oxidation and excessive rates of hepatic glucose production (HGP) has also been suggested (4,12,19,27).…”

Section: Introductionmentioning

confidence: 99%