Mechanism of impaired insulin-stimulated muscle glucose metabolism in subjects with insulin-dependent diabetes mellitus.

Cline, Gary W.; Magnusson, Inger; Rothman, Douglas L.; Petersen, Kitt Falk; Laurent, Didier; Shulman, Gerald I.

doi:10.1172/jci119395

Cited by 47 publications

(56 citation statements)

References 18 publications

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“…Although some of these effects of poorly controlled T1DM on lipid turnover have been observed previously (8, 18 -20), interpretation of such findings was limited because net changes in circulating lipid concentrations seemed to be insensitive surrogate markers for rates of lipolysis in peripheral tissues. Other studies have suggested that the failure of insulin to suppress lipolysis is a cause rather than a result of insulin resistance in diabetes, leading to increased availability of FFA for fat oxidation (5,21) and decreased peripheral glucose utilization. For example, Boden et al (6) infused lipids into healthy subjects and found an increase in fat oxidation and a decrease in peripheral glucose uptake.…”

Section: Discussionmentioning

confidence: 99%

In Situ Evidence That Peripheral Insulin Resistance in Adolescents with Poorly Controlled Type 1 Diabetes Is Associated with Impaired Suppression of Lipolysis: A Microdialysis Study

et al. 2003

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This study was undertaken to examine whether insulin resistance in adolescents with poorly controlled type 1 diabetes mellitus (T1DM) is associated with the failure of insulin to suppress lipolysis in adipose and muscle tissues. Using microdialysis techniques, extracellular fluid concentrations of glycerol was measured in adipose and muscle tissue 3 h before and 3 h during a 0.8 mU · kg Ϫ1 · min Ϫ1 · euglycemic clamp. Ten adolescents with poorly controlled T1DM (HbA 1c 10.2 Ϯ 0.2%) were compared with six healthy lean adolescent control subjects. Despite similar increases in plasma insulin in both groups, diabetic subjects exhibited a 39% reduction in peripheral glucose uptake compared with controls (p Ͻ 0.05). In contrast, hepatic glucose production was fully suppressed by insulin in diabetic subjects. At the end of the clamp, extracellular glycerol concentrations were significantly elevated in subjects with diabetes (muscle: 85 Ϯ 7 M for diabetics and 51 Ϯ 8 M for controls, p Ͻ 0.01; adipose: 149 Ϯ 23 M for T1DM and 82 Ϯ 11 M for controls, p Ͻ 0.05), indicating impaired in situ suppression of lipolysis in patients with diabetes. With all subjects considered, the rate of insulin-stimulated metabolism was inversely correlated to glycerol concentration in both adipose (r ϭ Ϫ0.63, p Ͻ 0.01) and muscle (r ϭ Ϫ0.63, p Ͻ 0.01). Our data suggest that failure of insulin to inhibit lipolysis in muscle and adipose tissue contributes to the severe peripheral insulin resistance that characterizes poorly controlled T1DM during adolescence. Type 1 diabetes mellitus (T1DM) in adolescents is a disease in which end organ resistance to insulin and deficiency of the hormone coexist (1). During normal puberty, responsiveness to insulin declines and this physiologic insulin resistance is exaggerated by poorly controlled diabetes (1-3). Compared with healthy lean preadolescents, healthy lean adolescents show a selective defect in insulin's ability to stimulate nonoxidative glucose disposal in peripheral (muscle and adipose) tissues; insulin-mediated increases in peripheral glucose oxidation are unaffected by normal puberty (4, 5). In contrast, the exaggerated insulin resistance in adolescents with poorly controlled T1DM involves defects in insulin's ability to stimulate both oxidative and nonoxidative glucose metabolism (5).An implication of the much debated glucose fatty-acid cycle (Randle cycle) is that increased FFA availability interferes with muscle glucose metabolism and contributes to the cause of many insulin-resistant states, including adolescence and T1DM (6 -8). Using the insulin clamp technique and indirect calorimetry, we have shown that severely insulin-resistant adolescents with poorly controlled T1DM fail to suppress circulating FFA levels or rates of fat oxidation in comparison with healthy adolescent controls in response to insulin levels similar to those achieved postprandially by healthy adolescents (5). The wholebody methods used in that study, however, did not allow us to distinguish the relative contributions of...

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Section: Discussionmentioning

confidence: 99%

In Situ Evidence That Peripheral Insulin Resistance in Adolescents with Poorly Controlled Type 1 Diabetes Is Associated with Impaired Suppression of Lipolysis: A Microdialysis Study

et al. 2003

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“…FFA, free fatty acid. measure rates of muscle glycogen synthesis as previously described (23,24). Intracellular glucose concentrations were measured by carbon-13 NMR spectroscopy from 180 to 240 min as described previously (21).…”

Section: Methodsmentioning

confidence: 99%

“…Increments in muscle glycogen concentration were determined from the change in [1-13 C]glycogen concentration and the plasma [1-13 C]glucose atom percent excess as described previously (24). Rates of glycogen synthesis were then calculated from the slope of the least-square linear fit to the glycogen concentration curve during the given time periods as described previously (24).…”

Section: Calculations and Data Analysesmentioning

confidence: 99%

Effects of free fatty acids on glucose transport and IRS-1–associated phosphatidylinositol 3-kinase activity

et al. 1999

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Increased plasma free fatty acid (FFA) concentrations are typically associated with many insulin-resistant states including obesity and type 2 diabetes mellitus (1-3). Furthermore, raising plasma FFA levels in healthy humans, by triglyceride/heparin infusions, can also acutely induce insulin resistance (4-11). Over thirty years ago, Randle et al. (12,13) demonstrated that FFAs compete with glucose for oxidation in isolated rat heart and diaphragmatic muscle preparations, and they speculated that increased fat oxidation may cause the insulin resistance associated with diabetes and obesity. They proposed that increased FFA oxidation leads to an increase in the intramitochondrial acetyl-coenzyme A (acetyl-CoA) and reduced/oxidized nicotinamide adenine dinucleotide (NADH/NAD + ) ratios, resulting in inactivation of pyruvate dehydrogenase activity. The consequent increase in intracellular citrate concentration causes inhibition of phosphofructokinase resulting in an increase in glucose-6-phosphate levels. The elevated glucose-6-phosphate levels would inhibit hexokinase II activity and then lead to decreased glucose uptake. However, recent studies by our group (14) and others (15,16) have called this mechanism into question. Boden and coworkers have shown that a reduction in carbohydrate oxidation was responsible for only one-third of the fatty acid-dependent decrease in glucose uptake, while impaired non-oxidative glucose metabolism accounted for the remainder (16). These workers suggested that two different defects might contribute to the impairment in nonoxidative glucose metabolism. At FFA concentrations of ∼0.75 mM, they found an increase in glucose-6-phosphate concentrations in muscle biopsies, suggesting an inhibitory effect of FFA on glycogen synthase activity, whereas at lower FFA concentrations (∼0.50 mM) they observed no difference in intramuscular glucose-6-phosphate concentration. In contrast, using carbon-13/phosphorous-31 nuclear magnetic resonance (NMR) spectroscopy under increased plasma FFA concentrations (∼1.8 mM), we observed a decrease in intramuscular glucose-6-phosphate concentration associated with a 50% reduction in insulin-stimulated muscle glycogen synthesis (14). These data suggest that acute elevations in plasma FFA levels in humans cause insulin resistance by initial inhibition of glucose transport and/or phosphorylation activity that is concurrently followed by a reduction in the rate of both muscle glycogen synthesis and glucose oxidation. Because glucose-6-phosphate (and not intracellular glucose) concentration was measured, it was not possible to distinguish between To examine the mechanism by which free fatty acids (FFA) induce insulin resistance in human skeletal muscle, glycogen, glucose-6-phosphate, and intracellular glucose concentrations were measured using carbon-13 and phosphorous-31 nuclear magnetic resonance spectroscopy in seven healthy subjects before and after a hyperinsulinemic-euglycemic clamp following a five-hour infusion of either lipid/heparin or glycerol/heparin. I...

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“…A combination of 13 C-and 31 P-MRS opens multiple views on the carbohydrate metabolism (131)(132)(133)(134), which is particularly promising in the different forms of insulinand non-insulin-dependent diabetes patients. While glucose-6-phosphate can observed in the 31 P-MR spectrum, 13 C-MRS gives access to glycogen and glucose, especially in connection with an infusion of 13 C-enriched [1-13 C]glucose.…”

Section: Combination Of 1 H-mrs Of Imcl and Other Mrs Techniquesmentioning

confidence: 99%

Role of proton MR for the study of muscle lipid metabolism

et al. 2006

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1 H-MR spectroscopy (MRS) of intramyocellular lipids (IMCL) became particularly important when it was recognized that IMCL levels are related to insulin sensitivity. While this relation is rather complex and depends on the training status of the subjects, various other influences such as exercise and diet also influence IMCL concentrations. This may open insight into many metabolic interactions; however, it also requires careful planning of studies in order to control all these confounding influences. This review summarizes various historical, methodological, and practical aspects of 1 H-MR spectroscopy (MRS) of muscular lipids. That includes a differentiation of bulk magnetic susceptibility effects and residual dipolar coupling that can both be observed in MRS of skeletal muscle, yet affecting different metabolites in a specific way. Fitting of the intra-(IMCL) and extramyocellular (EMCL) signals with complex line shapes and the transformation into absolute concentrations is discussed. Since the determination of IMCL in muscle groups with oblique fiber orientation or in obese subjects is still difficult, potential improvement with high-resolution spectroscopic imaging or at higher field strength is considered. Fat selective imaging is presented as a possible alternative to MRS and the potential of multinuclear MRS is discussed. 1 H-MRS of muscle lipids allows non-invasive and repeated studies of muscle metabolism that lead to highly relevant findings in clinics and patho-physiology.

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Mechanism of impaired insulin-stimulated muscle glucose metabolism in subjects with insulin-dependent diabetes mellitus.

Cited by 47 publications

References 18 publications

In Situ Evidence That Peripheral Insulin Resistance in Adolescents with Poorly Controlled Type 1 Diabetes Is Associated with Impaired Suppression of Lipolysis: A Microdialysis Study

In Situ Evidence That Peripheral Insulin Resistance in Adolescents with Poorly Controlled Type 1 Diabetes Is Associated with Impaired Suppression of Lipolysis: A Microdialysis Study

Effects of free fatty acids on glucose transport and IRS-1–associated phosphatidylinositol 3-kinase activity

Role of proton MR for the study of muscle lipid metabolism

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