Insulin resistance differentially affects the PI 3-kinase– and MAP kinase–mediated signaling in human muscle

Cusi, Kenneth; Maezono, Katsumi; Osman, Abdullah A.; Pendergrass, Merri; Patti, Mary Elizabeth; Pratipanawatr, Thongchai; DeFronzo, Ralph A.; Kahn, C. Ronald; Mandarino, Lawrence J.

doi:10.1172/jci7535

Cited by 1,015 publications

(879 citation statements)

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“…In two studies, PI3′-kinase activity at the clamp insulin concentration was found to be reduced in diabetic individuals [22] or FDR [4] compared to control subjects, whereas Akt phosphorylation was normal [22], or at least not statistically significantly impaired [4]. In several other studies, similar to our observation, IRS-1-associated PI3′-kinase activity and Akt phosphorylation at similar clamp insulin concentrations were not, or at least not statistically significantly, reduced in diabetic subjects [21,23] or FDR [5], and only the insulin-stimulated increments of IRS-1-associated PI3′kinase-activity [5,21] or Akt-phosphorylation [5] were smaller. As previously discussed for our data, that does not necessarily mean that signalling was impaired.…”

Section: Discussionsupporting

confidence: 88%

“…One potential reason why diabetes-associated differences in certain insulin signalling parameters have been observed in some previous studies with diabetic subjects [21,22], but not in another [23] and not in our present study could be the fact that in all but our study, diabetic subjects were severely hyperglycaemic until the euglycaemic glucose clamps were started. It is known that hyperglycaemia or an increased flux through the hexosamine pathway reduces insulin signalling at the level of PI3′-kinase or Akt in rat skeletal muscle [25,26].…”

Section: Discussioncontrasting

confidence: 67%

“…However, even if this scenario were true, the discrepancy between normal signalling levels and reduced glucose disposal would remain and suggest impairments of insulin signalling at non-studied locations. We must also point out that plasma insulin concentrations in the diabetic patients would also have been higher if glucose concentrations had not been normalised by the insulin infusion ( Table 1), and that in the previous studies pre-clamp plasma insulin concentrations were also higher in the hyperglycaemic diabetic patients [21,22,23] and FDR [4,5].…”

Section: Discussionmentioning

confidence: 83%

“…Moreover it needs to be taken into consideration that the reported alterations in Type II diabetes have been subtle. Thus, significant differences have often only been found between obese Type II diabetic subjects and lean, but not obese, control subjects [23,38]. We can therefore not exclude that a potential difference in glycogen synthase activity in the diabetic patients was missed due to the lower number of subjects.…”

Section: Discussionmentioning

confidence: 96%

“…In two of these studies the insulin concentrations at which the reductions were observed, were, however very high [12,22]. In another study [23] the reduced insulin effect in obese Type II diabetic patients compared to lean non-diabetic subjects appeared to be mainly due to their obesity because no difference was observed compared to obese non-diabetic subjects. Akt phosphorylation or activity has been found to be reduced in incubated muscle strips from Type II diabetic patients incubated in vitro [24], but in biopsies obtained at supraphysiological plasma insulin concentrations [22] no differences with control subjects was observed.…”

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confidence: 95%

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Insulin signalling in skeletal muscle of subjects with or without Type II-diabetes and first degree relatives of patients with the disease

et al. 2002

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Aims/hypothesis. Alterations in insulin signalling could contribute to insulin resistance in Type II (non-insulindependent) diabetes mellitus. Some of these alterations could be secondary to the diabetic state, ie. the hyperglycaemia or increased NEFA concentrations. We sought to exclude such secondary factors and to investigate whether Type II diabetes in itself is associated with altered insulin signalling in skeletal muscle. Methods. Hyperinsulinaemic-euglycaemic clamps were performed in 10 obese Type II diabetic patients whose glucose concentrations had been normalised for 8 h by plasma glucose-adapted insulin infusion, 10 BMImatched first-degree relatives of Type II diabetic patients, and 10 BMI-matched non-diabetic subjects. Muscle biopsies were obtained before and at the end of the clamps, and insulin receptor kinase activity, phosphatidylinositol-3′-kinase activity, Akt-Thr 308 -phosphorylation, and glycogen synthase activity determined. Results. At similar steady-state clamp insulin concentrations (~400 pmol/l) similar receptor kinase activities, phosphatidylinositol-3′-kinase activities, AktThr 308 -phosphorylation, and glycogen synthase activities were found in all subject groups although glucose disposal was reduced in the diabetic subjects and relatives. Pre-clamp signalling levels were different between subject groups, most likely due to different preclamp insulin concentrations. Conclusion/interpretation. Our results in subjects at risk for the development of diabetes and Type II diabetic patients with normalized glucose concentrations suggest that Type II diabetes in itself is not associated with reduced signalling intensity at the studied signalling molecules, at least not at the chosen clamp insulin concentration and under the chosen conditions. Alterations responsible for the reduced glucose disposal could be located downstream of the investigated steps or in alternative insulin signalling pathways. A different spatial organisation of the investigated signalling molecules can also not be excluded. [Diabetologia (2002) Type II (non-insulin-dependent) diabetes mellitus is associated with a reduced insulin-stimulated glucose disposal in skeletal muscle and other tissues [1]. Because insulin resistance is also observed in non-diabetic first-degree relatives of diabetic subjects [2,3,4,5], and because it seems to precede the development of frank diabetes [6], an inherited basis of at least a part of the diabetes-associated insulin resistance has been proposed [7]. On the other hand metabolic abnormalities in the diabetic state itself such as hyper-

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Section: Discussionsupporting

confidence: 88%

Section: Discussioncontrasting

confidence: 67%

Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 95%

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Insulin signalling in skeletal muscle of subjects with or without Type II-diabetes and first degree relatives of patients with the disease

et al. 2002

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Metabolic and Molecular Pathogenesis of Type 2 Diabetes Mellitus

DeFronzo

Mandarino

Ferrannini

2003

International Textbook of Diabetes Mellitus

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The maintenance of normal glucose homeostasis is dependent on a finely balanced dynamic interaction between tissue (muscle and liver) sensitivity to insulin and insulin secretion. Even in the presence of severe insulin resistance, a perfectly normal β‐cell is capable of secreting sufficient amounts of insulin to offset the defect in insulin action. Thus, the evolution of type 2 diabetes requires the presence of defects in both insulin secretion and insulin action, and both of these defects can have a genetic as well as an acquired component. When type 2 diabetic patients initially present to the physician, they will have had their diabetes for many years, and defects in insulin action and insulin secretion will be well established. At this stage, it is not possible to define which defect came first in the natural history of the disease. Nevertheless, it is now clear that in any given diabetic patient, whatever defect (insulin resistance or impaired insulin secretion) initiates the disturbance in glucose metabolism, it will eventually be followed by the emergence of its counterpart.

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The Syndrome of Insulin Resistance and Its Links to Atherosclerosis

Bonadonna

2003

International Textbook of Diabetes Mellitus

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Obesity, central fat distribution, altered glucose tolerance, dyslipidemia, and hypertension cluster together to a variable extent presumably because of the common pathogenetic denominator represented by insulin resistance. This cluster has been named insulin resistance syndrome, or dysmetabolic syndrome X, or metabolic syndrome, and possibly is involved in the etiology and/or pathophysiology of atherosclerosis, as also demonstrated by epidemiological studies in which hyperinsulinemia and insulin resistance are independent indicators/predictors of cardiovascular disease. This relationship may be explained by the presence of a common antecedent (“common soil” hypothesis), causing both insulin resistance and atherosclerosis, or by a direct causal role of insulin resistance/hyperinsulinemia in atherogenesis (“insulin‐resistance‐dependent atherosclerosis” hypothesis). At the molecular level, the common soil hypothesis may find its counterpart in the I‐κB‐kinase‐mediated activation of the transcription factor nuclear factor κB raised by the common soil hypothesis and by the insulin‐resistance‐dependent atherosclerosis hypothesis remains unsolved, largely because it may be inherently difficult to gauge the biological link(s) between one “complex” phenotype (the insulin resistance syndrome) and another “hypercomplex” phenotype (the atherosclerotic plaque).

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Insulin resistance differentially affects the PI 3-kinase– and MAP kinase–mediated signaling in human muscle

Cited by 1,015 publications

References 52 publications

Insulin signalling in skeletal muscle of subjects with or without Type II-diabetes and first degree relatives of patients with the disease

Insulin signalling in skeletal muscle of subjects with or without Type II-diabetes and first degree relatives of patients with the disease

Metabolic and Molecular Pathogenesis of Type 2 Diabetes Mellitus

The Syndrome of Insulin Resistance and Its Links to Atherosclerosis

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