How Insulin Resistant Are Patients with Noninsulin-Dependent Diabetes Mellitus?*

Reaven, Gerald M.; Chen, Y.-D. I.; Donner, C. C.; Fraze, E.; Hollenbeck, C. B.

doi:10.1210/jcem-61-1-32

Cited by 45 publications

(16 citation statements)

References 15 publications

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“…Whereas these diabetic tissues exhibit little or no change in insulin binding, the metabolic responses to insulin and the insulin receptor protein-tyrosine kinase activity are diminished (16,22,23). Since a variety of hormones can activate protein kinase C (1), it may be that the desensitization associated with diabetes involves protein kinase C activation by one of these agents.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase C directly phosphorylates the insulin receptor in vitro and reduces its protein-tyrosine kinase activity.

Bollag¹,

Roth²,

Beaudoin³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

240

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The (3 subunit of purified insulin receptor is phosphorylated on a serine residue by purified preparations of protein kinase C (ATP: protein phosphotransferase, EC 2.7.1.37). This phosphorylation is inhibited by antibodies to protein kinase C and stimulated by phospholipids, diacylglycerol, and Ca2+. The phosphorylation of the receptor by protein kinase C does not affect its insulin-binding activity but does inhibit by 65% the receptor's intrinsic tyrosine-specific protein kinase activity (ATP: protein-tyrosine O-phosphotransferase, EC 2.7.1.112). These results indicate that activators of protein kinase C, such as phorbol esters, desensitize cells to insulin by direct protein kinase C action on the insulin receptor. MATERIALS AND METHODSMaterials. Insulin receptor was purified on a monoclonal antibody affinity column (10). In most experiments, protein kinase C was purified by DEAE chromatography, ammonium sulfate fractionation, and AcA34 Ultrogel chromatography (11) and had a specific activity of 20-30 nmol of phosphate incorporated into H1 histone per min/mg of protein at 30'C (units/mg). In some experiments, protein kinase C was more extensively purified on DEAE-cellulose, phenyl-Sepharose, and phosphatidylserine columns (12). Monoclonal antibodies to the insulin receptor (24B7, inhibiting; MC51, noninhibiting) (13) and protein kinase C were purified by protein A-Sephadex chromatography. Phosphoamino acids and poly(Glu4,Tyr) (random copolymer, sodium glutamate/tyrosine, 4:1) were from Sigma.Methods. Phosphorylations were carried out as described in the figure legends. Samples were electrophoresed on NaDodSO4/polyacrylamide gels and visualized by autoradiography. Phosphoamino acid analysis was carried out as described (14). Insulin binding and protein-tyrosine kinase assays were as described in the figure legends. The monoclonal antibody (15B5) used in the insulin-binding experiments has been shown to recognize both phosphorylated and nonphosphorylated receptors (13). RESULTSIn the phosphorylation experiments, purified protein kinase C was incubated with purified insulin receptor in the presence of adenosine 5'-[y-32P]triphosphate under a variety of conditions. The reactions were then analyzed by NaDodSO4 gel electrophoresis and autoradiography. Whenever both proteins were included in the reaction mixture, phosphorylation of a 95-kDa protein and an 80-kDa protein was observed (Fig. 1). The 95-kDa protein was identified as the insulin receptor P subunit by immunoprecipitation with monoclonal antibodies to the receptor. The phosphorylation of protein kinase C (11) was also observed in these reactions, as evidenced by the labeled 80-kDa band.Since the insulin receptor is also a protein kinase that can autophosphorylate its 8 subunit (3), a number of tests were performed to test whether additional phosphorylation of the 95-kDa , subunit was due to protein kinase C. First, when the reaction was performed under conditions that inhibited insulin receptor autophosphorylation, the phosphorylation of the 95-kDa...

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Section: Discussionmentioning

confidence: 99%

Protein kinase C directly phosphorylates the insulin receptor in vitro and reduces its protein-tyrosine kinase activity.

Bollag¹,

Roth²,

Beaudoin³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

240

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“…In contrast, hyperglycemia is continuously present in patients with non-insulin-dependent diabetes mellitus (NIDDM), and questions remain as to the relative contribution of changes in R. and Rd to this state of abnormal physiological regulation. On the one hand, there is considerable evidence that Rd is markedly reduced in patients with NIDDM as compared with normal patients when measured during periods of physiological hyperinsulinemia (1,2). On the other hand, after an overnight fast Rd can be greater than normal in patients with NIDDM with significant fasting hyperglycemia (1).…”

mentioning

confidence: 99%

“…On the one hand, there is considerable evidence that Rd is markedly reduced in patients with NIDDM as compared with normal patients when measured during periods of physiological hyperinsulinemia (1,2). On the other hand, after an overnight fast Rd can be greater than normal in patients with NIDDM with significant fasting hyperglycemia (1). R. has also been shown to be increased in such patients (3)(4)(5)(6)(7)(8)(9) and statistically significant correlations have been documented between measurement of Ra and fasting plasma glucose concentration (3,4,(7)(8)(9).…”

mentioning

confidence: 99%

Relationship between plasma glucose and insulin concentration, glucose production, and glucose disposal in normal subjects and patients with non-insulin-dependent diabetes.

Chen¹,

Jeng²,

Hollenbeck³

et al. 1988

J. Clin. Invest.

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The changes in hepatic glucose production (R.), tissue glucose disposal (Rd), and plasma glucose and insulin concentration that took place over a 16-h period from 10 to 2 p.m. were documented in 14 individuals; 8 with non-insulin-dependent diabetes mellitus (NIDDM) and 6 with normal glucose tolerance. Values for R. were higher than normal in patients with NIDDM at 10 p.m. (4.73±0.41 vs. 3.51±0.36 mg/kg per min P < 0.001), but fell at a much faster rate throughout the night than that seen in normal subjects. As a consequence, the difference between R. in normal individuals and patients with NIDDM progressively narrowed, and by 2 p.m, had ceased to exist (1.75±0.61 vs. 1.67±0.47 mg/kg per min, P = NS).Plasma glucose concentration also declined in patients with NIDDM over the same period of time, but they remained quite hyperglycemic, and the value of 245±27 mg/dl at 2 p.m. was about three times greater than in normal individuals. Plasma insulin concentrations also fell progressively from 10 to 2 p.m., and were similar in both groups throughout most of the 16-h study period. Thus, the progressive decline in R. in patients with NIDDM occurred despite concomitant falls in both plasma glucose and insulin concentration. Glucose disposal rates also fell progressively in both groups, but the magnitude of the fall was greater in patients with NIDDM. Consequently, Rd in patients with NIDDM was higher at 10 p.m. (3.97±0.48 vs. 3.25±0.13 mg/kg per min, P < 0.001) and lower the following day at 2 p.m. (1.64±0.21 vs. 1.97±0.35 mg/kg per min, P < 0.01). These results indicate that a greatly expanded pool size can exist in patients with NIDDM at a time when values for R. are identical to those in normal subjects studied under comparable conditions, which suggests that fasting hyperglycemia in NIDDM is not simply a function of an increase in R1. Introduction Hyperglycemia can only develop when the rate of entry of

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“…3 Assuming that IGT is the forerunner of diabetes, one hypothesis holds that the initiating event is insulin resistance; at first insulin secretion is increased and preserves normoglycaemia but eventually pancreatic exhaustion leads to insulin deficiency and a self-perpetuating vicious circle. 4 Alternatively the primary lesion may be an inherited defect of insulin secretion5 which is without clinical consequences until insulin sensitivity is reduced by obesity, age, drugs, illness or other factors. Mathematical modelling by Turner et al 6 suggests that nearnormal basal plasma insulin levels can be maintained by hyperglycaemia when beta cell function is deficient and that diabetes only develops when 80% of beta cell function has been lost.…”

Section: Introductionmentioning

confidence: 99%

When to use insulin in the maturity onset diabetic

Tattersall¹,

Scott²

1987

Postgraduate Medical Journal

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How Insulin Resistant Are Patients with Noninsulin-Dependent Diabetes Mellitus?*

Cited by 45 publications

References 15 publications

Protein kinase C directly phosphorylates the insulin receptor in vitro and reduces its protein-tyrosine kinase activity.

Protein kinase C directly phosphorylates the insulin receptor in vitro and reduces its protein-tyrosine kinase activity.

Relationship between plasma glucose and insulin concentration, glucose production, and glucose disposal in normal subjects and patients with non-insulin-dependent diabetes.

When to use insulin in the maturity onset diabetic

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