Decreased kinase activity of insulin receptors from adipocytes of non-insulin-dependent diabetic subjects.

Freidenberg, Gary R.; Henry, Robert R.; Klein, Harald; Reichart, Donna; Olefsky, Jerrold M.

doi:10.1172/jci112789

Cited by 246 publications

(139 citation statements)

References 55 publications

(32 reference statements)

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“…In Vitro Receptor Kinase Activity-Kinase activity associated with the insulin and IGF-I receptors was determined in vitro as described previously (30). Briefly, wheat germ agglutinin-enriched receptors were quantified by insulin or IGF-I binding analysis.…”

Section: Materials-expressionmentioning

confidence: 99%

Protein-tyrosine Phosphatase 1B Is a Negative Regulator of Insulin- and Insulin-like Growth Factor-I-stimulated Signaling

Kenner

Anyanwu

Olefsky

et al. 1996

Journal of Biological Chemistry

410

269

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Section: Materials-expressionmentioning

confidence: 99%

Protein-tyrosine Phosphatase 1B Is a Negative Regulator of Insulin- and Insulin-like Growth Factor-I-stimulated Signaling

Kenner

Anyanwu

Olefsky

et al. 1996

Journal of Biological Chemistry

410

269

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“…A reduction in tyrosine phosphorylation of both the insulin receptor (IR) and the insulin receptor substrate-1 (IRS-1) has been noted in both animal and human non-insulin dependant diabetes mellitus (NIDDM). 4,5 Importantly, this appears to occur in all of the major insulin-sensitive tissues, namely the muscle, fat and liver. It is now clear that decreases in the intrinsic tyrosine kinase activity of the insulin receptor are important components of this disease.…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms of insulin resistance and the role of the adipocyte

2000

Int J Obes

236

145

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Insulin resistance is a common feature of obesity and predisposes the affected individuals to a variety of diseases, including hypertension, dyslipidemias, cardiovascular problems and type 2 diabetes mellitus. However, the molecular mechanisms underlying abnormal insulin action and these other pathological states are not well understood. We have been focusing on cytokines, particularly TNFa a and fatty acid binding proteins, as potential sites to study the molecular basis of these disorders. The role of TNFa a in insulin resistance and other pathologies associated with obesity, have been examined in several experimental systems including obese mice with homozygous null mutations at the TNFa a or TNF receptor loci. Analysis of these animals demonstrated that the genetic absence of TNF signaling in obesity: (i) signi®cantly improves insulin receptor signaling capacity and consequently insulin sensitivity; (ii) prevents brown adipose tissue atrophy and b b 3 -adrenoreceptor de®ciency and improves thermo-adaptive responses, (iii) decreases the elevated PAI-1 and TGFb b production; and (iv) lowers hyperlipidemia and hyperleptinemia. Hence, abnormal TNFa a action in adipocytes disturbs many aspects of metabolic homeostasis in obesity.

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“…One of these factors may be the tyrosine kinase activity of the insulin receptor. An acquired decrease in this activity is often observed in Type 2 diabetes [8,14]. In the heterozygous individuals studied in this paper, no indication for a decreased activity is observed.…”

Section: Discussionmentioning

confidence: 39%

“…The shaded area reflects the range in glucose and insulin levels of these control individuals. The diagnosis diabetes mellitus is given when glucose values rise above the glucose levels indicated in this figure by (,--,) [11] measured over a period of 180 min and the values were compared with data from a healthy non-obese control group [8][9][10][11]16]. The results are summarized in Figure 5.…”

Section: Resultsmentioning

confidence: 99%

Individuals with only one allele for a functional insulin receptor have a tendency to hyperinsulinaemia but not to hyperglycaemia

et al. 1989

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Summary. Recently, we described a leprechaun patient with a genetically transmitted severe insulin resistance due to the absence of functional insulin receptors as inferred from the loss of insulin binding to the patients' fibroblasts and the impaired autophosphorylation of the [~-chain of the receptor. This patient was homozygous for the genetic defect which was recently found to be a leucine to proline mutation at position 233 in the a-chain of the insulin receptor. In the present study we have examined insulin receptor functions in relatives of this patient. Some of these individuals are heterozygous for the genetic defect and have only one allele coding for a functional insulin receptor. Insulin binding to cultured fibroblasts from the heterozygous individuals is only 20-40% of control values indicating a Mendelian mode of inheritance of the binding defect. In contrast, insulin stimulated autophosphorylation of the [~-chain of the insulin receptor shows normal values, indicating compensation mechanisms operating on this process. The stimulation of the basal level of 2-deoxyglucose uptake by insulin in fibroblasts from the homozygous patient is 1.2 fold whereas the heterozygous and control individuals show stimulation values of approximately 1.65 ff)ld. Basal levels of 2-deoxyglucose uptake are similar in these fibroblasts. Oral glucose tolerance tests on the heterozygous individuals indicate an increased requirement for insulin of the target tissues as concluded from the tendency towards hyperinsulinaemia with no observed hyperglycaemia. The results show that individuals with a genetic lesion in the insulin receptor which leads to decreased insulin binding, have mild abnormalities in their glucose tolerance tests but do not seem to develop hyperglycaemia as seen in Type 2 (non-insulin-dependent) diabetes mellitus.Key words: Leprechaunism, insulin receptor, insulin resistance, autophosphorylation, insulin binding, glucose tolerance tests.A variety of genetic defects may result in an impaired glucose homeostasis due to insulin resistance of the target tissues for insulin such as the liver, muscle and adipose tissue. The inherited syndromes of acanthosis nigricans type A and leprechaunism, which are characterized by an extreme resistance to insulin, are the result of mutations in the gene for the insulin receptor as indicated by recent data on molecular cloning of the insulin receptor DNA from these patients [1,2]. Type 2 (non-insulin-dependent) diabetes mellitus, being a disease with a strong genetic component, is also characterized by insulin resistance of the target tissues. The genetic components involved in the predisposition to Type 2 diabetes are unknown and it seems possible that the disease is polygenic in nature, complicating the identification of the genes involved in the pathogenesis of the disease.To investigate the effect of lesions in the insulin receptor gene on glucose homeostasis, we have examined insulin receptor functions and glucose tolerance in relatives from a leprechaun patient. This lep...

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Decreased kinase activity of insulin receptors from adipocytes of non-insulin-dependent diabetic subjects.

Cited by 246 publications

References 55 publications

Protein-tyrosine Phosphatase 1B Is a Negative Regulator of Insulin- and Insulin-like Growth Factor-I-stimulated Signaling

Protein-tyrosine Phosphatase 1B Is a Negative Regulator of Insulin- and Insulin-like Growth Factor-I-stimulated Signaling

Molecular mechanisms of insulin resistance and the role of the adipocyte

Individuals with only one allele for a functional insulin receptor have a tendency to hyperinsulinaemia but not to hyperglycaemia

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