Insulin-Receptor Interaction in the Obese-Hyperglycemic Mouse

Kahn, C. Ronald; Dm, Neville; Roth, Jesse

doi:10.1016/s0021-9258(19)44468-2

Cited by 393 publications

(12 citation statements)

References 37 publications

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“…The NIDDM mouse provides a practical demonstra-is seen in these mice ‫)%05ف(‬ is found in tissues of obese insulin-resistant people (Bar et al, 1976), diabetic tion of epistatic interactions among different genes in the same pathway. The somewhat bimodal distribution patients (Kolterman et al, 1981;Prince et al, 1981;Olefsky et al, 1982;, and most of the of glucose concentrations into diabetic and nondiabetic animals suggests that only one or two additional genes obesity-linked rodent models of NIDDM (Kahn et al, 1973). Likewise, previous studies have shown a reduc-may be required to give rise to a "clinically apparent" phenotype.…”

Section: Ir/irs-1 (ϩ/ϫ) Mice Develop Normally While Ir/irs-1 (ϫ/ϫ) Mice Die From Diabetic Ketoacidosismentioning

confidence: 98%

Development of a Novel Polygenic Model of NIDDM in Mice Heterozygous for IR and IRS-1 Null Alleles

Brüning

Winnay

Bonner-Weir

et al. 1997

Cell

508

376

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NIDDM is a polygenic disease characterized by insulin resistance in muscle, fat, and liver, followed by a failure of pancreatic beta cells to adequately compensate for this resistance despite increased insulin secretion. Mice double heterozygous for null alleles in the insulin receptor and insulin receptor substrate-1 genes exhibit the expected approximately 50% reduction in expression of these two proteins, but a synergism at a level of insulin resistance with 5- to 50-fold elevated plasma insulin levels and comparable levels of beta cell hyperplasia. At 4-6 months of age, 40% of these double heterozygotes become overtly diabetic. This NIDDM mouse model in which diabetes arises in an age-dependent manner from the interaction between two genetically determined, subclinical defects in the insulin signaling cascade demonstrates the role of epistatic interactions in the pathogenesis of common diseases with non-Mendelian genetics.

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Section: Ir/irs-1 (ϩ/ϫ) Mice Develop Normally While Ir/irs-1 (ϫ/ϫ) Mice Die From Diabetic Ketoacidosismentioning

confidence: 98%

Development of a Novel Polygenic Model of NIDDM in Mice Heterozygous for IR and IRS-1 Null Alleles

Brüning

Winnay

Bonner-Weir

et al. 1997

Cell

508

376

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“…C. R. Kahn and D. M. Neville, Jr., unpublished observations. a 50-70% decrease in the number of insulin receptors on hepatocytes (75,76,140), adipocytes (43), thymocytes (139), and cardiac muscle (40) (Fig. 6).…”

Section: Regulation Of Hormone Receptor Concentrationmentioning

confidence: 99%

“…This alteration in insulin receptors is a specific membrane alteration. In the obese hyperglycemic mouse which has been most extensively studied (75,76,140,141), fully purified plasma membrane fractions of liver of the ob/ob mouse demonstrate a 70% decrease in insulin receptors but remain identical to those of the thin littermates with respect to morphologic appearance, activities of 5'-nucleotidase, and adenylate cyclase, and protein subunit composition. In addition, the membrane receptors for glucagon, growth hormone, and isoproterenol are not altered in these animals (Fig.…”

Section: Ronald Kahn Membrane Receptors For Hormones and Neurotransmittersmentioning

confidence: 99%

Membrane receptors for hormones and neurotransmitters.

Kahn¹

1976

The Journal of Cell Biology

569

174

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Receptors for peptide hormones and neurotransmitters are integral components of the plasma membrane of cells which serve to couple the external milieu to the intracellular regulators of metabolism. These macromolecules are usually high molecular weight glycoproteins, and in many cases appear to have more than one subunit capable of binding the hormone. The interaction of the hormone or neurotransmitter with its receptor is rapid, reversible, and of high affinity and specificity. Many receptors exhibit cooperative properties in hormone binding or biological function. The concentration of receptors on the membrane is a function of continued synthesis and degradation, and may be altered by a variety of factors including the hormone itself. The fluid mosaic nature of the membrane may allow hormone receptors and effectors to exist in free floating states. Further investigations of the hormone-receptor interaction will no doubt yield new insights into both the mechanism of hormone action and membrane structure and function.

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“…Pedro Cuatrecasas later showed that the primary action of insulin is at the cell membrane ( 78 ) and then used affinity chromatography and detergent solubilization methods to purify the insulin receptor from liver cell membranes ( 79 ). Ronald Kahn, David Neville, and Jesse Roth carried out the first receptor-binding assays and concluded that the levels of the insulin receptor are reduced in obese animals, providing a plausible explanation for insulin resistance ( 80 ). This was long before the regulation of downstream signaling events were studied.…”

Section: Discovery Of the Insulin Receptor And Its Tyrosine Kinase Activitymentioning

confidence: 99%