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Biomedical subjects

C R Kahn

Publications and source records attributed to C R Kahn.

439 records · Page 25Linked to original sources
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In vivo and in vitro studies of vanadate in human and rodent diabetes mellitus.

In vivo vanadate and vanadyl have been shown to mimic the action of insulin and to be effective treatment for animal models of both Type I and Type II diabetes. The molecular mechanism of action of the vanadium salts on insulin sensitivity remains uncertain, and several potential sites proposed for the insulin-like effects are reviewed. In human trials, insulin sensitivity improved in patients with NIDDM, as well as in some patients with IDDM after two weeks of treatment with sodium metavanadate. This increase in insulin sensitivity was primarily due to an increase in non-oxidative glucose disposal, whereas oxidative glucose disposal and both basal and insulin stimulated suppression of hepatic glucose output (HGP) were unchanged. Clinically, oral vanadate was associated with a small decrease in insulin requirements in IDDM subjects. Of additional benefit, there was a decrease in total cholesterol levels in both IDDM and NIDDM subjects. Furthermore, there was an increase in the basal activities of MAP and S6 kinases to levels similar to the insulin-stimulated levels in controls, but there was little or no further stimulation with insulin was seen. Further understanding of the mechanism of vanadium action may ultimately be useful in the design of drugs that improve glucose tolerance.

Animals↗
PubMedDate not supplied

Molecular determinants of insulin action.

Insulin elicits an array of biologic responses. Insulin exerts a regulatory role in almost all cells of the body and is the primary hormone responsible for signaling the storage and utilization of basic nutrients. On the molecular level, the actions of insulin are initiated by binding of insulin to the insulin receptor. Interaction of the alpha and beta subunits of the receptor results in tyrosine kinase activity, which is integral to the initiation of cascades of phosphorylation/dephosphorylation reactions that mediate a large number of the actions of insulin. Insulin-receptor substrate 1 may be central to phosphorylation reactions through a role in serine and threonine kinase activity. Insulin action may also involve the generation of low-molecular-weight mediators capable of modulating intracellular enzymes. The regulation of glucose transport is a primary feature of the physiologic role of insulin and is performed by a family of glucose-transporter proteins with different characteristics. One mechanism by which insulin exerts its effect on glucose transport is the stimulation of the translocation of the glucose transporter to the plasma membrane. Degradation of insulin occurs through diverse mechanisms at numerous sites in the body. Reversal of the insulin signal at the cellular level may be accomplished by a class of enzymes termed phosphotyrosine phosphatases, which may play a role in certain pathophysiologic states. Important roles for insulin-receptor kinase, glucose transporters, insulin-receptor substrate 1, and various intracellular enzymes in the actions of insulin have been demonstrated; nonetheless, the formulation of potential therapeutic strategies directed at particular stages of the insulin action cascade will require further elucidation of its components.

Amino Acid Sequence↗
PubMedDate not supplied

Insulin rapidly stimulates tyrosine phosphorylation of a Mr-185,000 protein in intact cells.

Phosphotyrosine-containing proteins are minor components of normal cells which appear to be associated primarily with the regulation of cellular metabolism and growth. The insulin receptor is a tyrosine-specific protein kinase, and one of the earliest detectable responses to insulin binding is activation of this kinase and autophosphorylation of its beta-subunit. Tyrosine autophosphorylation activates the phosphotransferase in the beta-subunit and increases its reactivity toward tyrosine phosphorylation of other substrates. When incubated in vitro with [gamma-32P]ATP and insulin, the purified insulin receptor phosphorylates various proteins on their tyrosine residues. However, so far no proteins other than the insulin receptor have been identified as undergoing tyrosine phosphorylation in response to insulin in an intact cell. Here, using anti-phosphotyrosine antibodies, we have identified a novel phosphotyrosine-containing protein of relative molecular mass (Mr) 185,000 (pp185) which appears during the initial response of hepatoma cells to insulin binding. In contrast to the insulin receptor, pp185 does not adhere to wheat-germ agglutininagarose or bind to anti-insulin receptor antibodies. Phosphorylation of pp185 is maximal within seconds after exposure of the cells to insulin and exhibits a dose-response curve similar to that of receptor autophosphorylation, suggesting that this protein represents the endogenous substrate for the insulin receptor kinase.

Amino Acids↗
PubMedDate not supplied

Risk of proliferative diabetic retinopathy in juvenile-onset type I diabetes: a 40-yr follow-up study.

The development of proliferative diabetic retinopathy was studied in three cohorts consisting of 292 patients with recent juvenile-onset, type I (insulin-dependent) diabetes who were followed 20-40 yr beginning in 1939, 1949, and 1959. The risk of this severe eye complication was almost nonexistent during the first 10 yr of diabetes, rose abruptly to its maximum level (approximately 30/100 person-years), and remained at that level for the next 25 yr. This pattern did not vary with sex, age at onset of diabetes, or level of glycemic control during the first 5 yr of diabetes. However, the risk of proliferative retinopathy was strongly related to the level of glycemic control during the several years preceding onset of this complication. This was a dose-dependent relationship, with patients in the highest quartile of the distribution of the index of frequency of hyperglycemia having a 10-fold higher risk than individuals in the lowest quartile. A virtually identical pattern was observed in patients who developed diabetes in 1959 as was observed in those who developed diabetes in 1949 or 1939. In contrast, diabetic nephropathy as evidenced by persistent proteinuria showed a lower incidence in the 1959 than in the 1939 cohort. In conclusion, these incidence data do not support the notion that the risk of proliferative retinopathy is mainly a function of duration of diabetes. Instead, the pattern of occurrence of this severe eye complication in type I diabetes suggests that the process leading to the development of proliferative retinopathy consists of two or more stages and that progression through each stage may be governed by different factors.

Adolescent↗
PubMedDate not supplied

Insulin receptors and syndromes of insulin resistance.

Whenever normal concentrations of insulin produce a biologic response that is less than normal, insulin resistance should be suspected. Insulin resistance may occur in many different disease states and may involve an entire organism, a single tissue or cell, or even a single metabolic pathway of insulin action. This report outlines current knowledge about the mechanism of insulin resistance, as well as specific examples of disease states in which it occurs.

Animals↗
PubMedDate not supplied

Suppression of catecholamine and melanin synthesis and promotion of cholinergic differentiation of quail neural crest cells by heart cell conditioned medium.

Quail neural crest cells in vitro give rise to melanocytes and to adrenergic and cholinergic neurons. By supplementing the culture medium with heart cell conditioned medium (HCM), we stimulated cholinergic differentiation as indicated by a significant increase in the specific activity of the enzyme choline acetyltransferase. Melanin and catecholamine synthesis were concomitantly blocked as indicated by a lack of melanin granules and catecholamine-specific histofluorescence. Inhibition of pigmentation was fully reversible for at least 8 days, whereas inhibition of adrenergic differentiation became irreversible when cultures were exposed to HCM for more than 2 days. HCM also promoted cell attachment and spreading on the collagen substratum. These results suggest that HCM affected differentiation of quail neural crest cell progeny.

Animals↗