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C R Kahn

Publications and source records attributed to C R Kahn.

At least 235 records · Page 13Linked to original sources
PubMed1988

Phorbol ester-induced serine phosphorylation of the insulin receptor decreases its tyrosine kinase activity.

The effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the function of the insulin receptor was examined in intact hepatoma cells (Fao) and in solubilized extracts purified by wheat germ agglutinin chromatography. Incubation of ortho[32P]phosphate-labeled Fao cells with TPA increased the phosphorylation of the insulin receptor 2-fold after 30 min. Analysis of tryptic phosphopeptides from the beta-subunit of the receptor by reverse-phase high performance liquid chromatography and determination of their phosphoamino acid composition suggested that TPA predominantly stimulated phosphorylation of serine residues in a single tryptic peptide. Incubation of the Fao cells with insulin (100 nM) for 1 min stimulated 4-fold the phosphorylation of the beta-subunit of the insulin receptor. Prior treatment of the cells with TPA inhibited the insulin-stimulated tyrosine phosphorylation by 50%. The receptors extracted with Triton X-100 from TPA-treated Fao cells and purified on immobilized wheat germ agglutinin retained the alteration in kinase activity and exhibited a 50% decrease in insulin-stimulated tyrosine autophosphorylation and phosphotransferase activity toward exogenous substrates. This was due primarily to a decrease in the Vmax for these reactions. TPA treatment also decreased the Km of the insulin receptor for ATP. Incubation of the insulin receptor purified from TPA-treated cells with alkaline phosphatase decreased the phosphate content of the beta-subunit to the control level and reversed the inhibition, suggesting that the serine phosphorylation of the beta-subunit was responsible for the decreased tyrosine kinase activity. Our results support the notion that the insulin receptor is a substrate for protein kinase C in the Fao cell and that the increase in serine phosphorylation of the beta-subunit of the receptor produced by TPA treatment inhibited tyrosine kinase activity in vivo and in vitro. These data suggest that protein kinase C may regulate the function of the insulin receptor.

Adenosine Triphosphate↗
PubMed1988

A cascade of tyrosine autophosphorylation in the beta-subunit activates the phosphotransferase of the insulin receptor.

We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. The receptor, purified from Fao hepatoma cells on immobilized wheat germ agglutinin, undergoes autophosphorylation at several tyrosine residues in its beta-subunit; however, anti-phosphotyrosine antibody (alpha-PY) inhibited most of the phosphorylation by trapping the initial sites in an inactive complex. Exhaustive trypsin digestion of the inhibited beta-subunit yielded two peptides derived from the Tyr-1150 domain (Ullrich, A, Bell, J. R., Chen, E. Y., Herrera, R., Petruzzelli, L. M., Dull, T. J., Gray, A., Coussens, L., Liao, Y.-C., Tsubokawa, M., Mason, A., Seeburg, P. H., Grunfeld, C., Rosen, O. M., and Ramachandran, J. (1985) Nature 313, 756-761) called pY4 and pY5. Both peptides contained 2 phosphotyrosyl residues (2Tyr(P], one corresponding to Tyr-1146 and the other to Tyr-1150 or Tyr-1151. In the absence of the alpha-PY additional sites were phosphorylated. The C-terminal domain of the beta-subunit contained phosphotyrosine at Tyr-1316 and Tyr-1322. Removal of the C-terminal domain by mild trypsinolysis did not affect the phosphotransferase activity of the beta-subunit suggesting that these sites did not play a regulatory role. Full activation of the insulin receptor during in vitro assay correlated with the appearance of two phosphopeptides in the tryptic digest of the beta-subunit, pY1 and pY1a, that were inhibited by the alpha-PY. Structural analysis suggested that pY1 and pY1a were derived from the Tyr-1150 domain and contained 3 phosphotyrosyl residues (3Tyr(P] corresponding to Tyr-1146, Tyr-1150, and Tyr-1151. The phosphotransferase of the receptor that was phosphorylated in the presence of alpha-PY at 2 tyrosyl residues in the Tyr-1150 domain was not fully activated during kinase assays carried out with saturating substrate concentrations which inhibited further autophosphorylation. During insulin stimulation of the intact cell, the 3Tyr(P) form of the Tyr-1150 domain was barely detected, whereas the 2Tyr(P) form predominated. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; 2) progression of the cascade to phosphorylation of the third tyrosyl residue fully activates the phosphotransferase during in vitro assay; 3) in vivo, the 2Tyr(P) form predominates, suggesting that progression of the autophosphorylation cascade to the 3Tyr(P) form is regulated during insulin stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies↗
PubMed1988

Transcriptional and posttranscriptional regulation of tyrosine aminotransferase by insulin in rat hepatoma cells.

The molecular mechanisms of induction of tyrosine aminotransferase (TAT) by insulin were studied in the well-differentiated rat hepatoma cell line Fao. Incubation of Fao cells with insulin resulted in a 2-fold increase in TAT activity and TAT mRNA measured by Northern blot analysis with an oligonucleotide probe to the 5' end of the gene. The effect of insulin on TAT activity had a lag period of 30-60 min and was maximal within 4-5 h. The insulin effect on TAT mRNA was rapid, half-maximal after 15 min, and complete within 1-2 h. Insulin dose-response curves for stimulation of TAT activity and TAT mRNA were almost identical. TAT mRNA levels and enzyme activity were also stimulated by anti-insulin receptor antibodies and dexamethasone but not by wheat germ agglutinin, concanavalin A, or phytohemagglutin. The effect of insulin on the TAT gene was further investigated by measuring the relative rate of transcription in isolated nuclei using genomic TAT clones. Insulin produced a 1.5-1.7-fold increase in the production of TAT RNA transcripts. Dexamethasone induced both TAT activity and TAT mRNA to a comparable extent. In the presence of dexamethasone, insulin produced an additional 2-fold stimulation of TAT activity but had no additional effect on the abundance of TAT mRNA. These data provide direct evidence that insulin can increase TAT activity by at least two distinct mechanisms: insulin alone appears to increase TAT activity and TAT mRNA due to a stimulation of the TAT gene transcription rate; while in the presence of glucocorticoids, insulin increases TAT activity but not TAT mRNA, suggesting an insulin effect at the posttranscriptional level.

Animals↗
PubMed1988

Decreased autophosphorylation of EGF receptor in insulin-deficient diabetic rats.

We have previously reported that despite an increase in receptor concentration, there is a decrease in autophosphorylation and tyrosine kinase activity of the insulin receptor in insulin-deficient diabetic rats. To determine if other tyrosine kinases might be altered, we have studied the epidermal growth factor (EGF) receptor kinase in wheat germ agglutinin-purified, Triton X-100-solubilized liver membranes from streptozotocin (STZ)-induced diabetic rats and the insulin-deficient BB rat. We find that autophosphorylation of EGF receptor is decreased in proportion to the severity of the diabetic state in STZ rats with a maximal decrease of 67% (P less than 0.01). A similar decrease in autophosphorylation was observed in diabetic BB rats that was partially normalized by insulin treatment. Separation of tryptic phosphopeptides by reverse-phase high-performance liquid chromatography revealed a decrease in labeling at all sites of autophosphorylation. A parallel decrease in EGF receptor phosphorylation was also found by immunoblotting with an anti-phosphotyrosine antibody. EGF receptor concentration, determined by Scatchard analysis of 125I-labeled EGF binding, was decreased by 39% in the STZ rat (P less than 0.05) and 27% in the diabetic BB rat (not significant). Thus autophosphorylation of EGF receptor, like that of the insulin receptor, is decreased in insulin-deficient rat liver. In the case of EGF receptor, this is due in part to a decrease in receptor number and in part to a decrease in the specific activity of the kinase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Insulin receptor function in fibroblasts from patients with leprechaunism. Differential alterations in binding, autophosphorylation, kinase activity, and receptor-mediated internalization.

Insulin receptor function was examined in cultured skin fibroblasts from three patients with leprechaunism (Ark-1, Minn-1, and Can-1), a rare syndrome of severe insulin resistance and neonatal growth retardation. All three patients cell lines demonstrated insulin binding less than 15% of control. This was primarily due to reduced affinity of the receptor in Can-1 and due to reduced number of receptors in the other two cell lines (Ark-1 and Minn-1). When expressed as a fraction of total insulin bound, the percentage of cell-associated insulin internalized and degraded did not differ between the patient cell lines and the controls. However, chloroquine, which inhibited degradation by 50% in the control cells, had no effect in the cells from the patients. When normalized to insulin binding, insulin receptor autophosphorylation was normal in cells from Can-1, but reduced in those of Ark-1 and Minn-1. In contrast, the receptor-associated tyrosine kinase activity toward exogenous substrates was decreased in all three patient cell lines. These results suggest that leprechaunism is a biochemically heterogenous disease associated with a variety of alterations in receptor function. Cells from Ark-1 and Minn-1 exhibit parallel alterations in receptor autophosphorylation and kinase activity. Cells from Can-1 demonstrate normal receptor autophosphorylation but reduced kinase activity, thus displaying a unique form of a mutant insulin receptor. Despite reduced kinase activity, all three cell lines exhibit normal rates of insulin internalization, but decreased lysosomal-mediated degradation. Our data imply that receptor autophosphorylation and kinase activity may be regulated separately and that kinase activity may be linked to insulin degradation, but not necessarily internalization.

Endocrine System Diseases↗
PubMed1988

The insulin receptor gene and its expression in insulin-resistant mice.

Defects of insulin receptor binding and tyrosine kinase activity have been described in genetically diabetic (db/db) and obese (ob/ob) mice. To determine if these changes were related to an abnormality in insulin receptor mRNA expression or structure of the receptor gene, we quantitated receptor mRNA from db/db and ob/ob homozygous, heterozygous (db/x, ob/x) and unaffected [db(x/x), ob(x/x)] mice and also analyzed restriction fragment length patterns of genomic DNA. Northern blot analysis of insulin receptor mRNA in livers from each of the genotypes revealed two major species of 7.5 and 9.5 kilobases. In contrast to known decreased receptor number in various tissues of ob/ob and db/db mice, quantitation of liver insulin receptor mRNA revealed that both homozygous affected strains had 2-fold or more increased levels of both major mRNA species compared to unaffected control groups. (P less than 0.05). Restriction fragment length analysis revealed no major insertion or deletion mutations in either the db/db or ob/ob insulin receptor gene. From the number and size of the fragments generated by this analysis, the minimal size of the mouse insulin receptor gene was calculated to be 97 kilobases, and the minimal number of exons was 16. These data indicate that the insulin receptor gene in ob/ob and db/db mice exhibits no major structural abnormality. Decreases in insulin receptor binding and/or kinase activity in affected mice appear to be due to a defect at the posttranscriptional level and occur despite increased levels of receptor mRNA.

Animals↗
PubMed1988

Dexamethasone-induced changes in phosphorylation of the insulin and epidermal growth factor receptors and their substrates in intact rat hepatocytes.

Dexamethasone-induced changes in insulin and epidermal growth factor (EGF) receptor number, autophosphorylation, and kinase activity were studied in intact rat hepatocytes. Hepatocytes were freshly isolated from Sprague-Dawley rats treated with dexamethasone (1 mg/kg) for 4 days and from untreated littermates. Dexamethasone had no effect on insulin receptor number, while EGF receptor binding was slightly increased (21.3% vs. 17.2% binding/10(6) cells) after dexamethasone treatment. In hepatocytes from both control and dexamethasone-treated animals labeled with 32P, insulin induced tyrosine phosphorylation of the beta-subunit of the insulin receptor as well as of a 175K protein believed to be its endogenous substrate. The degree of phosphorylation of the insulin receptor was decreased 34% by dexamethasone treatment compared to the control value when studied in fasted animals. In contrast, phosphorylation was increased to a similar extent by dexamethasone treatment in fed animals. In addition, the beta-subunit of the insulin receptor extracted from dexamethasone-treated animals migrated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with a slightly increased mobility compared to normal (89 +/- 1.2K vs. 92.5 +/- 0.4K). EGF induced tyrosine phosphorylation of its own receptor and of a 120K protein in intact hepatocytes. Their degree of phosphorylation was decreased by 30% as a result of dexamethasone treatment in the fasted animal and was unchanged in the fed animals. Our data indicate that glucocorticoids modulate insulin and EGF receptor kinase activity, but the nature of their effect depends on other factors, including the dietary state of the animal. These studies also suggest that postreceptor changes account for a major component of glucocorticoid-induced insulin resistance.

Animals↗
PubMed1988

Alterations in insulin receptor autophosphorylation in insulin resistance: correlation with altered sensitivity to glucose transport and antilipolysis to insulin.

We studied insulin binding, receptor autophosphorylation, and insulin action in isolated adipocytes from 23 Pima Indians with varying degrees of obesity over a range of glucose tolerance. [125I]Insulin binding varied widely and did not correlate with fasting plasma immunoreactive insulin levels or insulin sensitivity, as assessed by the ED50 values of insulin stimulation of glucose transport or insulin inhibition of lipolysis in isolated abdominal wall adipocytes obtained by biopsy from the patients. In contrast there was a significant correlation between loss of stimulation of autophosphorylation in solubilized receptors and loss of insulin sensitivity for both stimulation of glucose transport (r = -0.59; P less than 0.005) and inhibition of lipolysis (r = -0.54; P less than 0.01). There was also a significant inverse correlation between insulin's ability to stimulate receptor autophosphorylation and in vivo insulin resistance, as assessed by fasting plasma insulin levels (r = -0.46; P less than 0.05). These data indicate a significant correlation between changes in sensitivity of glucose transport and antilipolysis to insulin and receptor kinase activity in those patients and suggest that defective coupling of insulin binding to insulin action at the level of phosphorylation of the insulin receptor may cause the insulin resistance in this group of patients.

Adipose Tissue↗
PubMed1988

Altered expression and function of the insulin receptor in a family with lipoatrophic diabetes.

To determine the role of genetic defects in the insulin receptor in the insulin resistance of lipoatrophic diabetes mellitus, we studied insulin binding, insulin receptor autophosphorylation, and insulin receptor mRNA levels and performed Southern blot analysis of genomic DNA in four siblings, all of whom have some degree of insulin resistance and three of whom have lipoatrophy. The insulin receptor concentration in Epstein-Barr virus-transformed lymphocytes was about 30% of normal in all three lipoatrophic siblings (LA1, LA2, and LA3) and was 55% of normal in the nonlipoatrophic sibling (LAS). Insulin receptor mRNA concentrations in the lymphocytes paralleled insulin binding and ranged from 15-67% of the mean normal level. Insulin binding to fibroblasts was also reduced about 50% in the lipoatrophic siblings. In addition, insulin binding to fibroblasts of LAS and LA2 exhibited a rightward shift of the competition curve, suggesting reduced receptor affinity [ED50, 35 and 50 ng/mL (5845 and 8350 pmol/L); normal, 1-3 ng/mL (167-501 pmol/L)]. Receptor autophosphorylation determined using Triton X-100 extracts of the fibroblasts was decreased in LA1 and LA3, but normal in LA2 and LAS. Using restriction enzyme digests of genomic DNA and probes spanning the entire cDNA of the insulin receptor, no gross alterations in receptor gene structure were detected in any members of this family. In 2 of the lipoatrophic siblings (LA1 and LA3) and in the sibling with insulin resistance but no lipoatrophy (LAS), a unique variant BamHI site was detected using a probe to the alpha-subunit region. This site was not found in 200 normal or diabetic insulin receptor alleles. By use of probes 5' and 3' to the alpha-subunit probe and by genomic cloning analysis, this variant BamHI site was localized to an intron in the insulin receptor gene downstream of exon 3 which encodes amino acids 191-296 of the alpha-subunit of the receptor. These data indicate the complex nature of familial lipoatrophic diabetes mellitus, with alterations in insulin receptor expression and/or function in both clinically affected and non-affected siblings. Both the reduced insulin binding and reduced levels of insulin receptor mRNA in the lipoatrophic siblings suggest that an insulin receptor gene defect contributes to this syndrome. Several members of this family also carry a unique variant insulin receptor gene, which, however, could not be linked to a specific alteration in receptor expression or the presence of lipoatrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

DNA Restriction Enzymes↗
PubMed1988

Determinants of IDDM and perinatal mortality in children of diabetic mothers.

Offspring of women with insulin-dependent diabetes mellitus (IDDM) have a lower risk of developing IDDM than offspring of men with IDDM (1). To determine whether the risk of diabetes in offspring of diabetic mothers has changed after dramatic improvements in perinatal survival of these infants, we undertook a follow-up study of 1602 pregnancies of 739 women with IDDM who were patients at the Joslin Diabetes Center. Improvements in perinatal survival were abrupt rather than gradual. During the two decades before 1961, perinatal mortality was stable around 23%. After a sudden drop in 1961, it stabilized around 14% until 1975, when it was brought down to 4%, where it has remained. Of the 1391 offspring who survived the neonatal period, IDDM has developed in 21, a cumulative risk of 2.1 +/- 0.5% (SE) by age 20 yr. This is one-third the risk previously reported for offspring of fathers with IDDM and is independent of the calendar time of the births (1). The risk of diabetes in offspring of diabetic mothers is increased in young mothers and is otherwise independent of risk factors for perinatal mortality in this series. We conclude that there is no evidence that selective loss of diabetes-susceptible fetuses in perinatal deaths is a mechanism for the lower incidence of IDDM in the offspring of mothers with IDDM than in those of fathers with IDDM. The principal alternative mechanism is that exposure in utero to an affected mother can protect a fetus from developing IDDM later in life. Induction of immunologic tolerance to the autoantigens of the beta-cells is a plausible mechanism for this protective effect.

Adolescent↗
PubMed1988

Dietary carbohydrate, a Big Mac, and insulin requirements in type I diabetes.

Using the artificial beta-cell (Biostator), we determined the insulin requirements in five nonobese type I (insulin-dependent) diabetic subjects who received isocaloric 40 and 60% mixed-carbohydrate diets in a crossover randomized fashion for 4 days, each day consisting of four equal meals. This was followed on day 5 by a "Big Mac Attack" lunch consisting of a Big Mac, french fries, and milk shake. Insulin requirements to maintain normoglycemia were calculated for each 24-h period and for the 2 h after each meal. The mean 24-h insulin requirements to maintain normoglycemia was greater for the 60% carbohydrate diet than the 40% diet. Although the four meals were of equal size, in all patients the insulin required to cover breakfast greater than lunch greater than dinner greater than or equal to snack. Expressed as milliunits per kilocalorie, the amount of insulin to cover breakfast was greater for the 60% (P less than .05) than the 40% carbohydrate diet and greater for breakfast than the other meals (P less than .01). Insulin requirements for the Big Mac (43% carbohydrate) were 58% greater than for the 40% carbohydrate diet, even after correction for caloric differences. In summary, 1) increasing dietary carbohydrate from 40 to 60% results in an increased insulin requirement for meals only; 2) insulin requirements are greater in the morning than in the evening, even when meal size is constant; and 3) very large meals with high fat and carbohydrate content result in a major increase in insulin requirement. These data indicate that diet has an important impact on insulin requirements in diabetes.

Adult↗
PubMed1987

Characterization of an endogenous substrate of the insulin receptor in cultured cells.

Using antiphosphotyrosine antibodies, we have characterized the tyrosine phosphorylation of an endogenous substrate of the insulin receptor in Fao hepatoma cells and in Chinese hamster ovary cells transfected with a eukaryotic expression vector containing the human insulin receptor cDNA. In Fao cells, besides the beta-subunit of the insulin receptor, a protein with a molecular mass between 170 and 210 kDa designated pp185, undergoes tyrosine phosphorylation immediately after insulin stimulation reaching a maximum level within 30 s. After 4 h of continuous insulin stimulation, the labeling of pp185 decreased to less than half of its original intensity, whereas the insulin receptor was unchanged. After 24 h of insulin stimulation, the phosphotyrosine-containing insulin receptor decreased by 75% owing to down-regulation, whereas the pp185 was completely undetectable. By several biochemical and physiological criteria, the pp185 is distinct from the insulin receptor. The pp185 and the beta-subunit of the insulin receptor were strongly labeled with [32P]orthophosphate, but in contrast to the insulin receptor, the pp185 was not labeled by cross-linking with 125I-insulin or surface 125I iodination. Unlike the insulin receptor, the pp185 was extracted from Fao cells without detergent, and tryptic phosphopeptide mapping of the pp185 and the insulin receptor yielded distinct patterns. Thus, the pp185 is not located at the external face of the plasma membrane and does not bind insulin. Treatment of Fao cells with the phorbol ester, phorbol 12-myristate 13-acetate, stimulated the phosphorylation of two proteins with molecular weights of 170 and 210 kDa which were immunoprecipitated with the anti-phosphotyrosine antibody. Subsequent insulin stimulation increased the phosphorylation of the 210 kDa protein, but the pp185 was not detected. Increasing the concentration of the human insulin receptor in the Chinese hamster ovary cells by transfection with a plasmid containing the human insulin receptor cDNA caused a higher level of tyrosine phosphorylation of the beta-subunit and the pp185. These data support the notion that the insulin signal may be transmitted to a cellular substrate (pp185) which may initiate insulin action at intracellular sites.

Animals↗
PubMed1987

Visualization of viral clearance in the living animal.

The early events in viral dissemination via the bloodstream were identified by monitoring the fate of 123I-radiolabeled reovirus after it was injected intravenously in rats. Continuous scintillation camera imaging showed that reovirus serotypes 1 and 3 were cleared from the circulation in less than 10 minutes by specific and distinct target organs. Reovirus serotype 1 accumulated predominantly in the lungs and the liver, whereas serotype 3 accumulated in the liver and the spleen with very little virus uptake by the lungs. Incubation of reovirus serotype 1 with a monoclonal antibody directed against the viral hemagglutinin before injection totally inhibited the clearance of the virus by the lungs. Similar results were obtained when viruses biolabeled with 35S were used. These results demonstrate that viruses can be rapidly transported through the bloodstream to specific target organs and that the localization of the viruses depends on the interaction between specific viral surface components and the target organ.

Animals↗
PubMed1987

Separate domains of the insulin receptor contain sites of autophosphorylation and tyrosine kinase activity.

We have studied the structure and function of the solubilized insulin receptor before and after partial proteolytic digestion to define domains in the beta-subunit that undergo autophosphorylation and contain the tyrosine kinase activity. Wheat germ agglutinin purified insulin receptor from Fao cells was digested briefly at 22 degrees C with low concentrations (5-10 micrograms/mL, pH 7.4) of trypsin, staphylococcal V8 protease, or elastase. Autophosphorylation of the beta-subunit was carried out before and after digestion, and the [32P]phosphoproteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, detected by autoradiography, and analyzed by tryptic peptide mapping by use of reverse-phase high-performance liquid chromatography. Mild trypsin digestion reduced the apparent molecular mass of the beta-subunit from 95 to 85 kDa, and then to 70 kDa. The 85-kDa fragment was not immunoprecipitated by an antibody directed against the C-terminal domain of the beta-subunit (alpha Pep-1), indicating that this region of the receptor was lost. The 85-kDa fragment contained about half of the [32P]phosphate originally found in the beta-subunit, and tryptic peptide mapping showed that two major tryptic phosphopeptides (previously called pY2 and pY3) were removed. Three other tryptic phosphopeptides (pY1, pY1a, and pY4) were found in the 85- and 70-kDa fragments. Treatment of the intact receptor with staphylococcal V8 protease also converted the beta-subunit to an 85-kDa fragment that did not bind to alpha Pep-1, contained about 50% of the initial radioactivity, and lacked pY2 and pY3. Elastase rapidly degraded the receptor to inactive fragments between 37 and 50 kDa.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1987

Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus.

The risk of premature coronary artery disease (CAD) and its determinants were investigated in a cohort of 292 patients with juvenile-onset, insulin-dependent diabetes mellitus (IDDM) who were followed for 20 to 40 years. Although patients with juvenile-onset IDDM had an extremely high risk of premature CAD, the earliest deaths due to CAD did not occur until late in the third decade of life. After age 30 years, the mortality rate due to CAD increased rapidly, equally in men and women, and particularly among persons with renal complications. By age 55 years the cumulative mortality rate due to CAD was 35 +/- 5%. This was far higher than the corresponding rate for nondiabetic persons in the Framingham Heart Study, 8% for men and 4% for women. Angina and acute nonfatal myocardial infarction followed a similar pattern, as did asymptomatic CAD detected by stress test, so that their combined prevalence rate was 33% among survivors aged 45 to 59 years. Age at onset of IDDM and the presence of eye complications did not contribute to risk of premature CAD. This pattern suggests that juvenile-onset diabetes and its renal complications are modifiers of the natural history of atherosclerosis in that although they profoundly accelerate progression of early atherosclerotic lesions to very severe CAD, they may not contribute to initiation of atherosclerosis.

Adolescent↗