Zonulin, a protein that modulates intestinal permeability, is upregulated in several autoimmune diseases and is involved in the pathogenesis of autoimmune diabetes in the BB/Wor animal model of the disease. To verify the association between serum zonulin levels and in vivo intestinal permeability in patients with type 1 diabetes, both parameters were investigated in different stages of the autoimmune process. Forty-two percent (141 of 339) of the patients had abnormal serum zonulin levels, as compared with age-matched control subjects. The increased zonulin levels correlated with increased intestinal permeability in vivo and changes in claudin-1, claudin-2, and myosin IXB genes expression, while no changes were detected in ZO1 and occludin genes expression. When tested in serum samples collected during the pre-type 1 diabetes phase, elevated serum zonulin was detected in 70% of subjects and preceded by 3.5 ؎ 0.9 years the onset of the disease in those patients who went on to develop type 1 diabetes. Combined, these results suggest that zonulin upregulation is associated with increased intestinal permeability in a subgroup of type 1 diabetic patients. Zonulin upregulation seems to precede the onset of the disease, providing a possible link between increased intestinal permeability, environmental exposure to non-self antigens, and the development of autoimmunity in genetically susceptible individuals.
Objective: To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at nearnormal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy.Methods: Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome.Results: After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conven-tional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; PϽ.001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (PϽ.001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. Conclusion:The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning.
OBJECTIVE -To characterize the insulin sensitivity of overweight and obese 5-to 10-yearold (Tanner stage 1-3) African-American children screened for participation in a diabetes prevention study and to identify the association of insulin sensitivity with obesity, hyperlipidemia, and hypertension.RESEARCH DESIGN AND METHODS -Measures of insulin resistance (homeostasis model assessment) and insulin sensitivity (Matsuda and DeFronzo's whole-body insulin sensitivity) were calculated from a 2-h oral glucose tolerance test in 137 African-American children recruited into a diabetes prevention study. Measures of lipids (LDL, HDL, total cholesterol, and triglycerides), blood pressure, and body composition were obtained for a subset of the children.RESULTS -In response to a glucose challenge, girls and older and heavier children produced significantly more insulin. As BMI increased, there was a statistically significant decrease in insulin sensitivity, particularly in girls. Insulin sensitivity was inversely correlated with increases in blood pressure, triglycerides, subcutaneous fat, the percentage of total body fat, and Tanner stage, but it was not correlated with LDL and HDL.CONCLUSIONS -Reduced insulin sensitivity and the cluster of risk factors known as the insulin resistance syndrome (IRS) are already apparent in these overweight African-American children. Young African-American girls, in particular, already show evidence of hyperinsulinemia in response to a glucose load, suggesting that the early stages of metabolic decompensation that lead to type 2 diabetes are already occurring. Monitoring of those risk factors known to be part of IRS should become part of routine medical care for overweight or obese African-American children. Diabetes Care 24:1359 -1364, 2001T he prevalence of overweight/obesity is increasing in children, as is the diagnosis of type 2 diabetes (1-3). Obesity and insulin resistance are known risk factors for the development of type 2 diabetes in adults (4). For adults, type 2 diabetes and obesity are more prevalent in the African-American population than in European-Americans, especially among African-American women (5). Minority populations have also seen the greatest increase in childhood and adolescent diagnoses of type 2 diabetes (6).Studies in adults have consistently shown insulin resistance and hyperinsulinemia to be strong predictors of the development of type 2 diabetes (7). In addition to insulin resistance and -cell dysfunction, obesity (specifically central adiposity [8]), dyslipidemia (9 -10), and genetic predisposition (11) are risk factors for the development of impaired glucose tolerance and type 2 diabetes in adults.The clustering of insulin resistance, obesity, hypertension, dyslipidemia, and atherosclerosis has been referred to as the insulin resistance syndrome (IRS), the metabolic syndrome, or syndrome X (12). Increasing rates of type 2 diabetes in the pediatric population suggest the need to explore the development of insulin resistance and other risk factors (13) for type ...
Insulin-like growth factor I (IGF-I) mediates many of the systemic growth-promoting effects of growth hormone and also functions as a locally acting growth stimulator. In mammals, IGF-I gene expression is complicated, as the gene is transcribed and processed into multiple mRNAs (ranging in length from less than 1 to nearly 7.5 kb) that encode at least two protein precursors. As a step toward understanding the regulation of IGF-I, we report the complete organization of the rat IGF-I gene, including identification of the structural determinants for all IGF-I mRNA species, and an initial functional analysis of its promoters. The gene is composed of 6 exons distributed over nearly 80 kb of chromosomal DNA and is structurally heterogeneous. Several transcription start sites were identified within IGF-I exons 1 and 2, adjacent to presumptive promoters 1 and 2, respectively, and at least three polyadenylation sites were mapped to exon 6. To test promoter function, fusion genes were constructed linking fragments of IGF-I DNA to a reporter plasmid. Chimeric genes containing at least 395 bp of DNA from the 5'-flanking region of exon 1 enhanced luciferase activity after transfection into the IGF-I-producing SK-N-MC cell line, while fusion plasmids containing up to 1,300 bp of DNA from the 5'-flanking region of exon 2 were inactive. Relative levels of IGF-I mRNAs containing exons 1 or 2 varied among different rat tissues, although in response to acute or chronic growth hormone treatment both classes of transcripts were induced coordinately in rat liver. These observations represent the first thorough characterization of a mammalian IGF-I gene, and provide a starting point for defining the mechanisms by which growth hormone and other trophic factors regulate IGF-I gene expression.
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