Prevalence of insulin-gene mutations in non-insulin-dependent diabetes mellitus.
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Biomedical subjects
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Patients with non-insulin-dependent diabetes mellitus (NIDDM) who have chronic hyperglycemia lose acute incremental insulin responses to glucose but are able to briskly respond to other beta-cell secretagogues. To investigate whether this is a defect specific for glucose or represents a more general phenomenon, we measured the insulin responses to acute intravenous tolbutamide in 10 obese patients with NIDDM both before and during sulfonylurea therapy with tolazamide. Comparable glycemia was achieved with oral dextrose 2 h before intravenous testing. To assess beta-cell responsiveness to a nonsulfonylurea secretagogue, 1 mg glucagon was administered intravenously during tolazamide therapy. In seven patients, the mean peak insulin increment 5 or 10 min after intravenous tolbutamide was 54 +/- 11 microU/ml when not receiving tolazamide (0.14 +/- 1.3 microU/ml) with tolazamide (P less than .001), even though serum insulin responded rapidly to intravenous glucagon. In four patients tested for reversibility of their refractoriness to intravenous tolbutamide during chronic tolazamide therapy, the mean peak insulin increment 1 wk after discontinuing tolazamide was 79 +/- 22 microU/ml. A relatively rapid development of refractoriness was documented in four patients who were tested only 12 h after beginning tolazamide therapy; the mean peak insulin increments 5-10 min after intravenous tolbutamide were undetectable (-0.5 microU/ml), yet responses to intravenous glucagon were evident. In these NIDDM patients, exposure of pancreatic beta-cells to sustained levels of sulfonylureas induces a reversible state of refractoriness to acute stimulation with sufonylureas but not to another secretagogue.(ABSTRACT TRUNCATED AT 250 WORDS)
Recurrent episodes of spontaneous hypoglycemia developed in a 30-yr-old woman who had received a brief course of insulin therapy 10 yr previously. She denied surreptitious insulin administration, and the autoimmune hypoglycemia syndrome was considered. Her insulin levels could not be reliably measured because of the presence of circulating antiinsulin antibodies, which interfere with standard RIA techniques. Reverse phase high performance liquid chromatographic analysis of serum obtained during a hypoglycemic episode revealed a mixture of beef and pork insulins but no human insulin, firmly establishing the diagnosis of factitious hypoglycemia. This case illustrates the value of reverse phase high performance liquid chromatography in characterizing patients in whom the autoimmune hypoglycemia syndrome is suspected.
A polymorphic region 5' to the human insulin gene has been associated with diabetes in earlier studies. This polymorphic region is composed of tandem repeats that fall into 3 general size classes, designated class 1 (600 base pairs), class 2 (1300 base pairs), and class 3 (2500 base pairs). Frequencies of these classes of alleles vary among racial groups. American Blacks have been underrepresented in published studies of insulin gene polymorphism and diabetes. We undertook a cooperative study between two centers (San Francisco and St. Louis) to determine geno-types at the insulin locus in 313 unrelated American Blacks (132 nondiabetic, 27 with IDDM, and 154 with NIDDM). In both centers, nondiabetic individuals were younger and leaner than NIDDM patients. Allelic and genotypic frequencies at the insulin locus were not different between the two centers. Class 1 alleles represented 60% of all alleles, class 2 alleles 11%, and class 3 29%. No class of insulin allele was associated with NIDDM in this study. Subdivision of the study population by obesity, family history, or age at diagnosis failed to detect a subgroup for which the insulin allele was associated with NIDDM. Only 27 IDDM individuals were studied, and no significant association of class 1 alleles with this group was noted. However, examination of more IDDM individuals is required before a definitive statement can be made. Fasting serum triglyceride levels were determined retrospectively in 50 NIDDM individuals. No differences in triglyceride levels among genotypes were noted. The frequency of class 3 alleles in 13 hypertriglyceridemic NIDDM subjects was not different from that of the whole group.(ABSTRACT TRUNCATED AT 250 WORDS)
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