Despite excessive glucagon responses to infusion of arginine, plasma glucagon did not rise in six juvenile-type diabetics during severe insulin-induced hypoglycemia, whereas glucagon in the controls rose significantly. Thus in diabetics pancreatic alpha cells are insensitive to glucose even in the presence of large amounts of circulating insulin. An intrinsic defect common to both alpha and beta pancreatic cells-failure to recognize (or respond to) plasma glucose fluctuations-may be operative in juvenile diabetes.

No abstract

The length of a segment of DNA associated with the human insulin gene, which has been localized to the short arm of chromosome 11, is heterozygous in 63% of 52 individuals analyzed. This polymorphic region is approximately 500 base pairs from the nucleotide encoding the 5' end of insulin mRNA. The polymorphism appears to be due to an insertion or deletion of DNA sequences so that DNA fragments of different length are generated when DNA from a heterozygous individual is digested with selected restriction endonucleases.form and appear to be primarily oftwo classes: 0-600 and 1600-2200 hp. As a consequence ofthis length heterogeneity, the two parental insulin genes can be distinguished in 63% of the individdals examined. The physiological consequences of this length instability are unknown, but the observation demonstrates that substantial differences in length as well as less dramatic differences in nucleotide sequence can identify chromosome homologues.An indication of the DNA sequence variation among individual humans is emerging from studies of the structure of allelic segments of chromosomes (1-5). A comparison of the nucleotide sequence oftwo allelic human insulin genes [INS, chromosome 11 (6,7)] that included coding, intervening, and 5' and 3' flanking sequences indicated that only 4/1725 (0.23%) of the nucleotides varied (4). Two ofthese differences were in the region encoding the 3' untranslated portion of the mRNA, and the others were within the two intervening sequences. A similar analysis of the coding and intervening sequences of two alleles of the embryonic /-globin gene, VA, demonstrated 15 single base changes and 3 gaps of4, 4, and 18 base pairs (bp) in a segment of 1482 bp (1.0-1.2% variation) (5). With the exception ofa base substitution in the region encoding the 5' untranslated portion of the mRNA, the allelic differences were within the intervening sequences. Jeffreys (1) analyzed the entire (3globin gene region [NAG, chromosome 11 (8)] of60 individuals by restriction endonuclease digestion and hybridization techniques and estimated that 1% of the nucleotides in this region varied between individuals. In these studies, no nucleotide differences were observed in those gene regions that encode protein sequences. Thus, comparisons of DNA sequence variation of two different chromosomal segments, insulin and yA-globin, have revealed that the sequences ofthe alleles are similar, that most ofthe variability is a consequence ofbase substitutions, and that the amount ofsequence variation is not constant and varies from one gene to another. In addition, Wyman and White (9) have recently described a highly polymorphic locus not associated with any particular gene. Their analysis indicated that the polymorphism in restriction fragment length was a consequence of DNA rearrangement.In our continuing analysis of the human insulin gene region of chromosome 11, we have examined the insulin gene and flanking regions of 52 unrelated individuals. In contrast to the small differences between allelic DNA s...

To evaluate the role of glucagon in the pathogenesis of diabetic ketoacidosis in man, we studied the effect of suppression of glucagon secretion by somatostatin on changes in plasma beta-hydroxybutyrate and glucose concentrations (as well as changes in their precursors) after acute withdrawal of insulin from seven patients with juvenile-type diabetes. Suppression of glucagon secretion prevented the development of ketoacidosis for 18 hours after acute insulin withdrawal, whereas in control studies mild ketoacidosis occurred 10 hours after insulin was stopped. Plasma beta-hydroxybutyrate, glucose, free fatty acid, and glycerol levels were all markedly lower during suppression of glucagon secretion (p smaller than 0.001), whereas plasma alanine levels were higher (p smaller than 0.001). These studies indicate that insulin lack per se does not lead to fulminant diabetic ketoacidosis in man and that glucagon, by means of its gluconeogenic, ketogenic, and lipolytic actions, is a prerequisite to the development of this condition.

This study was conducted to assess the effect of noninsulin-dependent diabetes mellitus (NIDDM) and gender on the pharmacokinetics of metformin and to investigate whether or not metformin exhibits dose-dependent pharmacokinetics. The pharmacodynamic effects (on plasma glucose and insulin) of metformin in patients with NIDDM and in healthy subjects also were assessed. Nine patients with NIDDM and 9 healthy subjects received 4 single-blind single-dose treatments of metformin HCL (850 mg, 1,700 mg, 2,550 mg, and placebo) and a multiple-dose treatment of 850 mg metformin HCL (3 times daily for 19 doses). After each single-dose treatment and the final dose of the multiple-dose phase, multiple plasma and urine samples were collected for 48 hours and assayed for metformin levels. Plasma samples were also assayed for glucose and insulin levels. There were no significant differences in metformin kinetics in patients with NIDDM compared with healthy subjects, in men compared with women, or during multiple-dose treatment versus single-dose treatment. Plasma concentrations of metformin increase less than proportionally to dose, most likely due to a decrease in percent absorbed. In patients with NIDDM, single doses of 1,700-mg or higher of metformin significantly decrease postprandial, but not preprandial, glucose concentrations and do not influence insulin concentrations. With multiple doses, both preprandial and postprandial glucose concentrations and preprandial insulin concentrations were significantly lower than with placebo. The effect of metformin on glucose level is correlated with the average fasting plasma glucose level without drug. In healthy subjects, single and multiple doses of metformin showed no effect on plasma glucose, but significantly attenuated the rise in immediate postprandial insulin levels.