Showing papers by "Richard N. Bergman published in 1999"
TL;DR: In healthy young men, the acute and chronic FFA elevation induces insulin resistance; with acute F FA elevation, this insulin resistance is precisely countered by an FFA-induced increase in insulin secretion, such that DI does not change; and chronicFFA elevation disables this β-cell compensation.
Abstract: The in vivo effect of elevated free fatty acids (FFA) on β-cell function in humans remains extremely controversial. We examined, in healthy young men, the acute (90 min) and chronic (48 h) effects ...
249 citations
TL;DR: Evidence from this and other studies suggests at least two diabetes-susceptibility genes on chromosome 20, which has been screened for maturity-onset diabetes of the young 1, hepatic nuclear factor 4-a (HNF-4alpha) in 64 affected sibships with evidence for high chromosomal sharing at its location on chromosomes 20q.
Abstract: We are conducting a genome scan at an average resolution of 10 centimorgans (cM) for type 2 diabetes susceptibility genes in 716 affected sib pairs from 477 Finnish families. To date, our best evidence for linkage is on chromosome 20 with potentially separable peaks located on both the long and short arms. The unweighted multipoint maximum logarithm of odds score (MLS) was 3.08 on 20p (location, chi = 19.5 cM) under an additive model, whereas the weighted MLS was 2.06 on 20q (chi = 57 cM, recurrence risk,lambda(s) = 1. 25, P = 0.009). Weighted logarithm of odds scores of 2.00 (chi = 69.5 cM, P = 0.010) and 1.92 (chi = 18.5 cM, P = 0.013) were also observed. Ordered subset analyses based on sibships with extreme mean values of diabetes-related quantitative traits yielded sets of families who contributed disproportionately to the peaks. Two-hour glucose levels in offspring of diabetic individuals gave a MLS of 2. 12 (P = 0.0018) at 9.5 cM. Evidence from this and other studies suggests at least two diabetes-susceptibility genes on chromosome 20. We have also screened the gene for maturity-onset diabetes of the young 1, hepatic nuclear factor 4-a (HNF-4alpha) in 64 affected sibships with evidence for high chromosomal sharing at its location on chromosome 20q. We found no evidence that sequence changes in this gene accounted for the linkage results we observed.
217 citations
TL;DR: It is concluded that there is strong evidence for modest heritability of Minimal-Model-derived NIDDM-related quantitative traits in unaffected spouses and offspring of Finnish affected sibling pairs.
Abstract: Type 2 diabetes mellitus (NIDDM) is a complex disorder encompassing multiple metabolic defects. There exists strong evidence for a genetic component to NIDDM; however, to date there have been few repo
123 citations
TL;DR: Data imply that ANG II induces insulin resistance by an effect independent of a reduction in interstitial insulin, as measured during hyperinsulinemic euglycemic clamps in anesthetized dogs.
Abstract: We set out to examine whether angiotensin-driven hypertension can alter insulin action and whether these changes are reflected as changes in interstitial insulin (the signal to which insulin-sensit...
96 citations
TL;DR: In this paper, the authors examined the metabolic effects and interstitial fluid profiles of fatty acid acylated insulin, LysB29-tetradecanoyl, des-(B30) human insulin (NN304).
Abstract: Aims/hypothesis. The provision of stable, reproducible basal insulin is crucial to diabetes management. This study in dogs examined the metabolic effects and interstitial fluid (ISF) profiles of fatty acid acylated insulin, LysB29-tetradecanoyl, des-(B30) human insulin (NN304). Methods. Euglycaemic clamps were carried out under inhalant anaesthesia during equimolar intravenous infusions (3.6 pmol · min–1· kg–1 for 480 min) of human insulin or NN304 (n = 8 per group). Results. Steady-state total NN304 (albumin-bound and unbound) was considerably higher in plasma compared with human insulin (1895 ± 127 vs 181 ± 10 pmol/l, p 0.40; NN304 and human insulin, respectively). Similar to interstitial fluid, half times for Rd and endogenous glucose production were delayed during NN304 infusion (162 vs 46 min and 80 vs 31 min, respectively; p < 0.01 vs human insulin). Conclusion/interpretation. Firstly equivalency of steady-state action is found at equimolar physiologic infusions of human insulin and NN304. Secondly NN304 binding to plasma albumin results in slower NN304 appearance in the interstitial compartment compared with human insulin. Thirdly the delay in appearance of NN304 in interstitial fluid may not in itself be a source of the protracted action of this insulin analogue. The protracted effect is due primarily to albumin binding of the insulin analogue NN304. [Diabetologia (1999) 42: 1254–1263]
80 citations
74 citations
TL;DR: It is concluded that the W64R variant is unlikely to reduce HDL ratios in a dose-dependent, pathogenic manner.
Abstract: Recent studies have suggested an association between Type II (non-insulin-dependent) diabetes mellitus-related phenotypes and a cytosine-to-thymidine substitution that results in the replacement of tryptophan by arginine at codon 64 (Trp64Arg or W64R) of the β3-adrenergic receptor gene. Here, we present the results of possibly the largest association study to date on the variant in a sample of 526 families with a total of 1725 subjects, 1053 of whom had Type II diabetes. Preliminary calculations suggested that we had excellent power to detect the moderate associations which were reported in previous studies. No associations were found between the W64R variant and the following phenotypes in our sample: Type II diabetes, age at diagnosis for Type II diabetes, measures of obesity, fasting glucose, fasting insulin, minimal model variables, and systolic and diastolic blood pressures. In the analysis of plasma lipids, we detected an association between the variant and HDL ratios (HDL cholesterol/total cholesterol) (p = 0.013), which remained significant even after adjusting for sex, affection status and age. Since W64R homozygotes (n = 11) had the highest HDL ratios, however, heterozygotes had the lowest and the wild-type subjects had intermediate values, we conclude that the W64R variant is unlikely to reduce HDL ratios in a dose-dependent, pathogenic manner. [Diabetologia (1999) 42: 238–244]
42 citations
TL;DR: It is demonstrated that the baroreceptor reflex arc does not mediate the blood pressure response to acute hyperinsulinemia, and insulin and saline infusions did not change heart rates significantly in intact or denervated animals.
6 citations