Showing papers by "Richard N. Bergman published in 2002"

Accurate Assessment of β-Cell Function: The Hyperbolic Correction

Abstract: Only in the last decade did modeling studies predict, and knockout experiments confirm, that type 2 diabetes is a "2-hit" disease in which insulin resistance is necessarily accompanied by beta-cell defect(s) preventing the compensatory upregulation of insulin secretion. This long- delayed insight was associated with the development of a constant, the "disposition index," describing the beta-cell sensitivity-secretion relationship as a rectangular hyperbola. Shifts in insulin sensitivity are accompanied by compensatory alterations in beta-cell sensitivity to glucose. Insulin-sensitive subjects do not require a massive insulin response to exogenous glucose to maintain a normal blood glucose. But if their insulin sensitivity decreases by 80%, as in late pregnancy, they need a fivefold greater insulin response to achieve an identical disposition index. Women with gestational diabetes have an insulin response similar to that of normal volunteers; at first glance, this suggests similar islet function, but the utility of the disposition index is to normalize this response to the amplitude of third trimester insulin resistance, revealing severe beta-cell deficiency. The index is a quantitative, convenient, and accurate tool in analyzing epidemiologic data and identifying incipient impaired glucose tolerance. Separate major issues remain, however: the causes of insulin resistance, the causes of the failure of adequate beta-cell compensation in type 2 diabetes, and the nature of the signal(s) from insulin-resistant tissues that fail to elicit the appropriate beta-cell increment in sensitivity to glucose and other stimuli. The disposition index is likely to remain the most accurate physiologic measure for testing hypotheses and solutions to these challenges in whole organisms.

The evolution of beta-cell dysfunction and insulin resistance in type 2 diabetes.

Abstract: Insulin resistance and beta-cell dysfunction have important roles in the pathogenesis and evolution of type 2 diabetes. The development of precise methods to measure these factors has helped us to define the relationship between them and evidence is reviewed that changes in insulin sensitivity are compensated by inverse changes in beta-cell responsiveness such that the product of insulin sensitivity and insulin secretion (the disposition index) remains constant. While the disposition index promises to be a useful tool to predict individuals at high risk of developing type 2 diabetes, other factors that contribute to beta-cell dysfunction and mark disease onset and progression include impairments in proinsulin processing and insulin secretion, decreased beta-cell mass and islet amyloid deposition. Emerging data indicate that anti-diabetic agents, such as the thiazolidinediones that simultaneously target insulin resistance and beta-cell dysfunction, may have a beneficial impact on disease onset and progression. Several landmark clinical studies are underway to investigate if their initial promise is supported by data from large-scale trials.

Insulin Resistance and Associated Compensatory Responses in African-American and Hispanic Children

Abstract: Objective The objective of this study was to compare insulin resistance relative to body fat and the associated compensatory responses in 57 healthy children living in Los Angeles, California (14 Caucasians, 15 African-Americans, and 28 Hispanics). Research design and methods Insulin sensitivity and acute insulin response were determined by intravenous glucose tolerance test. Insulin secretion, hepatic insulin extraction, and insulin clearance were estimated by C-peptide and insulin modeling. Results Insulin sensitivity was significantly lower in Hispanics and African-Americans compared with Caucasian children, and acute insulin response was significantly higher in African-American children. No ethnic differences were noted in the first-phase secretion, but second-phase insulin secretion was significantly higher in Hispanic children than in African-American children (200 +/- 53 vs. 289 +/- 41 nmol/min; P = 0.03). The greater acute insulin response in African-Americans, despite lower secretion, was explained by a lower hepatic insulin extraction in African-Americans compared with Hispanics (36.6 +/- 2.9 vs. 47.3 +/- 2.2%; P = 0.0006). Conclusions In conclusion, Hispanic and African-American children are more insulin resistant than Caucasian children, but the associated compensatory responses are different across ethnic groups.

Extreme insulin resistance of the central adipose depot in vivo

Abstract: Despite the well-described association between obesity and insulin resistance, the physiologic mechanisms that link these two states are poorly understood. The present study was performed to elucidate the role of visceral adipose tissue in whole-body glucose homeostasis. Dogs made abdominally obese with a moderately elevated fat diet had catheters placed into the superior mesenteric artery so that the visceral adipose bed could be insulinized discretely. Omental insulin infusion was extracted at approximately 27%, such that systemic insulin levels were lower than in control (portal vein) insulin infusions. Omental infusion did not lower systemic free fatty acid levels further than control infusion, likely because of the resistance of the omental adipose tissue to insulin suppression and the confounding lower systemic insulin levels. The arteriovenous difference technique showed that local infusion of insulin did suppress omental lipolysis, but only at extremely high insulin concentrations. The median effective dose for suppression of lipolysis was almost fourfold higher in the visceral adipose bed than for whole-body suppression of lipolysis. Thus, the omental adipose bed represents a highly insulin-resistant depot that drains directly into the portal vein. Increased free fatty acid flux to the liver may account for hepatic insulin resistance in the moderately obese state.

Unique Effect of Visceral Fat on Insulin Sensitivity in Obese Hispanic Children With a Family History of Type 2 Diabetes

Abstract: OBJECTIVE —This study aimed to establish whether total fat or central fat was related to measures of insulin in obese Hispanic children with a family history of type 2 diabetes. RESEARCH DESIGN AND METHODS —Subjects were 32 children aged 8–13 years. Visceral fat and subcutaneous abdominal fat were determined by magnetic resonance imaging at the umbilicus and total body fat was determined by dual-energy X-ray absorptiometry. Insulin sensitivity ( S i) and acute insulin response (AIR) were determined by frequently sampled intravenous tolerance test with minimal modeling. RESULTS —Mean fasting glucose and insulin, S i, and AIR (± SD) were 5.3 ± 0.3 mmol/l, 206 ± 105 pmol/l, 11.8 ± 5.7 [× 10−4 min−1/(pmol/l)], and 17,175 ± 9,695 (pmol/l × 10 min), respectively. In multivariate regression analysis, total fat mass was independently and positively related to fasting insulin ( P < 0.01) and negatively related to S i ( P < 0.05) but was not related to AIR. Visceral fat was independently and positively related to fasting insulin ( P < 0.05) and AIR ( P < 0.01) and negatively related to S i ( P < 0.001). CONCLUSIONS —These findings support the hypothesis that specific accumulation of visceral fat in addition to overall adiposity in Hispanic children increases the risk of type 2 diabetes.

Increased proinsulin levels and decreased acute insulin response independently predict the incidence of type 2 diabetes in the insulin resistance atherosclerosis study.

Abstract: Previous studies have indicated that β-cell dysfunction predicts the development of diabetes, although it is unknown whether the use of combinations of insulin secretory measures further improves prediction. The Insulin Resistance Atherosclerosis Study is a prospective, multicenter, epidemiological study of the relationship between insulin sensitivity and the risk of diabetes and cardiovascular disease. At baseline, fasting concentrations of insulin, intact proinsulin (PI), and split PI were measured, and acute insulin response (AIR) was determined during a frequently sampled intravenous glucose tolerance test (FSIGTT). Subjects who were nondiabetic at baseline ( n = 903) were reexamined after 5 years of follow-up; 148 had developed diabetes. In separate logistic regression models adjusted for age, sex, clinic, and ethnicity, 1 SD differences in measures of β-cell dysfunction were associated with diabetes incidence (AIR: odds ratio [OR] 0.37, 95% CI 0.27–0.52; intact PI: OR 1.90, 95% CI 1.57–2.30; split PI: OR 1.94, 95% CI 1.63–2.31). After additional adjustment for BMI, impaired glucose tolerance, and insulin sensitivity, these measures continued to be significantly associated with risk of diabetes (all P < 0.0001). Furthermore, in models that included both PI and AIR, each was an independent predictor, and individuals who had combined low AIR and high PI experienced the highest diabetes risk. In conclusion, both low AIR and high PI independently predicted diabetes in a well-characterized multiethnic population. Although fasting PI is simpler to assess, determining AIR from an FSIGTT may further improve prediction. If pharmacological agents to prevent diabetes are proved to be efficacious in ongoing clinical trials, then it may be beneficial to perform FSIGTTs to identify better (for intensive intervention) prediabetic subjects who would ultimately require lifelong pharmacological therapy.

Albumin Binding of Acylated Insulin (NN304) Does Not Deter Action to Stimulate Glucose Uptake

Abstract: NN304 [Lys(B29)-tetradecanoyl des(B30) human insulin] is a potentially therapeutic insulin analog designed to exhibit protracted glucose-lowering action. In dogs with infusion rates similar to insulin itself, NN304 exhibits similar glucose uptake (R(d)) stimulation with delayed onset of action. This compartmental modeling study was to determine if NN304 action could be accounted for by the approximately 2% unbound NN304 concentration. NN304 (or human insulin) (n = 6 each) was infused at 10.2 pmol center dot min(-1) center dot kg(-1) under euglycemic clamp conditions in anesthetized dogs. NN304 appearance in lymph, representing interstitial fluid (ISF), was slow compared with insulin (t(1/2) = 70 +/- 7 vs. 14 +/- 1 min, P < 0.001). R(d) was highly correlated with the ISF concentration for insulin and NN304 (r = 0.86 and 0.93, respectively), suggesting that slow transendothelial transport (TET) is responsible for sluggish NN304 action. Insulin and NN304 concentration data were fit to a two-compartment (plasma and ISF) model. NN304 plasma elimination and TET were reduced to 10 and 7% of insulin, respectively. Thus, there was reduction of NN304 transport, but not to the degree expected. In ISF, there was no reduction in NN304 elimination. Thus, this acylated insulin analog demonstrates blunted kinetics in plasma, and full efficacy in the compartment of action, ISF.

Variation in three single nucleotide polymorphisms in the calpain-10 gene not associated with type 2 diabetes in a large Finnish cohort.

Abstract: Variations in the calpain-10 gene have recently been reported to be associated with type 2 diabetes in a Mexican-American population. We typed three single nucleotide polymorphisms (SNPs) in the calpain-10 gene (SNPs 43, 56, and 63) to test for association between variation at these loci and type 2 diabetes and diabetes-related traits in 1,603 Finnish subjects: two samples of 526 (Finland-U.S. Investigation of NIDDM Genetics [FUSION] 1) and 255 (FUSION 2) index case subjects with type 2 diabetes, 185 and 414 unaffected spouses and offspring of FUSION 1 index case subjects or their affected siblings, and 223 elderly normal glucose-tolerant control subjects. We found no significant differences in allele, genotype, haplotype, or haplogenotype frequencies between index case subjects with diabetes and the elderly and spouse control populations (all P > 0.087). Although variation in these three SNPs was associated with variation in some type 2 diabetes-related traits within each of the case and control groups, no consistent pattern of the implicated variant or combination of variants was discerned. We conclude that variation in these three SNPs in the calpain-10 gene is unlikely to confer susceptibility to type 2 diabetes in this Finnish cohort.

Pathogenesis and prediction of diabetes mellitus: lessons from integrative physiology.

Abstract: The molecular revolution in biology is providing an exponentially increasing body of data regarding subcellular events in normal and pathological conditions. The task of integrating even a small part of this deluge of information is a formidable challenge. Many integrative regulatory principles are still unknown. The present article argues that important principles may be discovered by the repetitive experimental testing of simple isomorphic computer or mathematical models of biological regulation. The system regulating the blood glucose is used as an example. Implicit in a minimal model, postulated more than 20 years ago, were specific but untested assumptions. These assumptions, which were tested over the ensuing decades, have enriched our understanding of metabolic regulation and the causes of diabetes. Currently accepted concepts emerging from modeling include: (a) the importance of sluggish insulin transport across the capillary endothelium in stimulation of glucose uptake; (b) the single gateway concept, that insulin transport across endothelium of adipose tissue suppresses free fatty acids, which act in turn to reduce endogenous glucose production by the liver; (c) the importance of the single gateway mechanism in the metabolic syndrome, whereby increased fat in the abdominal compartment relates to insulin resistance and risk for type 2 diabetes; and (d) the hyperbolic relationship between insulin action and insulin secretion, which provides an accurate prediction of diabetes risk. It is hoped that the experience with the metabolic system will provide a metaphor for other regulatory systems less subjected to critical quantitative analysis. Such analysis may well lead to analogous conceptual understanding of other important integrated biological systems, and provide approaches for early intervention in the pathogenic process of other chronic and devastating diseases.

Mode of transcapillary transport of insulin and insulin analog NN304 in dog hindlimb: evidence for passive diffusion.

Abstract: A defect in transcapillary transport of insulin in skeletal muscle and adipose tissue has been proposed to play a role in the insulin resistance that leads to type 2 diabetes, yet the mechanism of insulin transfer across the capillary endothelium from plasma to interstitium continues to be debated. This study examined in vivo the interstitial appearance of insulin in hindlimb using the fatty acid acylated insulin analog Lys(B29)-tetradecanoyl des-(B30) human insulin, or NN304, as a marker for insulin transport. If the insulin transport were a saturable process, then "swamping" the capillary endothelial insulin receptors with native insulin would suppress the subsequent appearance in interstitial fluid of the insulin analog NN304. This analog binds to insulin receptors with an affinity of about 50% of native insulin. Experimental conditions established a physiologic NN304 dose in the absence or presence of pharmacologic and saturating concentrations of regular human insulin. Euglycemic clamps were performed in dogs under inhalant anesthesia with deep hindlimb lymphatic sampling, representative of skeletal muscle interstitial fluid (ISF). In group 1 (n = 8), NN304 alone was infused (3.6 pmol center dot min(-1) center dot kg(-1)) from 60 to 360 min. In group 2 (n = 6), starting at time 0, human insulin was infused at a pharmacologic dose (60 pmol center dot min(-1) center dot kg(-1)) with the addition of NN304 infusion (3.6 pmol center dot min(-1) center dot kg(-1)) from 60 to 360 min. In group 3 (n = 4), the human insulin infusion was increased to a saturating dose (120 pmol center dot min(-1) center dot kg(-1)). Pharmacologic insulin infusion (group 2) established steady-state human insulin concentrations of 6,300 plus minus 510 pmol/l in plasma and 5,300 plus minus 540 pmol/l in ISF. Saturating insulin infusion (group 3) achieved steady-state human insulin concentrations of 22,000 plus minus 1,800 pmol/l in plasma and 19,000 plus minus 1,500 pmol/l in ISF. Total (bound and unbound) NN304 plasma concentrations rose from a steady state of 1,900 plus minus 110 (group 1) to 2,400 plus minus 200 pmol/l (group 2) and 3,100 plus minus 580 pmol/l (group 3), consistent with a competition-driven decline in NN304 clearance from plasma as the human insulin level increased (P < 0.05 by ANOVA). Steady-state interstitial NN304 concentrations also rose with increasing human insulin levels but did not achieve significance in comparison with analog alone (162 plus minus 15 vs. 196 plus minus 22 and 241 plus minus 53 pmol/l for group 1 versus groups 2 and 3, respectively; P = 0.20), yet the steady-state plasma:ISF ratio for NN304 remained essentially unchanged in the absence and presence of elevated human insulin levels (12.6 plus minus 1.2 vs. 12.4 plus minus 0.5 and 13.1 plus minus 1.5 for group 1 versus groups 2 and 3, respectively; P = 0.93). Last, NN304 rate of appearance in interstitial fluid (i.e., half-time to steady state) was similar between groups; mean half-time of 92 plus minus 4 min (NS between groups). In conclusion, appearance of the insulin analog NN304 in skeletal muscle interstitial fluid was constant whether in the absence or presence of human insulin concentrations sufficient to saturate the endothelial insulin receptors. These findings support the hypothesis, provided that the mechanism of insulin and NN304 transcapillary transport is similar, that transcapillary transport of insulin in skeletal muscle occurs primarily via a nonsaturable process such as passive diffusion via a paracellular or transcellular route.

Elevated glucagon-like peptide-1-(7-36)-amide, but not glucose, associated with hyperinsulinemic compensation for fat feeding.

Abstract: We previously developed a canine model of central obesity and insulin resistance by supplementing the normal chow diet with 2 g cooked bacon grease/kg body weight. Dogs fed this fatty diet maintained glucose tolerance with compensatory hyperinsulinemia. The signal(s) responsible for this up-regulation of plasma insulin is unknown. We hypothesized that meal-derived factors such as glucose, fatty acids, or incretin hormones may signal β-cell compensation in the fat-fed dog. We fed the same fat-supplemented diet for 12 wk to six dogs and compared metabolic responses with seven control dogs fed a normal diet. Fasting and stimulated fatty acid and glucose-dependent insulinotropic peptide concentrations were not increased by fat feeding, whereas glucose was paradoxically decreased, ruling out those three factors as signals for compensatory hyperinsulinemia. Fasting plasma glucagon-like peptide-1 (GLP-1) concentration was 2.5-fold higher in the fat-fed animals, compared with controls, and 3.4-fold higher after a...

Utility of a surrogate measure of insulin resistance in American Indians: the Strong Heart Study.

Abstract: OBJECTIVE 1) Determine in a sample of American Indians (AI) how well insulin sensitivity (SI) measured by the frequently sampled intravenous glucose test (FSIGT) correlates with a simpler measure of insulin resistance (IR) measured by the homeostasis assessment (HOMA) model; (2) compare insulin sensitivity in a sample of diabetic and non-diabetic Al in the Strong Heart Study (SHS) with that of White, Black, and Hispanic Americans in the Insulin Resistance Atherosclerosis Study (IRAS). DESIGN Cross sectional SETTING Community PARTICIPANTS Sixty-one Al participants in SHS MAIN OUTCOME MEASURES: Mean SI measured by FSIGT, a complex protocol to evaluate insulin sensitivity, and mean IR measured by the HOMA model, a method based on measures of fasting glucose and fasting insulin. RESULTS Although 70% of sample participants were non-diabetic, only 18% were insulin sensitive by SI. Diabetes status strongly confounded Si among Al in SHS. At non-diabetic levels of fasting glucose ( or = 126 mg/dL; rho = -0.13, P = n.s.). With the exception of some Hispanic participants in IRAS, mean SI of non-diabetic Al in SHS was lower than that of their non-diabetic IRAS counterparts. Diabetic Al participants in SHS had markedly lower mean SI than all diabetic participants in IRAS. CONCLUSIONS The HOMA model may be a useful tool to identify non-diabetic American Indians who might benefit from early CVD risk factor modification.