Ronald L. Prigeon

Quantification of the Relationship Between Insulin Sensitivity and β-Cell Function in Human Subjects: Evidence for a Hyperbolic Function

To determine the relationship between insulin sensitivity and β-cell function, we quantified the insulin sensitivity index using the minimal model in 93 relatively young, apparently healthy human subjects of varying degrees of obesity (55 male, 38 female; 18–44 yr of age; body mass index 19.5–52.2 kg/m2) and with fasting glucose levels <6.4 mM. SI was compared with measures of body adiposity and β-cell function. Although lean individuals showed a wide range of SI, body mass index and SI were related in a curvilinear manner (P < 0.0001) so that on average, an increase in body mass index was associated generally with a lower value for SI. The relationship between the SI and the β-cell measures was more clearly curvilinear and reciprocal for fasting insulin (P < 0.0001), first-phase insulin response (AIRglucose; P < 0.0001), glucose potentiation slope (n = 56; P < 0.005), and β-cell secretory capacity (AIRmax; n = 43; P < 0.0001). The curvilinear relationship between SI and the β-cell measures could not be distinguished from a hyperbola, i.e., SI × β-cell function = constant. This hyperbolic relationship described the data significantly better than a linear function (P < 0.05). The nature of this relationship is consistent with a regulated feedback loop control system such that for any difference in SI, a proportionate reciprocal difference occurs in insulin levels and responses in subjects with similar carbohydrate tolerance. We conclude that in human subjects with normal glucose tolerance and varying degrees of obesity, β-cell function varies quantitatively with differences in insulin sensitivity. Because the function governing this relationship is a hyperbola, when insulin sensitivity is high, large changes in insulin sensitivity produce relatively small changes in insulin levels and responses, whereas when insulin sensitivity is low, small changes in insulin sensitivity produce relatively large changes in insulin levels and responses. Percentile plots based on knowledge of this interaction are presented for evaluating β-cell function in populations and over time.

Oral Disposition Index Predicts the Development of Future Diabetes Above and Beyond Fasting and 2-h Glucose Levels

OBJECTIVE—We sought to determine whether an oral disposition index (DIO) predicts the development of diabetes over a 10-year period. First, we assessed the validity of the DIO by demonstrating that a hyperbolic relationship exists between oral indexes of insulin sensitivity and β-cell function. RESEARCH DESIGN AND METHODS—A total of 613 Japanese-American subjects (322 men and 291 women) underwent a 75-g oral glucose tolerance test (OGTT) at baseline, 5 years, and 10 years. Insulin sensitivity was estimated as 1/fasting insulin or homeostasis model assessment of insulin sensitivity (HOMA-S). Insulin response was estimated as the change in insulin divided by change in glucose from 0 to 30 min (ΔI0–30/ΔG0–30). RESULTS—ΔI0–30/ΔG0–30 demonstrated a curvilinear relationship with 1/fasting insulin and HOMA-S with a left and downward shift as glucose tolerance deteriorated. The confidence limits for the slope of the loge-transformed estimates included −1 for ΔI0–30/ΔG0–30 versus 1/fasting insulin for all glucose tolerance groups, consistent with a hyperbolic relationship. When HOMA-S was used as the insulin sensitivity measure, the confidence limits for the slope included −1 only for subjects with normal glucose tolerance (NGT) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) but not diabetes. On the basis of this hyperbolic relationship, the product of ΔI0–30/ΔG0–30 and 1/fasting insulin was calculated (DIO) and decreased from NGT to IFG/IGT to diabetes (P < 0.001). Among nondiabetic subjects at baseline, baseline DIO predicted cumulative diabetes at 10 years (P < 0.001) independent of age, sex, BMI, family history of diabetes, and baseline fasting and 2-h glucose concentrations. CONCLUSIONS—The DIO provides a measure of β-cell function adjusted for insulin sensitivity and is predictive of development of diabetes over 10 years.

Ghrelin Suppresses Glucose-Stimulated Insulin Secretion and Deteriorates Glucose Tolerance in Healthy Humans

OBJECTIVE The orexigenic gut hormone ghrelin and its receptor are present in pancreatic islets. Although ghrelin reduces insulin secretion in rodents, its effect on insulin secretion in humans has not been established. The goal of this study was to test the hypothesis that circulating ghrelin suppresses glucose-stimulated insulin secretion in healthy subjects. RESEARCH DESIGN AND METHODS Ghrelin (0.3, 0.9 and 1.5 nmol/kg/h) or saline was infused for more than 65 min in 12 healthy patients (8 male/4 female) on 4 separate occasions in a counterbalanced fashion. An intravenous glucose tolerance test was performed during steady state plasma ghrelin levels. The acute insulin response to intravenous glucose (AIRg) was calculated from plasma insulin concentrations between 2 and 10 min after the glucose bolus. Intravenous glucose tolerance was measured as the glucose disappearance constant (Kg) from 10 to 30 min. RESULTS The three ghrelin infusions raised plasma total ghrelin concentrations to 4-, 15-, and 23-fold above the fasting level, respectively. Ghrelin infusion did not alter fasting plasma insulin or glucose, but compared with saline, the 0.3, 0.9, and 1.5 nmol/kg/h doses decreased AIRg (2,152 ± 448 vs. 1,478 ± 2,889, 1,419 ± 275, and 1,120 ± 174 pmol/l) and Kg (0.3 and 1.5 nmol/kg/h doses only) significantly (P < 0.05 for all). Ghrelin infusion raised plasma growth hormone and serum cortisol concentrations significantly (P < 0.001 for both), but had no effect on glucagon, epinephrine, or norepinephrine levels (P = 0.44, 0.74, and 0.48, respectively). CONCLUSIONS This is a robust proof-of-concept study showing that exogenous ghrelin reduces glucose-stimulated insulin secretion and glucose disappearance in healthy humans. Our findings raise the possibility that endogenous ghrelin has a role in physiologic insulin secretion, and that ghrelin antagonists could improve β-cell function.

Gastric Bypass Surgery Enhances Glucagon-Like Peptide 1–Stimulated Postprandial Insulin Secretion in Humans

OBJECTIVE Gastric bypass (GB) surgery is associated with postprandial hyperinsulinemia, and this effect is accentuated in postsurgical patients who develop recurrent hypoglycemia. Plasma levels of the incretin glucagon-like peptide 1 (GLP-1) are dramatically increased after GB, suggesting that its action contributes to alteration in postprandial glucose regulation. The aim of this study was to establish the role of GLP-1 on insulin secretion in patients with GB. RESEARCH DESIGN AND METHODS Twelve asymptomatic individuals with previous GB (Asym-GB), 10 matched healthy nonoperated control subjects, and 12 patients with recurrent hypoglycemia after GB (Hypo-GB) had pre- and postprandial hormone levels and insulin secretion rates (ISR) measured during a hyperglycemic clamp with either GLP-1 receptor blockade with exendin-(9–39) or saline. RESULTS Blocking the action of GLP-1 suppressed postprandial ISR to a larger extent in Asym-GB individuals versus control subjects (33 ± 4 vs.16 ± 5%; P = 0.04). In Hypo-GB patients, GLP-1 accounted for 43 ± 4% of postprandial ISR, which was not significantly higher than that in Asym-GB subjects (P = 0.20). Glucagon was suppressed similarly by hyperglycemia in all groups but rose significantly after the meal in surgical individuals but remained suppressed in nonsurgical subjects. GLP-1 receptor blockade increased postprandial glucagon in both surgical groups. CONCLUSIONS Increased GLP-1–stimulated insulin secretion contributes significantly to hyperinsulinism in GB subjects. However, the exaggerated effect of GLP-1 on postprandial insulin secretion in surgical subjects is not significantly different in those with and without recurrent hypoglycemia.

The Contribution of Insulin-Dependent and Insulin-Independent Glucose Uptake to Intravenous Glucose Tolerance in Healthy Human Subjects

Glucose disposal occurs by both insulin-independent and insulin-dependent mechanisms, the latter being determined by the interaction of insulin sensitivity and insulin secretion. To determine the role of insulin-independent and insulin-dependent factors in glucose tolerance, we performed intravenous glucose tolerance tests on 93 young healthy subjects (55 male, 38 female; 18–44 years of age; body mass index, 19.5–52.2 kg/m2). From these tests, we determined glucose tolerance as the glucose disappearance constant (Kg), calculated β-cell function as the incremental insulin response to glucose for 19 min after an intravenous glucose bolus (IIR0-19), and derived an insulin sensitivity index (SI) and glucose effectiveness at basal insulin (SG) using the minimal model of glucose kinetics. To eliminate the effect of basal insulin on SG and estimate insulin-independent glucose uptake, we calculated glucose effectiveness at zero insulin (GEZI = SG [SI × basal insulin]). Insulin-dependent glucose uptake was estimated as SI × IIR0-19, because the relationship between SI and β-cell function has been shown to be hyperbolic. Using linear regression to determine the influence of these factors on glucose tolerance, we found that GEZI was significantly related to Kg (r = 0.70; P < 0.0001), suggesting a major contribution of insulin-independent glucose uptake to glucose disappearance. As expected, SI × IIR0-19 also correlated well with Kg (r = 0.74; P < 0.0001), confirming the importance of insulin-dependent glucose uptake to glucose tolerance. Although IIR0-19 alone correlated with Kg (r = 0.35; P = 0.0005), SI did not (r = 0.18; P > 0.08). By multiple regression, 72% of the variance in Kg could be explained by GEZI and S1 × IIR0-19 (r = 0.85; P < 0.0001). We conclude that insulin-independent glucose uptake is a major determinant of intravenous glucose tolerance and that the interaction of insulin sensitivity and insulin levels are more important than either factor alone as a determinant of intravenous glucose tolerance.

Proinsulin as a Marker for the Development of NIDDM in Japanese-American Men

Disproportionate hyperproinsulinemia is one manifestation of the B-cell dysfunction observed in non-insulin-dependent diabetes mellitus (NIDDM), but it is unclear when this abnormality develops and whether it predicts the development of NIDDM. At baseline, measurements of proinsulin (PI) and immunoreactive insulin (IRI) levels were made in 87 second-generation Japanese-American men, a population at high risk for the subsequent development of NIDDM, and, by using World Health Organization criteria, subjects were categorized as having normal glucose tolerance (NGT; n = 49) or impaired glucose tolerance (IGT; n = 38). After a 5-year follow-up period, they were recategorized as NGT, IGT, or NIDDM using the same criteria. After 5 years, 16 subjects had developed NTODM, while 71 had NGT or IGT. Individuals who developed NIDDM were more obese at baseline, measured as intra-abdominal fat (IAF) area on computed tomography (P = 0.046) but did not differ in age from those who continued to have NGT or IGT. At baseline, subjects who subsequently developed NIDDM had higher fasting glucose (P = 0.0042), 2-h glucose (P = 0.0002), fasting C-peptide (P = 0.0011), and fasting PI levels (P = 0.0033) and disproportionate hyperproinsulinemia (P = 0.056) than those who continued to have NGT or IGT after 5 years of follow-up. NIDDM incidence was positively correlated with the absolute fasting PI level (relative odds = 2.35; P = 0.0025), even after adjustment for fasting IRI, IAF, and body mass index (relative odds = 2.17; P = 0.013). Because 12 of the 16 subjects who developed NTODM had IGT at baseline, the 38 IGT subjects were also examined separately. In this cohort, the same risk factors (fasting and 2-h glucose, fasting C-peptide, and fasting PI levels) were predictive for the development of NIDDM. We conclude that Japanese-American men who subsequently develop NIDDM have more IAF and increased glucose, C-peptide, and PI levels. These data suggest that alterations in PI may be a new marker for the subsequent development of NTODM.

Enteral Enhancement of Glucose Disposition by Both Insulin-Dependent and Insulin-Independent Processes: A Physiological Role of Glucagon-Like Peptide I

Glucagon-like peptide I (GLP-I)(7–36) amide is secreted by intestinal L-cells in response to food ingestion. GLP-I is a potent insulin secretagogue and also inhibits glucagon release. Inaddition, when given to humans in pharmacological amounts, GLP-I increases glucose disposal independent of its effects on islet hormone secretion. To test the hypothesis that this extrapancreatic effect of GLP-I on glucose disposition is present at physiological levels of GLP-I, we performed intravenous glucose tolerance tests (IVGTTs) 1 h after the following interventions: 1) the ingestion of 50 g fat to stimulate GLP-I secretion or the ingestion of water as a control and 2) infusion of GLP-I to attain physiological levels or a control infusion of saline. The results of the IVGTTs were analyzed using the minimal model technique to determine the insulin sensitivity index (SI) and indexes of insulin-independent glucose disposition, glucose effectiveness at basal insulin (SG), and glucose effectiveness at zero insulin (GEZI), as wellas the glucose disappearance constant (kg) and the acute insulin response to glucose (AIRg). These parameters were compared between conditions of elevated circulating GLP-I and control conditions. After ingestion of fat and infusion of synthetic hormone, plasma GLP-I increased to similar levels; GLP-I did not change with water ingestion or saline infusion. Elevated levels of GLP-I, whether from fat ingestion or exogenous infusion, caused increased glucose disappearance (kg: fat versus water 2.67 ± 0.2 vs. 1.72 ± 0.2, P < 0.001; GLP-I versus saline 2.42 ± 0.2 vs. 1.96 ± 0.2 %/min, P = 0.045), insulin secretion (AIRg: fat versus water 427 ± 50 vs. 284 ± 41, P = 0.001; GLP-I versus saline 376 ± 65 vs. 258 ± 16 pmol/1, P = 0.03), and glucose effectiveness (SG: fat versus water 2.5 ± 0.1 vs. 1.8 ± 0.2, P = 0.001; GLP-I versus saline 2.5 ± 0.2 vs. 1.8 ± 0.2%/min, P = 0.014; GEZI: fat versus water 1.9 ± 0.2 vs. 1.3 ± 0.2%/min, P = 0.003; GLP-I versus saline 1.9 ± 0.2 vs. 1.3 ± 0.2,P = 0.006) but no difference in insulin sensitivity. These results suggestthat GLP-I, released after meals, promotes glucose assimilation both by augmenting insulin secretion and through a separate effect to increase glucose uptake and/or inhibit hepatic glucose output.

Evidence That Plasma Leptin and Insulin Levels are Associated With Body Adiposity Via Different Mechanisms

OBJECTIVE Like insulin, the adipocyte hormone, leptin, circulates at levels proportionate to body adiposity. Because insulin may regulate leptin secretion, we sought to determine if plasma leptin levels are coupled to body adiposity via changes in circulating insulin levels or insulin sensitivity and whether leptin secretion from adipocytes is impaired in subjects with NIDDM. RESEARCH DESIGN AND METHODS We used multiple linear regression to analyze relationships between BMI (a measure of body adiposity) and fasting plasma levels of leptin and insulin in 98 nondiabetic human subjects (68 men/30 women) and 38 subjects with NIDDM (27 men/11 women). The insulin sensitivity index (S1) was also determined in a subset of nondiabetic subjects (n = 38). RESULTS Fasting plasma leptin concentrations were correlated to both BMI (r = 0.66, P = 0.0001) and fasting plasma insulin levels (r = 0.65, P = 0.0001) in nondiabetic men and women (r = 0.58, P = 0.0009 for BMI; r = 0.47, P = 0.01 for insulin). While the plasma leptin level was also inversely related to S1 (r = −0.35; P = 0.03), this association was dependent on BMI, whereas the association between insulin and S1 was not. Conversely, the relationship between plasma leptin and BMI was independent of S1, whereas that between insulin and BMI was dependent on S1. The relationship between plasma leptin levels and BMI did not differ significantly among NIDDM subjects from that observedin nondiabetic subjects. CONCLUSIONS We conclude that 1) body adiposity, sex, and the fasting insulin level are independently associated with plasma leptin level; 2) because NIDDM doesnot influence leptin levels, obesity associated with NIDDM is unlikely to result from impaired leptin secretion; and 3) insulin sensitivity contributes to the association between body adiposity and plasma levels of insulin, but not leptin. The mechanisms underlying the association between body adiposity and circulating levels of these two hormones, therefore, appear to bedifferent.

The effect of insulin dose on the measurement of insulin sensitivity by the minimal model technique. Evidence for saturable insulin transport in humans.

Administration of exogenous insulin during an intravenous glucose tolerance test allows the use of the minimal model technique to determine the insulin sensitivity index in subjects with reduced endogenous insulin responses. To study the effect of different insulin administration protocols, we performed three intravenous glucose tolerance tests in each of seven obese subjects (age, 20-41 yr; body mass index, 30-43 kg/m2). Three different insulin administration protocols were used: a low-dose (0.025 U/kg) infusion given over 10 min, a low-dose (0.025 U/kg) bolus injection, and a high-dose (0.050 U/kg) bolus injection, resulting in peak insulin concentrations of 1,167 +/- 156, 3,014 +/- 483, and 6,596 +/- 547 pM, respectively. The mean insulin sensitivity index was 4.80 +/- 0.95 x 10(-5), 3.56 +/- 0.53 x 10(-5), and 2.42 +/- 0.40 x 10(-5) min-1/pM respectively (chi +/- SEM; P = 0.01). The association of higher peak insulin concentrations with lower measured insulin sensitivity values suggested the presence of a saturable process. Because results were not consistent with the known saturation characteristics of insulin action on tissue, a second saturable site involving the transport of insulin from plasma to interstitium was introduced, leading to a calculated Km of 807 +/- 165 pM for this site, a value near the 1/Kd of the insulin receptor. Thus, the kinetics of insulin action in humans in these studies is consistent with two saturable sites, and supports the hypothesis for transport of insulin to the interstitial space. Saturation may have an impact on minimal model results when high doses of exogenous insulin are given as a bolus, but can be minimized by infusing insulin at a low dose.

Diagnostic utility of the history and physical examination for peripheral vascular disease among patients with diabetes mellitus

BACKGROUND We assessed the value of the medical history and physical examination in the diagnosis of peripheral vascular disease in diabetic subjects. METHODS We performed a cross-sectional study in 631 diabetic veteran enrollees of a general internal medicine clinic that compared data obtained from a history and clinical evaluation with the presence of severe peripheral vascular disease defined as an ankle-arm index (AAI) < or = 0.5 derived from Doppler blood pressure measurement. RESULTS We identified 90 limbs with an AAI < or = 0.5. Results presented below apply to the right leg, but do not differ from the left. Diminished or absent foot peripheral pulses (sensitivity 65%, specificity 78%), venous filling time > 20 sec (sensitivity 22%, specificity 93.9%), age > 65 years (sensitivity 83%, specificity 54%), claudication symptoms in < 1 block (sensitivity 50%, specificity 87%), and patient reported history of physician diagnosed peripheral vascular disease (PVD) (sensitivity 80%, specificity 70%) had the largest positive (or smallest negative) likelihood ratios. Capillary refill time > 5 sec or foot characteristics (absent hair, blue/purple color, skin coolness, or atrophy) conveyed little diagnostic information. Individual factors did not change disease probability to a clinically important degree. A stepwise logistic regression model identified four factors significantly (p < 0.05) associated with low AAI: absent or diminished peripheral pulses, patient reported history of PVD, age, and venous filling time. Substitution of < 1 block claudication for PVD history in this model resulted in a small reduction in model accuracy. CONCLUSIONS Many purportedly useful historical and exam findings need not be elicited in diabetic patients suspected of having severe peripheral vascular disease, since most information related to probability of this disorder may be obtained from patient age, self-reported history of physician diagnosed PVD (or < 1 block claudication), peripheral pulse palpation, and venous filling time.