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Background: Age is associated with both impaired glucose and insulin metabolism. To what extent the age-related changes in insulin resistance (IR) and beta-cell function contribute to the increase in prevalence of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) is less known, and this is investigated in this study., Methods: This study included 6610 men and 7664 women of different ethnic groups aged 30-69 years. IR and beta-cell function were examined by the homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of beta-cell function (HOMA-B). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression analysis adjusting for body mass index and study., Results: In Chinese men, the ORs (95% CIs) for IFG were 2.69 (1.70, 4.26), 2.51 (1.49, 4.21) and 2.89 (1.68, 4.97), respectively, in age groups of 40-49, 50-59 and 60-69 years compared with 30-39 years (p < 0.001 for trend); the corresponding figures for IGT were 1.73 (1.25, 2.38), 2.54 (1.78, 3.63) and 3.57 (2.46, 5.19) (p < 0.001 for trend). Similar trends for IGT were observed also in Chinese women and other ethnic groups, but not for IFG in Mauritius Indian and Creole men. Adjustment for HOMA-IR and HOMA-B reduced the ORs in all age groups of all ethnicities for both IFG and IGT, but the risk gradient between age groups remained particularly for the IGT., Conclusions: The age-related increase in glucose intolerance may not be fully explained by the defect in HOMA-IR and HOMA-B. As HOMA-IR and HOMA-B are only surrogate measures of insulin sensitivity and insulin secretion, the results need to be further investigated.

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 (Si) 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 Si (r = -0.35; P = 0.03), this association was dependent on BMI, whereas the association between insulin and Si was not. Conversely, the relationship between plasma leptin and BMI was independent of Si, whereas that between insulin and BMI was dependent on Si. The relationship between plasma leptin levels and BMI did not differ significantly among NIDDM subjects from that observed in 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 does not 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 be different.

Fasting insulin has been used as a surrogate measure of insulin sensitivity in studies of non-insulin-dependent diabetes mellitus (NIDDM) risk, but the fasting insulin-NIDDM association may be confounded by insulin secretion, which correlates negatively with NIDDM risk and positively with fasting insulin level. In a prospective 5-year study of 137 nondiabetic Japanese-American men in King County, Washington State, higher fasting insulin was not strongly related to NIDDM (odds ratio (OR) = 1.37, 95% confidence interval (CI) 0.80-2.34), but this odds ratio increased substantially after adjustment for insulin secretion (OR = 2.92, 95% CI 1.41-6.06). Research on NIDDM risk in relation to fasting insulin may yield biased effect measures unless adjusted for insulin secretion.

Disproportionate hyperproinsulinaemia is a manifestation of the beta-cell dysfunction observed in NIDDM. However, it is unclear when this abnormality develops and whether it predicts the development of the disease. To examine whether changes in proinsulin levels predict the development of NIDDM, baseline measurements of proinsulin and immunoreactive insulin levels were made in 87 second-generation Japanese-American men, a population at high risk for the subsequent development of NIDDM. Subjects were categorized at baseline using WHO criteria as having normal glucose tolerance (NGT; n = 49) or impaired glucose tolerance (IGT; n = 38). After a 5-year follow-up period, subjects were recategorized as having NGT, IGT or NIDDM using the same criteria. During follow-up, 16 subjects developed NIDDM while 71 were NGT or IGT. At baseline, individuals who subsequently developed NIDDM were more obese as measured by intra-abdominal fat area on computed tomography (p = 0.046), had higher fasting glucose (p = 0.0042), 2-h glucose (p = 0.0002), fasting C-peptide (p = 0.0011), fasting proinsulin levels (p = 0.0033), and had disproportionate hyperproinsulinaemia (p = 0.056) when compared to those who remained NGT or IGT after 5 years of follow-up. These findings suggest that alterations in proinsulin levels may also predict the subsequent development of NIDDM.

Objective: To examine the associations among visceral and subcutaneous adiposity, body-mass-index (BMI), fasting plasma insulin, lipid, and lipoprotein levels., Design: Cross-sectional observational study., Subjects: Non-diabetic second- (Nisei, n = 290) and third-generation (Sansei, n = 229) Japanese Americans., Measurements: Intra-abdominal (IAF) and subcutaneous abdominal fat (SAF) area were measured using computed tomography. Fasting plasma insulin, lipid, and lipoprotein levels were measured using standard methods., Results: Higher fasting insulin was significantly related to greater mean IAF and SAF area, plasma triglycerides, total HDL and HDL2 cholesterol in men and women of both generations. In a multiple linear regression analysis model among Nisei adjusted for gender, age, SAF, antihypertensive medication use, smoking, alcohol use, and exercise energy expenditure, IAF area and fasting insulin level were independently correlated with plasma triglycerides (IAF r = 0.22, fasting insulin r = 0.23), total HDL (IAF r = -0.29, fasting insulin r = -0.28), HDL2 (IAF r = -0.30, fasting insulin r = -0.27), and HDL3 cholesterol (IAF r = -0.19, fasting insulin r = -0.19). Among Sansei, similar associations were seen, except that fasting insulin was unrelated to total HDL or HDL3 cholesterol. These effects differed by gender in several instances., Conclusions: Both visceral adiposity and fasting insulin level are significantly and independently related to adverse levels of lipids and lipoproteins in both generations of nondiabetic Japanese Americans. The association between adverse lipid profile and visceral obesity is not mediated solely through detrimental effects of intra-abdominal fat deposition on fasting insulin level.

Insulin resistance and hyperinsulinemia occur more frequently in subjects with greater visceral adiposity, but it is not known whether these metabolic abnormalities precede or follow visceral fat accumulation. We prospectively studied the development of visceral adiposity in relation to fasting and stimulated insulin and C-peptide levels. We followed 137 nondiabetic, second-generation Japanese-American men for changes in visceral adiposity over 5 years. Intra-abdominal fat (IAF) area (square centimeters) was measured at the umbilicus by computed tomography at baseline and after 5 years. Plasma insulin and C-peptide levels were measured after an overnight fast and during an oral glucose tolerance test. Beta-cell function was measured by the insulin secretion ratio (30-0 min plasma insulin difference)/(30-0 min plasma glucose difference). After adjustment for baseline IAF in multiple linear regression models, baseline fasting insulin (coefficient = 0.241, P = 0.048) and C-peptide (coefficient = 38.538, P < 0.001) levels were positively correlated, while the baseline insulin secretion ratio was negatively correlated with IAF change (coefficient = -0.099, P = 0.027). With IAF difference coded as a dichotomous variable (> 0 cm2 vs. < or = 0 cm2), the highest versus lowest tertile of baseline fasting insulin (odds ratio [OR] = 3.0, 95% CI 1.0-9.7) and fasting C-peptide (OR = 8.1, 95% CI 2.4-26.8) levels and the lowest versus highest tertile of the insulin secretion ratio (OR = 3.3, 95% CI 1.0-10.0) were associated with higher odds of IAF gain. Greater insulin resistance and reduced insulin secretion precede visceral fat accumulation in nondiabetic Japanese-American men.

OBJECTIVE--To identify risk factors for development of non-insulin-dependent diabetes mellitus (NIDDM) during a 5-year longitudinal follow-up of second-generation Japanese-American (Nisei) men. RESEARCH DESIGN AND METHODS--For 5 years, 137 initially nondiabetic Nisei men were followed with 75-g oral glucose tolerance tests at the initial visit and at 2.5- and 5-year follow-up visits. Body fat distribution was assessed by computed tomography (CT) and body mass index (BMI) calculated at each visit. Fasting insulin and C-peptide, the increment of insulin and C-peptide at 30 min after the oral glucose load, intra-abdominal and total subcutaneous fat by CT, and BMI were compared between those who remained nondiabetic (non-DM) and those who had developed NIDDM at 2.5 years (DM-A) and 5 years (DM-B). RESULTS--At baseline, the DM-A group had significantly increased intra-abdominal fat, elevated fasting plasma C-peptide, and lower C-peptide response at 30 min after oral glucose. At the 2.5-year follow-up, this group had markedly increased fasting plasma insulin and decreased 30-min insulin and C-peptide response to oral glucose. The DM-B group also had significantly lower insulin response at 30 min after oral glucose at baseline but no significant difference in intra-abdominal fat or fasting plasma insulin and C-peptide levels. When this group developed NIDDM by 5-year follow-up, however, an increase of intra-abdominal fat was found superimposed on the pre-existing lower insulin response. Fasting plasma insulin and C-peptide remained low. CONCLUSION--In DM-A, lower 30-min insulin response to oral glucose (an indicator of beta-cell lesion) and increased intra-abdominal fat and fasting C-peptide (indicators of insulin resistance) were the risk factors related to the development of NIDDM. DM-B subjects had a lower 30-min insulin response to oral glucose at baseline and increased intra-abdominal fat at 5-years, when they were found to have NIDDM. Thus, both insulin resistance and impaired beta-cell function contribute to the development of NIDDM in Japanese-Americans, and impaired beta-cell function may be present earlier than visceral adiposity in some who subsequently develop NIDDM.

A causal role in the pathogenesis of obesity has been proposed for hyperinsulinemia and insulin resistance in populations with a high prevalence of a "thrifty genotype." An alternative hypothesis is that obesity-induced hyperinsulinemia is an adaptation which, by increasing central nervous system insulin signaling (which suppresses food intake), confers resistance to weight gain. To characterize the relationship between the level of insulin secretion and the risk of weight gain, we examined whether any of three different measures of the level of insulin secretion (the area under the plasma insulin curve during both a meal tolerance test and an oral glucose tolerance test, and the acute insulin secretory response to iv glucose) was predictive of weight gain in a prospective study of 97 Pima Indians (64 males and 33 females) with normal glucose tolerance. During a mean (+/- SD) follow-up period of more than 3 yr (males, 3.58 +/- 1.46 yr; females, 3.02 +/- 1.73 yr), average weight increased 2.1 +/- 3.0%/yr in males and 3.5 +/- 3.6%/yr in females, reflecting a mean annual increase in body fat content of 6.9%/yr in both sexes. Insulin secretion was negatively associated with the rate of weight gain, whether assessed by the insulin response during the meal tolerance test (r = -0.35; P < 0.001), the oral glucose tolerance test (r = -0.30; P = 0.004), or the acute insulin secretory response to iv glucose (r = -0.28; P = 0.002). Moreover, the significance of the relationship between each measure of insulin secretion and weight gain persisted after controlling for differences in age, sex, initial body weight, and insulin sensitivity. Relatively reduced insulin secretion, therefore, is a significant and independent predictor of the tendency to gain weight and adiposity in Pima Indians. The presence of relative insulin resistance also conferred an independent reduction in the risk of weight gain in some regression analyses. We conclude that insulin resistance and hyperinsulinemia are unlikely to play a causal role in the development of obesity, and that relatively reduced insulin secretion is a marker of an increased risk of weight gain in this population. These conclusions support the hypothesis that the level of insulin secretion plays an important role in long term body weight regulation.

Obesity is associated with noninsulin-dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD), and these interactions have usually been related to changes in immunoreactive insulin (IRI) levels. A role of proinsulin (PI) in this association has been suggested. We, therefore, examined IRI, PI, and true insulin levels and the PI/IRI ratio by glucose tolerance or CHD status in a cross-sectional study of 170 Japanese-American men (45-74 yr old) in whom 2 measures of adiposity (body mass index and intraabdominal fat) were made to assess potential associations in this population with a high prevalence of both NIDDM and CHD. Subjects were classified as having normal glucose tolerance (n = 58), impaired glucose tolerance (IGT; n = 55), or NIDDM (n = 57) or were classified by CHD status (without CHD, n = 127; with CHD, n = 43). A positive linear relationship existed between obesity, determined either as the body mass index or intraabdominal fat, and IRI, PI, and true insulin, but not the PI/IRI ratio. In the NIDDM subjects, PI levels were disproportionately greater than those in subjects with normal glucose tolerance or IGT, so the PI/IRI ratio was significantly greater in the NIDDM group [mean (95% confidence interval): normal glucose tolerance, 11.8% (range, 10.4-13.5); IGT, 12.8% (range, 10.8-15.1); NIDDM, 19.2% (range, 15.4-24.0); P = 0.0002] even when adjusted for obesity (P = 0.0004). In subjects with CHD compared to subjects without CHD, IRI (P = 0.0026) and true insulin levels (P = 0.0043) were increased, but PI levels were not. However, these differences were not present after adjustment for obesity. In contrast, when intraabdominal fat was adjusted for IRI or true insulin, a significant effect of intraabdominal fat on CHD risk was maintained (P = 0.045 and P = 0.029, respectively), suggesting that another factor(s) associated with central obesity may be involved in CHD risk. Thus, in Japanese-American men, elevated PI and PI/IRI ratio are markers of B-cell dysfunction, and these are not the result of obesity. An elevated true insulin level is present in those with CHD, but this appears to be the result of obesity. In contrast, central adiposity confers an additional risk for CHD independent of insulin.

Objective: To examine the associations among blood pressure, body mass index (BMI), intra-abdominal fat, and fasting plasma insulin levels among nondiabetic subjects., Research Design and Methods: Second- (Nisei, n = 290) and third- (Sansei, n = 230) generation Japanese-American subjects without non-insulin-dependent diabetes mellitus (NIDDM) were selected from a community-based study of NIDDM incidence and complications. A cross-sectional comparison of measures obtained at the baseline visit was performed. Intra-abdominal fat (IAF) area was assessed using computed tomography. Associations among blood pressure, fasting insulin, and adiposity measures were assessed by comparison of mean values and multiple linear regression analysis., Results: Hypertensive men and women had significantly higher mean IAF areas. Fasting insulin levels were somewhat higher in hypertensive subjects, with the only significant difference occurring among Sansei men. Both systolic and diastolic blood pressure correlated more strongly with IAF than BMI or skinfold thicknesses among Nisei, whereas among Sansei, IAF and BMI correlated equally well with either blood pressure. Significant positive correlations were found between fasting insulin level and blood pressure among Sansei only, even after adjustment for IAF and BMI (diastolic blood pressure-insulin coefficient = 0.24, P = 0.0043; systolic blood pressure-insulin coefficient = 0.36, P = 0.0025)., Conclusions: IAF correlated more strongly with blood pressure than BMI or skinfold thicknesses among older, second-generation Japanese-Americans and was positively correlated with blood pressure among Sansei independent of fasting insulin level. Fasting insulin was significantly correlated with blood pressure independent of visceral and overall adiposity among third-generation Japanese-Americans.

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 beta-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 x basal insulin]). Insulin-dependent glucose uptake was estimated as SI x IIR0-19, because the relationship between SI and beta-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 x 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).(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To explore the associations between blood pressure and both fasting insulin and C-peptide levels., Research Design and Methods: A cross-sectional analysis was conducted of 895 normoglycemic members of a bi-ethnic community in Colorado who were selected from a control group recruited for a geographically based study of diabetes mellitus prevalence and risk factors. All subjects included in this study had normal glucose tolerance as judged by a 75-g oral glucose tolerance test interpreted using World Health Organization criteria. None of the subjects were taking antihypertensive medication. Multiple linear regression analysis was used to examine relationships between fasting insulin and C-peptide levels and blood pressure., Results: Among all subjects, diastolic blood pressure was found to significantly increase with increasing levels of both hormones (insulin coefficient = 0.197, P = 0.013; C-peptide coefficient = 0.0436, P = 0.004), whereas systolic blood pressure was significantly related to fasting C-peptide level (coefficient = 0.0295, P = 0.050). These relationships were similar in magnitude for both Hispanic and non-Hispanic white subjects, but were diminished among women and subjects with a higher body mass index., Conclusions: Higher fasting insulin and C-peptide levels are associated with higher blood pressure, but these relationships are modified by sex and degree of obesity.

Objective: To ascertain whether childbearing would decrease oral glucose-stimulated insulin and C-peptide levels and increase the risk of NIDDM and impaired glucose tolerance in a population of Hispanic and non-Hispanic white women residing in the San Luis Valley of Colorado. Several investigators have related childbearing to subsequent abnormal glucose tolerance., Research Design and Methods: In a population-based case-control epidemiological study, diabetic patients 20-74 yr of age (n = 196) and randomly sampled control women subjects (n = 735) underwent a glucose tolerance test, a physical examination, and an in-person standardized interview. The relations between the live-birth number and fasting and oral glucose stimulated glucose, insulin and C-peptide concentrations, and NIDDM and impaired glucose tolerance were estimated using linear or logistic regression to adjust for extraneous variables., Results: In women selected as control subjects, the live-birth number was related to a significant decrease in the sum of 1- and 2-h C-peptide concentrations (coefficient = -0.077, P < 0.001) and the logarithm of the sum of 1- and 2-h insulin concentrations (coefficient = -0.014, P = 0.02). After adjustment for subscapular skin-fold thickness, the relative odds of NIDDM for the live-birth number, which was small and of borderline significance, diminished (odds ratio = 1.04 for one birth, P = 0.18). Findings were similar for impaired glucose tolerance., Conclusions: Childbearing was related to lower C-peptide and insulin levels in Hispanic and non-Hispanic women of the San Luis Valley. It had little apparent effect on later risk of NIDDM or impaired glucose tolerance.

Hyperinsulinemia has been demonstrated in Hispanics with normal glucose tolerance and in other populations at higher risk for non-insulin-dependent diabetes mellitus (NIDDM). We compared fasting and glucose-stimulated insulin and C-peptide levels in a community-based sample of 464 Hispanic and 676 non-Hispanic white adult residents of the San Luis Valley of Colorado. All subjects had normal glucose tolerance as confirmed by oral glucose tolerance testing interpreted with World Health Organization criteria. Mean fasting and 1- and 2-h post-glucose load insulin levels were significantly higher in Hispanics versus non-Hispanic whites (fasting 0.08 vs. 0.07 nM, P = 0.0026; 1 h 0.52 vs. 0.47 nM, P = 0.0129; 2 h 0.36 vs. 0.27 nM, P less than 0.0001), even after adjustment for age, sex, body mass index, waist-hip ratio, family history of diabetes mellitus, concurrent plasma glucose level, and fasting insulin level. Mean fasting and 1- and 2-h glucose-stimulated C-peptide levels in Hispanics also significantly exceeded those in non-Hispanic whites (fasting 0.58 vs. 0.54 nM, P = 0.0119; 1 h 2.72 vs. 2.46 nM, P less than 0.0001; 2 h 2.25 vs. 1.97 nM, P less than 0.0001). The C-peptide-insulin molar ratio was greater in non-Hispanic whites than Hispanics at all times measured. These findings confirm that Hispanics with normal glucose tolerance are hyperinsulinemic and that increased insulin secretion is at least partly responsible for this phenomenon. The lower levels of C-peptide compared with insulin in Hispanics suggest that the hyperinsulinemia seen in this ethnic group may be due in part to decreased hepatic insulin extraction.

Objective: We conducted a prospective study among Japanese Americans of diabetes incidence in relation to visceral and regional adiposity, fasting insulin and C-peptide, and a measure of insulin secretion, because little prospective data exist on these associations.Research Design and Methods: Baseline variables included plasma glucose, C-peptide, and insulin measured after an overnight fast and 30 and 120 min after a 75-g oral glucose tolerance test; abdominal, thoracic, and thigh fat areas by computed tomography (CT); BMI (kg/m2); and insulin secretion (incremental insulin response [IIR]).Results: Study subjects included 290 second-generation (nisei) and 230 third-generation (sansei) Japanese Americans without diabetes, of whom 65 and 13, respectively, developed diabetes. Among nisei, significant predictors of diabetes risk for a 1 SD increase in continuous variables included intra-abdominal fat area (IAFA) (odds ratio, 95% CI) (1.6, 1.1-2.3), fasting plasma C-peptide (1.4, 1.1-1.8), and the IIR (0.5, 0.3-0.9) after adjusting for age, sex, impaired glucose tolerance, family diabetes history, and CT-measured fat areas other than intra-abdominal. Intra-abdominal fat area remained a significant predictor of diabetes incidence even after adjustment for BMI, total body fat area, and subcutaneous fat area, although no measure of regional or total adiposity was related to development of diabetes. Among sansei, all adiposity measures were related to diabetes incidence, but, in adjusted models, only IAFA remained significantly associated with higher risk (2.7, 1.4-5.4, BMI-adjusted).Conclusions: Greater visceral adiposity precedes the development of type 2 diabetes in Japanese Americans and demonstrates an effect independent of fasting insulin, insulin secretion, glycemia, total and regional adiposity, and family history of diabetes. [ABSTRACT FROM AUTHOR]

Islet amyloid is a characteristic feature of type 2 diabetes. Its major component is the normal beta-cell secretory product amylin, or islet amyloid polypeptide (IAPP). To determine whether increased or disproportionate release of amylin may explain the propensity for amyloid deposition in type 2 diabetes, we measured plasma amylin-like immunoreactivity (ALI) and immunoreactive insulin (IRI) release in response to an oral glucose load in 94 Japanese-American subjects with normal glucose tolerance (NGT; n=56), impaired glucose tolerance (IGT; n=10), and type 2 diabetes (n=28) as defined by World Health Organization criteria. The incremental increase in ALI, IRI, and glucose (G) at 30 min after oral glucose ingestion was used to calculate deltaALI/deltaG and deltaIRI/deltaG as measures of beta-cell function. Overall glucose metabolism was assessed as the incremental glucose area (glucose AUC) during the 2 h of the oral glucose tolerance test. As expected, plasma glucose concentrations at both fasting (NGT, 5.0+/-0.4; IGT, 5.5+/-0.1; type 2 diabetes, 6.2+/-0.3 mmol/l; P < 0.0001) and 2 h (NGT, 6.7+/-0.1; IGT, 9.4+/-0.3; type 2 diabetes, 13.2 +/-0.5 mmol/l; P < 0.0001) were elevated in individuals with IGT and type 2 diabetes. In response to glucose ingestion, plasma IRI and ALI increased in all subjects, but these increments were lower in individuals with reduced glucose tolerance, as reflected in the deltaIRI/deltaG (NGT, 119+/-10.3; IGT, 60.7+/-7.1; type 2 diabetes, 49.7 +/-5.4 pmol/l; P < 0.0001) and deltaALI/deltaG (NGT, 2.6+/-0.2; IGT, 1.8+/-0.3; type 2 diabetes, 1.2+/-0.1 pmol/l; P < 0.0001). Moreover, these reductions in the 30-min incremental ALI and IRI responses were proportionate such that the molar ratio of ALI to IRI was not different among the three groups (NGT, 2.6+/-0.2; IGT, 2.9 +/-0.3; type 2 diabetes, 2.9+/-0.3%; NS). Further, the relationship between beta-cell function, measured as either deltaIRI/deltaG or deltaALI/deltaG, and glucose metabolism, assessed as glucose AUC, was nonlinear and inverse in nature, with r2 values of 0.38 (P < 0.0001) and 0.33 (P < 0.0001), respectively. We conclude that the reduced beta-cell function of IGT and type 2 diabetes includes proportionate reductions in both IRI and ALI release. Thus, it is unlikely that the development of islet amyloid in type 2 diabetes is the result of increased release of ALI. [ABSTRACT FROM AUTHOR]