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Fasting hyperinsulinemia is a widely used surrogate measure of insulin resistance and predicts type 2 diabetes in various populations. Whether fasting hyperinsulinemia predicts diabetes independent of insulin resistance is unknown. In 319 Pima Indians with normal glucose tolerance, fasting plasma insulin concentration and insulin-stimulated glucose disposal (M) (hyperinsulinemic clamp) were inversely related, but at any given M, there was substantial variation, with some subjects being hyperinsulinemic and others being hypoinsulinemic relative to their degree of insulin sensitivity. In 262 of the 319 subjects followed prospectively over 6.4 +/- 3.9 years, a high fasting plasma insulin concentration was a significant independent predictor of diabetes, in addition to low M and low acute insulin response (AIR) (intravenous glucose challenge). In 161 of the 319 subjects with follow-up measurements of M and AIR (5.1 +/- 3.9 years), a high relative fasting plasma insulin concentration predicted a decline in AIR but not in M before the onset of diabetes. The adjusted fasting plasma insulin concentration was a familial trait (heritability of 0.52) and in a genome-wide scan, there was suggestive evidence of linkage (logarithm of odds score 1.77) to a region on chromosome 3q, which harbors the gene encoding GLUT2. These results provide the first prospective evidence in humans that fasting hyperinsulinemia itself has a primary role in the pathogenesis of diabetes, independent of insulin resistance. Whether amelioration of basal insulin hypersecretion will prevent diabetes remains to be elucidated. [ABSTRACT FROM AUTHOR]

With the release of the new 1997 American Diabetes Association diagnostic criteria, a new category was introduced, termed "impaired fasting glucose" (IFG). The metabolic abnormalities of individuals with IFG, compared with those with impaired glucose tolerance (IGT) (World Health Organization criteria), remain to be elucidated. We assessed insulin action (hyperinsulinemic clamp), insulin secretion (25-g intravenous glucose tolerance test), and endogenous glucose output (EGO) (3-(3)H-glucose) in 434 nondiabetic Pima Indians with either normal (NFG; <6.1 mmol/l) or impaired (IFG; 6.1-7.0 mmol/l) fasting glucose and with either normal (NGT; 2-h glucose <7.8 mmol/l) or impaired (IGT; 2-h glucose 7.8-11.1 mmol/l) glucose tolerance: NFG/NGT (n = 307), IFG/NGT (n = 11), NFG/IGT (n = 98), and IFG/IGT (n = 18). Compared with the NFG/NGT group, individuals with IFG/NGT had lower maximal insulin-stimulated glucose disposal (M; -20%, P < 0.01), a lower acute insulin response (AIR) to intravenous glucose (-33%, P < 0.05), and higher EGO (8%, P = 0.055). Individuals with NFG/IGT also had lower M (-21%, P < 0.001) and lower AIR (-8%, P < 0.05), but normal EGO (-1%, NS). Individuals with IFG/IGT showed the most severe abnormalities in M (-27%), AIR (-51%), and EGO (+13%) (all P < 0.001 compared with NFG/NGT). These group differences could be explained by the observation that AIR and EGO, but not M, were more strongly related to the fasting than to the 2-h glucose concentration. Thus, Pima Indians with isolated IFG and isolated IGT show similar impairments in insulin action, but those with isolated IFG have a more pronounced defect in early insulin secretion and, in addition, increased EGO. More severe metabolic abnormalities are present in Pima Indians with combined IFG and IGT. [ABSTRACT FROM AUTHOR]

Pancreatic polypeptide (PP) is released from the pancreas in response to a meal. In humans, low-circulating PP levels have been observed in obesity, and administration of pharmacological doses of PP has been shown to decrease food intake. The aim of the present study was to investigate whether low circulating PP is associated with weight gain in Pima Indians. Plasma PP concentrations were measured after an overnight fast and 30 min after a standardized mixed meal in 33 nondiabetic male subjects who had a follow-up visit 4.9 +/- 2.5 years later. Cross-sectionally, fasting and postprandial PP levels were negatively associated with body size and adiposity. Prospectively, the change in PP response to the meal was negatively associated with the change in body weight (r = -0.53, P = 0.002). In contrast, a high fasting PP level was positively associated with change in body weight (r = 0.45, P = 0.009). In conclusion, our results provide evidence that, even within the physiological range, PP contributes to the regulation of energy balance in humans. However this contribution appears to be more complex than anticipated because of the opposite effect of fasting and postprandial PP on the risk of future weight gain.

There is evidence from animal models of obesity and type 2 diabetes that increased parasympathetic vagal input to the pancreas contributes to hyperinsulinemia. Compared with Caucasians, Pima Indians have a high risk of type 2 diabetes and exhibit marked hyperinsulinemia and elevated plasma levels of pancreatic polypeptide (PP), an islet hormone considered a surrogate marker of parasympathetic nervous system (PNS) drive to the pancreas. To test if hyperinsulinemia in Pima Indians is due to increased vagal input to the beta-cell, we examined the effect of PNS blockade in 17 Caucasian (aged 35 +/- 8 years, body fat 23 +/- 7% [mean +/- SD]) and 17 Pima Indian males (aged 28 +/- 8 years, body fat 29 +/- 5%) with normal glucose tolerance. Each participant underwent four consecutive standardized liquid meal tests (64% carbohydrate, 22% fat, and 14% protein) during which a primed infusion of atropine was administered for 120 min at the following doses: 0, 2.5, 5, and 10 micro g. kg fat-free mass (FFM)(-1). h(-1). Areas under the curve for early (AUC(0-30 min)) and total (AUC(0-120 min)) postprandial insulin and PP secretory responses were calculated. Early postprandial insulin and PP secretory responses were higher in Pima Indians compared with those of Caucasians (both P = 0.01). Secretion of insulin and PP was inhibited by atropine (both P < 0.001). Increasing doses of atropine attenuated the ethnic difference in PP (P = 0.01) but not in early insulin secretory responses (P = 0.6), an effect that was not due to differences in gastric emptying rate (acetaminophen test) and/or circulating glucose. Similar results were observed for total secretory responses. These results confirm that compared with Caucasians, Pima Indians have an exaggerated PNS drive to pancreatic F-cells that secrete PP. However, the hyperinsulinemia of this population does not appear to be due to increased vagal input to pancreatic beta-cells.

Objective: High plasma adiponectin is associated with reduced risk of type 2 diabetes, probably a consequence of its insulin-sensitizing properties. In vivo data in rodents suggest that the insulin-sensitization responsible for improvement of glycemia occurs in muscle and liver. Whereas associations of plasma adiponectin with muscle insulin sensitivity in humans have been examined, this has not been done for the liver., Research Design and Methods: We therefore analyzed the relationship between fasting plasma adiponectin and basal endogenous glucose production [EGP]-basal) and insulin-suppressed EGP (EGP-insulin, isotope dilution technique) in 143 Pima Indians (94 with normal glucose tolerance, 36 with impaired glucose tolerance, and 16 with type 2 diabetes)., Results: Fasting plasma adiponectin concentrations were negatively correlated with EGP-basal and EGP-insulin before (P = 0.006 and P < 0.0001, respectively) as well as after adjustment for age, sex, percent body fat, and insulin-stimulated whole-body glucose uptake (P = 0.007 and P = 0.0005, respectively)., Conclusions: These findings are compatible with the hypothesis that adiponectin increases hepatic insulin sensitivity. Consistent with data in animals, adiponectin may have generalized insulin-sensitizing effects in humans.

The offspring of Pima Indians with early onset type 2 diabetes are at high risk for developing diabetes at an early age. This risk is greater among those whose mothers were diabetic during pregnancy. To define the metabolic abnormalities predisposing individuals in these high-risk groups to diabetes, we conducted a series of studies to measure insulin secretion and insulin action in healthy adult Pima Indians. In 104 normal glucose-tolerant subjects, acute insulin secretory response (AIR) to a 25-g intravenous glucose challenge correlated with the age at onset of diabetes in the mother (r = 0.23, P = 0.03) and, in multiple regression analyses, the age at onset of diabetes in the father (P = 0.02), after adjusting for maternal age at onset and after allowing for an interaction between these terms. In contrast, insulin action (hyperinsulinemic glucose clamp) did not correlate with the age at onset of diabetes in the parents. To determine whether early onset diabetes in the parents affected insulin secretion in the offspring across a range of glucose concentrations, responses to a stepped glucose infusion were measured in 23 subjects. Insulin secretion rates were lower in individuals whose mothers had developed diabetes before 35 years of age (n = 8) compared with those whose parents remained nondiabetic until at least 49 years of age (n = 15) (average insulin secretory rates: geometric mean [95% CI] 369 [209-652] vs. 571 [418-780] pmol/min, P = 0.007). Finally, the AIR was lower in individuals whose mothers were diabetic during pregnancy (n = 8) than in those whose mothers developed diabetes at an early age but after the birth of the subject (n = 41) (740 [510-1,310] vs. 1,255 [1,045-1,505] pmol/l, P < 0.02). Thus, insulin secretion is lower in normal glucose tolerant offspring of people with early onset type 2 diabetes. This impairment may be worsened by exposure to a diabetic environment in utero.

Objective: Plasma concentrations of interleukin-6 (IL-6), a proinflammatory cytokine produced and released in part by adipose tissue, are elevated in people with obesity and type 2 diabetes. Because recent studies suggest that markers of inflammation predict the development of type 2 diabetes, we examined whether circulating plasma IL-6 concentrations were related to direct measures of insulin resistance and insulin secretory dysfunction in Pima Indians, a population with high rates of obesity and type 2 diabetes., Research Methods and Procedures: Fasting plasma IL-6 concentrations (enzyme-linked immunosorbent assay), body composition (DXA), insulin action (M; hyperinsulinemic euglycemic clamp), and acute insulin secretory responses to glucose (25 g intravenous glucose tolerance test) were measured in 58 Pima Indians without diabetes (24 women, 34 men)., Results: Fasting plasma IL-6 concentrations were positively correlated with percentage of body fat (r = 0.26, p = 0.049) and negatively correlated with M (r = -0.28, p = 0.031), but were not related to acute insulin response (r = 0.13, p = 0.339). After adjusting for percentage of body fat, plasma IL-6 was not related to M (partial r = -0.23, p = 0.089)., Discussion: Fasting plasma IL-6 concentrations are positively related to adiposity and negatively related to insulin action in Pima Indians. The relationship between IL-6 and insulin action seems to be mediated through adiposity.

Objective: Differences in the metabolic response to overfeeding and starvation may confer susceptibility or resistance to obesity in humans. To further examine this hypothesis, we assessed the changes in 24 h energy metabolism in response to short-term overfeeding and fasting in Caucasians (C) and Pima Indians (I), a population with a very high propensity for obesity., Methods: We measured the changes in 24 h energy expenditure (24 -EE) and 24 h respiratory quotient (24-RQ) in response to 48 h of mixed diet overfeeding (100% above energy requirements) and fasting in a whole body respiratory chamber in 14 male subjects (7 C/7 I, age 30+/-6 y, mean+/-s.d.). Results were compared to a 24 h measurement under eucaloric conditions., Results: Mean 24-EE increased in response to overfeeding and decreased in response to fasting (all changes P<0.01), with no differences between C (+9.1% and -9.1%) and I (+8.6% and -9.6%). Similarly, mean 24-RQ increased/decreased in response to overfeeding/fasting, respectively (all changes P<0.01), again with no differences between C (+0.06 and -0.05) and I (+0.05 and -0.05). The changes in 24-EE in response to overfeeding and fasting were positively correlated (r=0.70, P<0.01), whereas those in 24-RQ were not (r=0.40, NS)., Conclusions: Pima Indians do not appear to have an impaired metabolic response to short-term overfeeding and fasting that could explain their propensity for obesity. Individuals with a large increase in energy expenditure in response to overfeeding appear to have a small decrease in energy expenditure in response to starvation (spendthrift phenotype) and vice versa (thrifty phenotype).

Large subcutaneous abdominal adipocyte size (s.c. abd. AS) is associated with insulin resistance and predicts type 2 diabetes in Pima Indians. Because type 2 diabetes is familial, we aimed to determine whether mean s.c. abd. AS is also familial and if so, to identify chromosomal regions linked to this measure. Body composition (hydrodensitometry) and mean s.c. abd. AS (fat biopsy) were measured in 295 Pima Indians (179 with normal, 80 with impaired, and 36 with diabetic glucose tolerance) representing 164 nuclear families. Mean s.c. abd. AS, adjusted for age, sex, and percentage body fat was a familial trait (heritability h(2) = 0.48, P < 0.0001). A genome-wide autosomal scan revealed suggestive evidence for linkage (LOD 1.73) of adjusted mean s.c. abd. AS to chromosome 1q21--q23, a region containing LMNA, the gene encoding for the nuclear envelope proteins lamin A/C. Rare mutations in LMNA were recently shown to underlie familial partial lipodystrophy (FPLD), a syndrome characterized by regional loss of adipose tissue, insulin resistance, and glucose intolerance. A common (allelic frequency 0.43) single nucleotide polymorphism (silent 1908C --> T substitution) in exon 10 of LMNA (GenBank X03444) was associated with reduced age-, sex- and percentage body fat-adjusted mean s.c. abd. AS [0.80 +/- 0.17 (CC), 0.76 +/- 0.15 (CT), 0.73 +/- 0.16 (TT) microg lipid/cell, P < 0.05 for CC vs TT]. These findings indicate that approximately half of the variance in mean s.c. abd. AS can be attributed to familial factors and that genetic variation in LMNA might not only underlie rare cases of FPLD, but may also contribute to variation in adipocyte size in the general population., (Copyright 2001 Academic Press.)

Vagally-mediated hyperinsulinemia is a common abnormality in various rodent models of genetic and hypothalamic obesity that have a high propensity for type 2 diabetes. We hypothesized that Pima Indians, a population with a high prevalence of hyperinsulinemia, obesity, and type 2 diabetes also have an increased parasympathetic drive to the pancreas. To test this, we measured plasma concentrations of insulin and pancreatic polypeptide (PP), a surrogate marker of pancreatic vagal tone, in lean and obese Pima Indian and Caucasian children (n = 43, 26P/17C, 7 +/- 1 y) and adults (n = 92, 61P/31C, 31 +/- 5 y). Pima Indian children had approximately 2-fold higher fasting insulin and 57% higher fasting PP concentrations than age- and sex-matched Caucasian children (P < .05). Although there was no difference in fasting PP concentration between Pima Indian and Caucasian adults, in response to a mixed meal, Pima Indians had a 51% higher early (30 minutes) PP concentration and 2-fold higher early insulin concentration than Caucasians (P < .05). PP concentrations at 60 minutes and 120 minutes after the meal were also markedly higher in both lean and obese Pima Indians compared with lean and obese Caucasians. These results suggest that Pima Indians may have an increased parasympathetic drive to the pancreas, which could lead to a primary hypersecretion of insulin and contribute to their high propensity for obesity and diabetes, as is the case in various rodent models of obesity.

Objective: Epidemiological studies suggest that high birth weight might be associated with an increased risk of obesity later in life. Programming of metabolic, endocrine, and/or autonomic pathways during intrauterine development has been proposed to explain this association., Research Methods and Procedures: To determine the relationship between birth weight and body composition and energy metabolism later in life, we measured fat mass and fat-free mass (hydrodensitometry or double-energy X-ray absorptiometry), 24-hour energy expenditure, sleeping metabolic rate, and 24-hour respiratory quotient (respiratory chamber) in 272 adult nondiabetic Pima Indians (161 males/ 111 females, age 25 +/- 5 years, mean +/- SD). In these subjects, birth weight varied over a wide range (2,000 to 5,000 g). Individuals known to be offspring of diabetic pregnancies were excluded. In 44 of the 272 subjects, muscle sympathetic nerve activity was assessed by microneurography., Results: Birth weight was positively correlated with adult height (r = 0.20, p < 0.001) and fat-free mass (r = 0.21, p < 0.001), but not with fat mass (r = 0.01, not significant). Sleeping metabolic rate, adjusted for age, sex, fat-free mass, and fat mass, was negatively related to birth weight (r = -0.13, p < 0.05), whereas adjusted 24-hour energy expenditure (r = 0.07, not significant) and 24-hour respiratory quotient (r = -0.09, not significant) were not. There was no relationship between birth weight and muscle sympathetic nerve activity (r = 0.12, not significant, n = 44)., Discussion: In Pima Indians who are not offspring of diabetic pregnancies, high birth weight is associated with increased height and lean body mass, but not with increased adiposity later in life. Although high birth weight may be associated with relatively low resting energy expenditure, it is not associated with major abnormalities in 24-hour energy metabolism or with low muscle sympathetic nerve activity later in life.

Objective: An elevated C3 concentration has been reported in people with obesity, type 2 diabetes, hypertension, and dyslipidemia, and has been proposed to play a role in the development of atherosclerosis. We hypothesized that an elevated C3 concentration might be linked to insulin resistance and/or hyperinsulinemia, abnormalities commonly observed in association with the above conditions., Research Design and Methods: Fasting concentrations of C3 and acylation stimulating protein (ASP, C3adesarg), a cleavage product of C3 recently found to stimulate glucose uptake in vitro, were measured in 33 healthy nondiabetic Pima Indians (14 women and 19 men; age 27 +/- 1 and body fat 33 +/- 1%, means +/- SEM). Subjects were characterized for body composition dual-energy X-ray absorptiometry, insulin action (insulin-stimulated glucose disposal [M], hyperinsulinemic glucose clamp), and glucose tolerance (75-g oral glucose tolerance test)., Results: Fasting C3 and ASP concentrations were positively correlated (r = 0.43, P < 0.05). Fasting C3 concentration was closely related to percent body fat (r = 0.77), M (r = -0.75), and fasting insulin concentration (r = 0.72) (all P < 0.0001). Fasting C3 concentrations remained significantly related to M and fasting insulin after adjusting for percent body fat (partial r = -0.53 and 0.33, both P < 0.05). In subjects with impaired glucose tolerance, fasting C3 concentrations were higher than in those with normal glucose tolerance--a difference that remained after adjustment for percent body fat and M. We found that fasting ASP concentrations were significantly related to percent body fat (r = 0.37, P < 0.05), but not to M or fasting insulin., Conclusions: In Pima Indians, fasting C3 concentration is closely related to adiposity, insulin action, and fasting insulin levels and may thus be a mediator for the postulated link between obesity, insulin resistance, hyperinsulinemia, and possibly atherosclerosis.

Aims/hypothesis: We aimed to quantify changes in insulin action and insulin secretion associated with long-term gain, loss, regain, and maintenance of body weight in subjects with normal (NGT) or impaired (IGT) glucose tolerance., Methods: Insulin action (hyperinsulinaemic clamp) and insulin secretion (intravenous glucose challenge) were measured longitudinally in 209 Pima Indians body weight 94.4 +/- 22.8 kg (means +/- SD) 89 women/120 men, 151 NGT/58 IGT[, who either lost (n = 110) or gained (n = 99) weight (-23% to +29%) over 2.6 +/- 2.0 years. Insulin action and insulin secretion were reassessed on a third occasion in 33 subjects who lost at least 5% body weight over 1.5 +/- 0.8 years and then either regained or maintained weight over the subsequent 1.8 +/- 1.1 years., Results: There was a linear negative relation between changes in body weight and changes in insulin-stimulated glucose disposal in subjects with normal glucose tolerance (r = -0.51, p < 0.0001) and impaired glucose tolerance (r = -0.54, p < 0.0001). In contrast, changes in the acute insulin response were positively related to weight changes in subjects with normal glucose tolerance (r = +0.26, p < 0.005) but negatively in those with impaired glucose tolerance (r = -0.51, p < 0.0001). Improvements in insulin action after an average of 10% weight loss were lost with weight regain but largely preserved with weight maintenance., Conclusion/interpretation: Improvements in insulin action are proportional to the amount of weight loss, similar in magnitude to the impairment in insulin action with weight gain, preserved with long-term weight maintenance and similar between subjects with normal and with impaired glucose tolerance. Weight gain could, however, have more detrimental effects in people with impaired glucose tolerance, in whom insulin secretion decreases rather than increases to compensate for the decreased insulin action.

Objective: ASP stimulates the clearance of free fatty acids (FFA) from the circulation and the synthesis of triglycerides (TG) in adipose tissue. We tested whether fasting and post-prandial plasma ASP concentrations are increased in Pima Indians, a population with a very high prevalence of obesity, but a remarkably low prevalence of dyslipidemia., Research Methods and Procedures: Plasma concentrations of ASP, TG, FFA, total cholesterol (CHOL), and insulin (INS) were measured in 15 Pima Indians (P) and 15 Caucasians (C) closely matched for age, sex, and body weight [7 lean and 8 obese subjects, body mass index (BMI) cut-off 30 kg/m2], before and for 4 hours after a standard mixed meal (20% of daily caloric requirements, 41% carbohydrate, 44% fat, 15% protein)., Results: Fasting ASP was positively related to percent body fat (dual energy X-ray absorptiometry; r=0.49, p<0.01) and to TG and FFA, independently of percent body fat (partial r = 0.42 and 0.46, respectively, both p<0.05). There were no differences in fasting TG, FFA, CHOL, INS, or ASP between lean C and lean P. In contrast, obese P had lower TG, lower CHOL, higher INS and, on average, 27% lower ASP compared to obese C. The ethnic difference in ASP remained after adjustment for TG, FFA, and percent body fat. ASP decreased in response to the meal in all four groups with no differences between groups. There was a significant inverse correlation between preprandial ASP and the change in FFA 60 minutes after the meal (r=-0.56, p<0.001)., Discussion: Pima Indians do not have higher plasma ASP concentrations than Caucasians. Whether other alterations in the ASP-pathway, such as increased sensitivity of adipocytes to ASP, contribute to the high prevalence of obesity and low prevalence of dyslipidemia in Pima Indians, remains to be elucidated.