Richard W. Bergstrom

Association of Elevated Fasting C-Peptide Level and Increased Intra-Abdominal Fat Distribution With Development of NIDDM in Japanese-American Men

The Japanese-American population of King County, Washington, is known to have a high prevalence of non-insulin-dependent diabetes mellitus (NIDDM). As part of a community-based study, we reexamined 146 second-generation Japanese-American men who had been initially classified as nondiabetic. At a mean follow-up period of 30 mo, 15 men had developed NIDDM, and 131 remained nondiabetic. The variables measured at the initial visit that distinguished the 15 diabetic men from the 131 nondiabetic men were older age, higher serum glucose level at 2 h after 75 g oral glucose, higher fasting plasma C-peptide level, and increased cross-sectional intra-abdominal fat area as determined by computed tomography. Both older age and higher 2-h glucose levels are variables that have been associated with the development of NIDDM, but the association of higher fasting C-peptide level and greater intra-abdominal fat area with subsequent development of NIDDM were new observations. The elevated fasting C-peptide level persisted after adjustment for fasting serum glucose. The elevated C-peptide level represents hypersecretion of insulin and was interpreted to reflect a compensatory response to an underlying insulin-resistant state that antedates the development of NIDDM. The fasting C-peptide level was correlated with the intra-abdominal fat area, suggesting that the intra-abdominal fat area may be associated with insulin resistance. Thus, in individuals who develop NIDDM, insulin resistance, increased insulin secretion, and increased intra-abdominal fat are present before diabetic glucose tolerance can be demonstrated.

Earlier appearance of impaired insulin secretion than of visceral adiposity in the pathogenesis of NIDDM. 5-Year follow-up of initially 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 β-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 β-cell function contribute to the development of NIDDM in Japanese-Americans, and impaired β-cell function may be present earlier than visceral adiposity in some who subsequently develop NIDDM.

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.

Diabetes and diabetes risk factors in second- and third-generation Japanese Americans in Seattle, Washington

In Seattle, Washington, the prevalence of diabetes was 20% in second-generation (Nisei) Japanese-American men and 16% in Nisei women 45-74 years old, while the prevalence of impaired glucose tolerance (IGT) was 36% in Nisei men and 40% in Nisei women. Hyperglycemia was less and duration of diabetes shorter in women. Related to diabetes and IGT in Nisei were higher fasting plasma insulin levels and central (visceral) adiposity. Prevalence of diabetes was low among the younger (34-53 years old) third-generation (Sansei) men and women. Among self-reported non-diabetic Sansei, however, prevalence of IGT was 19% in men and 29% in women, and IGT was associated with both increased fasting plasma insulin levels and more visceral fat, suggesting that many Sansei are at risk of future diabetes. An important lifestyle factor in the development of NIDD in Japanese Americans appeared to be dietary saturated (animal) fat. Another factor may be physical inactivity. In Japanese-American women, menopause also appeared to be an important risk factor. These risk factors may be related to fostering the accumulation of visceral fat and the development of insulin resistance. Five-year follow-up examinations performed in non-diabetic Nisei men and women have yielded additional information concerning the prognosis of IGT. Of those women who were IGT at baseline, 34% were diabetic at follow-up while 17% returned to normal. In men who had been IGT at baseline, 18% were diabetic at follow-up while 36% returned to normal. Over the 5-yr follow-up interval, proportionally more women progressed from normal to IGT (54%) then went from IGT to normal (17%). For men, roughly equal proportions went from normal to IGT (37%) as from IGT to normal (36%). It would therefore appear that greater proportions of Nisei women are progressing to IGT and to NIDD than are Nisei men. This observation may be related to the increased risk of developing central obesity and insulin resistance following menopause. Prevalence of cardiovascular disease (hypertension, peripheral vascular disease, and/or coronary heart disease) was increased in Japanese Americans with IGT and NIDD. Neuropathy and retinopathy were associated only with NIDD.

Low insulin secretion and high fasting insulin and C-peptide levels predict increased visceral adiposity : 5-year follow-up among initially nondiabetic Japanese-American men

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, β-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. ≤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.

Visceral Adiposity, Fasting Plasma Insulin, and Blood Pressure in Japanese-Americans

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 intolrrance and diabetic complications among Japanese-American women

The prevalence of glucose intolerance and diabetic complications was determined in second-generation Japanese-American (Nisei) women and compared to previously obtained results in Nisei men. A volunteer study sample of 191 Nisei women 45-74 years old was enrolled from a study population of 1489 Nisei women born 1913-1942, raised and educated in the U.S., and residing in King County, Washington. The enrolled sample included 72 with normal glucose tolerance, 67 with impaired glucose tolerance (IGT), and 52 with non-insulin-dependent diabetes. A random sample was also drawn from the study population to form a reference sample of 157 women. Based upon observations in the reference and enrolled samples, an estimated 16% of Nisei women in the study population have diabetes and 40% IGT. These rates compare to 20% diabetes and 36% IGT previously estimated for Nisei men 45-74 years old. The prevalence of cardiovascular disease (hypertension, peripheral vascular disease, and/or coronary heart disease) was highest among diabetic women, lowest in those with normal glucose tolerance, and intermediate in women with IGT. In comparison to diabetic men, there was a significantly lower frequency of neuropathy, peripheral vascular disease, and coronary heart disease in diabetic women. However, hypertension occurred equally often in both. Thus Japanese-American men and women 45-74 yr old have a similar prevalence of glucose intolerance, although less severe in women, and complications, except for hypertension, are reduced in women.

Association of plasma triglyceride and C-peptide with coronary heart disease in Japanese-American men with a high prevalence of glucose intolerance

SummaryIn a community-based study of second-generation Japanese-American men known to have a high prevalence of both Type 2 (non-insulin-dependent) diabetes and impaired glucose tolerance, there was a highly significant association of coronary heart disease with glucose intolerance in a study sample of 219 men. Intra-abdominal cross sectional fat area determined by computed tomography was significantly elevated in men with coronary heart disease even after adjustment for glucose intolerance and body mass index (p=0.026). Other differences that were significantly related to coronary heart disease after adjustment for glucose intolerance were lower high density lipoprotein cholesterol levels (p=0.001), elevated total triglyceride and very low density lipoprotein triglyceride (p<0.001), and elevated fasting insulin and C-peptide levels p=0.001. When these variables were tested in a stepwise multiple logistic regression model, significant independent associations with coronary heart disease were found only for total triglyceride and fasting C-peptide after adjustment for glucose tolerance status. Variables identified to be associated with coronary heart disease were interpreted as representing or manifesting an insulin resistant state. Thus, insulin resistance may be the underlying risk factor aetiologically linking glucose intolerance with coronary heart disease.

Metabolic and adipose risk factors for NIDDM and coronary disease in third-generation Japanese-American men and women with impaired glucose tolerance.

SummarySince second-generation (Nisei) Japanese Americans are prone to develop the insulin resistance syndrome, younger third-generation (Sansei) Japanese Americans from a cross-sectional 10% volunteer sample of Sansei men (n = 115) and women (n = 115) 34 years or older in King County, Washington with normal glucose tolerance or IGT were examined for metabolic and adipose risk factors associated with this syndrome. After an overnight 10-h fast, blood samples were taken for measurement of glucose, insulin, C-pep-tide, lipids, and lipoproteins, followed by a 3-h 75-g oral glucose tolerance test with blood samples taken for glucose, insulin, and C-peptide measurement. BMI (kg/m2), skinfolds, and body fat areas (by computed tomography) were measured. IGT was diagnosed in 19 % of the men and 31 % of the women. Men with IGT had more adiposity, both overall and in thoracic and visceral sites, had higher fasting plasma insulin and C-peptide, and tended to have higher fasting triglyceride and lower HDL cholesterol than men with normal glucose tolerance. Women with IGT had more thoracic subcutaneous fat and intra-abdominal fat and lower fasting HDL cholesterol than women with normal glucose tolerance, and tended to have higher fasting triglyceride and LDL cholesterol. Women with IGT also had higher fasting plasma insulin than women with normal glucose tolerance but tended to be less hyperinsuli-naemic than men. Differences in fasting insulin, C-peptide, and lipids were best predicted by intra-abdominal fat. Thus metabolic (higher fasting insulin and a tendency to higher triglyceride and lower HDL cholesterol) and adipose (visceral adiposity) risk factors associated with the insulin resistance syndrome are identifiable among Sansei men and women with IGT, who may therefore be at increased risk of future development of NIDDM and CHD.

On the mechanisms of inhibition of insulin action by small-molecular-weight trypsin inhibitors.

Evidence from a number of laboratories has suggested that the mechanism of insulin action involves the release of an intracellular mediator polypeptide from the plasma membrane. It has been proposed that activation of a protease with trypsin-like specificity is involved in release of the putative mediator. In an effort to assess the potential role of such a protease in intact cells, the present study tested the effects of a variety of low-mol-wt protease inhibitors on insulins metabolic action in isolated rat epididymal fat cells. The protease inhibitors studied included paminobenzamidine, benzamidine, phenylguanidine, diisopropylflubrophosphate, leupeptin, and the competitive substrate N-α-tosyl-L-arginine methylester. Leupeptin was devoid of activity. Most of the other inhibitors used were able to interfere with insulin-stimulated metabolism if used in sufficiently high concentrations, concentrations considerably higher than those required for inhibition of known proteases or inhibition of intracellular processes in a previously described system which involves a trypsin-like enzyme. Moreover, they displayed various activities unrelated to protease inhibition that could explain their effects on insulin action better than protease inhibition. While none of the data on individual inhibitors were by themselves convincing enough to either confirm or reject the hypothesis concerning the involvement of a protease with trypsin-like specificity in insulin action, taken together our results do weaken the hypothesis considerably and in particular render the involvement of an extracellular trypsin-like enzyme improbable.