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Objectives - To study if type-2 (non-insulin-dependent) diabetes mellitus (NIDDM) is associated with cognitive dysfunction independently of clinically diagnosed dementia in an elderly population. Material and methods - Cognitive function was investigated with a brief neuropsychological test battery in a non-demented elderly population consisting of 183 NIDDM (World Health Organization, 1985) patients and 732 non-diabetic subjects. Results - Patients with NIDDM were impaired in the Trail-Making Test parts A and C, which may be a reflection of mildly affected frontal lobe/executive functions. Women with NIDDM performed better than non-diabetic subjects in the Mini-Mental State Examination. Conclusions - We conclude that NIDDM per se is not associated with impaired memory in the elderly, and the minor defects observed in tests of frontal lobe/executive functions are unlikely to affect daily living. In the non-demented population aged 69-78 years, NIDDM does not carry a significant risk of cognitive dysfunction, when compared to the non-diabetic subjects.

Objective: We set out to assess whether hyperproinsulinaemia is an early finding in latent autoimmune diabetes in adults (LADA). Research design and methods: We measured plasma proinsulin and C-peptide responses during a 2-h oral glucose tolerance test (OGTT) and in the hyperglycaemic clamp in 21 normoglycaemic offspring of LADA patients testing positive for glutamic acid decarboxylase antibodies (GADA) or islet cell antibodies (ICA), and in 17 healthy control subjects without a family history of diabetes. Results: The study groups had comparable areas under the curves of blood glucose, plasma proinsulin, C-peptide and proinsulin/C-peptide in the OGTT. However, the offspring of LADA patients had higher proinsulin/C-peptide in the hyperglycaemic clamp (P < 0.01 versus the control group). The offspring of GADA-positive LADA patients (n = 9) had higher proinsulin and proinsulin/C-peptide than did the control group in the OGTT (P < 0.05 for both comparisons) and in the hyperglycaemic clamp (P < 0.001 and P < 0.05 respectively). They also had higher proinsulin than the offspring of ICA-positive LADA patients (n = 12) (P < 0.001) in the hyperglycaemic clamp. The offspring of ICA-positive LADA patients did not clearly show hyperproinsulinaemia during the tests, but they had lower maximal glucose-stimulated insulin secretory capacity than the control group (P < 0.05) and the offspring of GADA-positive LADA patients (P < 0.05) in the hyperglycaemic clamp. Conclusions: These results suggested that insulin secretion in the offspring of GADA-positive LADA patients is characterised by subtle defects in the processing of insulin precursors. Furthermore, various proinsulin responses among the offspring of LADA patients with different autoimmune markers provided further evidence that LADA is a heterogeneous disorder.

OBJECTIVE—In a few previous studies, cardiovascular disease (CVD) risk factors (RFs) have been shown to predict diabetes. Our objective was to determine whether the presence of CVD RFs predict the eventual development of diabetes after controlling for known RFs, such as directly measured insulin resistance and obesity. RESEARCH DESIGN AND METHODS—We studied 872 participants with normal or impaired glucose tolerance (IGT) who were enrolled at baseline in the Insulin Resistance Atherosclerosis Study (IRAS). Of these, 143 (16%) developed type 2 diabetes in 5 years. Using these participants, a series of logistic regression models were fit to address the question. RESULTS—Significant RFs for developing type 2 diabetes included high plasminogen activator inhibitor-1, hypertension, high triglycerides, low levels of HDL cholesterol, and IGT. The 5-year cumulative incidence of type 2 diabetes by the number of RFs (0–5) was as follows: no RFs, 11 of 230 = 5%; one RF, 31 of 278 = 11%; two RFs, 36 of 202 = 18%; three RFs, 41 of 110 = 37%; four RFs, 19 of 42 = 45%; and five RFs, 5 of 10 = 50% (P < 0.001). The odds ratio (OR) for conversion to type 2 diabetes for each additional RF was 2.1 (95% CI 1.78–2.46) after adjusting for age, sex, ethnicity, and center. After further adjustment for insulin resistance, determined by the frequently sampled intravenous glucose tolerance test and waist circumference, each additional CVD RF increased the risk of type 2 diabetes significantly (OR 1.81, 95% CI 1.49–2.20). CONCLUSIONS—Individuals with multiple CVD RFs are at increased risk of type 2 diabetes, which is only partially mediated by insulin resistance or central adiposity. This information should be useful for identifying high-risk patients for developing diabetes through RF assessments.

OBJECTIVE—To determine the meaning of Si = 0 derived from the frequently sampled intravenous glucose tolerance test. RESEARCH DESIGN AND METHODS—The issue of assessing insulin resistance in large studies is important because the most definitive method (“gold standard”), the hyperinsulinemic-euglycemic clamp, is expensive and invasive. The frequently sampled intravenous glucose tolerance test (FSIGTT) has been widely used, but in insulin-resistant subjects (especially diabetic subjects), it yields considerable numbers of subjects whose Si is zero. The interpretation of an Si equaling zero is unknown. RESULTS—To address this issue, we examined 1,482 subjects from the Insulin Resistance Atherosclerosis Study (IRAS) using an insulin-modified FSIGTT and minimal model calculation of Si. The proportion of insulin-resistant subjects (Si < 1.61 × 10−4 [min−1 · μU−1 · ml−1] based on the median of the nondiabetic population) was 38.6% in subjects with normal glucose tolerance (NGT), 74% in subjects with impaired glucose tolerance (IGT), and 92% in subjects with type 2 diabetes. The proportion of subjects with Si = 0 was 2.2% in subjects with NGT, 13.2% in subjects with IGT, and 35.7% in subjects with type 2 diabetes. In subjects with IGT, those with Si = 0 had significantly lower HDL cholesterol levels and higher BMI, waist circumference, fibrinogen, plasminogen-activator inhibitor 1 (PAI-1), C-reactive protein (CRP), and 2-h insulin levels than insulin-resistant subjects with Si > 0. In type 2 diabetes, subjects with Si = 0 had significantly greater BMI and waist circumference and higher triglyceride, PAI-1, CRP, fibrinogen, and fasting and 2-h insulin levels than insulin-resistant subjects with Si > 0. In addition, diabetic subjects with Si = 0 had more metabolic disorders related to the insulin resistance syndrome than diabetic insulin-resistant subjects with Si > 0. CONCLUSIONS—We found very few subjects with Si = 0 among subjects with NGT and few subjects with Si = 0 among subjects with IGT. In contrast, Si = 0 was common in subjects with diabetes. Subjects with Si = 0 tended to have more features of the insulin resistance syndrome than other insulin-resistant subjects with Si > 0, as would be expected of subjects with almost no insulin-mediated glucose disposal, thus suggesting that subjects with Si = 0 are correctly classified as being very insulin resistant rather than having failed the minimal model program.

Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: The Insulin Resistance Atherosclerosis Study.BackgroundMicroalbuminuria is a risk factor for cardiovascular disease, but the underlying pathomechanisms are still poorly understood. A relationship between C-reactive protein (CRP), a sensitive marker of inflammation, and atherosclerotic disease has been reported recently.MethodsWe hypothesized that microalbuminuria might be associated with chronic inflammation and investigated the relationship of urinary albumin excretion, as assessed from the albumin-to-creatinine ratio (ACR), in an untimed morning urine specimen, and two inflammatory markers (CRP and fibrinogen) in the large, triethnic population of the Insulin Resistance Atherosclerosis Study (IRAS). After exclusion of subjects with macroalbuminuria, 1481 subjects were studied.ResultsBoth inflammatory markers were related to urinary ACR (r = 0.17 for CRP and r = 0.14 for fibrinogen, both P = 0.0001), an association that remained significant after adjustment for demographic variables, diabetic status, smoking, and use of angiotensin-converting enzyme inhibitors (P < 0.01). Mean levels of CRP and fibrinogen were elevated in microalbuminuric (N = 262) versus normoalbuminuric (N = 1219) subjects (5.37 ± 0.47 vs. 3.80 ± 0.15 mg/L and 295.7 ± 4.0 vs. 278.2 ± 1.6 mg/dL, both P < 0.0001). The associations were consistent among nondiabetic and type 2 diabetic subjects and among the three ethnic groups of the IRAS (non-Hispanic whites, blacks, Hispanics). In a logistic regression model, fibrinogen was independently associated with microalbuminuria (P = 0.047), along with hypertension, female gender, waist circumference, and fasting blood glucose, while CRP was not independently related to microalbuminuria in this model (P = 0.26).ConclusionWe have shown an association of CRP and fibrinogen with urinary albumin excretion in the microalbuminuric range in type 2 diabetic and nondiabetic individuals. Chronic inflammation therefore emerges as a potential mediator between microalbuminuria and macrovascular disease.

Dyslipidemias and insulin resistance often present simultaneously, as in familial combined hyperlipidemia (FCHL), and therefore may have a common genetic background. In our previous study the Pro12A1a substitution of peroxisome proliferator receptor gamma 2 (PPARgamma2) associated with insulin sensitivity, low body mass index (BMI) and high-density lipoprotein (HDL) cholesterol levels. In this study, we investigated the role of this substitution in dyslipidemias. Therefore, 228 nondiabetic members of FCHL families and 866 nondiabetic elderly subjects with (n=217) and without dyslipidemia (n=649) were genotyped. The allele frequencies of the Pro12A1a substitution did not differ between elderly subjects with or without dyslipidemia or 27 probands with FCHL. However, this substitution was associated with low fasting insulin levels both in FCHL family members (P = 0.036 adjusted for gender and age) and elderly subjects with dyslipidemia (P=0.050) but not in elderly subjects without dyslipidemia (P=0.080). In addition, the Ala12 allele of PPARgamma2 was associated with low BMI (P= 0.034) and low total triglycerides (P=0.027), and increased HDL-cholesterol (P < 0.001) in elderly subjects with dyslipidemia (n=299) but not among any other study groups. We conclude that the Ala12 isoform of PPARgamma2 ameliorates the insulin resistance and unfavorable lipid and lipoprotein profiles in FCHL and hyperlipidemic elderly subjects.

Type-2 diabetes mellitus is associated with a 2- to 4-fold increase in the risk of clinical coronary artery disease (CAD). It has been suggested that diabetic subjects without clinical CAD should be treated as aggressively for cardiovascular risk factors as subjects with CAD. This would be warranted if diabetic subjects without clinical CAD would have accelerated CAD similar to that of nondiabetic subjects with symptomatic CAD. To assess this suggestion, we compared the intima-media wall thickness in the common carotid artery (CCA) and internal carotid artery (ICA) in 43 diabetic subjects with clinical CAD, 446 diabetic subjects without clinical CAD, 47 nondiabetic subjects with clinical CAD, and 975 nondiabetic subjects without clinical CAD (all aged 40 to 70 years) in the Insulin Resistance Atherosclerosis Study. All data were adjusted for age, gender, ethnicity, and clinical results. Both diabetes and CAD were associated with increased atherosclerosis in the CCA. Likewise, diabetes was significantly associated with increased atherosclerosis in the ICA; however, CAD was not associated with ICA intima-media wall thickness. As expected, diabetic subjects with CAD had the greatest intima-media wall thickness, whereas nondiabetic subjects without CAD had the least atherosclerosis. Subjects with diabetes but without CAD had slightly greater intima-media wall thickness than nondiabetic subjects with CAD, although these differences were not statistically significant. Thus, diabetic subjects even without CAD had extensive atherosclerosis in the carotid artery. These results support the suggestion that diabetic subjects should be treated as aggressively for cardiovascular risk factor management as subjects with pre-existing CAD.

OBJECTIVE: Elevated heart rate has been predictive of cardiovascular disease and has been proposed as a global index of the autonomic nervous system influence on the heart. Hyperinsulinism has been shown to trigger sympathetic activity experimentally; however, the clinical and epidemiological data on the association of heart rate with hyperinsulinism and insulin resistance are conflicting. RESEARCH DESIGN AND METHODS: Insulin sensitivity (S(I)) and the acute insulin response (AIR) to glucose were assessed by a frequently sampled intravenous glucose tolerance test and related to resting heart rate in the tri-ethnic nondiabetic population (n = 1,000) of the Insulin Resistance Atherosclerosis Study. RESULTS: Heart rate was related to fasting insulin (r = 0.20), intact proinsulin (r = 0.15), split proinsulin (r = 0.17), and AIR (r = 0.18), and an inverse relation was found between heart rate and S(I) (r = -0.19) (all P values

Background —Subjects who convert to type 2 diabetes mellitus have increased cardiovascular risk factors relative to nonconverters. However, it is not known whether these atherogenic changes in the prediabetic state are predominantly due to insulin resistance, decreased insulin secretion, or both. Methods and Results —We examined this issue in the 7-year follow-up of the San Antonio Heart Study, in which 195 of 1734 subjects converted to type 2 diabetes. At baseline, converters had significantly higher body mass index, waist circumference, triglyceride concentration, and blood pressure and lower HDL cholesterol than nonconverters. Atherogenic changes in converters were markedly attenuated (and no longer significant) after adjustment for the homeostasis model assessment of insulin resistance (HOMA IR, a surrogate for insulin resistance); in contrast, the differences in risk factors between converters and nonconverters increased after adjustment for the ratio of early insulin increment to early glucose increment (ΔI 30-0 /ΔG 30-0 ) during an oral glucose tolerance test (a surrogate for insulin secretion). We also compared converters who had a predominant insulin resistance (high HOMA IR and high ΔI 30-0 /ΔG 30-0 ) (n=56) and converters who had a predominant decrease in insulin secretion (low HOMA IR and low ΔI 30-0 /ΔG 30-0 ) (n=31) with nonconverters (n=1539). Only the converters who were insulin resistant had higher blood pressure and triglyceride levels and lower HDL cholesterol levels than nonconverters. Conclusions —Our data suggest that atherogenic changes in the prediabetic state are mainly seen in insulin-resistant subjects and that strategies to prevent type 2 diabetes might focus on insulin-sensitizing interventions rather than interventions that increase insulin secretion because of potential effects on cardiovascular risk.

Apolipoprotein E4 (ApoE4) phenotype is a known risk factor for development of Alzheimer’s disease (AD). Contradictory results exist concerning the role of ApoE4 in the rate of decline and mortality in AD. Conflicting findings have also been reported about ApoE and gender interactions with respect to survival. We examined the survival of subjects with AD and non-AD controls with respect to ApoE phenotype and gender in a population-based longitudinal study. Cognitive evaluation was performed for a total of 980 subjects (then aged 69–78 years), and 48 cases with AD were identified. ApoE4 phenotype was more frequently present among subjects with AD. In the whole study population, survival was not related to the presence of AD or ApoE4 phenotype. Risk of death was increased for men compared to women, independently of the ApoE4 phenotype (HR 0.5, 95% confidence interval 0.44–0.69). In subjects with AD, the presence of ApoE4 alone did not influence survival. However, in the AD group, ApoE4-negative men had significantly increased risk of mortality compared to the risk in ApoE4-negative women (p < 0.01). We conclude that the presence of ApoE4 phenotype or AD did not influence mortality in the aged population. Once AD had become manifest, ApoE4 alone did not relate to survival. However, in subjects with AD not carrying ApoE4, men had reduced survival compared to women.

OBJECTIVE: LDL particles are heterogeneous in terms of size and density; small dense LDL particles are considered more atherogenic than larger LDL particles. The aim of this study was to investigate the interrelationships among LDL size, insulin, proinsulin (intact and split), and insulin sensitivity in a tri-ethnic population with varying degrees of glucose tolerance (n = 1,549) in the Insulin Resistance Atherosclerosis Study. RESEARCH DESIGN AND METHODS: Insulin sensitivity was assessed by a frequently sampled intravenous glucose tolerance test with minimal model analysis. Proinsulin levels were measured using highly sensitive assays without detectable cross-reactivity with insulin, and LDL size was determined by gradient-gel electrophoresis. RESULTS: In univariate analyses, LDL size was related to various features of the insulin resistance syndrome, including fasting insulin (r = -0.18), intact proinsulin (r = -0.24), split proinsulin (r = -0.24), the proinsulin-to-insulin ratio (r = -0.14), and insulin sensitivity (r = 0.21; all P < 0.0001). In a multivariate regression model (adjusted for age, BMI, ethnicity, and clinic), triglyceride levels (P = 0.0001), HDL cholesterol (P = 0.0001), sex (P = 0.002), and proinsulin (P = 0.01) were significantly related to LDL size. In the same model stratified by sex, LDL size was significantly inversely related to proinsulin in men (P = 0.005 and P = 0.04 after further adjustment for the glucose tolerance status), but not in women (P > 0.15). CONCLUSIONS: We found an inverse relation of proinsulin to LDL particle size in a large tri-ethnic population with varying degrees of glucose tolerance. This relation was independent of age, BMI, and triglyceride and HDL cholesterol concentrations, and was more pronounced in men than in women.

Abstract —The prevalence of cardiovascular disease (CVD) and atherosclerosis varies among several minority ethnic groups in the United States. Recently, small, dense low density lipoprotein (LDL) particle size has been recognized as a risk factor for CVD. We examined LDL size as a possible explanation for differences in CVD rates in 1571 subjects from the Insulin Resistance Atherosclerosis Study (IRAS), a multiethnic study of insulin resistance and cardiovascular risk factors. LDL size (Å) was significantly different by ethnic group (African Americans 262.1±0.6, Hispanics 257.6±0.6, and non-Hispanic whites 259.2±0.4, P

Aims/hypothesis. Proinsulin concentrations are increased relative to insulin concentrations in subjects with Type II (non-insulin-dependent) diabetes mellitus. This could be secondary to hyperglycaemia or insulin resistance or due to a defect in insulin secretion. Methods. We investigated the association between fasting insulin, intact proinsulin and the intact proinsulin: insulin ratio with insulin sensitivity, estimated by a frequently sampled intravenous glucose tolerance test and the minimal model and with acute insulin response (AIR) in 182 newly diagnosed Type II diabetic subjects aged 40 to 69 years. None of the subjects was receiving hypoglycaemic medication. Results. Insulin sensitivity correlated inversely with fasting insulin (r s = –0.42) and intact proinsulin (r s = –0.32) (p < 0.001). The intact proinsulin:insulin ratio was not correlated with insulin sensitivity. AIR correlated positively with intact proinsulin (r s = 0.23) and inversely with the intact proinsulin:insulin ratio (r s = –0.29, p < 0.001). Fasting glucose correlated positively with intact proinsulin (r s = 0.34) and the intact proinsulin:insulin ratio (r s = 0.24, p < 0.001). The intact proinsulin:insulin ratio increased by decreasing AIR (quartiles of AIR from high to low: 7.8, 8.2, 9.7 and 12.1 %, p < 0.001). This association was independent of age, sex, ethnicity, body mass index, fasting glucose, and insulin sensitivity. Conclusion/interpretation. Insulin resistance (low insulin sensitivity) was not related to the intact proinsulin:insulin ratio in subjects with Type II diabetes. In contrast, both low AIR and high fasting glucose concentrations were associated with a disproportionate increase in proinsulin concentration. These results suggest that increased intact proinsulin:insulin ratio is a marker of a defect in insulin secretion in Type II diabetic subjects. [Diabetologia (1999) 42: 1060–1066]

Background —The role of a cluster of risk factors characteristic for the insulin resistance syndrome as a predictor for coronary heart disease (CHD) has not been studied previously. Methods and Results —Clustering of cardiovascular risk factors was analyzed by factor analysis to investigate whether these clusters (factors) predict CHD events (CHD death or nonfatal myocardial infarction) in a nondiabetic population of 1069 subjects 65 to 74 years old from eastern Finland followed up for 7 years. There were 151 CHD events (92 for men, 59 for women) during the follow-up period. In men, factor 1 (the insulin resistance factor, which reflected primarily body mass index, waist-to-hip ratio, triglycerides, fasting plasma glucose, and insulin) (hazards ratio [HR] with 95% CI, 1.33, CI 1.08, 1.65, P =0.008), factor 2 (alcohol consumption, high HDL cholesterol, low triglycerides) (HR 0.78, CI 0.63, 0.96, P =0.020), factor 3 (age, systolic blood pressure, urinary albumin/creatinine ratio, left ventricular hypertrophy) (HR 1.52, CI 1.26, 1.83, P P =0.002) predicted CHD events in multivariate Cox regression analysis. In women, the insulin resistance factor did not predict CHD events (HR 1.06, CI 0.82, 1.36), but factor 2 (previous stroke, low HDL cholesterol and high triglycerides) (HR 1.34, CI 1.06, 1.69, P =0.014) and factor 3 (age, systolic blood pressure, urinary albumin/creatinine ratio, left ventricular hypertrophy) (HR 1.44, CI 1.15, 1.82, P =0.002) predicted CHD events. Conclusions —Our study supports the notion that the insulin resistance syndrome is a risk factor for CHD in elderly men.

OBJECTIVE: Among nondiabetic subjects, insulin resistance has been associated with increased cardiovascular risk factors, including dyslipidemia, hypertension, impaired fibrinolysis, and coagulation. Less is known about the relationship between insulin resistance and cardiovascular risk factors in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: To examine this issue, we determined insulin sensitivity (SI) in 479 type 2 diabetic subjects by minimal model analyses of frequently sampled intravenous glucose tolerance tests in the Insulin Resistance Atherosclerosis Study (IRAS), a large multicenter study of insulin sensitivity and cardiovascular disease in African-Americans, Hispanics, and non-Hispanic whites. We defined insulin-sensitive subjects as having SI > or = 1.61 x 10(-4) min-1.microU-1.ml-1 (above median in nondiabetic subjects of all ethnic groups in the IRAS). Using this definition, only 37 type 2 diabetic subjects were insulin sensitive, and the remaining 442 were insulin resistant. RESULTS: After adjustment for age, sex, ethnicity, and clinic, insulin resistance was significantly correlated with total triglycerides, VLDL cholesterol, VLDL triglyceride, fibrinogen, PAI-1, and fasting glucose, and was inversely correlated with HDL cholesterol level and LDL size. Carotid intimal-medial thickness was greater in insulin-resistant than in insulin-sensitive subjects, but this difference was not statistically significant. After further adjustment for waist circumference (marker of visceral adiposity), insulin-resistant subjects continued to have higher plasminogen activator inhibitor 1 and VLDL triglyceride levels, lower HDL cholesterol levels, and smaller LDL particle size than did insulin-sensitive subjects. After further adjustment for fasting glucose levels, these results were very similar. CONCLUSIONS: We conclude that insulin-resistant type 2 diabetic subjects have more atherogenic cardiovascular risk factor profiles than insulin-sensitive type 2 diabetic subjects and that this is only partially related to increased obesity and an adverse body fat distribution.

HAFFNER, STEVEN M., LEENA MYKKANEN, DAVID L. RAINWATER, PAULI KARHAPAA, AND MARKU LAAKSO. Is leptin concentration associated with the insulin resistance syndrome in nondiabetic men? Obes Res. Objective Insulin resistance has been strongly associated with cardiovascular risk. Recently, leptin, a hormone that regulates appetite, has been associated with both obesity and insulin resistance. However, the possible relation of leptin to the insulin resistance syndrome has been controversial. Research Methods and Procedures To explore this issue, we examined the relation of leptin to blood pressure, lipid levels, low density lipoprotein (LDL) size, and glucose levels in 87 normoglycemic men. Results Leptin levels were significantly correlated with body mass index (BMI) (r = 0.494), fasting insulin (r = 0.576), whole-body glucose disposal rate (GDR) (r = −0.566), fasting glucose (r = 0.510), total triglycerides (r= 0.294), apolipoprotein B 0 = 0.223), systolic blood pressure (r= O.223), and LDL size (r = −0.244). After adjustment for BMI and GDR, leptin levels remained significantly correlated with fasting insulin, fasting glucose, triglyceride, apolipoprotein B, and systolic blood pressure. Leptin levels were also correlated with the number of metabolic risk factors (dyslipidemia, systolic blood pressure, and fasting glucose). Discussion We conclude that leptin concentrations may be associated with several cardiovascular risk factors related to insulin resistance syndrome. These associations are only partly explained by leptin's relationship with BMI and GDR.

INTRODUCTION: Leptin (the product of the human OB gene) is increased in obese individuals, suggesting resistance to its effect. However, there is considerable variability in leptin levels at each level of body mass index (BMI), suggesting that genetic and environmental factors may regulate leptin concentrations. Previous data have suggested that leptin levels are associated with insulin resistance and in a few reports with impaired insulin secretion. We examined whether non-diabetic subjects, with elevated specific insulin and proinsulin levels, had increased leptin levels. METHODS: We used a radioimmunoassay (RIA) to measure serum leptin levels in 197 non-diabetic Mexican Americans and non-Hispanic whites from the San Antonio Heart Study. We also evaluated whether leptin levels were associated with impaired insulin secretion or increased beta cell stress, as evaluated by the fasting proinsulin/insulin ratio. (Higher fasting proinsulin/insulin ratios are thought to reflect impaired insulin secretion.) RESULTS: Leptin levels were significantly correlated with fasting specific insulin (r=0.55, P

Background and Purpose —Insulin resistance and hyperinsulinemia have been associated with atherosclerosis. Recent attention has focused on the possible role of proinsulin because most radioimmunoassays for insulin cross-react with proinsulin. Therefore, it is not known which of the two, insulin per se or proinsulin, is more strongly related to atherosclerosis. Methods —We examined the relation between fasting proinsulin, fasting split proinsulin, fasting and 2-hour insulin (after oral glucose load), and intima-media wall thickness (IMT) in the common carotid artery (CCA) and internal carotid artery (ICA) in 985 nondiabetic subjects from the Insulin Resistance Atherosclerosis Study, a multiethnic study of insulin resistance and atherosclerosis. Results —In the overall population, a weak but significant relation between proinsulin and CCA IMT was observed ( r =0.07, P =0.029). However, the relation between proinsulin and IMT was stronger in Hispanics and non-Hispanic whites than in African Americans. In non-Hispanic whites and Hispanics, significant correlations between CCA and proinsulin ( r =0.087) and between ICA and proinsulin ( r =0.101), split proinsulin ( r =0.092), and fasting insulin ( r =0.087) were observed. The significant correlations became more attenuated (and nonsignificant) after adjustment for cardiovascular risk factors, especially plasminogen activator inhibitor-1 (PAI-1). Conclusions —The association between proinsulin and IMT, while weak, appears to be stronger than the association between insulin and IMT. Adjustment for PAI-1 markedly attenuated the association between proinsulin and IMT, suggesting a possible mediating role for PAI-1 in this association. It is possible that proinsulin may represent a marker of atherosclerosis rather than a causal factor for atherosclerosis. Studies of the insulin resistance syndrome and atherosclerosis that use insulin as a surrogate for insulin resistance should consider the use of specific insulin assays as well as determination of proinsulin concentrations.

OBJECTIVE To study cognitive function in an elderly population with persistent impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS Fasting and postload 2-h plasma glucose and insulin levels were determined at baseline in a population-based sample of 1,300 people and repeated an average of 3.5 years later in 980 subjects. At follow-up, cognitive function was evaluated in subjects with persistent normal glucose tolerance (NGT; n = 506) and IGT (n = 80) with a brief neuropsychological test battery. RESULTS Subjects with persistent IGT scored lower in the Mini-Mental State Examination (MMSE) and in the Buschke Selective Reminding Test long-term memory scores. Multiple linear regression analysis revealed that age, education, and insulin levels (either fasting or 2-h value) were associated with the MMSE score in subjects with persistent IGT. Other potential risk factors for impaired cognitive function were not significantly associated with the MMSE score. CONCLUSIONS Our study showed that persistent IGT in the elderly is associated with mildly impaired cognitive function, and hyperinsulinemia may account for this association.

Plasma levels of proinsulin and its conversion intermediates are elevated in NIDDM patients. Recent studies have suggested that proinsulin levels are also increased relative to insulin levels in subjects who subsequently develop NIDDM. This may be due to insulin resistance or a defect in proinsulin processing or insulin secretion. If insulin resistance is the trigger, the proinsulinto-insulin ratio would be higher in insulin-resistant subjects than in insulin-sensitive subjects. We examined the association of fasting proinsulin, 32,33 split proinsulin, and the proinsulin-to-insulin ratio with insulin sensitivity (SI), estimated by a frequently sampled intravenous glucose tolerance test and the minimal model in 138 normoglycemic subjects ages 53–61 years. We also investigated the relation of proinsulins and the proinsulin-to-insulin ratio to acute insulin response (AIR). Fasting specific insulin (r = −0.64), intact proinsulin (r = −0.43), and 32,33 split proinsulin (r = −0.54) concentrations were inversely correlated and the proinsulin-to-insulin ratio positively (r = 0.31) correlated with SI (P < 0.001). Fasting specific insulin (r = 0.64), intact proinsulin (r = 0.35), and 32,33 split proinsulin (r = 0.45) concentrations were positively correlated and proinsulin-to-insulin ratio (r = −0.40) inversely correlated with AIR (P < 0.001). The proinsulin-to-insulin ratio increased by increasing levels of SI (quartiles of 5, from low to high: 0.048, 0.078, 0.078, 0.068; P = 0.012) and decreased by increasing SI (quartiles of SI from low to high: 0.088, 0.068, 0.058, 0.058; P = 0.005). These associations were independent of age, sex, BMI, and waist-to-hip ratio. Furthermore, the relation between the proinsulin-to-insulin ratio and AIR was independent of SI In conclusion, in normoglycemic subjects, insulin resistance (low SI was associated with a low rather than a high proinsulin-to-insulin ratio. Subjects who maintained normoglycemia with a low AIR had an increased proinsulin-to-insulin ratio compared with those who needed high to maintain normoglycemia. These results suggest that, in subjects with normal glucose tolerance, insulin resistance does not induce increased proinsulin relative to insulin secretion, but rather is associated with enhanced processing of proinsulin.

Leptin, the product of the human OB gene, is increased in obese individuals, suggesting resistance to its effect. However, there is variability in leptin levels at each level of body mass index, suggesting that genetic and environmental factors other than overall adiposity may regulate leptin concentrations. Leptin concentrations are higher in women relative to men, a difference that is only partially explained by the increased fat depots in women. The authors hypothesized that higher estrogen levels in women might be responsible for the sexual dimorphism in leptin concentrations. To test this hypothesis, they measured leptin concentrations in premenopausal women not on oral contraceptives (PRE) in = 53), postmenopausal women on hormone replacement therapy (POSTY) (n = 28), and postmenopausal women not on hormone replacement therapy (POSTN) (n = 28) in the San Antonio Heart Study, a population-based study of diabetes and cardiovascular risk factors. Analyses were restricted to nondiabetic Mexican Americans. Subjects were well matched on obesity as assessed by body mass index (kg/m 2 : PRE = 31.0, POSTY = 29.8, and POSTN = 31.6. Leptin concentrations (ng/ml) were not significantly different among the three groups (PRE = 27.6, POSTY = 28.3, and POSTN = 27.8). The authors conclude that differences in estrogen levels are not likely to explain the sexual dimorphism in leptin concentrations.

Background and Purpose Microalbuminuria is associated with cardiovascular mortality in subjects with non–insulin-dependent diabetes mellitus (NIDDM). However, little is known about this association in nondiabetic subjects. Specifically, it is not known whether microalbuminuria is related to an early stage of atherosclerosis manifested as increased intima-media thickness (IMT) of carotid arteries. We investigated the relationship between microalbuminuria and carotid artery IMT in 991 nondiabetic and 450 NIDDM subjects aged 40 to 69 years. Methods Microalbuminuria was defined as albumin-to-creatinine ratio ≥2 mg/mmol in a morning spot urine sample. B-mode ultrasound was used to assess the IMT of the common and internal carotid arteries. Results Altogether 13.9% of nondiabetic and 27.6% of NIDDM subjects had microalbuminuria, and 31.1% of nondiabetic and 50.8% of NIDDM subjects had hypertension. Subjects with microalbuminuria had greater common carotid artery (CCA) IMT than those without microalbuminuria (nondiabetic: 0.84±0.02 versus 0.80±0.01 mm, P =.010; NIDDM: 0.89±0.02 versus 0.86±0.01 mm, P =.152; combined: 0.86±0.01 versus 0.82±0.01, P =.005). The association of microalbuminuria and CCA IMT was independent of age, sex, ethnicity, smoking, and lipoprotein levels. Although further adjustment for hypertension in the multivariate linear regression analysis attenuated the difference in CCA IMT between subjects with and without microalbuminuria, this difference continued to be significant (combined: 0.86±0.01 versus 0.83±0.01, P =.015). In contrast to CCA IMT, microalbuminuria was not related to ICA IMT. Conclusions Microalbuminuria was associated with increased CCA IMT. This relationship was only partly mediated by hypertension. Thus, microalbuminuria is related to atherosclerosis at an early stage of the disease process.

Although insulin resistance and decreased insulin secretion are characteristic of established non-insulin-dependent diabetes mellitus (NIDDM), which of these metabolic abnormalities is the primary determinant of NIDDM is still controversial. A disproportionate increase in the proinsulin to insulin ratio has been proposed as a marker of compromised insulin secretion. We examined the association of fasting immunoreactive insulin (which cross-reacts with proinsulin), specific insulin (which does not cross-react with proinsulin), total immunoreactive proinsulin (or insulin precursors), and the fasting proinsulin/specific insulin ratio to the risk of developing NIDDM in the 3.25-year follow-up of the Mexico City Diabetes Study. These measurements were made in 85 subjects who subsequently converted to NIDDM (prediabetic subjects) and in 85 age and gender matched subjects who remained non-diabetic at follow-up (control subjects). Immunoreactive insulin, proinsulin and the proinsulin/specific insulin ratio were significantly higher in prediabetic than in control subjects. However, the relation between specific insulin and the development of NIDDM was weaker than for proinsulin or immunoreactive insulin. After further adjustment for obesity, body fat distribution and glucose tolerance status, proinsulin and the proinsulin/specific insulin ratio, but not specific or immunoreactive insulin, predicted conversion to NIDDM. A high proinsulin/specific insulin ratio predicted conversion to NIDDM both in subjects with normal and those with impaired glucose tolerance at baseline. We conclude that in prediabetic subjects increased proinsulin, a marker of islet cell distress or compromised insulin secretion, is associated with rapid conversion (within 3.25 years) to NIDDM even in obese populations.

NIDDM is usually characterized by β-cell failure decreased and insulin sensitivity. It has been reported that a high proportion of African-American NIDDM subjects are insulin sensitive. To examine this issue, we determined insulin sensitivity (SI) in 479 NIDDM subjects by minimal model analyses of frequently sampled intravenous glucose tolerance (FSIGT) from the Insulin Resistance Atherosclerosis Study (IRAS), a large multicenter study of insulin sensitivity and cardiovascular risk in African-Americans, Hispanics, and non-Hispanic whites. The African-Americans and non-Hispanic whites were sampled in Los Angeles and Oakland, California. The non-Hispanic whites and Hispanics were sampled in San Antonio, Texas, and San Luis Valley, Colorado. We defined the proportion of insulin-sensitive (SI) subjects as ≥1.61 min−1 · μU−1 · ml−1, which is above the median for nondiabetic subjects of all ethnic groups in the IRAS. Using this definition, the proportion of insulin-sensitive diabetic subjects was very low in all ethnic groups (non-Hispanic whites [14.3%] vs. African- Americans [6.5%], P = 0.039 in Los Angeles and Oakland; non-Hispanic whites [6.8%] vs. Hispanics [4.9%], P = 0.737 in San Luis Valley and San Antonio). These results were also similar in newly diagnosed mildly hyperglycemic diabetic subjects. In addition, these results were not affected by the adjustment for differences in obesity, body fat distribution, and severity of hyperglycemia. Even in nonobese subjects (with BMI

Insulin resistance and impaired insulin secretion are thought to be the primary defects in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM). Disproportionately increased proinsulin relative to insulin levels are suggested to be an early indicator of a failing pancreas. We examined the relationship of fasting specific insulin, proinsulin, and 32, 33 split proinsulin concentrations, and the proinsulin: insulin ration to the risk of developing NIDDM 3.5 years later in 65-74-year-old non-diabetic Finnish subjects participating in a population-based study (n=892) on diabetes and heart disease. Altogether 69 subjects developed NIDDM over a 3.5-year follow-up (cases). The cases were compared to randomly-selected gender-matched control subjects (n=69) and control subjects matched for gender, glucose tolerance status (normal or impaired), and body mass index (n=69). There were no differences in insulin concentrations between cases and random or matched control subjects [median and interquartile range: 123 (77-154), 108 (74-143), 118 (83-145) pmol/l, p=0.271]. Random control subjects had lower proinsulin and 32, 33 split proinsulin concentrations and split proinsulin: insulin ratios compared to cases [5.7 (3.8-9.0) vs 7.3 (4.8-10.0) pmol/l, p=0.005; 7.3 (4.5-13.0 vs 10.4 (7.1-18.0) pmol/l, p=0.002; 0.073 (0.057-0.110) vs 0.097 (0.060- 0.135), p=0.003]. Matched control subjects had lower proinsulin concentrations and proinsulin: insulin ratios compared to cases [5.9 (4.0-7.7) vs 7.3 (4.8-10.0) pmol/l, p=0.019; 0.048 (0.035-0.071) vs 0.064 (0.045-0.100), p=0.008]. When cases were compared to matched control subjects a 1 SD increase in baseline proinsulin: insulin ratio was associated with a 1.37-fold risk (p=0.020) of developing diabetes. Moreover, this association was independent of fasting glucose concentration at baseline. Thus, in elderly prediabetic subjects disproportionately increased proinsulin concentration, an indicator of defective insulin secretion, is associated with conversion to diabetes over a short time period.

OBJECTIVE: To examine the clinical course of age-associated memory impairment (AAMI) and to evaluate the value of neuropsychological tests in predicting cognitive decline in AAMI subjects in a follow-up period of more than 3 years. DESIGN: Prospective cohort study. SETTING: The outpatient Memory Research Unit of the Department of Neurology at the University of Kuopio in Eastern Finland. PARTICIPANTS: A sample of 229 subjects (mean age 71.7 years) identified in two screening studies as having AAMI. MEASUREMENTS: A battery of neuropsychological tests and a structured inquiry for health status and subjective memory complaints were performed at baseline and follow-up to diagnose AAMI according to the criteria proposed by a National Institute of Mental Health work group. RESULTS: Of the 229 subjects, 176 (76.9%) participated in the follow-up for, on average, 3.6 years after the baseline. Of the participants, 104 (59.1%) still met the AAMI criteria. Other subjects were classified into five subgroups: (1) subjects showing decline in cognition meeting dementia diagnosis (16, 9.1% (13 of them AD)); (2) subjects with mild cognitive decline meeting neither dementia nor AAMI criteria (13, 7.4%); (3) subjects with memory performance now superior to AAMI criteria (17, 9.7%); (4) subjects having a disease classified as exclusion in the criteria (15, 8.5%); (5) subjects not now reporting subjective memory loss in everyday life (9, 5.1%). Two subjects (1.1%) were not classified because of incomplete data. Neuropsychological tests predicted which subjects would develop dementia during the follow-up period. The best discriminators between these subjects and those who remained AAMI were memory and verbal fluency tests. CONCLUSION: The study suggests that, in general, AAMI is nonprogressive, but the AAMI population also includes subjects with early dementia and subjects without genuine memory loss. However, these subjects can be differentiated with a more detailed neuropsychological evaluation. J Am Geriatr Soc 43:1007–1015, 1995.

Background Both hyperinsulinemia and microalbuminuria have been shown to increase coronary heart disease (CHD) risk, but the interaction among hyperinsulinemia, microalbuminuria, and the risk for CHD has not been investigated in previous studies. Methods and Results The risk of CHD in relation to hyperinsulinemia and microalbuminuria was examined in a cohort of 1069 elderly nondiabetic subjects from Kuopio, east Finland, during 3.5 years of follow-up. The overall incidence of CHD death was 2.8%, and 6.9% of study subjects died of CHD or had a nonfatal myocardial infarction (later referred to as all CHD events). In the highest fasting-insulin quintile (fasting insulin ≥114.0 pmol/L), there was a slightly but insignificantly higher incidence rate of both CHD mortality and all CHD events compared with lower quintiles. The incidence rates of CHD mortality and all CHD events were significantly higher in the highest urinary albumin/creatinine ratio (ACR) quintile (ACR ≥3.22 mg/mmol) compared with lower quintiles ( P P P P P P =.002). Multivariate logistic regression analyses were also performed, including sex, current smoking, waist-hip ratio, systolic blood pressure, and HDL cholesterol, with insulin, ACR, or both as independent variables. Even after adjustment for these variables, hyperinsulinemic microalbuminuria remained a strong predictor of CHD death (OR, 7.91; P P =.014). The group with hyperinsulinemic microalbuminuria was characterized by the most adversely affected risk factor pattern (high triglycerides ≥2.3 mmol/L, low HDL cholesterol ≤0.9 mmol/L in men and ≤1.20 mmol/L in women, and hypertension). Conclusions Simultaneous occurrence of hyperinsulinemia and microalbuminuria identifies a group of subjects with a highly increased risk for CHD in elderly nondiabetic subjects.

OBJECTIVE Increased lipoprotein(a) [Lp(a)] concentrations have been recognized as a risk factor for coronary heart disease. Little data exists on the relationship of Lp(a) concentrations to insulin resistance. RESEARCH DESIGN AND METHODS We examined insulin resistance (as determined by the euglycemic clamp) together with indirect calorimetry in relation to Lp(a) concentrations, apolipoprotein(a) [apo(a)] molecular weight, and apo(a) phe-notype in 87 normoglycemic men. RESULTS Lp(a) concentrations were significantly related to total (r = 0.225) and nonoxidative (r = 0.256) whole-body glucose disposal. These results suggest a positive but weak association between insulin sensitivity (restricted to the nonoxidative whole-body glucose disposal) and Lp(a) concentrations. However, after adjustment for apo(a) molecular weight [which accounts for some of the genetic influences on Lp(a) levels], total and nonoxidative body glucose disposal were not significantly related to Lp(a) concentrations. CONCLUSIONS Normoglycemic insulin-resistant subjects do not have elevated Lp(a) concentrations.

OBJECTIVE Coronary heart disease (CHD) is increased two- to fourfold in subjects with NIDDM compared with normoglycemic subjects. This excess risk is only partially explained by conventional risk factors. We studied the effect of non-insulin-dependent diabetes mellitus (NIDDM) on the size of low-density lipoproteins (LDL). RESEARCH DESIGN AND METHODS We examined the effect of NIDDM on LDL size and subclass pattern B (LDL size < 253.5 Å) in 95 diabetic subjects and 371 nondiabetic subjects from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. RESULTS LDL size (Å) was significantly lower in diabetic subjects (men: 252.2 ± 1.8; women: 254.7 ± 1.3) than in nondiabetic subjects (men: 256.1 ± 0.8; women: 259.7 ± 0.7) (P = 0.007). After the use of analysis of covariance to adjust for triglyceride and high-density lipoprotein cholesterol, LDL size was still significantly lower in diabetic women than in nondiabetic women. In men, however, diabetes was no longer significantly associated with LDL size after similar adjustments. Fasting glucose was more strongly correlated with LDL size in women (r = −0.30) than in men (r = −0.18). CONCLUSIONS We conclude that LDL size is significantly lower in diabetic subjects of both sexes than in nondiabetic subjects, but that diabetic dyslipidemia accounts for the association in diabetic men. The stronger association between LDL size and diabetes in women than in men may partially explain the greater relative risk of CHD observed in women with NIDDM in some studies.

BACKGROUND Few data are available on the prevalence of hypertension in Mexico. METHODS AND RESULTS We compared the prevalence of mild hypertension (systolic blood pressure > or = 140 mm Hg and/or diastolic blood pressure > or = 90 mm Hg and/or use of antihypertensive medications) in 1500 low-income Mexican Americans who participated in the San Antonio Heart Study and 2280 low-income Mexicans who participated in the Mexico City Diabetes Study. The crude prevalence of mild hypertension was 17.1% in Mexican men versus 24.4% in Mexican American men (P = .001) and 17.4% in Mexican women versus 22.0% in Mexican American women (P = .005). After adjustment for age, body mass index (BMI), waist-to-hip ratio (WHR), non-insulin dependent diabetes mellitus (NIDDM), educational attainment, and percent native American genetic admixture (Caucasian and native American), the odds ratio (Mexico City/San Antonio) was 0.55 (95% CI, 0.39, 0.77; P < .001) in men and 0.81 (CI, 0.54, 1.12; P = .201) in women. In a pooled model including both men and women, the odds ratio was 0.67 (95%, CI, 0.53, 0.84; P < .001). In the pooled model, city, age, female sex, NIDDM, BMI, WHR, and low educational attainment were significantly related to the prevalence of hypertension. CONCLUSIONS The causes for these differences in hypertension prevalence are not known but may reflect a less modernized lifestyle in Mexico City, including greater physical activity, less obesity, and the consumption of a high-carbohydrate, low-fat diet.

The aim of this study was to evaluate whether noninsulin-dependent diabetes (NIDDM) and its metabolic control and duration predict coronary heart disease (CHD) events during a 3.5-year follow-up in a randomly selected Finnish population sample 65–74 years of age at baseline. Of 1,298 subjects participating in the baseline study, 1,069 were nondiabetic and 229 had NIDDM. During the follow-up, 3.4% of nondiabetic and 14.8% of NIDDM subjects died from CHD or had a nonfatal myocardial infarction (MI). The impact of NIDDM on CHD mortality and morbidity was more marked in women than in men. Odds ratios (ORs) and their 95% confidence intervals for CHD death and nonfatal MI in women with NIDDM compared with women with normal glucose tolerance were 11.7 (3.8–36.4) and 4.7 (3.6–6.1). In men, the corresponding ORs were 0.43 (0.1–1.9) and 1.4 (0.6–3.2). In multiple logistic regression analyses including all study subjects, NIDDM (P < 0.01), male sex (P < 0.05), and previous MI (P < 0.01) predicted CHD death (n = 45). NIDDM (P < 0.01), male sex (P < 0.05), previous MI (P < 0.05), current smoking (P < 0.001), systolic blood pressure (P < 0.001), and low high-density lipoprotein cholesterol (P < 0.01) predicted all CHD events (CHD death or nonfatal MI) (n = 107). In NIDDM subjects, only glycated hemoglobin A1c (GHbsA1c) at baseline (P < 0.01) and duration of diabetes (P < 0.05) predicted CHD death (n = 15) and all CHD events (n = 33). There was a significant increase in the risk of CHD death and all CHD events in NIDDM subjects with GHbA1c levels higher than 7.0% compared with diabetic subjects with lower GHbA1c (ORs 4.3 [1.1–16.7] and 2.2 [1.0–5.1]). In conclusion, NIDDM and its metabolic control and the duration of diabetes are important predictors of CHD in elderly subjects, particularly in women.

Non-insulin-dependent diabetes mellitus (NIDDM) is a major risk factor for stroke in the middle-aged population, but few prospective population-based studies are available in the elderly. Moreover, the importance of metabolic control and the duration of diabetes in diabetic subjects has remained controversial. There are no previous studies on association of insulin with the risk of stroke. The present study examined whether NIDDM, its metabolic control and duration, and insulin level predict stroke. We measured cardiovascular risk factors including glucose tolerance, plasma insulin, and glycosylated hemoglobin A1c in a Finnish cohort of 1298 subjects aged 65 to 74 years and investigated the impact of these risk factors on the incidence of both fatal and nonfatal stroke during 3.5 years of follow-up. Of 1298 subjects participating in the baseline study, 1069 did not have diabetes and 229 had NIDDM. During the 3.5-year follow-up, 3.4% (n = 36) of nondiabetic subjects and 6.1% (n = 14) of NIDDM subjects had a nonfatal or fatal stroke. The incidence of stroke was significantly higher in diabetic women compared with nondiabetic women (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.65 to 3.06). In contrast, the risk of stroke was not significantly higher in diabetic men than in nondiabetic men (OR, 1.36; 95% CI, 0.44 to 4.18). In multivariate logistic regression analyses including all study subjects, fasting and 2-hour glucose (P < .01 and P < .05, respectively), glycosylated hemoglobin A1c (P < .01), atrial fibrillation (P < .05), hypertension (P < .05), and previous stroke (P < .01) predicted stroke events. In diabetic subjects, fasting and 2-hour glucose (P < .01 and P < .05, respectively), glycosylated hemoglobin A1c (P < .05), the duration of diabetes (P < .05), and atrial fibrillation (P < .05) were the baseline variables predicting stroke events. Finally, fasting insulin (P < .05), hypertension (P < .05), and previous stroke (P < .01) were associated with stroke incidence in nondiabetic subjects. Our 3.5-year follow-up study provides evidence that NIDDM, its metabolic control, and the duration of diabetes are important predictors of stroke in elderly subjects, particularly in women. Moreover, fasting insulin level appears to be a risk factor for stroke in elderly nondiabetic subjects.

Although many studies indicate that increased androgenicity is associated with insulin resistance and hyperinsulinemia in both premenopausal and postmenopausal women, relatively few data are available on this relationship in men. We examined the association of sex hormone-binding globulin (SHBG), total and free testosterone, dehydroepiandrosterone sulfate (DHEA-SO4), and estradiol to glucose and insulin concentrations before and during an oral glucose tolerance test in 178 men from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Total and free testosterone and DHEA-SO4 were significantly inversely associated with insulin concentrations. Free testosterone and DHEA-SO4 were also significantly inversely correlated with glucose concentrations. SHBG was weakly positively associated with glucose concentrations. Estradiol was not related to glucose or insulin concentrations. After adjustment for age, obesity, and body fat distribution, insulin concentrations remained significantly inversely correlated with free testosterone (r = -.23), total testosterone (r = -.21), and DHEA-SO4 (r = -.21; all P < .01). In conclusion, we observed that increased testosterone and DHEA-SO4 are associated with lower insulin concentrations in men. This is in striking contrast to women, where increased androgenicity is associated with insulin resistance and hyperinsulinemia.

Several studies have indicated that insulin resistance, elevated blood pressure (BP), and dyslipidemia precede the onset of non-insulin-dependent diabetes mellitus (NIDDM). Little data, however, exist on the presence of renal disease in prediabetic subjects. We measured albumin excretion in a cross-sectional population study in subjects 65–74 years of age living in eastern Finland in relation to the risk of developing diabetes 3.5 years later. The prevalence of microalbuminuria (urinary albumin-to-urinary creatinine ratio ≥ 2 mg/mmol) was 1.3-, 1.8-, and 2.0-fold higher among subjects with impaired glucose tolerance (n = 242), newly diagnosed NIDDM subjects (n = 92), and previously diagnosed NIDDM subjects (n = 136), respectively, compared with subjects with normal glucose tolerance (n = 826). Nondiabetic subjects with microalbuminuria had multiple abnormalities in cardiovascular risk factors including elevated BP, high triglyceride concentration, high insulin concentration, and a low high-density lipoprotein cholesterol concentration, a cluster of risk factors typical for prediabetic individuals. The relationship between microalbuminuria and the incidence of NIDDM over the 3.5-year follow-up was studied in 891 subjects who were free of diabetes at baseline. Converters to diabetes (n = 69) had a higher prevalence of hypertension (68.1 vs. 54.4%, P < 0.05) and a higher prevalence of microalbuminuria (43.5 vs. 30.4%, P < 0.05) than nonconverters (n = 822). In logistic regression analysis, microalbuminuria predicted the development of NIDDM independently of BP level. However, after adjustment for plasma glucose and insulin levels at baseline, the difference in the prevalence of microalbuminuria between converters and nonconverters was not statistically significant. These results suggest that microalbuminuria may be a feature of the prediabetic state and that the increase in albumin excretion rate may be related to increases in glucose and insulin concentrations.

Several studies have shown that hyperinsulinemia and insulin resistance are associated with high triglyceride and low high-density lipoprotein (HDL) cholesterol levels. However, previous studies have been cross-sectional, and thus the presence of hyperinsulinemia or insulin resistance could be a consequence of the underlying lipid disorder instead of its cause. Therefore, we examined the relation of fasting insulin level measured in a cross-sectional study in nondiabetic subjects 65 to 74 years old (n = 881) to the risk of developing lipid disorders 3.5 years later. The incidence of the following lipid abnormalities was calculated: hypertriglyceridemia (n = 49/732, incident cases/subjects free of the particular disorder at baseline), high low-density lipoprotein (LDL) cholesterol level (n = 43/696), low HDL cholesterol level (n = 33/708), high apolipoprotein (apo) B level (n = 72/699), low apoAI level (n = 47/711), low serum LDL cholesterol/serum apoB ratio (n = 55/685), and low serum HDL cholesterol/serum apoAI ratio (n = 48/707). Baseline insulin level was not significantly associated with the development of high LDL cholesterol or low HDL cholesterol levels. Baseline insulin was associated with the development of hypertriglyceridemia (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.12 to 2.40; P = .011), high apoB (OR, 1.54; 95% CI, 1.13 to 2.10; P = .006), low apoAI (OR, 1.72; 95% CI, 1.22 to 2.42; P = .002), low LDL cholesterol/apoB ratio (OR, 1.99; 95% CI, 1.36 to 2.90; P < .001), and low HDL cholesterol/apoAI ratio (OR, 1.93; 95% CI, 1.34 to 2.79; P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Although many studies have suggested that increased androgenicity is associated with insulin resistance and hyperinsulinemia in both pre- and postmenopausal women, relatively few data are available on this relationship in men. We examined the association of body mass index (BMI), waist-to-hip ratio (WHR), sex hormone–binding globulin (SHBG), total and free testosterone, dehydroepiandrosterone sulfate (DHEA-SO4), and estradiol with insulin concentrations and whole-body glucose disposal in 87 men from a population-based study in Kuopio, Finland. BMI was significantly correlated with fasting insulin (r = 0.46), total whole-body glucose disposal (r = −0.30), glucose oxidation (r = −0.21), and nonoxidative glucose disposal (r = −0.25). WHR also was significantly associated with fasting insulin (r = 0.61), total whole-body glucose disposal (r = −0.54), glucose oxidation (r = −0.23), and nonoxidative whole-body glucose disposal (r = −0.50). SHBG and total and free testosterone were significantly associated with insulin concentrations and total and nonoxidative glucose disposal but not with glucose oxidation. DHEA-SO4 and estradiol were not associated with insulin, glucose concentrations, or whole-body glucose disposal in univariate analysis. In multivariate analysis, total whole-body glucose disposal was associated negatively with WHR and positively associated with total testosterone and SHBG; nonoxidative whole-body glucose disposal was associated negatively with WHR and positively associated with total and free testosterone. Glucose oxidation was significantly associated only with WHR. In conclusion, higher WHR and lower testosterone were strongly associated with a decrease in total and nonoxidative whole-body glucose disposal in men.

Objective: To evaluate the relationship between objectively measured memory functions and subjective complaints of memory disturbance and whether subjective complaints are affected by some personality traits or affective states. Design: Cross-sectional two-group comparison. Setting: The city of Kuopio in Eastern Finland, considered representative of the urban elderly population of Finland. Participants: Originally 403 subjects aged 67–78 years from the random sample and then two matched study groups initially including eighteen subjects but only ten in the final analysis. Measurements: Screening and follow-up examinations of subjects with and without subjective memory complaints: (1) Memory functions: Benton's visual retention test and the paired-associated learning subtest of Wechsler Memory Scale. (2) Memory complaints: Memory Complaint Questionnaire. (3) Personality traits and affective state: Two subscales from Minnesota Multiphasic Personality Inventory and Geriatric Depression Scale. Results: Complaints of memory loss did not correlate with the actual memory performance in the tests. However, those subjects who most emphatically complained of memory disturbance had greater tendencies toward somatic complaining, higher feelings of anxiety about their physical health, and more negative feelings of their own competence and capabilities than those who did not complain of memory deterioration associated with aging. Conclusions: The study suggests that subjective feelings of memory impairment are more closely associated with personality traits than with actual memory performance in normal elderly people. J Am Geriatr Soc 42:1–4, 1994

Subjects with insulin-dependent diabetes mellitus (IDDM) have an increased incidence of coronary heart disease. Several studies have suggested that Lp(a) levels may be increased in IDDM subjects, although these studies have been limited by the lack of information on apo(a) phenotype and urinary albumin excretion. We compared Lp(a) concentrations in 66 children with IDDM and 18 non-diabetic children; all were non-Hispanic whites and none had detectable albuminuria. Lp(a) concentrations (mg/dl) were lower in subjects with IDDM than in non-diabetic subjects (12.0 ± 2.2 vs. 20.0 ± 6.1, respectively), although these means were not significantly different (P = 0.276). Postpubertal subjects, particularly males, had increased Lp(a) concentrations relative to prepubertal subjects (P = 0.041). Higher apo(a) molecular weight was associated with decreased Lp(a) concentrations in both diabetic and non-diabetic subjects. However, apo(a) size was not different in diabetic and non-diabetic subjects. Lp(a) concentrations were not significantly correlated with glycosylated hemoglobin levels in diabetic subjects (r = 0.11, P = NS). We also found similar Lp(a) concentrations in postpubertal IDDM subjects compared with adult non-Hispanic white non-diabetic subjects (n = 208) from the San Antonio Heart Study, a population-based study. These observations do not support increased Lp(a) concentrations in young normoalbuminuric IDDM subjects.

We investigated the significance of the variants of the IRS-2 gene in patients with type 2 diabetes. The entire coding part of the IRS-2 gene was screened by single-strand conformation polymorphism analysis in 40 Chinese and 40 Finnish patients with late-onset type 2 diabetes. The association of the variants of the IRS-2 gene with type 2 diabetes was studied in 85 Finnish diabetic patients and 82 Finnish control subjects and in 100 Chinese diabetic patients and 85 Chinese control subjects. The four variants predicting structural changes in the insulin receptor substrate (IRS)-2 protein included an insertion of AAC (Asn) in the Asn repeat sequence centered around codons 29–36 (allele frequencies of 0 vs. 0.6% and 1.5 vs. 0%), the Ala157Thr substitution (0 vs. 0% and 0.5 vs. 0%), the Leu647Val substitution (0.6 vs. 0% and 0 vs. 0%), and the Gly1057Asp polymorphism (31 vs. 31% and 35 vs. 30%) (P = NS for all comparisons). Furthermore, six silent variants were observed (CGC147CGG, CCC155CCG, GCC156GCT, AGT723AGC, TGT816TGC, and CCC829CCT). The Gly1057Asp polymorphism was not associated with insulin resistance or impaired insulin secretion in Finnish subjects with normal glucose tolerance (n = 295) or impaired glucose tolerance (n = 38). These data indicate that structural variants of the IRS-2 gene were uncommon in Finnish and Chinese patients with type 2 diabetes. Thus, the variants in the coding part of the IRS-2 gene are unlikely to have a major role in the development of type 2 diabetes in Finnish or Chinese subjects.

Inter- and intraobserver variation and diagnostic accuracy in estimation of heart size and pulmonary vasculature were evaluated for conventional film-screen technique and image intensifier photofluorography. Interpretation of 218 p.a. and lateral chest films by both imaging techniques was performed independently by 4 readers. Heart size relative to body surface area measured from the plain chest films was used as the reference in cardiac size determination. Overall diagnostic accuracies of conventional radiography and image intensifier photofluorography for cardiomegaly were close to each other, 0.70 vs 0.68, respectively. Specificity of film-screen radiography was better than that of photofluorography (0.92 vs 0.84, p

The goal of this study was to investigate the prevalence of impaired glucose tolerance (IGT) and non-insulin-dependent diabetes mellitus (NIDDM) in elderly subjects and their association with obesity, central obesity, and a family history of diabetes. A representative population sample of 1300 subjects (471 men, 829 women) aged 65-74 yr participated in the study. The participation rate was 71%. The prevalence rates of previously and newly diagnosed NIDDM and IGT, based on a history of diabetes and an oral glucose tolerance test, were 8.7, 7.0, and 17.8% in men and 11.7, 7.1, and 19.1% in women. Thus, 33.8% of men and 37.9% of women had abnormal glucose tolerance according to World Health Organization criteria. Obesity (body mass index greater than or equal to 27 kg/m2 in men and greater than or equal to 25 kg/m2 in women) and central obesity (waist-hip ratio greater than or equal to 0.98 in men and greater than or equal to 0.89 in women) doubled the prevalence of IGT or NIDDM. The combination of obesity and a family history of diabetes was associated with a more marked increase in the prevalence of IGT or NIDDM in men than in women. Simultaneous presence of obesity, central obesity, and a family history of diabetes was associated with a threefold increase in the prevalence of IGT or NIDDM (65.4 vs. 24.1% in men, 52.8 vs. 19.6% in women, P less than 0.001). The major risk factors for NIDDM, e.g., obesity, central fat distribution, and a family history of diabetes, explained 10% of the variance in 2-h glucose values in multiple regression analysis. In conclusion, the prevalence of IGT and NIDDM was high in elderly subjects. Although obesity, central fat distribution, and a family history of diabetes were significantly associated with the increased prevalence of IGT or NIDDM, they explained only a minor proportion of the variance in 2-h glucose values.

We tested the hypothesis that insulin resistance, rather than high insulin level, is associated with lipid and lipoprotein changes favoring atherosclerosis independently of the glucose tolerance status. To this aim, 50 subjects with normal glucose tolerance, 28 subjects with impaired glucose tolerance, and 54 subjects with noninsulin-dependent diabetes (NIDDM) were studied. Subjects with low glucose disposal rate (GDR) or a high degree of insulin resistance as measured by the euglycemic hyperinsulinemic clamp technique had lower high density lipoprotein (HDL) cholesterol and higher total and very low density lipoprotein (VLDL) triglycerides than did subjects with high GDR (highest GDR tertile). These associations were independent of fasting insulin level and other confounding factors. In stepwise multiple linear regression analysis, GDR was the most important single variable associated with HDL cholesterol and VLDL triglyceride level independently of age, obesity, distribution of obesity (waist/hip ratio), 2-hour glucose level, and free fatty acid concentration. We conclude: 1) insulin resistance measured by the euglycemic clamp technique is associated with adverse lipid and lipoprotein changes favoring atherosclerosis not only in nondiabetic subjects (as shown in previous studies) but also in impaired glucose tolerance and NIDDM subjects; 2) the association of high insulin level with adverse lipid and lipoprotein changes indirectly reflects the association of insulin resistance with lipid and lipoprotein levels; and 3) HDL cholesterol and VLDL triglycerides are independently associated with insulin-mediated glucose uptake, which may indicate that these lipoproteins have separate sites of interaction with insulin action.

Leptin, the product of the human ob gene, is increased in obese individuals, suggesting resistance to its effect. However, there is a variability in leptin levels at each level of body mass index, suggesting that genetic and environmental factors other than overall adiposity may regulate leptin concentrations. No data currently exist on the relation of sex hormones to leptin concentrations in men. We examined the relation of leptin levels to sex hormone-binding globulin, total and free testosterone, dehydroepiandrosterone sulfate, estradiol, and cortisol in 87 normoglycemic men. Leptin levels were significantly correlated with free testosterone (r = −0.14; P < 0.05), sex hormone-binding globulin (r = −0.26; P < 0.05), total testosterone (r = −0.32; P < 0.01), and cortisol(r = −0.09; P = NS). However, after adjustment for body mass index (or, alternatively, waist or hip circumference), leptin concentrations were not significantly related to sex hormones or cortisol. Our data suggest that in men, sex hormon...

Volume loading is considered the golden standard of the confirmatory tests in the diagnostics of primary aldosteronism (PA). However, it is time-consuming, and it is unclear to what extent it improves the diagnostics of PA in comparison to simple screening tests. To study this question, the diagnostics with and without oral sodium loading (OSL) were evaluated by receiver operating characteristic curves analyses in 77 consecutive OSL patients. The final diagnosis was essential hypertension in 39 cases and PA in 38 cases, determined by review of the patient records, biochemical tests, imaging findings, and the response to therapy with spironolactone and/or operation. Plasma aldosterone-to-renin-activity ratio (ARR) and daily urinary aldosterone had a good diagnostic ability that did not significantly improve by accomplishing OSL. Cut-off values with optimal sensitivity and specificity were >or=1050 pmol/l per ng/ml/h for upright ARR, and >or=45 nmol/day for daily urinary aldosterone. To conclude, carefully conducted outpatient tests are sufficient for the diagnostics of PA, when the diagnosis is justified by the positive response to treatment. However, volume loading serves as an additional diagnostic tool in the most problematic cases, improving slightly the discriminative ability of urinary aldosterone determination.

Objective: The melanocortin-4 receptor (MC4R) regulates energy intake. On the basis of animal studies, it may also regulate energy expenditure. Research Methods and Procedures: The effect of the Val103Ile polymorphism of the MC4R gene on energy metabolism was studied in 229 middle-aged nondiabetic subjects (Group 1, age 51.2 ± 9.8 years, BMI 26.8 ± 4.5 kg/m2) and on weight gain in 1013 elderly subjects (Group 2, age 69.9 ± 2.9 years, BMI 27.4 ± 4.1 kg/m2) during a 3.5-year follow-up study. In Group 1, insulin sensitivity, energy expenditure, and substrate oxidation were measured with the hyperinsulinemic euglycemic clamp combined with indirect calorimetry. Results: In Group 1, the Val103Ile genotype was associated with high rates of energy expenditure (63.42 ± 13.40 in eight subjects with the Val103Ile genotype vs. 59.86 ± 7.33 J/kg per minute in 221 subjects with the Val103Val genotype, p = 0.007), high rates of glucose oxidation (8.90 ± 6.15 vs. 6.07 ± 4.38 μmol/kg per minute, p = 0.020), and low levels of free fatty acids (0.45 ± 0.18 vs. 0.56 ± 0.23 mM, p = 0.029) in the fasting state, and with high rates of glucose oxidation during the clamp (18.88 ± 4.63 vs. 17.60 ± 3.24 μmol/kg per minute, p = 0.031). In Group 2, the 103Ile allele was associated with an increase in weight gain during the follow-up (0.78 ± 3.98 vs. −0.82 ± 3.98 kg, p = 0.038). Discussion: The Val103Ile polymorphism of the MC4R gene is associated with energy expenditure in humans. Furthermore, it may associate with glucose oxidation, free fatty acid levels, and weight gain.

To determine the meaning of S(i) = 0 derived from the frequently sampled intravenous glucose tolerance test.The issue of assessing insulin resistance in large studies is important because the most definitive method ("gold standard"), the hyperinsulinemic-euglycemic clamp, is expensive and invasive. The frequently sampled intravenous glucose tolerance test (FSIGTT) has been widely used, but in insulin-resistant subjects (especially diabetic subjects), it yields considerable numbers of subjects whose S(i) is zero. The interpretation of an S(i) equaling zero is unknown.-To address this issue, we examined 1482 subjects from the Insulin Resistance Atherosclerosis Study (IRAS) using an insulin-modified FSIGTT and minimal model calculation of S(i). The proportion of insulin-resistant subjects (S(i)1.61 x 10(-4) [min(-1). microU(-1) x ml(-1)] based on the median of the nondiabetic population) was 38.6% in subjects with normal glucose tolerance (NGT), 74% in subjects with impaired glucose tolerance (IGT), and 92% in subjects with type 2 diabetes. The proportion of subjects with S(i) = 0 was 2.2% in subjects with NGT, 13.2% in subjects with IGT, and 35.7% in subjects with type 2 diabetes. In subjects with IGT, those with S(i) = 0 had significantly lower HDL cholesterol levels and higher BMI, waist circumference, fibrinogen, plasminogen-activator inhibitor 1 (PAI-1), C-reactive protein (CRP), and 2-h insulin levels than insulin-resistant subjects with S(i)0. In type 2 diabetes, subjects with S(i) = 0 had significantly greater BMI and waist circumference and higher triglyceride, PAI-1, CRP, fibrinogen, and fasting and 2-h insulin levels than insulin-resistant subjects with S(i)0. In addition, diabetic subjects with S(i) = 0 had more metabolic disorders related to the insulin resistance syndrome than diabetic insulin-resistant subjects with S(i)0.We found very few subjects with S(i) = 0 among subjects with NGT and few subjects with S(i) = 0 among subjects with IGT. In contrast, S(i) = 0 was common in subjects with diabetes. Subjects with S(i) = 0 tended to have more features of the insulin resistance syndrome than other insulin-resistant subjects with S(i)0, as would be expected of subjects with almost no insulin-mediated glucose disposal, thus suggesting that subjects with S(i) = 0 are correctly classified as being very insulin resistant rather than having failed the minimal model program.

OBJECTIVE—To investigate whether cardiovascular risk factors cluster with hyperinsulinemia in elderly type 2 diabetic subjects and, if so, whether this clustering predicts coronary heart disease (CHD) events during a 7-year follow-up. RESEARCH DESIGN AND METHODS—Clustering of cardiovascular risk factors was analyzed by factor analysis. Cox regression models were used to investigate whether these clusters (factors) predict CHD events (CHD death or nonfatal myocardial infarction) during a 7-year follow-up in 229 type 2 diabetic subjects aged 65–74 years. RESULTS—There were 70 CHD events (21 in men and 49 in women) during the follow-up period. In diabetic men, components of the insulin resistance syndrome (IRS) loaded on Factor 1 (the insulin resistance factor), which reflected high fasting insulin, obesity (high BMI), central obesity (high waist-to-hip ratio), high total triglycerides, and a short duration of diabetes. Only this IRS factor predicted CHD events in multivariate Cox regression analysis (hazard ratio [HR] 1.71, 95% CI 1.08–2.71, P = 0.022). In diabetic women, components of IRS loaded on two factors, none of which predicted CHD events. In women, only Factor 4, characterized by advanced age, left ventricular hypertrophy on electrocardiogram, high alcohol consumption, high systolic blood pressure, and albuminuria, predicted CHD events in multivariate Cox regression analysis (1.34, 1.03–1.74, P = 0.03). CONCLUSIONS—IRS is a risk factor for CHD in elderly type 2 diabetic men.

To investigate whether the APOE-epsilon4 allele is associated with weight loss in patients with AD or in nondemented elderly subjects.Weight loss has been considered a typical feature of AD. APOE-epsilon4 is a risk factor for AD and was recently proposed to be associated with weight loss in elderly women. It is not known whether APOE-epsilon4 is associated with weight loss in patients with AD or in the general population.Weight and BMI measurements at an average interval of 3.5 years and APOE phenotype determination were performed in an elderly population (n = 980), including 46 patients with AD and 911 control subjects at the end of the follow-up.On average, patients with AD with the epsilon4 allele lost 1.9 +/- 4.0 kg (BMI 0.8 +/- 1.8 kg/m2) whereas epsilon4 noncarriers gained 1.2 +/- 3.8 kg (BMI 0.4 +/- 1.5 kg/m2) (both p0.05), after controlling for diabetes and exercise. However, when men and women were analyzed separately, weight loss was observed only in those women with AD with the epsilon4 allele. Clinically significant weight loss, defined as loss ofor = 5% of body weight, occurred more frequently in both patients with AD (30% versus 6%; p0.05) and control subjects (28% versus 18%; p0.001) carrying the epsilon4 allele.The APOE-epsilon4 allele may contribute to the unexplained weight loss in AD, especially in women.

A prolonged QT interval has been identified as a risk factor for cardiovascular disease; however, knowledge about etiologic factors is limited. We studied determinants of QT interval duration in the Insulin Resistance Atherosclerosis Study, a large, triethnic population (n = 1,577) with varying degrees of glucose tolerance. In particular, we sought to investigate the relation of QT interval with blood pressure (BP), left ventricular (LV) mass, estimated using electrocardiographic criteria, and insulin sensitivity, directly measured by a frequently sampled intravenous glucose tolerance test. QT interval was measured electronically on electrocardiograms at rest and corrected for heart rate using standard equations. The QT interval was related to various components of the insulin resistance syndrome, including BP and insulin sensitivity. Multivariate analyses showed that BP and LV mass were the main determinants of the QT interval in diabetic and nondiabetic subjects. Additionally, prevalent coronary artery disease was related to the QT interval in subjects with newly diagnosed diabetes. In conclusion, we found that BP and LV mass were the strongest and most consistent determinants of the QT interval in nondiabetic and diabetic subjects. Additional factors potentially contributing to QT interval prolongation in diabetic patients include insulin sensitivity and prevalent coronary artery disease.