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1.
Diabetes Care ; 24(9): 1629-33, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11522711

ABSTRACT

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.


Subject(s)
Coronary Disease/epidemiology , Diabetes Mellitus, Type 2/physiopathology , Insulin Resistance/physiology , Aged , Alcohol Drinking , Blood Glucose/metabolism , Blood Pressure , Body Mass Index , Chest Pain/epidemiology , Cholesterol/blood , Cholesterol, HDL/blood , Cohort Studies , Coronary Disease/physiopathology , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Diabetic Angiopathies/epidemiology , Diabetic Angiopathies/physiopathology , Electrocardiography , Female , Follow-Up Studies , Humans , Hypertension/epidemiology , Insulin/blood , Longitudinal Studies , Male , Proportional Hazards Models , Regression Analysis , Risk Factors , Sex Characteristics , Smoking , Surveys and Questionnaires , Time Factors
2.
Diabetes ; 50(8): 1949-51, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11473060

ABSTRACT

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.


Subject(s)
Diabetes Mellitus, Type 2/genetics , Genetic Variation , Phosphoproteins/genetics , Age of Onset , Amino Acid Substitution , Asian People , Base Sequence , Blood Glucose/metabolism , China/ethnology , Exons , Finland , Glucose Intolerance/genetics , Glucose Tolerance Test , Humans , Insulin Receptor Substrate Proteins , Insulin Resistance , Intracellular Signaling Peptides and Proteins , Phosphoproteins/chemistry , Point Mutation , Polymorphism, Genetic , Receptor, Insulin/physiology , Reference Values , White People
3.
Neurology ; 56(5): 655-9, 2001 Mar 13.
Article in English | MEDLINE | ID: mdl-11245719

ABSTRACT

OBJECTIVE: To investigate whether the APOE-epsilon4 allele is associated with weight loss in patients with AD or in nondemented elderly subjects. BACKGROUND: 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. METHODS: 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. RESULTS: 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 p < 0.05), 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 of > or = 5% of body weight, occurred more frequently in both patients with AD (30% versus 6%; p < 0.05) and control subjects (28% versus 18%; p < 0.001) carrying the epsilon4 allele. CONCLUSIONS: The APOE-epsilon4 allele may contribute to the unexplained weight loss in AD, especially in women.


Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/physiopathology , Apolipoproteins E/genetics , Weight Loss/genetics , Weight Loss/physiology , Aged , Apolipoprotein E4 , Body Weight/genetics , Body Weight/physiology , Female , Humans , Male , Population Surveillance , Random Allocation
4.
Am J Cardiol ; 86(10): 1117-22, 2000 Nov 15.
Article in English | MEDLINE | ID: mdl-11074210

ABSTRACT

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.


Subject(s)
Blood Pressure , Coronary Disease/complications , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/metabolism , Hypertrophy, Left Ventricular/complications , Hypertrophy, Left Ventricular/pathology , Insulin Resistance , Long QT Syndrome/complications , Analysis of Variance , Case-Control Studies , Coronary Disease/physiopathology , Diabetes Mellitus, Type 2/diagnosis , Electrocardiography , Female , Glucose Tolerance Test , Heart Rate , Humans , Hypertrophy, Left Ventricular/physiopathology , Linear Models , Long QT Syndrome/diagnosis , Long QT Syndrome/physiopathology , Male , Middle Aged , Multivariate Analysis , Predictive Value of Tests , Prevalence , Risk Factors
5.
Neuroepidemiology ; 19(6): 327-32, 2000.
Article in English | MEDLINE | ID: mdl-11060507

ABSTRACT

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.


Subject(s)
Alzheimer Disease/genetics , Apolipoproteins E/genetics , Population Surveillance , Aged , Alzheimer Disease/mortality , Catchment Area, Health , Cognition Disorders/diagnosis , Cohort Studies , Female , Finland/epidemiology , Follow-Up Studies , Humans , Male , Neuropsychological Tests , Survival Rate
6.
Diabetes Care ; 23(10): 1533-8, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11023148

ABSTRACT

OBJECTIVE: To determine the role of the hepatocyte nuclear factor (HNF)-1alpha and HNF-4alpha genes in the etiology of late-onset type 2 diabetes in Finnish and Chinese subjects. RESEARCH DESIGN AND METHODS: The whole coding regions of the genes encoding for HNF-1alpha and HNF-4alpha, including approximately 800 bp of the HNF-1alpha promoter, were investigated in 40 Finnish subjects (fasting C-peptide 50-570 pmol/l) and 47 Chinese subjects with type 2 diabetes by single-strand conformation polymorphism (SSCP) analysis. Frequencies of the variants of these genes were analyzed by restriction fragment-length polymorphism analysis in additional samples of 100 Finnish diabetic patients and 82 Finnish control subjects and in 58 Chinese diabetic patients and 51 Chinese control subjects. RESULTS: No previously reported gene defects were detected, but one novel functionally silent GCC-->GCG variant (nucleotide 73, exon 10) was observed in the HNF-4alpha gene in a Chinese diabetic patient. Interestingly, the Ala98Val substitution of the HNF-1alpha gene occurred at a significantly higher frequency in 140 Finnish diabetic patients compared with 82 control subjects (P = 0.014). The Ala98Val variant was not, however, associated with abnormalities in insulin secretion evaluated by oral and intravenous glucose tolerance tests in subjects with normal (n = 295) or impaired (n = 38) glucose tolerance. CONCLUSIONS: Variants in the HNF-1alpha and HNF-4alpha genes are unlikely to play a major role in the pathogenesis of late-onset type 2 diabetes in Finnish and Chinese subjects. However, the association of the Ala98Val variant of the HNF-1alpha gene with type 2 diabetes in Finnish subjects may indicate a diabetogenic locus close to the HNF-1alpha gene.


Subject(s)
Asian People/genetics , Diabetes Mellitus, Type 2/genetics , Genetic Variation , Nuclear Proteins , Phosphoproteins/genetics , Transcription Factors/genetics , White People/genetics , Adult , Age of Onset , Aged , Alanine , Amino Acid Substitution , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , C-Peptide/blood , China , DNA-Binding Proteins/genetics , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/physiopathology , Exons , Female , Finland , Glucose Tolerance Test , Hepatocyte Nuclear Factor 1 , Hepatocyte Nuclear Factor 1-alpha , Hepatocyte Nuclear Factor 1-beta , Hepatocyte Nuclear Factor 4 , Humans , Male , Middle Aged , Polymerase Chain Reaction , Valine
7.
Kidney Int ; 58(4): 1703-10, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11012904

ABSTRACT

BACKGROUND: Microalbuminuria 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. METHODS: We 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. RESULTS: Both 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). CONCLUSION: We 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.


Subject(s)
Albuminuria/diagnosis , Arteriosclerosis/diagnosis , Diabetes Mellitus, Type 2/diagnosis , Insulin Resistance/immunology , Kidney Failure, Chronic/diagnosis , Albuminuria/immunology , Arteriosclerosis/immunology , Arteriosclerosis/urine , Biomarkers , Blood Pressure , Body Mass Index , C-Reactive Protein/metabolism , Creatinine/urine , Diabetes Mellitus, Type 2/immunology , Diabetes Mellitus, Type 2/urine , Female , Fibrinogen/metabolism , Glucose Tolerance Test , Humans , Hypertension, Renal/diagnosis , Hypertension, Renal/immunology , Hypertension, Renal/urine , Kidney Failure, Chronic/immunology , Male , Middle Aged , Nephritis/diagnosis , Nephritis/immunology , Nephritis/urine
8.
Atherosclerosis ; 151(2): 567-74, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10924736

ABSTRACT

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.


Subject(s)
Hyperlipidemia, Familial Combined/genetics , Hyperlipidemia, Familial Combined/physiopathology , Hyperlipidemias/genetics , Hyperlipidemias/physiopathology , Insulin/physiology , Receptors, Cytoplasmic and Nuclear/genetics , Transcription Factors/genetics , Adult , Aged , Alleles , Amino Acid Substitution , Body Mass Index , Fasting/blood , Female , Gene Frequency , Genotype , Humans , Hyperlipidemia, Familial Combined/blood , Hyperlipidemia, Familial Combined/pathology , Hyperlipidemias/blood , Hyperlipidemias/pathology , Insulin/blood , Male , Middle Aged , Phenotype , Triglycerides/blood
9.
Circulation ; 102(1): 42-7, 2000 Jul 04.
Article in English | MEDLINE | ID: mdl-10880413

ABSTRACT

BACKGROUND: Inflammation has been suggested as a risk factor for the development of atherosclerosis. Recently, some components of the insulin resistance syndrome (IRS) have been related to inflammatory markers. We hypothesized that insulin insensitivity, as directly measured, may be associated with inflammation in nondiabetic subjects. METHODS AND RESULTS: We studied the relation of C-reactive protein (CRP), fibrinogen, and white cell count to components of IRS in the nondiabetic population of the Insulin Resistance Atherosclerosis Study (IRAS) (n=1008; age, 40 to 69 years; 33% with impaired glucose tolerance), a multicenter, population-based study. None of the subjects had clinical coronary artery disease. Insulin sensitivity (S(I)) was measured by a frequently sampled intravenous glucose tolerance test, and CRP was measured by a highly sensitive competitive immunoassay. All 3 inflammatory markers were correlated with several components of the IRS. Strong associations were found between CRP and measures of body fat (body mass index, waist circumference), S(I), and fasting insulin and proinsulin (all correlation coefficients >0.3, P<0.0001). The associations were consistent among the 3 ethnic groups of the IRAS. There was a linear increase in CRP levels with an increase in the number of metabolic disorders. Body mass index, systolic blood pressure, and S(I) were related to CRP levels in a multivariate linear regression model. CONCLUSIONS: We suggest that chronic subclinical inflammation is part of IRS. CRP, a predictor of cardiovascular events in previous reports, was independently related to S(I). These findings suggest potential benefits of anti-inflammatory or insulin-sensitizing treatment strategies in healthy individuals with features of IRS.


Subject(s)
Arteriosclerosis/immunology , Insulin Resistance/immunology , Adult , Aged , Arteriosclerosis/ethnology , Biomarkers , C-Reactive Protein/analysis , Female , Fibrinogen/analysis , Humans , Leukocyte Count , Linear Models , Male , Middle Aged , Risk Factors , Triglycerides/blood
10.
Eur J Endocrinol ; 143(2): 251-60, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10913945

ABSTRACT

OBJECTIVE: The purpose of this work was to study whether there are differences in plasma proinsulin levels and proinsulin-to-specific insulin ratio in the offspring of patients with different phenotypes of type II diabetes. DESIGN: Eleven glucose-tolerant offspring of type II diabetic patients with deficient insulin secretion phenotype (IS group), nine glucose-tolerant offspring of patients with insulin-resistant phenotype (IR group), and fourteen healthy control subjects without a family history of diabetes were studied. METHODS: Plasma specific insulin, plasma proinsulin, and plasma C-peptide levels were measured during a 2-h oral glucose tolerance test and during hyperglycemic clamp. RESULTS: Plasma proinsulin levels during the oral glucose tolerance test and the hyperglycemic clamp did not differ among the study groups. The IR group had a lower fasting plasma proinsulin-to-specific insulin ratio (10.3+/-1.7%) than the control group (15.4+/-1.4%; P<0.05) and the IS group (18.6+/-2.7%; P<0.05). Furthermore, the IR group had lower plasma proinsulin-to-specific insulin ratio at 30, 60 and 90 min after the oral glucose load than the IS group. However, there were no significant differences in proinsulin-to-C-peptide ratio during the oral glucose tolerance test among the study groups. In stepwise multiple regression analysis, hepatic specific insulin extraction in the fasting state (beta =0.65; P<0.001) and fasting blood glucose (beta =0.32; P<0.05) together explained 52% of the variation in fasting plasma proinsulin-to-specific insulin ratio. CONCLUSIONS: Hyperproinsulinemia is not a characteristic finding in glucose-tolerant offspring of type II diabetic probands with deficient insulin secretion or insulin-resistant phenotype. The differences in proinsulin-to-specific insulin ratios were most likely explained by different hepatic extraction among the study groups.


Subject(s)
Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/genetics , Phenotype , Proinsulin/blood , Adult , Blood Glucose/analysis , C-Peptide/blood , Fasting , Glucose Clamp Technique , Glucose Tolerance Test , Humans , Insulin/blood , Insulin/metabolism , Insulin Secretion , Kinetics , Linear Models , Middle Aged , Regression Analysis
11.
Diabetes Care ; 23(5): 624-8, 2000 May.
Article in English | MEDLINE | ID: mdl-10834420

ABSTRACT

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 <0.0001, adjusted for age, sex, ethnicity, glucose tolerance status, and smoking). In a multiple linear regression analysis (adjusting for age, sex, ethnicity, clinical center, glucose tolerance status, and smoking), heart rate was significantly and independently associated with AIR, proinsulin, and S(I). CONCLUSIONS: Proinsulin, acute insulin secretion, and S(I) are associated with heart rate in nondiabetic subjects.


Subject(s)
Heart Rate , Hyperinsulinism/physiopathology , Insulin Resistance , Body Constitution , Body Mass Index , Ethnicity , Female , Glucose Tolerance Test , Humans , Hypertension/physiopathology , Linear Models , Male , Middle Aged
12.
Diabetes Care ; 23(1): 70-3, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10857971

ABSTRACT

OBJECTIVE: To investigate the possible association of the variants in the nucleotide binding fold regions of the sulfonylurea receptor 1 (SUR1) gene with gestational diabetes mellitus (GDM), type 2 diabetes, and altered insulin secretion in Finnish subjects. RESEARCH DESIGN AND METHODS: The nucleotide binding fold regions of the SUR1 gene were amplified with polymerase chain reaction and screened by the single-strand conformational polymorphism analysis in 42 subjects with GDM and 40 subjects with type 2 diabetes. Detected variants were further investigated in 377 normoglycemic subjects by restriction fragment-length polymorphism analysis. The effect of the variants of the SUR1 gene on first-phase insulin secretion was studied in 295 normoglycemic subjects. RESULTS: In subjects with GDM or type 2 diabetes, one amino acid change (S1369A), four silent substitutions (R1273R, L829L, T759T, and K649K), and three intron variants were identified in the nucleotide binding fold regions of the SUR1 gene. A tagGCC allele of exon 16 splice acceptor site was more frequent in subjects with GDM (0.55 allele frequency, n = 42) and type 2 diabetes (0.60, n = 40) than in normoglycemic subjects (0.43, n = 377) (P1 = 0.024 and P2 = 0.009, respectively). Similarly, an AGG allele of the R1273R polymorphism was more common in subjects with GDM (0.87) and type 2 diabetes (0.87) than in normoglycemic subjects (0.74) (P1 = 0.009 and P2 = 0.001, respectively). However, the S1369A, R1273R, and cagGCC-->tagGCC variants of the SUR1 gene were not associated with altered first-phase insulin secretion in 295 normoglycemic subjects. CONCLUSIONS: These results suggest that a functional variant that contributes to the risk of GDM and type 2 diabetes may locate close to the SUR1 gene.


Subject(s)
ATP-Binding Cassette Transporters , Diabetes Mellitus, Type 2/genetics , Diabetes, Gestational/genetics , Genetic Variation , Insulin/metabolism , Polymorphism, Single-Stranded Conformational , Potassium Channels, Inwardly Rectifying , Potassium Channels/genetics , Receptors, Drug/genetics , Adult , Aged , Amino Acid Substitution , Exons , Family , Female , Glucose Tolerance Test , Humans , Insulin/blood , Insulin Secretion , Introns , Male , Point Mutation , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , Pregnancy , Sulfonylurea Receptors
13.
Am J Cardiol ; 85(12): 1395-400, 2000 Jun 15.
Article in English | MEDLINE | ID: mdl-10856382

ABSTRACT

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.


Subject(s)
Arteriosclerosis/complications , Carotid Artery Diseases/complications , Coronary Disease/complications , Diabetes Mellitus, Type 2/complications , Adult , Aged , Arteriosclerosis/pathology , Carotid Artery Diseases/pathology , Carotid Artery, Common/anatomy & histology , Carotid Artery, Common/diagnostic imaging , Carotid Artery, Common/pathology , Carotid Artery, Internal/anatomy & histology , Carotid Artery, Internal/diagnostic imaging , Carotid Artery, Internal/pathology , Female , Humans , Male , Middle Aged , Tunica Intima/anatomy & histology , Tunica Intima/pathology , Tunica Media/anatomy & histology , Tunica Media/pathology , Ultrasonography
14.
Circulation ; 101(9): 975-80, 2000 Mar 07.
Article in English | MEDLINE | ID: mdl-10704163

ABSTRACT

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 (DeltaI(30-0)/DeltaG(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 DeltaI(30-0)/DeltaG(30-0)) (n=56) and converters who had a predominant decrease in insulin secretion (low HOMA IR and low DeltaI(30-0)/DeltaG(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.


Subject(s)
Arteriosclerosis/etiology , Diabetes Complications , Diabetes Mellitus/etiology , Insulin Resistance , Insulin/blood , Adult , Blood Glucose/metabolism , Blood Pressure , Cholesterol, HDL/blood , Coronary Disease/prevention & control , Diabetes Mellitus/physiopathology , Female , Glucose Tolerance Test , Humans , Infant, Newborn , Insulin/metabolism , Insulin Secretion , Male , Middle Aged , Risk Factors , Triglycerides/blood
15.
Int J Clin Pract Suppl ; (113): 40-5, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11965831

ABSTRACT

Patients with diabetes without a prior myocardial infarction are at a similar risk of coronary heart disease (CHD) events as non-diabetic subjects with a prior myocardial infarction. Furthermore, prognosis after the first myocardial infarction is worse in diabetic compared to non-diabetic patients. Therefore, management of cardiovascular risk factors in subjects with diabetes should be as vigorous as in patients with known CHD who have had a myocardial infarction. Randomised controlled trials have shown that efficacy of cholesterol lowering and antihypertensive therapy in type 2 diabetes is at least as effective as in non-diabetic subjects in preventing macrovascular disease. Antiplatelet therapy with aspirin reduces the risk of CHD events in high-risk patients and the benefit is similar in subjects with and without diabetes. Improved glycaemic control has a modest beneficial effect on CHD risk. There is residual excess risk of CHD in type 2 diabetes, which is not explained by traditional cardiovascular risk factors. Insulin resistance may partly mediate this. Prediabetic subjects who are insulin resistant have more adverse levels of triglycerides, high density lipoprotein (HDL)-cholesterol and blood pressure than those who are insulin sensitive. Moreover, factors associated with insulin resistance are significant predictors of CHD events in subjects with diabetes, in addition to conventional risk factors. The thiazolidinedione, pioglitazone, improves glycaemia and insulin sensitivity in hyperglycaemic patients. It also improves insulin and triglyceride levels and lowers blood pressure. Thiazolidinediones have been found to have vasculo-protective effects in both acute and chronic vascular injury in animal models. For prevention of CHD in type 2 diabetes a multi-factorial approach should be considered, including improved glycaemic control, aggressive management of dyslipidaemia and hypertension, anti-platelet therapy, reduction of insulin resistance and use of agents that improve insulin sensitivity.


Subject(s)
Coronary Disease/prevention & control , Diabetes Mellitus, Type 2/drug therapy , Diabetic Angiopathies/prevention & control , Humans , Hypoglycemic Agents/therapeutic use , Risk Factors , Thiazoles/therapeutic use
16.
Arterioscler Thromb Vasc Biol ; 19(11): 2742-8, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10559020

ABSTRACT

A predominance of small, dense, low density lipoprotein (LDL) particles has consistently been associated with coronary heart disease (CHD) in young and middle-aged subjects in cross-sectional studies. Recently, 3 prospective, case-control studies showed that decreased LDL size is a predictor of CHD in middle-aged subjects. However, it is not known whether decreased LDL size is mainly associated with premature CHD or whether it continues to play a role in CHD risk at older ages also. We performed a prospective, nested case-control study in 86 subjects (58 nondiabetic and 28 type 2 diabetic) aged 65 to 74 years who were free of myocardial infarction at baseline and who then had a myocardial infarction or CHD death during a 3.5-year follow-up (cases) and in 172 controls matched for sex and diabetes status but who remained free of CHD during follow-up. LDL particle size determined by gradient gel electrophoresis (268.2+/-0.9 versus 268.5+/-0.7 A, P=0.782) and the proportion of subjects with LDL subclass phenotype B (20.9 versus 21. 5, P=0.914) were similar among cases and controls. Furthermore, diastolic blood pressure, total cholesterol, high density lipoprotein cholesterol, triglycerides, apolipoprotein A(1), fasting glucose, fasting insulin, waist-to-hip ratio, and body mass index were not associated with CHD risk. However, smoking and increased systolic blood pressure, apolipoprotein B levels, and the total cholesterol-high density lipoprotein cholesterol ratio were significant predictors of CHD events both in univariate and multivariate analyses. Our findings indicate that LDL size is not a predictor of CHD events in elderly white subjects after controlling for diabetes status.


Subject(s)
Cholesterol, LDL/blood , Cholesterol, LDL/chemistry , Coronary Disease/metabolism , Aged , Case-Control Studies , Coronary Disease/epidemiology , Coronary Disease/genetics , Female , Humans , Logistic Models , Male , Molecular Weight , Phenotype , Prospective Studies , Risk Factors
17.
Diabetes Care ; 22(10): 1688-93, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10526736

ABSTRACT

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.


Subject(s)
Arteriosclerosis/epidemiology , Blood Glucose/metabolism , Cardiovascular Diseases/epidemiology , Insulin Resistance , Insulin/blood , Lipoproteins, LDL/blood , Proinsulin/blood , Body Mass Index , Cholesterol/blood , Cholesterol, HDL/blood , England , Ethnicity , Female , Glucose Tolerance Test , Humans , Lipoproteins, LDL/chemistry , Male , Multivariate Analysis , Regression Analysis , Risk Factors , Sex Characteristics , Triglycerides/blood , United States
18.
Arterioscler Thromb Vasc Biol ; 19(9): 2234-40, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10479667

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 (A) 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<0.001). Ethnic differences in LDL size continued to be statistically significant after adjustment for upper body adiposity, insulin resistance, and glucose tolerance status. However, after further adjustment for other cardiovascular risk factors, especially ethnic differences in triglyceride and high density lipoprotein (HDL) cholesterol levels, the ethnic differences in LDL size were markedly attenuated and in general no longer statistically significant. The relation of triglyceride, HDL cholesterol, insulin resistance, and adiposity to LDL size in each ethnic group was similar. LDL size differs by ethnic group, which is independent of obesity or insulin resistance. These ethnic differences appear to be due to ethnic variations in dyslipidemia (especially differences in triglyceride levels); ethnic differences in LDL size are not consistent with previously reported ethnic dissimilarities in CVD or atherosclerosis.


Subject(s)
Black People , Lipoproteins, LDL/chemistry , White People , Adipose Tissue/anatomy & histology , Arteriosclerosis/blood , Arteriosclerosis/ethnology , Blood Glucose/metabolism , Cardiovascular Diseases/blood , Cardiovascular Diseases/ethnology , Cholesterol, HDL/blood , Female , Humans , Hyperlipidemias/blood , Hyperlipidemias/ethnology , Insulin Resistance , Lipoproteins, LDL/blood , Male , Middle Aged , Organ Size , Particle Size , Triglycerides/blood
19.
Stroke ; 30(8): 1566-71, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10436102

ABSTRACT

BACKGROUND AND PURPOSE: We studied the relationship of heart rate-corrected QT interval with subclinical atherosclerosis, as determined by ultrasonographic measurement of carotid intima-media thickness (IMT) in nondiabetic subjects in the Insulin Resistance Atherosclerosis Study (IRAS). Prolonged heart rate-corrected QT interval is an unfavorable prognostic factor of cardiovascular morbidity and mortality, and QT interval prolongation may be the result of atherosclerosis. METHODS: B-mode ultrasound imaging of the carotid artery IMT was performed in a large, triethnic, nondiabetic population free of clinical coronary artery disease (n=912). QT interval was measured on resting electrocardiograms with use of a computer program and corrected for heart rate with standard equations. RESULTS: IMT of the common carotid artery correlated significantly with heart rate-corrected QT interval duration (r=0.15 for QT(60) and r=0.14 for QTc), whereas no relationship between IMT of the internal carotid artery and QT interval was found (r=-0.01). The association was somewhat stronger in women than in men. In a multiple regression analysis adjusting for demographic variables, the association of common carotid artery IMT to heart rate-corrected QT interval remained highly significant, but adjustment for cardiovascular risk factors weakened the relationship. CONCLUSIONS: We found a significant relation of heart rate-corrected QT interval to carotid atherosclerosis in nondiabetic subjects that was stronger in women and partly mediated by cardiovascular risk factors, including hypertension. QT interval may therefore serve as a marker for clinically undetected ("subclinical") atherosclerotic disease.


Subject(s)
Arteriosclerosis/diagnosis , Carotid Artery Diseases/diagnosis , Electrocardiography , Heart Rate , Insulin Resistance , Arteriosclerosis/blood , Arteriosclerosis/physiopathology , Black People , Blood Glucose/metabolism , Carotid Artery Diseases/blood , Carotid Artery Diseases/physiopathology , Female , Glucose Tolerance Test , Humans , Insulin/blood , Male , Middle Aged , Plasminogen Activator Inhibitor 1/blood , Prognosis , Sex Factors , Surveys and Questionnaires , Triglycerides/blood , White People
20.
Acta Neurol Scand ; 100(2): 97-101, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10442450

ABSTRACT

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.


Subject(s)
Brain Damage, Chronic/diagnosis , Cognition Disorders/diagnosis , Diabetes Mellitus, Type 2/diagnosis , Activities of Daily Living/psychology , Aged , Brain Damage, Chronic/psychology , Cognition Disorders/psychology , Dementia/diagnosis , Dementia/psychology , Diabetes Mellitus, Type 2/psychology , Diabetic Angiopathies/diagnosis , Diabetic Angiopathies/psychology , Female , Humans , Intracranial Arteriosclerosis/diagnosis , Intracranial Arteriosclerosis/psychology , Male , Mental Status Schedule , Neuropsychological Tests , Risk Factors
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