Oxidative stress: introduction.
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Blood Glucose↗
Biomedical subjects
S M Haffner
Publications and source records attributed to S M Haffner.
Clinical relevance of the oxidative stress concept.
Subjects with type 2 diabetes have markedly increased rates of coronary heart disease (CHD) that are only partly explained by the increased levels of conventional cardiovascular risk factors such as total cholesterol, hypertension, and smoking. Although an increasing number of studies have suggested a role for glycemia in cardiovascular disease, considerable controversy remains. This issue may be resolved when the results of the UK Prospective Diabetes Study (UKPDS) are presented. One possible promising relatively new risk factor that may explain high levels of CHD in diabetic subjects is increased oxidative stress. Type 2 diabetic subjects have an increased preponderance of small dense low-density lipoprotein (LDL), which predisposes to the oxidation of LDL. Almost all studies show that diabetic subjects have increased oxidative stress. In addition, they may have lower levels of alpha-tocopherol. In most studies, increased oxidative stress has been associated with cardiovascular disease, although prospective data are lacking. If levels of oxidative stress are increased, what are the best levels to reduce it to? Improved glycemic control has been associated with decreased oxidative stress. Antioxidant replacement such as alpha-tocopherol may also be beneficial. Interestingly, some special properties of hypoglycemic agents have been described. Gliclazide has been reported to favorably affect both free radicals and platelet reactivity. Gliclazide may have a more favorable effect on tissue plasminogen activator (tPA) than tolbutamide. In conclusion, increased levels of oxidative stress may underlie some of the increased risk of cardiovascular disease in diabetic subjects. Interventions to decrease levels of oxidative stress by methods such as improved glycemic control, antioxidant therapy (ie, alpha-tocopherol), and gliclazide are indicated.
Blood Glucose↗
Obesity and the metabolic syndrome: the San Antonio Heart Study.
Obesity, especially visceral adiposity, is a major determinant of the development of type 2 diabetes. Both visceral adiposity and insulin resistance are strongly related to cardiovascular risk factors in diabetic and non-diabetic subjects. One of the areas where the correlation between visceral fat (upper body adiposity) and cardiovascular risk is most apparent is the prediabetic state. We have recently shown that only prediabetic subjects (those who later develop type 2 diabetes) who are insulin resistant and with upper body adiposity have increased triglycerides, decreased HDL cholesterol and high blood pressure.
Adult↗
Sex hormones, obesity, fat distribution, type 2 diabetes and insulin resistance: epidemiological and clinical correlation.
Increased androgenicity as assessed by increased testosterone and decreased SHBG is strongly associated with an unfavorable body fat distribution and increased glucose and insulin concentrations and insulin resistance in both pre- and postmenopausal women. However, the temporal direction of the association between androgens and insulin is uncertain. In men, the association between SHBG and insulin levels is much weaker and is probably inverse.
Adipose Tissue↗
Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: The Insulin Resistance Atherosclerosis Study.
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.
Albuminuria↗
Hyperlipidemia: diagnostic and therapeutic perspectives.
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Cholesterol, HDL↗
Hyperproinsulinemia is not a characteristic feature in the offspring of patients with different phenotypes of type II diabetes.
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.
Adult↗
Associations between alcohol consumption and insulin sensitivity and cardiovascular disease risk factors: the Insulin Resistance and Atherosclerosis Study.
OBJECTIVE: Light-to-moderate alcohol consumption has been associated with reduced cardiovascular disease (CVD) mortality, which may be explained by increased insulin sensitivity (SI) and an improved lipoprotein and blood pressure profile. Prior research has shown improved SI with light-to-moderate alcohol intake even though somewhat imprecise measures of SI were used. RESEARCH DESIGN AND METHODS: Relationships between alcohol use and SI and CVD risk factors were assessed in a cross-sectional analysis of 1,196 white, African-American, and Hispanic men and women from the Insulin Resistance and Atherosclerosis Study (IRAS). Five categories of previous-year alcohol use (never, <0.5 drinks/day, 0.5-0.99 drinks/day, 1-2.99 drinks/day, and > or =3 drinks/day) and log SI + 1 (frequently sampled intravenous glucose tolerance test with Bergman minimal model analysis), log fasting insulin, log triglycerides, HDL cholesterol, and systolic/diastolic blood pressure were examined using analysis of variance. RESULTS: Univariate analysis showed an inverse U-shaped relationship between SI and alcohol intake, with a peak at the 0.5-0.99 drinks/day category. A U-shaped relationship was observed between fasting insulin and the lipid and blood pressure measures. After adjustment for demographic (clinic, sex, ethnicity, age), lifestyle (smoking, dietary energy/fat intake, physical activity), and physical (BMI, waist circumference) variables, the alcohol/insulin association was attenuated, but the association with lipids and blood pressure remained for high-intake categories. CONCLUSIONS: These data suggest that the enhanced SI associated with light-to-moderate alcohol consumption may be a function solely of a BMI and central adiposity profile more favorable to higher SI.
Black or African American↗
Heart rate in relation to insulin sensitivity and insulin secretion in nondiabetic subjects.
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.
Body Constitution↗
Lipoprotein concentrations and carotid atherosclerosis by diabetes status: results from the Insulin Resistance Atherosclerosis Study.
OBJECTIVE: Lipoprotein concentrations are associated with the development of atherosclerosis in people with and without diabetes. The relative strength of these associations could differ by diabetes status as a result of diabetes-related lipoprotein modifications. RESEARCH DESIGN AND METHODS: The associations between lipoprotein concentrations and internal and common carotid artery intimal-medial thickness (IMT) assessed by B-mode ultrasonography were examined by diabetes status in a cross-sectional analysis among 1,391 participants in the Insulin Resistance Atherosclerosis Study. Participants included 442 individuals with type 2 diabetes, 308 with impaired glucose tolerance, and 641 with normal glucose tolerance. RESULTS: The differences in internal and common carotid IMT between the highest and lowest tertiles of LDL were 58.1 microm (P = 0.054) and 51.0 microm (P < 0.001), respectively. The differences in internal and common carotid IMT between the lowest and highest tertiles of HDL were 56.2 microm (P = 0.07) and 37.8 microm (P = 0.003), respectively Triglycerides and VLDL were not associated with IMT. These associations did not differ significantly because of diabetes status. CONCLUSIONS: These results support the importance of dyslipidemia as a major risk factor for atherosclerosis in people with diabetes. Future research in humans should measure lipoprotein oxidizability, glycation, size, and composition directly in people of differing glucose tolerance status to address the importance of diabetes-related lipoprotein modifications more conclusively.
Carotid Arteries↗
Predicting risk reduction of coronary disease in patients who are glucose intolerant: a comparison of treatment with fenofibrate and other lipid-modifying agents.
A clinical outcomes model was developed to estimate the ability of fibrates and statins to reduce the relative and absolute risk of developing coronary heart disease (CHD) in patients with diabetes. A database was constructed, drawing on results from 83 applicable published studies. Risk factor outcomes reported by the model were chosen according to those found to be statistically significant in the data set parameters from the Framingham Heart Study. In the analysis, fenofibrate was compared with gemfibrozil (an earlier fibrate) and six 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase-inhibitor or "statin" agents. Among the agents studied, only fenofibrate was found to significantly affect all six cardiovascular disease risk factors used in this analysis. For men with diabetes, the estimated absolute risk of developing CHD after five years of treatment was lowered equally and most effectively by fenofibrate, simvastatin, and atorvastatin, from 10% to 6%. For women with diabetes, fenofibrate and simvastatin reduced absolute risk from 9% to 6% over five years of treatment, while atorvastatin reduced risk from 9% to 6%. An accompanying cost comparison analysis found that reducing absolute risk of CHD in these patients would result in significant reductions in the medical expense of treating cardiac events, and that significant differences in the amount saved were driven by treatment choice. Fenofibrate, simvastatin, and atorvastatin produced the greatest long-term savings.
Coronary Disease↗
Patients with type 2 diabetes: the case for primary prevention.
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Blood Glucose↗
Rapid rise in the incidence of type 2 diabetes from 1987 to 1996: results from the San Antonio Heart Study.
BACKGROUND: The prevalence of type 2 diabetes has increased in the early part of the 20th century, particularly in developing countries. There is now evidence that the prevalence also continues to increase in developed countries, including the United States. However, it is unknown whether this increase is due to a rise in the incidence of diabetes or to decreasing diabetic mortality or both. METHODS: Participants in the San Antonio Heart Study, who were nondiabetic at baseline and who returned for a 7- to 8-year follow-up examination, were examined for secular trends in the incidence of type 2 diabetes. Risk factors for diabetes, such as obesity, were also examined. Patients were enrolled in the San Antonio Heart Study from 1979 to 1988 and 7- to 8-year incidence of diabetes was determined from 1987 to 1996. RESULTS: A significant secular trend in the 7- to 8-year incidence of type 2 diabetes was observed in Mexican Americans (5.7% for participants enrolled in 1979 to 15.7% for participants enrolled in 1988). In non-Hispanic whites, the incidence increased from 2.6% for participants enrolled in 1980 to 9.4% for participants enrolled in 1988 (P = .07) . After adjusting for age and sex, the secular trend remained significant in Mexican Americans and borderline significant in non-Hispanic whites. This indicates that between 1987 and 1996 the 7- to 8-year incidence of type 2 diabetes approximately tripled in both ethnic groups. The overall secular trend also remained significant after adjusting for additional risk factors for diabetes, such as obesity. A rising secular trend in obesity was also observed. CONCLUSIONS: There has been a significant increasing secular trend in the incidence of type 2 diabetes in Mexican Americans and a borderline significant trend in non-Hispanic whites participating in the San Antonio Heart Study. Unlike other cardiovascular risk factors such as lipid levels, cigarette smoking, and blood pressure, which are either declining or under progressively better medical management and control, and unlike cardiovascular mortality, which is also declining, obesity and type 2 diabetes are exhibiting increasing trends. Thus, obesity and diabetes could easily become the preeminent US public health problem.
Adult↗
Epidemiology of insulin resistance and its relation to coronary artery disease.
The relation of insulin resistance to cardiovascular risk, particularly for coronary artery disease (CAD), has been well established in many prospective studies. The clustering of insulin resistance and/or hyperinsulinemia, hypertriglyceridemia, hypertension, and low HDL is now considered a feature of the insulin resistance syndrome. However, the association is complex and the pathways by which elevated insulin adversely affects both CAD risk factors and the risk of developing CAD have yet to be elucidated. Postprandial lipemia may be a mechanistic link between insulin resistance and CAD. Hyperinsulinemia appears to be a weak, but positive, independent cardiovascular risk factor. The strongest relations are seen in middle-aged rather than older persons and at higher elevations of plasma insulin levels. Individuals with type 2 diabetes have a risk of myocardial infarction (MI) equivalent to that of nondiabetic persons who have had a previous MI. Given the relatively weak association between duration of diabetes and severity of hyperglycemia and cardiovascular disease, common antecedents may underlie both CAD and type 2 diabetes.
Aged↗
Diabetes, hyperlipidemia, and coronary artery disease.
Type 2 diabetes is associated with a marked increase in the risk of coronary artery disease. Dyslipidemia is believed to be a major source of this increased risk. Several studies in diabetic patients have demonstrated a decreased incidence of coronary artery disease with the use of drugs that lower the level of low-density lipoprotein in diabetic patients, but other forms of dyslipidemia, such as hypertriglyceridemia, are believed to play a role in the etiology of coronary artery disease in diabetes. Drugs, such as fenofibrate, which improve these other forms of dyslipidemia, are being investigated in diabetic patients to determine if they decrease mortality and morbidity from coronary artery disease.
Apolipoproteins B↗
Role of fibrates in the management of hypertriglyceridemia.
Elevated plasma triglyceride levels are increasingly recognized as a risk factor for cardiovascular disease. Fibric acid derivatives (fibrates) substantially decrease triglyceride levels and have been demonstrated to decrease clinical cardiovascular events in some trials. Ongoing research will elucidate the molecular mechanisms by which fibrates modify lipoprotein metabolism, clarify their use in combination with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), and determine their role in the prevention of cardiovascular events.
Anticholesteremic Agents↗
Is leptin concentration associated with the insulin resistance syndrome in nondiabetic men?
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 (r = 0.223), systolic blood pressure (r = 0.223), 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.
Apolipoproteins B↗
The relation of proinsulin and insulin to insulin sensitivity and acute insulin response in subjects with newly diagnosed type II diabetes: the Insulin Resistance Atherosclerosis Study.
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.
Adult↗