Manuel J. Quiñones

Role of endothelial dysfunction in insulin resistance

The endothelium regulates vascular tone through the release of vasodilating and vasoconstricting substances. The most important of these vasodilating substances is nitric oxide (NO), which is also vascular protective and inhibits inflammation, oxidation, vascular smooth muscle cell proliferation, and migration. Damage to the endothelium causes endothelial dysfunction with impaired release of NO and loss of its antiatherogenic protection. Traditional risk factors for coronary artery disease, including diabetes, hypercholesterolemia, hypertension, and low levels of high-density lipoprotein cholesterol, are associated with endothelial dysfunction and thus promote the atherogenic process. More recently, insulin resistance in the absence of overt diabetes or the metabolic syndrome has been associated with endothelial dysfunction. This association provides evidence that the atherosclerotic process may actually begin earlier in the spectrum of insulin resistance, ultimately resulting in a progression of the metabolic syndrome to prediabetes and then to type 2 diabetes. Aggressive treatment of dyslipidemia and hypertension, even before the onset of type 2 diabetes, would appear prudent in decreasing the progression of the atherosclerotic process. The thiazolidinediones are peroxisome proliferator-activated receptor-gamma agonists that improve glucose and lipid metabolism. These agents have recently been shown to improve endothelial function in the early stages of insulin resistance. Results from ongoing trials with thiazolidinediones will reveal whether they will also reduce cardiovascular end points.

Coronary Circulatory Dysfunction in Insulin Resistance, Impaired Glucose Tolerance, and Type 2 Diabetes Mellitus

Background—Abnormal coronary endothelial reactivity has been demonstrated in diabetes and is associated with an increased rate of cardiovascular events. Our objectives were to investigate the presence of functional coronary circulatory abnormalities over the full spectrum of insulin resistance and to determine whether these would differ in severity with more advanced states of insulin resistance. Methods and Results—Myocardial blood flow (MBF) was measured with positron emission tomography and 13N-ammonia to characterize coronary circulatory function in states of insulin resistance without carbohydrate intolerance (IR), impaired glucose tolerance (IGT), and normotensive and hypertensive type 2 diabetes mellitus (DM) compared with insulin-sensitive (IS) individuals. Indices of coronary function were total vasodilator capacity (mostly vascular smooth muscle–mediated) during pharmacological vasodilation and the nitric oxide–mediated, endothelium-dependent vasomotion in response to cold pressor testing. Total vasodilator capacity was similar in normoglycemic individuals (IS, IR, and IGT), whereas it was significantly decreased in normotensive (−17%) and hypertensive (−34%) DM patients. Compared with IS, endothelium-dependent coronary vasomotion was significantly diminished in IR (−56%), as well as in IGT and normotensive and hypertensive diabetic patients (−85%, −91%, and −120%, respectively). Conclusions—Progressively worsening functional coronary circulatory abnormalities of nitric oxide–mediated, endothelium-dependent vasomotion occur with increasing severity of insulin-resistance and carbohydrate intolerance. Attenuated total vasodilator capacity accompanies the more clinically evident metabolic abnormalities in diabetes.

A Genome-Wide Scan for Carotid Artery Intima-Media Thickness The Mexican-American Coronary Artery Disease Family Study

Background and Purpose— Carotid artery intima-media thickness (CIMT), a subclinical measure of atherosclerosis, is associated with coronary artery disease (CAD), and stroke. CIMT is also an important predictor of clinical cardiovascular events. To systematically identify the genetic determinants of CIMT, we performed a genome-wide scan using data from 91 2-generation Mexican American families ascertained via a parent with CAD diagnosed. Methods— CIMT was measured in 274 adult offspring (mean age, 34.6 years) using high-resolution B-mode ultrasound; 413 subjects, including adult offspring and their parents, were genotyped using Marshfield screen set 12 (380 microsatellite markers at ≈10-cM interval). Heritability was estimated using the variance component approach implemented in SOLAR. Linkage analyses were performed using both the sib-pair regression approach and the variance component approach. Results— The estimated heritability was 0.68, 0.45, and 0.40 for unadjusted, gender- and age-adjusted, and multivariate-adjusted CIMT, respectively. The strongest evidence of linkage was found on chromosome 2 at D2S2944 (logarithm of the odds [LOD]=3.08). Other suggestive linkages were also found on chromosome 6 at D6S1022 to D6S2410 (LOD=2.21) and chromosome 13 at D13S796 to D13S895 (LOD=1.34). Conclusions— These results show that there is a strong genetic effect on CIMT in these Mexican American CAD families. The linkage peak on chromosome 2 suggests that there is a gene (or genes) at this chromosome location influencing CIMT.

SORCS1: A Novel Human Type 2 Diabetes Susceptibility Gene Suggested by the Mouse

OBJECTIVE—A small number of susceptibility genes for human type 2 diabetes have been identified by candidate gene analysis or positional cloning. Genes found to influence diabetes or related traits in mice are likely to be susceptibility genes in humans. SorCS1 is the gene identified as responsible for the mouse chromosome 19 T2dm2 quantitative trait locus for fasting insulin levels, acting via impaired insulin secretion and increased islet disruption in obese females. Genes that impair compensatory insulin secretion in response to obesity-induced insulin resistance may be particularly relevant to human diabetes. Thus, we sought to determine whether variation in the human SORCS1 gene was associated with diabetes-related traits. RESEARCH DESIGN AND METHODS—We assessed the contribution of variation in SORCS1 to human insulin–related traits in two distinct Mexican-American cohorts. One cohort (the Mexican-American Coronary Artery Disease [MACAD] cohort) consisted of nondiabetic individuals, allowing assessment of genetic association with subclinical intermediate insulin-related traits; the second cohort (the San Antonio Family Diabetes Study [SAFADS]) contained individuals with diabetes, allowing association analyses with overt disease. RESULTS—We first found association of SORCS1 single nucleotide polymorphisms and haplotypes with fasting insulin levels and insulin secretion in the MACAD cohort. Similar to our results in the mice, the genetic association was strongest in overweight women. We then observed association with diabetes risk and age at diagnosis in women of the SAFADS cohort. CONCLUSIONS—Identification of SORCS1 as a novel gene affecting insulin secretion and diabetes risk is likely to provide important insight into the biology of obesity-induced type 2 diabetes.

Determination and use of haplotypes: ethnic comparison and association of the lipoprotein lipase gene and coronary artery disease in Mexican-Americans.

Purpose: To illustrate an approach of deriving haplotypes for genetic association studies, using the lipoprotein lipase (LPL) gene and coronary artery disease.Methods: Six polymorphisms sufficient to distinguish the most common haplotypes in the 3′ end of LPL were identified by genotyping 10 polymorphisms in a small pilot population. These were used to haplotype LPL in large family samples of Mexican-Americans and non-Hispanic Caucasians. A case-control association study was performed comparing Mexican-Americans with and without coronary artery disease.Results: The two ethnic groups exhibited significant genetic differences. Among Mexican-Americans, homozygosity for LPL haplotype 1 was protective against coronary artery disease (OR = 0.50, 95% CI 0.27–0.91).Conclusion: This study outlines the haplotype structure of the LPL gene, illustrates the utility of haplotype-based analysis in association studies, and demonstrates the importance of defining haplotype frequencies for different ethnic groups.

Improvement in coronary vascular dysfunction produced with euglycaemic control in patients with type 2 diabetes

Objective: To determine the effect of plasma glucose lowering on coronary circulatory function in type 2 diabetes mellitus. Methods: Twenty patients with type 2 diabetes and 18 weight-matched controls were studied. At baseline, myocardial blood flow (MBF) was measured with [13N]ammonia and positron emission tomography at rest, during cold pressor testing (CPT), and during adenosine hyperaemia. In diabetic patients, MBF and blood chemistry were analysed again after 3 months of glucose-lowering treatment with glyburide and metformin. Results: Although hyperaemic MBF did not differ significantly between the patients and controls (1.81 (0.38) v 1.97 (0.43) ml/min/g; mean (SD)), the CPT-induced MBF increase (ΔMBF) was significantly less in diabetic patients than in controls (0.07 (0.07) v 0.25 (0.12) ml/min/g; p<0.001). Treatment with glyburide and metformin significantly decreased plasma glucose concentrations from 207 (76) to 134 (52) mg/dl (p<0.001). This decrease in plasma glucose was paralleled by a significant increase in ΔMBF in response to CPT (0.20 (0.16) from 0.07 (0.07) ml/min/g; p<0.001), which tended to be lower than in controls at baseline (0.20 (0.16) v 0.25 (0.12) ml/min/g; p  =  NS). The decrease in plasma glucose concentrations correlated significantly with the improvement in ΔMBF in response to CPT (r = 0.67, p<0.01). Conclusions: Type 2 diabetes mellitus is associated with abnormal MBF response to CPT, which can be significantly improved by euglycaemic control with glyburide and metformin. The close association between the decrease in plasma glucose concentration and the improvement in coronary vasomotor function in response to CPT suggests a direct adverse effect of raised plasma glucose concentration on diabetes-related coronary vascular disease.

Genetic Effects on Obesity Assessed by Bivariate Genome Scan: The Mexican-American Coronary Artery Disease Study

Objective: To identify the genetic determinants of obesity using univariate and bivariate models in a genome scan.

Hypertriglyceridemia and Recurrent Pancreatitis following Splenectomy.

Hyperlipoproteinemia represents a constellation of clinical syndromes that frequently includes hypertriglyceridemia. Because of the degree of elevation in the triglyceride levels frequently seen in these syndromes, they are associated with complications not generally observed among those patients with essential hypertriglyceridemia, including as in this case report, recurrent pancreatitis. Here, we present a case of a patient with hyperlipoproteinemia who developed acute worsening of his hypertriglyceridemia and onset of acute panceatitis that became recurrent following elective splenectomy for suspected lymphoma. In particular, we discuss the dietary management of hypertriglyceridemia which significantly reduced the number of episodes of acute pancreatitis in this patient.