Many studies have shown that hyperinsulinemia and/or insulin resistance are related to various metabolic and physiological disorders including hypertension, dyslipidemia, and non-insulin-dependent diabetes mellitus. This syndrome has been termed Syndrome X. An important limitation of previous studies has been that they all have been cross sectional, and thus the presence of insulin resistance could be a consequence of the underlying metabolic disorders rather than its cause. We examined the relationship of fasting insulin concentration (as an indicator of insulin resistance) to the incidence of multiple metabolic abnormalities in the 8-yr follow-up of the cohort enrolled in the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease in Mexican Americans and non-Hispanic whites. In univariate analyses, fasting insulin was related to the incidence of the following conditions: hypertension, decreased high-density lipoprotein cholesterol concentration, increased triglyceride concentration, and non-insulin-dependent diabetes mellitus. Hyperinsulinemia was not related to increased low-density lipoprotein or total cholesterol concentration. In multivariate analyses, after adjustment for obesity and body fat distribution, fasting insulin continued to be significantly related to the incidence of decreased high-density lipoprotein cholesterol and increased triglyceride concentrations and to the incidence of non-insulin-dependent diabetes mellitus. Baseline insulin concentrations were higher in subjects who subsequently developed multiple metabolic disorders. These results were not attributable to differences in baseline obesity and were similar in Mexican Americans and non-Hispanic whites. These results support the existence of a metabolic syndrome and the relationship of that syndrome to multiple metabolic disorders by showing that elevations of insulin concentration precede the development of numerous metabolic disorders.

Prospective Analysis of The Insulin-Resistance Syndrome (Syndrome X)

This statement was reviewed by the American Diabetes Association. The recommendations contained herein are consistent with the American Diabetes Association’s Clinical Practice Recommendations. 

Atherosclerotic cardiovascular disease is the No. 1 killer in the adult population of Western societies,1 but the pathological processes and risk factors associated with its development have been shown to begin during childhood.2 Obesity plays a central role in the insulin resistance syndrome, which includes hyperinsulinemia, hypertension, hyperlipidemia, type 2 diabetes mellitus, and an increased risk of atherosclerotic cardiovascular disease. The incidence of type 2 diabetes reported in children has increased alarmingly.3,4

Resistance of the body to the actions of insulin results in increased production of this hormone by the pancreas and ensuing hyperinsulinemia. Obesity beginning in childhood often precedes the hyperinsulinemic state. Other components of the insulin resistance syndrome are also present in children and adolescents.5,6 An association between obesity and insulin resistance has been reported in the young, as has the link between insulin resistance, hypertension, and abnormal lipid profile. There is an increasing amount of data showing that being overweight during childhood and adolescence is significantly associated with insulin resistance, dyslipidemia, and elevated blood pressure in young adulthood. Weight loss by obese youngsters results in a decrease in insulin concentration and improvement in insulin sensitivity. Moreover, it has been determined that increased left ventricular mass, which is an independent risk factor for cardiovascular disease in adults, is present in childhood. Recent research has found that left ventricular hypertrophy is related to other risk factors, including obesity and insulin resistance in children and adolescents.7 The specifics of the transition from risk factors in childhood to diabetes and cardiovascular disease are not clear, but compelling evidence points to their association with overt disease in adults. On the basis of current knowledge …

Obesity, Insulin Resistance, Diabetes, and Cardiovascular Risk in Children An American Heart Association Scientific Statement From the Atherosclerosis, Hypertension, and Obesity in the Young Committee (Council on Cardiovascular Disease in the Young) and the Diabetes Committee (Council on Nutrition, Physical Activity, and Metabolism)

Many clinical studies have shown an increased insulin response to oral glucose in patients with ischemia of the heart, lower limbs, or brain. Hyperinsulinemia also occurs in patients with angiographically proved atherosclerosis without ischemia and thus appears to be related to arterial disease and not to be a nonspecific response to tissue injury. Fasting insulin levels and insulin responses to intravenous stimuli, including glucose, tolbutamide, and arginine, are normal, suggesting a gastrointestinal factor may be involved in the increased insulin response to oral glucose. In patients with atherosclerosis, insulin sensitivity appears to be normal or enhanced with respect to both glucose and lipid metabolism. Five population studies have shown that insulin responses to glucose are higher in populations at greater risk of cardiovascular disease. Many of the hyperinsulinemic populations also had upper-body obesity, hypertriglyceridemia, lower highdensity lipoprotein (HDL) levels, and hypertension. These prospective studies support an independent association between hyperinsulinemia and ischemic heart disease, although their results differ in detail. Hyperinsulinemia is associated with raised triglyceride and decreased HDL cholesterol levels. Total and lowdensity lipoprotein (LDL) cholesterol is less closely related to hyperinsulinemia. Upper-body adiposity is associated (in separate studies) with coronary heart disease, diabetes, hyperinsulinemia, and hypertriglyceridemia. Insulin and blood pressure are closely related in both normotensive and hypertensive people. Although obesity and diabetes are often found in hypertensive people, hyperinsulinemia also occurs in nonobese nondiabetic hypertensive people. Thus, hyperinsulinemia is closely associated with a cluster of From the Department of Geriatric Medicine, The Queen9s University of Belfast, Belfast, Northern Ireland. Address correspondence and reprint requests to Professor R.W. Stout, Department of Geriatric Medicine, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland. cardiovascular risk factors, i.e., hypertriglyceridemia, low HDL levels, hypertension, hyperglycemia, and upper-body obesity. There is a possibility that insulin has a role in the sex differences in ischemic heart disease incidence and their absence in diabetes, but additional work is required for its clarification. Long-term treatment with insulin results in lipidcontaining lesions and thickening of the arterial wall in experimental animals. Insulin also inhibits regression of diet-induced experimental atherosclerosis, and insulin deficiency inhibits the development of arterial lesions. Insulin stimulates lipid synthesis in arterial tissue; the effect of insulin is influenced by hemodynamic factors and may be localized to certain parts of the artery. In physiological concentrations, insulin stimulates proliferation and migration of cultured arterial smooth muscle cells but has no effect on endothelial cells cultured from large vessels. Insulin also stimulates cholesterol synthesis and LDL binding in both arterial smooth muscle cells and monocyte macrophages. The multiple effects of insulin provide evidence of a potential direct role for this hormone in the development of atherosclerosis. The combination of clinical, epidemiological, and experimental evidence favors a direct role of insulin in the development of atherosclerosis. Insulin may also promote atherogenesis by its effects on lipids and blood pressure. If hyperinsulinemia has a role in atherogenesis, regular physical exercise and avoidance of obesity should be effective in preventing atherosclerosis.

Insulin and Atheroma: 20-Yr Perspective

Despite compliance with lifestyle recommendations, some children and adolescents with high-risk hyperlipidemia will require lipid-lowering drug therapy, particularly those with familial hypercholesterolemia. The purpose of this statement is to examine new evidence on the association of lipid abnormalities with early atherosclerosis, discuss challenges with previous guidelines, and highlight results of clinical trials with statin therapy in children and adolescents with familial hypercholesterolemia or severe hypercholesterolemia. Recommendations are provided to guide decision-making with regard to patient selection, initiation, monitoring, and maintenance of drug therapy.

https://www.medpagetoday.com/upload/2007/3/22/kidlipid.pdf

Drug Therapy of High-Risk Lipid Abnormalities in Children and Adolescents A Scientific Statement From the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, With the Council on Cardiovascular Nursing

It has been proposed that excessive insulin resistance in Asian Indians living in urban areas or migrated to western countries is responsible for the higher incidence of type 2 diabetes and coronary heart disease observed in this population. To evaluate whether Asian Indians are more insulin resistant than Caucasians and to define the role of generalized and truncal adiposity, we performed hydrodensitometry, skinfold measurements, and euglycemic-hyperinsulinemic clamps in 21 healthy Asian Indian men and 23 Caucasian men of similar age and body fat content. The glucose disposal rate (Rd) was significantly lower in the Asian Indians than in the Caucasians (3.7+/-1.3 vs. 5.3+/-2.0 mg/min x kg lean body mass, respectively; P = 0.003). Despite similar total body fat content, Asian Indians had higher truncal adiposity than Caucasians (sum of truncal skinfolds, 117+/-37 and 92.4+/-38 mm, respectively). In both Asian Indians and Caucasians, the insulin sensitivity index (Rd/plasma insulin concentrations) was inversely correlated with both total body fat (r = -0.49; P<0.03 and r = -0.67; P<0.001, respectively) and sum of truncal skinfold thickness (r = -0.55; P<0.001 and r = -0.61; P<0.002, respectively). After adjustment for total body fat and truncal skinfold thickness, Asian Indians still had a significantly lower glucose disposal rate (P = 0.04). These results show that Asian Indian men are more insulin resistant than Caucasian men independently of generalized or truncal adiposity. The excessive insulin resistance in Asian Indians is probably a primary metabolic defect and may account for the excessive morbidity and mortality from diabetes and coronary heart disease in this population.

Relationship between generalized and upper body obesity to insulin resistance in Asian Indian men

In epidemiologic studies, hyperinsulinemia has been found to be an independent risk factor for coronary heart disease (CHD). However, the mechanisms responsible for its role in atherogenesis remain unclear. We studied the relationship of in vivo insulin action and plasma lipids and lipoproteins in 44 normotriglyceridemic white men (aged 18 to 34 years). The euglycemic, hyperinsulinemic glucose clamp technique was used to quantitate insulin-mediated glucose disposal (MI value) at a plasma insulin concentration of approximately 100 μU/mL. The MI value correlated negatively with plasma triglycerides (r = −0.553, P < .0001), as well as with fasting plasma insulin levels (r = −0.483, P < .001), independent of age, body mass index, and fasting plasma glucose levels. A negative correlation of the MI value was also observed with very low density lipoprotein (VLDL)-cholesterol (r = −0.347, P < .05), VLDL-triglycerides (r = −0.474, P < 0.005), and total cholesterol/high density lipoprotein (HDL)-cholesterol ratio (r = −0.431, P < .01). The relationship between the MI value and the total cholesterol/HDL-cholesterol ratio was independent of VLDL-cholesterol and VLDL-triglycerides, however, not independent of plasma triglycerides. No relationship was observed between insulin-mediated glucose uptake and total cholesterol, low density lipoprotein (LDL)-cholesterol, and HDL-cholesterol values. Individual differences in plasma triglycerides, fasting insulin concentration, and the total cholesterol/HDL-cholesterol ratio accounted for about half the variance observed in the MI value. In conclusion, our findings in normal healthy men support the contention that hyperinsulinemia or insulin resistance may enhance the risk of CHD by adversely affecting lipoprotein levels such as VLDL-cholesterol, VLDL-triglyceride, and the ratio of total cholesterol/HDL-cholesterol.

Romulo Ayuso

Papers

Relationship between lipoprotein levels and in vivo insulin action in normal young white men