Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in ∼25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the β-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration.Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulinstimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one. However, even if insulin resistance and hyperinsulinemia are not involved in the etiology of hypertension, it is likely that the increased risk of coronary artery disease (CAD) in patients with hypertension and the fact that this risk if not reduced with antihypertensive treatment are due to the clustering of risk factors for CAD, in addition to high blood pressure, associated with insulin resistance. These include hyperinsulinemia, IGT, increased plasma triglyceride concentration, and decreased high-density lipoprotein cholesterol concentration, all of which are associated with increased risk for CAD. It is likely that the same risk factors play a significant role in the genesis of CAD in the population as a whole. Based on these considerations the possibility is raised that resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of three major related diseases— NIDDM, hypertension, and CAD.

Role of Insulin Resistance in Human Disease

The metabolic syndrome has received increased attention in the past few years. This statement from the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) is intended to provide up-to-date guidance for professionals on the diagnosis and management of the metabolic syndrome in adults.

The metabolic syndrome is a constellation of interrelated risk factors of metabolic origin— metabolic risk factors —that appear to directly promote the development of atherosclerotic cardiovascular disease (ASCVD).1 Patients with the metabolic syndrome also are at increased risk for developing type 2 diabetes mellitus. Another set of conditions, the underlying risk factors , give rise to the metabolic risk factors. In the past few years, several expert groups have attempted to set forth simple diagnostic criteria to be used in clinical practice to identify patients who manifest the multiple components of the metabolic syndrome. These criteria have varied somewhat in specific elements, but in general they include a combination of both underlying and metabolic risk factors.

The most widely recognized of the metabolic risk factors are atherogenic dyslipidemia, elevated blood pressure, and elevated plasma glucose. Individuals with these characteristics commonly manifest a prothrombotic state and a pro-inflammatory state as well. Atherogenic dyslipidemia consists of an aggregation of lipoprotein abnormalities including elevated serum triglyceride and apolipoprotein B (apoB), increased small LDL particles, and a reduced level of HDL cholesterol (HDL-C). The metabolic syndrome is often referred to as if it were a discrete entity with a single cause. Available data suggest that it truly is a syndrome, ie, a grouping of ASCVD risk factors, but one that probably has more than one cause. Regardless of cause, the syndrome identifies individuals at an elevated risk for ASCVD. The magnitude of the increased risk can vary according to which components of the syndrome are …

https://www.lipidcenter.com/pdf/metabolic.pdf

Diagnosis and Management of the Metabolic Syndrome An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement

Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement.

Ten per cent of the world’s school-aged children are estimated to be carrying excess body fat (Fig. 1), with an increased risk for developing chronic disease. Of these overweight children, a quarter are obese, with a significant likelihood of some having multiple risk factors for type 2 diabetes, heart disease and a variety of other co-morbidities before or during early adulthood. The prevalence of overweight is dramatically higher in economically developed regions, but is rising significantly in most parts of the world. In many countries the problem of childhood obesity is worsening at a dramatic rate. Surveys during the 1990s show that in Brazil and the USA, an additional 0.5% of the entire child population became overweight each year. In Canada, Australia and parts of Europe the rates were higher, with an additional 1% of all children becoming overweight each year. The burden upon the health services cannot yet be estimated. Although childhood obesity brings a number of additional problems in its train – hyperinsulinaemia, poor glucose tolerance and a raised risk of type 2 diabetes, hypertension, sleep apnoea, social exclusion and depression – the greatest health problems will be seen in the next generation of adults as the present childhood obesity epidemic passes through to adulthood. Greatly increased rates of heart disease, diabetes, certain cancers, gall bladder disease, osteoarthritis, endocrine disorders and other obesityrelated conditions will be found in young adult populations, and their need for medical treatment may last for their remaining life-times. The costs to the health services, the losses to society and the burdens carried by the individuals involved will be great. The present report has been written to focus attention on the issue and to urge policy-makers to consider taking action before it is too late. Specifically, the report:

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1467-789X.2004.00133.x

Obesity in children and young people: a crisis in public health.

This report is the continuation of two earlier reports that defined human arterial intima and precursors of advanced atherosclerotic lesions in humans. This report describes the characteristic components and pathogenic mechanisms of the various advanced atherosclerotic lesions. These, with the earlier definitions of precursor lesions, led to the histological classification of human atherosclerotic lesions found in the second part of this report. The Committee on Vascular Lesions also attempted to correlate the appearance of lesions noted in clinical imaging studies with histological lesion types and corresponding clinical syndromes. In the histological classification, lesions are designated by Roman numerals, which indicate the usual sequence of lesions progression. The initial (type I) lesion contains enough atherogenic lipoprotein to elicit an increase in macrophages and formation of scattered macrophage foam cells. As in subsequent lesion types, the changes are more marked in locations of arteries with adaptive intimal thickening. (Adaptive thickenings, which are present at constant locations in everyone from birth, do not obstruct the lumen and represent adaptations to local mechanical forces). Type II lesions consist primarily of layers of macrophage foam cells and lipid-laden smooth muscle cells and include lesions grossly designated as fatty streaks. Type III is the intermediate stage between type II and type IV (atheroma, a lesion that is potentially symptom-producing). In addition to the lipid-laden cells of type II, type III lesions contain scattered collections of extracellular lipid droplets and particles that disrupt the coherence of some intimal smooth muscle cells. This extracellular lipid is the immediate precursor of the larger, confluent, and more disruptive core of extracellular lipid that characterizes type IV lesions. Beginning around the fourth decade of life, lesions that usually have a lipid core may also contain thick layers of fibrous connective tissue (type V lesion) and/or fissure, hematoma, and thrombus (type VI lesion). Some type V lesions are largely calcified (type Vb), and some consist mainly of fibrous connective tissue and little or no accumulated lipid or calcium (type Vc).

A Definition of Advanced Types of Atherosclerotic Lesions and a Histological Classification of Atherosclerosis A Report From the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association

Serum lipids (total cholesterol and triglycerides) and lipoprotein cholesterol fractions (low density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol, and high density lipoprotein (HDL) cholesterol) have been measured approximately every 3 years on children and young adults since 1973-1974 in Bogalusa, Louisiana, a community of approximately 22,000 individuals, one-third of whom are black and two-thirds of whom are white. A total of 1,586 children were examined both at baseline (1973-1974) and at the most recent survey (1984-1986), providing 12 years of follow-up. The decreases in levels noted during puberty for total cholesterol and LDL cholesterol, primarily for boys, were followed by a rise until age 26 years. HDL cholesterol levels, particularly for white boys, continued to drop after age 14 years, yielding increasingly high LDL cholesterol/HDL cholesterol ratios. Tracking, as measured by both correlation coefficients and persistence at extreme quartiles, was evident for all of the lipids and lipoproteins. The 12-year correlation coefficients were greatest for LDL cholesterol and no trend in the magnitude of the correlation coefficients with age was noted. Tracking for HDL cholesterol was better after age 9 years, particularly for white males. Approximately 50% of those children who had total cholesterol levels or LDL cholesterol levels above the 75th percentile at baseline remained elevated 12 years later. For HDL cholesterol, a trend with age was noted for white boys: 42% of those aged 9-14 years in the lower most quartile persisted in this rank 12 years later. The best predictor of follow-up lipid or lipoprotein level was baseline level. The next best predictor was increase in weight as defined by weight/height, an index of obesity. That serum lipid and lipoprotein levels continue to track from childhood into young adulthood points to the necessity of measurement early in life and, where indicated, the introduction of preventive and interventional programs aimed at developing healthy lifestyles.

Tracking of serum lipids and lipoproteins from childhood to adulthood. The Bogalusa Heart Study.

A cross-sectional study of 4074 children, ages 5--17 years, in Bogalusa, Louisiana indicated significant changes of serum lipids and lipoproteins occurring during puberty. These changes could be related to both age and maturation and likely reflect the influence of sex hormones on serum lipoprotein metabolism. Considerable differences were observed in the race/sex groups, with boys showing a more marked decrease of serum total cholesterol, reflecting decreases of beta- and alpha- lipoproteins. While the ratio of mean beta-lipoprotein cholesterol/mean alpha-lipoprotein cholesterol for the white girls and black children remained relatively constant over the age span, the ratio beginning around age 11 years rose dramatically in white boys, reflecting an inordinate decrease of alpha-lipoprotein and an earlier beginning rise of beta-lipoprotein. The observations have important implications for earlier coronary artery disease in white men.

Dynamic changes of serum lipoproteins in children during adolescence and sexual maturation

The relation of obesity to clustering of systolic blood pressure, fasting insulin, and ratio of low and very low density lipoprotein cholesterol to high density lipoprotein cholesterol [LDL-C + VLDL-C)/HDL-C) was investigated in 3,503 subjects aged 5-24 years in Bogalusa, Louisiana, from September 1981 to September 1983. Risk ratios (RR) were calculated as the number of subjects with risk factor variables in the upper tertile divided by the expected number. The variables showed strong clustering (RR = 3.1); however, after adjusting for obesity, clustering of systolic pressure, (LDL-C + VLDL-C)/HDL-C, and insulin was reduced (RR = 1.3). Lean subjects (lower tertile of obesity) showed less clustering than expected (RR = 0.4), while more obese subjects (upper tertile of obesity) had greater clustering than expected (RR = 3.1). Furthermore, trunk fat deposition (subscapular skinfold) had a greater impact on clustering at high levels than limb fat deposition (triceps skinfold). Since obesity is related to clustering of risk factor variables in children and young adults, the prevention of the onset of obesity in early life may be important to reducing the risk of coronary heart disease in later life.

Relation of obesity to clustering of cardiovascular disease risk factors in children and young adults. The Bogalusa Heart Study.

Serum lipoprotein profiles in 3182 children, ages 5-14 years, were studied in a biracial community as part of the Bogalusa Heart Study to describe the early natural history of atherosclerosis. White and black children showed similar mean levels of beta-lipoproteins. Pre-beta-lipoprotein levels, however, were significantly higher in white shildren, while significantly higher levels of alpha-lipoprotein were found in black children. Girls had generally higher levels of beta- and pre-beta-lipoprotein and lower levels of alpha-lipoprotein than boys, although the differences were not significant at each age group. With age there was little change in alpha-lipoprotein levels, a significant increase in pre-beta-lipoprotein levels and a slight but significant decrease between 11 and 14 years in beta-lipoprotein levels. The correlation of alpha-lipoprotein was negative with beta-lipoprotein and, to a greater extent, with pre-beta-lipoprotein. The above inverse relationships were significantly greater in white children than in black children, suggesting differences in lipoprotein profiles in the two groups. Lipoprotein values from a total community study are now available for comparison with the currently recommended upper normal limits for lipoproteins. Since only a very small percentage of children could be considered as hyperlipoproteinemic by those specific levels in this community, we suggest that distributions and percentiles be used to evaluate children for hyperlipoproteinemia.

Serum lipoprotein profile in children from a biracial community: the Bogalusa Heart Study.

The need to recognize Coronary Artery Disease (CAD) risk factors at an early age is becoming increasingly important. Serum cholesterol has long been known to be a major independent risk factor for CAD in adults (1). More recently, the level of serum triglycerides has been incriminated as a CAD risk factor independent of cholesterol (2) although the evidence for independence is not conclusive (3).

Sathanur R. Srinivasan

Papers

Tracking of serum lipids and lipoproteins from childhood to adulthood. The Bogalusa Heart Study.

Dynamic changes of serum lipoproteins in children during adolescence and sexual maturation

Relation of obesity to clustering of cardiovascular disease risk factors in children and young adults. The Bogalusa Heart Study.

Serum lipoprotein profile in children from a biracial community: the Bogalusa Heart Study.

Serum cholesterol and triglyceride levels in 3,446 children from a biracial community: the Bogalusa Heart Study.