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

Background Type 2 diabetes mellitus is increasingly common, primarily because of increases in the prevalence of a sedentary lifestyle and obesity. Whether type 2 diabetes can be prevented by interventions that affect the lifestyles of subjects at high risk for the disease is not known. Methods We randomly assigned 522 middle-aged, overweight subjects (172 men and 350 women; mean age, 55 years; mean body-mass index [weight in kilograms divided by the square of the height in meters], 31) with impaired glucose tolerance to either the intervention group or the control group. Each subject in the intervention group received individualized counseling aimed at reducing weight, total intake of fat, and intake of saturated fat and increasing intake of fiber and physical activity. An oral glucose-tolerance test was performed annually; the diagnosis of diabetes was confirmed by a second test. The mean duration of follow-up was 3.2 years. Results The mean (±SD) amount of weight lost between base line and the end of ye...

Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance.

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

Obesity alters adipose tissue metabolic and endocrine function and leads to an increased release of fatty acids, hormones, and proinflammatory molecules that contribute to obesity associated complications. To further characterize the changes that occur in adipose tissue with increasing adiposity, we profiled transcript expression in perigonadal adipose tissue from groups of mice in which adiposity varied due to sex, diet, and the obesity-related mutations agouti (Ay) and obese (Lepob). We found that the expression of 1,304 transcripts correlated significantly with body mass. Of the 100 most significantly correlated genes, 30% encoded proteins that are characteristic of macrophages and are positively correlated with body mass. Immunohistochemical analysis of perigonadal, perirenal, mesenteric, and subcutaneous adipose tissue revealed that the percentage of cells expressing the macrophage marker F4/80 (F4/80+) was significantly and positively correlated with both adipocyte size and body mass. Similar relationships were found in human subcutaneous adipose tissue stained for the macrophage antigen CD68. Bone marrow transplant studies and quantitation of macrophage number in adipose tissue from macrophage-deficient (Csf1op/op) mice suggest that these F4/80+ cells are CSF-1 dependent, bone marrow-derived adipose tissue macrophages. Expression analysis of macrophage and nonmacrophage cell populations isolated from adipose tissue demonstrates that adipose tissue macrophages are responsible for almost all adipose tissue TNF-alpha expression and significant amounts of iNOS and IL-6 expression. Adipose tissue macrophage numbers increase in obesity and participate in inflammatory pathways that are activated in adipose tissues of obese individuals.

/pdf/obesity-is-associated-with-macrophage-accumulation-in-130af7ivca.pdf

Obesity is associated with macrophage accumulation in adipose tissue

DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1α and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.

/pdf/pgc-1alpha-responsive-genes-involved-in-oxidative-1t3qxw5cbf.pdf

PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes

In a prospective study of risk factors for ischaemic heart disease 792 54 year old men selected by year of birth (1913) and residence in Gothenburg agreed to attend for questioning and a battery of anthropometric and other measurements in 1967. Thirteen years later these baseline findings were reviewed in relation to the numbers of men who had subsequently suffered a stroke, ischaemic heart disease, or death from all causes. Neither quintiles nor deciles of initial indices of obesity (body mass index, sum of three skinfold thickness measurements, waist or hip circumference) showed a significant correlation with any of the three end points studied. Statistically significant associations were, however, found between the waist to hip circumference ratio and the occurrence of stroke (p = 0.002) and ischaemic heart disease (p = 0.04). When the confounding effect of body mass index or the sum of three skinfold thicknesses was accounted for the waist to hip circumference ratio was significantly associated with all three end points. This ratio, however, was not an independent long term predictor of these end points when smoking, systolic blood pressure, and serum cholesterol concentration were taken into account. These results indicate that in middle aged men the distribution of fat deposits may be a better predictor of cardiovascular disease and death than the degree of adiposity.

https://www.bmj.com/content/bmj/288/6428/1401.full.pdf

Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: 13 year follow up of participants in the study of men born in 1913.

The distribution of adipose tissue thickness, fat cell weight (FCW), and number (FCN) were studied in four regions in randomly selected middle-aged men and women and in 930 obese individuals. Both the obese and the randomly selected men were found to have the largest adipose tissue thickness in the abdominal region. Women, however, showed a relative preponderance for the gluteal and femoral regions. FCW increased with expanding body fat up to a maximal size of approximately 0.7-0.8 micrograms/cell in each region. After this increase in FCW, a more rapid increase in FCN was found. For the same degree of relative overweight, men had higher triglyceride, fasting glucose, and insulin levels; higher sums of glucose and insulin levels during an oral glucose tolerance test; and higher blood pressure. Furthermore, elevated fasting glucose levels (greater than 7.4 mM) occurred twice as often in the males. These differences between males and females persisted even after body fat matching. A male risk profile was seen in women characterized by abdominal obesity (high waist/hip circumference ratio) as compared to women with the typical peripheral obesity. Stepwise multiple regression analyses in both women and men showed the obesity complications to be associated in a first step to waist/hip circumference or body fat and in a second to abdominal fat cell size. It may thus be concluded that: (a) In both obese and nonobese subjects, regional differences exist between the sexes with regard to adipose tissue distribution. (b) Moderate expansion of body fat is mainly due to FCW enlargement, which is subsequently followed by increased FCN. (c) Men and women with a male abdominal type of obesity are more susceptible to the effect of excess body fat on lipid and carbohydrate metabolism.

/pdf/impact-of-obesity-on-metabolism-in-men-and-women-importance-1urtb46155.pdf

Impact of obesity on metabolism in men and women. Importance of regional adipose tissue distribution.

"Portal" adipose tissue as a generator of risk factors for cardiovascular disease and diabetes.

'Stress' embraces the reaction to a multitude of poorly defined factors that disturb homeostasis or allostasis. In this overview, the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system have been utilized as objective measurements of stress reactions. Although long-term activation of the sympathetic nervous system is followed by primary hypertension, consequences of similar activation of the HPA axis have not been clearly defined. The focus of this overview is to examine whether or not repeated activation of these two stress centres may be involved in the pathogenesis of abdominal obesity and its comorbidities. In population studies adrenal hormones show strong statistical associations to centralization of body fat as well as to obesity. There is considerable evidence from clinical to cellular and molecular studies that elevated cortisol, particularly when combined with secondary inhibition of sex steroids and growth hormone secretions, is causing accumulation of fat in visceral adipose tissues as well as metabolic abnormalities (The Metabolic Syndrome). Hypertension is probably due to a parallel activation of the central sympathetic nervous system. Depression and 'the small baby syndrome' as well as stress exposure in men and non-human primates are followed with time by similar central and peripheral abnormalities. Glucocorticoid exposure is also followed by increased food intake and 'leptin resistant' obesity, perhaps disrupting the balance between leptin and neuropeptide Y to the advantage of the latter. The consequence might be 'stress-eating', which, however, is a poorly defined entity. Factors activating the stress centres in humans include psychosocial and socioeconomic handicaps, depressive and anxiety traits, alcohol and smoking, with some differences in profile between personalities and genders. Polymorphisms have been defined in several genes associated with the cascade of events along the stress axes. Based on this evidence it is suggested that environmental, perinatal and genetic factors induce neuroendocrine perturbations followed by abdominal obesity with its associated comorbidities.

Do stress reactions cause abdominal obesity and comorbidities

In a prospective study of risk factors for ischemic heart disease, 792 54-yr-old men selected by year of birth (1913) and residence in Goteborg, Sweden, agreed to attend for questioning and a number of anthropometric and other measurements in 1967. Thirteen and one-half years later, these baseline findings were reviewed in relation to the number of men who had subsequently developed diabetes mellitus. This analysis focused on the importance of abdominal adipose tissue distribution, measured as the waist-to-hip circumference ratio, as a predictor for development of diabetes. Even when the confounding effect of body mass index, as a measure of the total body fat mass, was accounted for, the waist-to-hip ratio was positively and significantly associated with the risk for diabetes. These results from a prospective study strongly support previous cross-sectional findings indicating that not only the degree of obesity but also the localization of fat is a risk factor for diabetes.

The Influence of Body Fat Distribution on the Incidence of Diabetes Mellitus: 13.5 Years of Follow-up of the Participants in the Study of Men Born in 1913

Per Björntorp

Papers

Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: 13 year follow up of participants in the study of men born in 1913.

Impact of obesity on metabolism in men and women. Importance of regional adipose tissue distribution.

"Portal" adipose tissue as a generator of risk factors for cardiovascular disease and diabetes.

Do stress reactions cause abdominal obesity and comorbidities

The Influence of Body Fat Distribution on the Incidence of Diabetes Mellitus: 13.5 Years of Follow-up of the Participants in the Study of Men Born in 1913