Chronic (5-16 hr) exposure of cultured human lymphocytes to 10-8 M insulin at 37° in vitro produced a decrease in insulin receptor concentrations unaccounted for by simple occupancy of sites; acute exposure (0-2 hr) was without effect. These results reproduced observations in vivo where chronic hyperinsulinemia (e.g., 10-8 M insulin in the circulation of obese insulinresistant hyperglycemic mice) is associated with a substantial reduction in the concentration of insulin receptors per cell, while acute hyperinsulinemia in vivo has no effect on receptor concentration. These data suggest a reciprocal relationship between insulin in the extracellular fluid and the concentration of insulin receptors per cell, which is mediated at the target cell itself by intracellular insulin-sensitive regulatory processes and directly affects target-cell sensitivity to hormone.

https://www.pnas.org/content/pnas/71/1/84.full.pdf

Insulin-Dependent Regulation of Insulin Receptor Concentrations: A Direct Demonstration in Cell Culture

Publisher Summary This chapter discusses the endocrine and metabolic effects of the experimental obesity in humans. All the changes witnessed in spontaneous obesity except for the increase in adipocyte number have been reproduced in experimental obesity. It has been found that endocrine and metabolic changes are associated with gain in weight. Normal subjects fattened by eating a mixed diet require more calories in relation to their body surface area for maintenance of the obese state than they require when at their natural weight and also more than the spontaneously obese generally require. There are marked differences in the ability of normal individuals to gain weight by taking calories in excess of those required for maintenance. When weight is gained by normal increase in the intake of fat alone, there is a higher proportion of weight gained to calories ingested, and the weight gained may be maintained by an intake that is no greater than that required to maintain the initial weight. The chapter also describes the hormonal and circulating factors that affect the resistance to insulin in experimental obesity. It also presents evidence for cellular factors in resistance to insulin in experimental obesity and their response to gain in weight and to dietary carbohydrate.

Endocrine and metabolic effects of experimental obesity in man.

Introduction Weight loss is a major concern for the US population. Surveys consistently show that most adults are trying to lose or maintain weight (1). Nevertheless, the prevalence of overweight and obesity has increased steadily over the past 30 years. Currently, 50% of all adult Americans are considered overweight or obese (2,3). These numbers have serious public health implications. Excess weight is associated with increased mortality (4) and morbidity (5). It is associated with cardiovascular disease, type 2 diabetes, hypertension, stroke, gallbladder disease, osteoarthritis, sleep apnea and respiratory problems, and some types of cancer (6,7). Most people who are trying to lose weight are not using the recommended combination of reducing caloric intake and increasing physical activity (1). Although over 70% of persons reported using each of the following strategies at least once in 4 years, increased exercise (82.2%), decreased fat intake (78.7%), reduced food amount (78.2%,) and reduced calories (73.2%), the duration of any one of these behaviors was brief. Even the most common behaviors were used only 20% of the time (8). Obesity-related conditions are significantly improved with modest weight loss of 5% to 10%, even when many patients remain considerably overweight (6). The Institute of Medicine (9) defined successful long-term weight loss as a 5% reduction in initial body weight (IBW) that is maintained for at least 1 year. Yet data suggest that such losses are not consistent with patients’ goals and expectations. Foster (10) reported that in obese women (mean body mass index [BMI] of 36.3 6 4.3) goal weights targeted, on average, a 32% reduction in IBW, implying expectations that are unrealistic for even the best available treatments. Interestingly, the most important factors that influenced the selection of goal weights were appearance and physical comfort rather than change in medical condition or weight suggested by a doctor or health care professional. Is it any wonder that overweight individuals are willing to try any new diet that promises quick, dramatic results more in line with their desired goals and expectations than with what good science supports? The proliferation of diet books is nothing short of phenomenal. A search of books on Amazon.com using the key words “weight loss” revealed 1214 matches. Of the top 50 best-selling diet books, 58% were published in 1999 or 2000 and 88% were published since 1997. Many of the top 20 best sellers at Amazon.com promote some form of carbohydrate (CHO) restriction (e.g., Dr. Atkins’ New Diet Revolution, The Carbohydrate Addict’s Diet, Protein Power, Lauri’s Low-Carb Cookbook). This dietary advice is counter to that promulgated by governmental agencies (US Department of Agriculture [USDA]/Department of Health and Human Services, National Institutes of Health) and nongovernmental organizations (American Dietetic Association, American Heart Association, American Diabetes Association, American Cancer Society, and Shape Up America!). What is really known about popular diets? Is the information scientifically sound? Are popular diets effective for weight loss and/or weight maintenance? What is the effect, if any, on composition of weight loss (fat vs. lean body mass), micronutrient (vitamin and mineral) status, metabolic parameters (e.g., blood glucose, insulin sensitivity, blood pressure, lipid levels, uric acid, and ketone bodies)? Do they affect hunger and appetite, psychological well-being, and reduction of risk for chronic disease (e.g., coronary heart disease, diabetes, and osteoporosis)? What are the effects of these diets on insulin and leptin, long-term hormonal regulators of energy intake and expenditure? The objective of this article is to review the scientific literature on various types of popular diets based on their macronutrient composition in an attempt to answer these questions (see Appendix for diet summaries). Address correspondence to Dr. Janet King, U.S. Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, University of California, 1 Shield Avenue, Building Surge IV, Room 213, Davis, CA 95616. E-mail: jking@ whnrc.usda.gov Copyright © 2001 NAASO

Popular Diets: A Scientific Review

The association of obesity and hypertension is well recognized. Although the frequency of hypertension in obese subjects varies depending upon the age, race, and sex of the population studied, as well as the definitions employed for 'hypertension' and 'obesity", several reports suggest that as many as 50 to 60 percent of overweight people have high blood pressure [1, 2]. Hypertension, more importantly, is probably the major factor accounting for increased cardiovascular disease in the obese [3, 4]. Despite the importance of the clinical problem, the fundamental nature of the association between obesity and hypertension has been obscure. Recent epidemiological and physiological studies, however, suggest that insulin and the sympathetic nervous system may be involved, and that the hypertension of obesity may be the unfortunate by-product of mechanisms that establish energy balance and limit weight gain.

Diet, Obesity and Hypertension: An Hypothesis Involving Insulin, the Sympathetic Nervous System, and Adaptive Thermogenesis

https://deepblue.lib.umich.edu/bitstream/handle/2027.42/25560/0000102.pdf?sequence=1

Sweet tooth reconsidered: Taste responsiveness in human obesity

During two successive three-week periods, seven obese subjects were fed isocaloric diets, the first low, the second high in carbohydrate. In all, basal plasma insulin levels decreased 50 per cent on the low-carbohydrate diet and increased on the high-carbohydrate diet. Three obese subjects were fed, during three successive four-week periods, 1500-calorie diets with high, then low, and then high-carbohydrate content. Basal plasma insulin levels were significantly reduced on the low-carbohydrate diet. Refeeding of the high-carbohydrate diet, despite continued weight loss, resulted in markedly increased basal plasma insulin. In both protocols, most patients also exhibited a decreased insulin secretory response to oral glucose when on a low intake of carbohydrate and an increased response on a high intake. Thus the hyperinsulinemia characteristic of obesity may be a result, in part, of dietary factors rather than exclusively a consequence of the insulin antagonism associated with obesity.

https://www.nejm.org/doi/pdf/10.1056/NEJM197110072851504?listPDF=true

Effect of Diet Composition on the Hyperinsulinemia of Obesity

The present study was undertaken to determine whether alterations in ketone body utilization and hepatic production, independent of the FFA load, were also involved in the development of fasting ketosis. Plasma Beta-OH butyric acid (Beta-OHB) increased to 2.5-4.5 mM and plasma FFA to 1,000-1,400 muEq/L. in normal weight individuals after five to seven days' starvation and in obese subjects after ten to fourteen days' fasting. Acute elevations fo the plasma FFA greater than 1,500 muEq/L. for sixty minutes in fed normal weight and obese subjects with a fat meal-heparin regimen resulted in peak elevations of plasma Beta-OHB (0.25-0.45mM), only 10 percent of that seen during fasting. When plasma FFA were lowered acutely during fasting with the antilipolytic agent Pyrazole to control levels (400-600 muEq/L.), plasma Beta-OHB decreased 35 plus or minus 5 per cent. Comparable lowering of plasma FFA in normal weight or obese starved subjects given dexamethasone to maintain elevated fasting plasma insulin levels resulted in an 87 plus or minus 3 per cent decrease in plasma Beta-OHB. Similar studies in obese fasted subjects pretreated with an intravenous infusion of insulin (1.0 U/hr. for eight hours) before receiving Pyrazole resulted in a 65 plus or minus 5 per cent decrease in plasma Beta-OHB. Plasma Beta-OHB half-life, determined after injections of 12 gm. Beta-OHB, increased significantly during fasting (110 plus or minus 15 minutes) and was decreased when the fasting subjects were maintained on dexamethasone (65 plus or minus 7 minutes). These studies indicate that accelerated hepatic ketogenesis during starvation is a result of both enhanced activity of the enzymatic system(s) involved in ketone body production as well as an increased FFA load. The increase in plasma Beta-OHB during fasting reflects not only an accelerated rate of hepatic ketogenesis but also an impairment of peripheral utilization, both processes apparently being sensitive to insulin. Diabetes 24:10-16, January, 1975.

Neil J Grey

Papers

Effect of Diet Composition on the Hyperinsulinemia of Obesity

Physiologic Mechanisms in the Development of Starvation Ketosis in Man