The prevalence of obesity is rapidly increasing globally. Epidemiological studies have associated obesity with a range of cancer types, although the mechanisms by which obesity induces or promotes tumorigenesis vary by cancer site. These include insulin resistance and resultant chronic hyperinsulinaemia, increased bioavailability of steroid hormones and localized inflammation. Gaining a better understanding of the relationship between obesity and cancer can provide new insight into mechanisms of cancer pathogenesis.

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Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms

Iatrogenic hypoglycemia causes recurrent morbidity in most people with type 1 diabetes and many with type 2 diabetes, and it is sometimes fatal. The barrier of hypoglycemia generally precludes maintenance of euglycemia over a lifetime of diabetes and thus precludes full realization of euglycemia’s long-term benefits. While the clinical presentation is often characteristic, particularly for the experienced individual with diabetes, the neurogenic and neuroglycopenic symptoms of hypoglycemia are nonspecific and relatively insensitive; therefore, many episodes are not recognized. Hypoglycemia can result from exogenous or endogenous insulin excess alone. However, iatrogenic hypoglycemia is typically the result of the interplay of absolute or relative insulin excess and compromised glucose counterregulation in type 1 and advanced type 2 diabetes. Decrements in insulin, increments in glucagon, and, absent the latter, increments in epinephrine stand high in the hierarchy of redundant glucose counterregulatory factors that normally prevent or rapidly correct hypoglycemia. In insulin-deficient diabetes (exogenous) insulin levels do not decrease as glucose levels fall, and the combination of deficient glucagon and epinephrine responses causes defective glucose counterregulation. Reduced sympathoadrenal responses cause hypoglycemia unawareness. The concept of hypoglycemia-associated autonomic failure in diabetes posits that recent antecedent hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness. By shifting glycemic thresholds for the sympathoadrenal (including epinephrine) and the resulting neurogenic responses to lower plasma glucose concentrations, antecedent hypoglycemia leads to a vicious cycle of recurrent hypoglycemia and further impairment of glucose counterregulation. Thus, short-term avoidance of hypoglycemia reverses hypoglycemia unawareness in most affected patients. The clinical approach to minimizing hypoglycemia while improving glycemic control includes 1 ) addressing the issue, 2 ) applying the principles of aggressive glycemic therapy, including flexible and individualized drug regimens, and 3 ) considering the risk factors for iatrogenic hypoglycemia. The latter include factors that result in absolute or relative insulin excess: drug dose, timing, and type; patterns of food ingestion and exercise; interactions with alcohol and other drugs; and altered sensitivity to or clearance of insulin. They also include factors that are clinical surrogates of compromised glucose counterregulation: endogenous insulin deficiency; history of severe hypoglycemia, hypoglycemia unawareness, or both; and aggressive glycemic therapy per se, as evidenced by lower HbA 1c levels, lower glycemic goals, or both. In a patient with hypoglycemia unawareness (which implies recurrent hypoglycemia) a 2- to 3-week period of scrupulous avoidance of hypoglycemia is advisable. Pending the prevention and cure of diabetes or the development of methods that provide glucose-regulated insulin replacement or secretion, we need to learn to replace insulin in a much more physiological fashion, to prevent, correct, or compensate for compromised glucose counterregulation, or both if we are to achieve near-euglycemia safely in most people with diabetes.

https://care.diabetesjournals.org/content/diacare/26/6/1902.full.pdf

Hypoglycemia in Diabetes

Endometrial cancer is a disease of the affluent, developed world, where epidemiological studies have shown that > or =40% of its incidence can be attributed to excess body weight. An additional proportion may be because of lack of physical activity. Alterations in endogenous hormone metabolism may provide the main links between endometrial cancer risk, and excess body weight and physical inactivity. Epidemiological studies have shown increased endometrial cancer risks among pre- and postmenopausal women who have elevated plasma androstenedione and testosterone, and among postmenopausal women who have increased levels of estrone and estradiol. Furthermore, there is evidence that chronic hyperinsulinemia is a risk factor. These relationships can all be interpreted in the light of the "unopposed estrogen" hypothesis, which proposes that endometrial cancer may develop as a result of the mitogenic effects of estrogens, when these are insufficiently counterbalanced by progesterone. In our overall synthesis, we conclude that development of ovarian hyperandrogenism may be a central mechanism relating nutritional lifestyle factors to endometrial cancer risk. In premenopausal women, ovarian hyperandrogenism likely increases risk by inducing chronic anovulation and progesterone deficiency. After the menopause, when progesterone synthesis has ceased altogether, excess weight may continue increasing risk through elevated plasma levels of androgen precursors, increasing estrogen levels through the aromatization of the androgens in adipose tissue. The ovarian androgen excess may be because of an interaction between obesity-related, chronic hyperinsulinemia with genetic factors predisposing to the development of ovarian hyperandrogenism.

https://cebp.aacrjournals.org/content/cebp/11/12/1531.full.pdf

Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review.

The aetiology of Polycystic Ovary Syndrome (PCOS) is complex and multifactorial. There is much evidence, however, to suggest that adipose tissue plays an important role in the development and maintenance of PCOS pathology. There is a close correlation between adiposity and symptom severity in women with PCOS, and even modest reductions in weight generally translate into significant improvements in menstrual regularity, fertility and hyperandrogenic features. This review article considers the various mechanisms that might underlie this link between excess adiposity and PCOS - including the effects of differential insulin sensitivity, abnormal steroid hormone metabolism and adipocytokine secretion. Greater attention to the therapeutic options available to reduce the impact of excess adiposity on ovarian and metabolic function is essential to the management of PCOS.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2265.2006.02587.x

Obesity and polycystic ovary syndrome

This Opinion of the EFSA Panel on Dietetic Products, Nutrition, and Allergies (NDA) deals with the establishment of Dietary Reference Values for carbohydrates and dietary fibre. Nutritionally, two broad categories of carbohydrates can be differentiated: “glycaemic carbohydrates”, i.e. carbohydrates digested and absorbed in the human small intestine, and ‘dietary fibre’, non-digestible carbohydrates passing to the large intestine. In this Opinion, dietary fibre is defined as non-digestible carbohydrates plus lignin. The absolute dietary requirement for glycaemic carbohydrates is not precisely known but will depend on the amount of fat and protein ingested. The Panel proposes 45 to 60 E% as the reference Intake range for carbohydrates applicable to both adults and children older than one year of age. Although high frequency of intake of sugar-containing foods can increase the risk of dental caries, there are insufficient data to set an upper limit for (added) sugar intake. Based on the available evidence on bowel function, the Panel considers dietary fibre intakes of 25 g/day to be adequate for normal laxation in adults. A fibre intake of 2 g/MJ is considered adequate for normal laxation in children from the age of one year. Although there is some experimental evidence that a reduction of the dietary glycaemic index and glycaemic load may have favourable effects on some metabolic risk factors such as serum lipids, the evidence for a role in weight maintenance and prevention of diet-related diseases is inconclusive.

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Scientific Opinion on Dietary Reference Values for carbohydrates and dietary fibre

Physical activity has a beneficial effect on insulin sensitivity in normal as well as insulin resistant populations. A distinction should be made between the acute effects of exercise and genuine training effects. Up to two hours after exercise, glucose uptake is in part elevated due to insulin independent mechanisms, probably involving a contraction-induced increase in the amount of GLUT4 associated with the plasma membrane and T-tubules. However, a single bout of exercise can increase insulin sensitivity for at least 16 h post exercise in healthy as well as NIDDM subjects. Recent studies have accordingly shown that acute exercise also enhances insulin stimulated GLUT4 translocation. Increases in muscle GLUT4 protein content contribute to this effect, and in addition it has been hypothesized that the depletion of muscle glycogen stores with exercise plays a role herein. Physical training potentiates the effect of exercise on insulin sensitivity through multiple adaptations in glucose transport and metabolism. In addition, training may elicit favourable changes in lipid metabolism and can bring about improvements in the regulation of hepatic glucose output, which is especially relevant to NIDDM. It is concluded that physical training can be considered to play an important, if not essential role in the treatment and prevention of insulin insensitivity.

H. A. Keizer

Papers

Exercise and insulin sensitivity: a review.