Obesity, diabetes and the central nervous system

Abstract

Nearly 25 years ago, one of us wrote a collaborative review entitled ªObesity and Diabetes, the Odd Coupleº [1]. At that time we pointed out that obesity was a risk factor for diabetes mellitus, despite the fact that most obese people do not have and never will develop diabetes. We also pointed out that obesity is associated with insulin resistance and hyperinsulinaemia, whereas in the non-obese, diabetes is characterized by hypoinsulinaemia and hyperglycaemia. We asked, how is it that such different syndromes interact so closely? We concluded that while these two syndromes are likely to have independent risk factors and mechanisms, their known interactions made it likely that shared metabolic defects are involved in their pathogenesis. We concluded that further studies into the pathophysiology of these syndromes were needed to explain this apparently paradoxical association.In the intervening years, considerable advance has been made into the pathophysiology of both syndromes. First, it is now clear that hyperglycaemia in Type II (non-insulin-dependent) diabetes is not the result of a regulatory failure, but is an adaptive response to impaired beta-cell function and insulin resistance, and we have reviewed this extensively [2]. More recently, obesity has similarly been shown to result from a dysregulation of food intake and energy expenditure rather than a loss of control over food intake [3±5]. In either case the critical variable (blood glucose or body adiposity) is defended at an abnormal level due to a regulatory defect, and both hyperglycaemia and obesity have undesirable long-term metabolic and vascular complications. What is now apparent is that there is overlap among the hormones, neuropeptides, and receptors involved in these two disorders, and it is our belief that it is this sharing which plays a prominent role in their association.In this article, we review our present understanding of the major elements of the feedback loops for body weight regulation in order to provide a comprehensive framework within which to place a torrent of new studies. We focus primarily on recent data implicating insulin, leptin, and hypothalamic neuropeptides as major elements. In this process we point out where the energy balance and glucose regulating systems intersect and indicate where common signalling mechanisms participate in their association. We conclude by synthesizing this information into a model that can explain how a single underlying set of pathophysiological factors can lead first to obesity and subsequently to Type II diabetes. Diabetologia (1998) 41: 863±881

Afferent signals regulating food intake

“…In contrast, chronic infusion of low doses of insulin inhibits feeding (VanderWeele et al 1982). Infusion of insulin into the ventricular system decreases food intake and body weight of baboons (Woods et al 1979) and rodents (Brief & Davis, 1984;Arase et al 1988;McGaowan et al 1993;Schwartz et al 1994;Porte et al 1998). A similar finding was reported for animals eating a highcarbohydrate diet but not in those eating a high-fat diet (Arase et al 1988).…”

Insulin resistance as a modifier of the relationship between dietary fat intake and weight gain

“…As previously discussed, weight gain must be the result of positive energy balance, so how can these observations Macronutrient composition of diet and weight change CL Mosca et al increasing evidence that insulin acts on the central nervous system to inhibit hunger, 31 the reduced insulin excursions may promote greater intake in those on a high-fat diet compared to individuals on a high-carbohydrate diet. It is possible that high fat intake could lead to under-reporting or underestimation of total energy intake, so those who consumed a high-fat diet were in fact consuming more total calories.…”

“…10 There is increasing evidence that insulin acts on the central nervous system to limit hunger as body mass increases. 11 In addition, increased insulin resistance may create a metabolic environment that limits fat storage and increases fat oxidation. 12 These mechanisms would be theoretically protective, promoting weight stabilization in a negative feedback manner.…”

Comments on the relation among GAD-65, IA-2 antibodies and body adiposity

“…The mechanism for this association was not further discussed. Assuming that these autoantibodies indicate prior beta-cell immune damage [2] followed by impaired beta-cell function in this population, we would like to suggest as postulated in our recent review [3] that these findings can be explained by the effect of reduced insulin secretion to increase food intake by reducing the suppressive effect of insulin on the CNS. This is due to insulin's ability to suppress, critical hypothalamic hyperphagic food intake regulatory neuropeptides, particularly neuropeptide-g.…”