Insulin Signaling in the Central Nervous System

A Critical Role in Metabolic Homeostasis and Disease From C. elegans to Humans

Daniel Porte, Jr.; Denis G. Baskin; Michael W. Schwartz

Disclosures

Diabetes. 2005;54(5):1264-1276. 

In This Article

Implications for the Association of Type 2 Diabetes With Obesity

A major mechanism linking obesity and type 2 diabetes is the effect of excessive body fat deposition to induce peripheral tissue insulin resistance, thereby increasing the demand on the β-cell, and if the increased secretory demand cannot be met, hyperglycemia ensues. However, this mechanism in and of itself may not fully explain the close association between obesity and diabetes, and viable alternatives warrant careful consideration. It is possible, for example, that a shared defect contributes to the pathogenesis of both disorders. According to this hypothesis, an underlying genetic defect or set of defects that are sensitive to environmental factors predispose first to positive energy balance and weight gain and, as the disorder progresses, to impaired glucose homeostasis and diabetes (Fig. 2). Since glucose intolerance is clearly exacerbated by obesity-induced peripheral insulin resistance, this model proposes that a feed-forward process is set in motion, whereby the more weight is gained the greater the deterioration of glucose homeostasis. Here, we suggest that although several factors can set this pathophysiological sequence in motion, impaired insulin signal transduction in tissues throughout the body, including the CNS, plays a fundamental role.

Model for the link between diabetes and obesity related to insulin. Obesity (increased adipose mass) and diabetes (increased plasma glucose) are linked by a common dependence on insulin action and secretion in peripheral tissues and brain.

As should now be evident, both body weight regulation and glucose homeostasis rely in part on a common set of intracellular signaling mechanisms. It therefore follows that both processes would be impaired if reduced insulin signaling were to occur in tissues throughout the body. Due to defects in either insulin secretion or cellular insulin sensitivity (or both), insulin action is by definition reduced in tissues of individuals with type 2 diabetes. It therefore follows that unless tissue-specific defects are present in type 2 diabetes that spare the brain, CNS insulin action is likely to be reduced in affected individuals as well. If this were to occur early in the natural history of this disorder, excessive weight gain would be expected and could therefore serve as an initiating event.[92]

Any of several mechanisms—defective insulin secretion, reduced blood-brain barrier insulin transport, or reduced neuronal responsiveness to insulin—can be invoked to explain how insulin action in the brain of affected individuals might be attenuated. Perhaps because of their overlapping roles in reproduction and nutrition, the same neuronal targets and signal transduction mechanisms used by insulin are also used by leptin. Hence, disruption of this signaling system is predicted to compromise negative feedback from all known adiposity signals, and increased caloric intake and storage is the predicted outcome.

Based on these considerations, impaired insulin secretion can also be viewed as a primary event, at least in some cases, since it is expected to favor weight gain, with other factors remaining unchanged. Because deficient insulin signaling in peripheral tissues increases hepatic glucose production and decreases glucose utilization, such weight gain should be coupled to a predisposition to hyperglycemia, depending on the magnitude of the secretory defect and the ability of islet β-cells to compensate.

Examples from the clinical literature are instructive for the evaluation of this hypothesis. Among them are patients with maturity-onset diabetes of the young type 2, characterized by a mild isolated defect of insulin secretion due to a coding region mutation of the glucokinase gene. Because this defect is readily and almost completely compensated for by hyperglycemia, at least initially, the underlying defect is difficult to detect.[93] In such individuals, the contribution of an isolated mild impairment of insulin secretion to the development of obesity is inherently limited, since insulin levels remain near normal as glucose levels increase promptly. However, if the demand placed on the islet increases due to environmental factors (e.g., consumption of a high-fat diet) or when present in combination with a genetic propensity toward obesity, then the need to increase insulin secretion rises in a curvilinear fashion to compensate for the associated insulin resistance.[94] Under these conditions, the insulin secretory defect may become more overt, and food intake and body weight will increase as a result. As weight increases, so does insulin resistance, and while this response may initially help to normalize plasma insulin levels and limit further weight gain, hyperglycemia will result if this β-cell compensation is incomplete. These considerations highlight the interwoven nature of consequences arising from reduced insulin signaling in both CNS and periphery that favor the association of diabetes with obesity.

The association between these two disorders may be further strengthened by peripheral metabolic consequences of reduced neuronal insulin signaling. For example, recent studies[27,28] demonstrate that reduced hypothalamic neuronal insulin signaling causes hepatic insulin resistance. If β-cell function is intact, increased insulin output can compensate completely or almost completely for insulin resistance, and both hyperglycemia and excessive storage of body fat will be minimized. However, any limitation to β-cell compensation will permit hyperglycemia to develop once insulin secretion falls below that needed to suppress hepatic glucose output and maintain normal glucose levels, and the propensity for obesity will again be increased. This vicious cycle can theoretically progress until insulin deficiency becomes severe, at which point glycosuria and unrestrained lipolysis become prominent and prevent further weight gain. Thus, whether the initial defect lies in the capacity to secrete insulin or to activate insulin signal transduction (in brain or periphery), food intake and weight will rise and the associated insulin resistance will lead to the development of hyperglycemia if β-cell compensation is impaired.

The rapid increase in obesity prevalence over the past 10-15 years in our society is, not unexpectedly, paralleled by an alarming increase in the prevalence of type 2 diabetes. Among many factors implicated in this trend is the ready availability of high-density, highly palatable foods of relatively low cost[95,96] and a lifestyle that demands little in the way of physical activity. The opportunity to study a population of Japanese Americans in Seattle, who have maintained their genetic identity by intermarriage into the second and third generation, allowed us to evaluate this progression prospectively to identify risk factors for the development of type 2 diabetes and the associated risk of cardiovascular disease.[97] Among the potential risk factors in this population was a polymorphism in the β-cell glucokinase promoter that was both common (frequency 25%) and associated with a 30% reduction in the early insulin response to glucose and a significantly increased risk of impaired glucose tolerance.[98,99] The functional significance of this -30 G/A polymorphism in Caucasians was recently confirmed and extended by Weedon et al..[100]

In studies by Fujimoto and colleagues,[97,101] Japanese Americans progressing to type 2 diabetes were compared with those who did not at baseline and after 2.5 and 5 years of observation. While both progressor groups had impaired early insulin secretion at baseline compared with nonprogressors, increased abdominal obesity was present at baseline only among those progressing to diabetes within 2.5 years, while those who developed diabetes at 5 years did not develop excess intra-abdominal fat until that assessment. Thus, this population is characterized by a genetic risk factor for impaired insulin secretion whose progression from normal glucose tolerance to diabetes was associated with impaired insulin secretion 5 years before the development of intra-abdominal fat, the best obesity-related correlate of insulin resistance identified so far.[102]

Based on the high prevalence of the glucokinase promoter polymorphism in this population, a high proportion of the population is hypothesized to have inherited a mild defect of insulin secretion that was not expressed clinically as long as body weight was not excessive. As the population aged and consumed an increasingly high-fat, highly palatable western diet, the frequency of obesity and impaired glucose tolerance increased. While a high-fat diet may induce a reduction of central insulin action to increase food intake and lead to obesity,[103] we hypothesize that increased calorie ingestion in this population was also facilitated by relatively impaired insulin secretion, which in turn favored increased deposition of intra-abdominal fat and subsequent insulin resistance. Increased body fat in this situation can therefore be interpreted as compensation, in part, for a genetic defect in insulin secretion leading to increased insulin levels until a new steady state of obesity and hyperglycemia is reached. Final progression from impaired glucose tolerance or early type 2 diabetes to overt clinical hyperglycemia is associated with a progressive deterioration of β-cell function. This delayed deterioration is well described and may relate to toxic factors secondary to lipid[104] or glucose excess[105] and/or to amyloid deposition in islet β-cells,[106,107] leading to β-cell death and further impairment of insulin secretion despite treatment.[108]

These observations support a model in which diabetes and obesity can be functionally linked to one another by β-cell abnormalities that predispose to both weight gain and hyperglycemia. This progression is exacerbated by environmental factors and common gene variants that favor weight gain and further increase the demand on the β-cell. Genetic defects that can contribute to this pathophysiological sequence are likely to be common, varied in nature, and modest with respect to their functional consequences. Inheritance of one or more of these gene variants, in combination with environmental factors, is presumably required to produce the obesity and insulin resistance syndromes. In addition to primary lesions affecting insulin secretion, candidate genes could also include those predisposing to insulin resistance. In isolation, such defects may have a limited impact, but in the presence of environmental factors that predispose to β-cell stress and/or damage (such as high fat feeding,[104] mild chronic hyperglycemia,[105] or peripheral insulin resistance) could suffice to set this pathophysiological sequence in motion. Regardless of whether underlying gene defects affect insulin secretion or action, those individuals with impaired β-cell responses would tend to be the most obese and therefore have the greatest risk for the development of the obesity-diabetes syndrome.

From this perspective, preventive treatments aimed at either insulin resistance or impaired insulin secretion should slow the progression of hyperglycemia. While supporting this hypothesis, recent experience with the thiazolidinedione class of insulin-sensitizing drugs, which reduce hyperglycemia and hyperinsulinemia, demonstrates a key problem: a high prevalence of undesirable weight gain.[109] This weight gain may be related to the propensity of these agents to differentiate preadipocytes into mature cells and to favor fat deposition. However, the insulin- and leptin-lowering effects of these drugs might aggravate obesity by reducing adiposity-related signaling in the hypothalamus.

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