Mechanisms by Which the Atypical Antipsychotic Agents May Cause Diabetes Mellitus

There are a number of ways in which the atypical antipsychotic medications could lead to hyperglycemia and diabetes mellitus. As discussed earlier in this chapter, decreased sensitivity (increased resistance) to insulin and decreased insulin secretion as a result of decreased beta cell function are involved in the development of type II diabetes mellitus. A few controlled studies suggest that the atypical antipsychotic medications affect insulin resistance rather than causing a primary defect in insulin secretion (Henderson et al. 2000b; Selke et al. 2000). The insulin resistance seen during atypical antipsychotic treatment may be a result of increased central adiposity, or it may arise from the direct effect of the medication's action on the glucose transporter function (Haupt and Newcomer 2001). Dwyer et al. (1999) studied the effects of atypical antipsychotic agents on glucose transporter function. They suggested that a structure-function relationship exists in which similar drugs, such as clozapine and olanzapine, achieve relatively higher intracellular concentrations and bind to, and thus interfere with, the function of the glucose transporter proteins (Haupt and Newcomer 2001).

Another mechanism by which the atypical antipsychotic agents may lead to hyperglycemia and diabetes mellitus is antagonism of the serotonin 5-HT1A receptors. Antagonism of the 5-HT1A receptors may decrease pancreatic beta cell responsiveness to blood sugar levels, resulting in disturbances in glucose metabolism secondary to decreased insulin secretion (Wirshing et al. 1998). Melkersson and colleagues, however, found that patients treated with olanzapine had higher fasting insulin levels on comparison of baseline to 5-month follow-up, suggesting that impaired beta cell function is an unlikely cause for olanzapine-associated diabetes mellitus (Melk-ersson et al. 2000). Their group found that although 11 of 14 olanzapine-treated patients (79%) were normoglycemic, and only 3 showed increased blood glucose values, the majority of patients (10 of 14, or 71%) had insulin levels above the normal limit. The report also noted increased rates of hyperleptinemia, hypertriglyceridemia, and hypercholesterolemia. In short, Melkersson and colleagues found that olanzapine treatment was associated with weight gain and elevated levels of insulin, leptin, and blood glucose levels as well as insulin resistance, with 3 patients diagnosed with diabetes mellitus (Melkersson et al. 2000). The elevated insulin values argue against the theory that antagonism of the serotonin receptors by some atypical anti-psychotic agents, a property that could theoretically lead to decreased beta cell insulin production, causes hyperglycemia and diabetes mellitus. It is also worth noting that olanzapine has little affinity for 5-HT1A receptors.

Central obesity is a significant risk factor for the development of type II diabetes mellitus in schizophrenic patients as well as in the general population. The risk for the development of type II diabetes in mildly obese individuals has been reported as 2-fold, in moderately obese individuals

5-fold, and in severely obese individuals 10-fold (Pi-Snyder 1993). It seems, however, that the duration of obesity is a greater determinant of risk than simply being obese. That is, if a patient gains a considerable amount of weight and maintains this weight, his or her risk of developing hyperglycemia or type II diabetes mellitus appears to be increased (Henderson 2001a).

Notably, in several of the case studies and research studies mentioned in this chapter, weight gain was not associated with the development of diabetes mellitus or DKA during atypical antipsychotic therapy. Indeed, many of the individuals who developed diabetes mellitus or DKA were of normal weight. Thus, while all obese individuals are at increased risk for the development of type II diabetes mellitus, the added obesity caused by the atypical antipsychotic medications does not appear to be the sole reason for the development of diabetes mellitus or DKA in schizophrenia patients. Nevertheless, if a schizophrenia patient gains a considerable amount of weight and maintains that weight, his or her risk of developing type II diabetes is significantly increased.

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