International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #4: Classification of Diabetes Mellitus and Other Categories of Glucose Intolerance Part 4 of 6

Antipsychotic agents

There is accumulating evidence supporting an association of certain psychiatric conditions with type 2 diabetes which can be attributed to side-effects of treatment and a high baseline risk of diabetes in this patient group [48]. Diabetes can be induced by the use of atypical antipsychotics including clozapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. These drugs have a direct effect of raising blood glucose and also lead to weight gain, [48] which subsequently may increase blood glucose levels.

Clozapine and olanzapine have been associated with a higher risk of diabetes than other antipsychotic agents in several studies [48]. These drugs have been associated with new-onset diabetes, exacerbation of pre-existing diabetes, and presentations with complications such as ketoacidosis.The data on risperidone and quetiapine in the studies mentioned earlier show inconsistent findings [48].

Atypical antipsychotics may have an independent effect on insulin sensitivity. Studies comparing insulin sensitivity in patients taking clozapine, olanzapine, or risperidone showed that those in clozapine and olanzapine groups had significantly decreased insulin sensitivity compared to risperidone groups. While there is generally less long-term data on aripiprazole and ziprasidone, a comparison of olanzapine and aripiprazole use in schizophrenic patients showed an increase in glucose in the olanzapine group [48].

Anti-HIV agents

Diabetes is fourfold more common in HIV-infected men exposed to highly active antiretroviral therapy (HAART) than HIV-negative men. Although most of the diabetes observed in this group is type 2 there has been a recent report of autoimmune diabetes and the development of anti-GAD antibodies after immune system recovery post HAART therapy [49], which suggests that type 1 diabetes can also arise in this group from treatment.

HAART is based on the use of a class of drugs known as protease inhibitors (PIs) and include atazanavir, darunavir, saquinavir, and ritonavir. PIs have been shown to increase insulin resistance and reduce insulin secretion, by interfering with GLUT-4 mediated glucose transport. PIs interfere with cellular retinoic acid-binding protein type 1 which interacts with peroxisomal proliferator-activated gamma (PPARγ) receptor. Inhibition of PPARγ promotes adipocyte inflammation, release of free fatty acids and insulin resistance [49]. Hyperglycemia resolves in almost all patients when PIs are discontinued [49] and all PIs do not have the same metabolic effects, with some drugs having a worse adverse effect than others.

Apart from HAART, another class of anti-HIV drugs associated with diabetes are the nucleoside analogs (reverse transcriptase inhibitors) (NRTIs) [50] especially when used for long periods of time [51]. The risk of diabetes is highest with stavudine, but the risk is also significant with zidovudine and didanosine. Proposed mechanisms include insulin resistance, lipodystrophy, and mitochondrial dysfunction [51]. It is postulated that PIs confer acute metabolic risks, while NRTIs confer cumulative risks of diabetes in predisposed, exposed persons. The use of both classes of drugs may be additive for diabetes risk [51].

Glucocorticoids

Glucocorticoids are the most common cause of drug-induced diabetes. They are used in the treatment of many medical conditions but are mostly prescribed for their anti-inflammatory effects [52]. They act through multiple pathways at the cellular and molecular levels, suppressing the cascades that would otherwise result in inflammation and promoting pathways that produce anti-inflammatory protein [53]. The mechanism by which glucocorticoids cause diabetes is thought to be mainly via insulin resistance, but there is also some evidence of effects on insulin secretion [54].

The effect of glucocorticoids is mainly on nonfasting glucose rather than fasting glucose levels [52], but there is uncertainty as to whether this reflects a relationship with clock time (perhaps linked to dosing times), or to a predominant effect on postprandial blood glucose levels.

Infections

Certain viruses have been associated with β-cell destruction. Diabetes occurs in some patients with congenital rubella [55]. Coxsackie B, cytomegalovirus, and other viruses (e.g. adenovirus and mumps) have been implicated in inducing diabetes [56–58].

Uncommon but specific forms of immune-mediated diabetes mellitus

Diabetes may be associated with several immunologic diseases with a pathogenesis or etiology different from that which leads to the type 1 diabetes process. Postprandial hyperglycemia of a severity sufficient to fulfill the criteria for diabetes has been reported in rare individuals who spontaneously develop insulin autoantibodies. However, these individuals generally present with symptoms of hypoglycemia rather than hyperglycemia [59]. The “stiff man syndrome” is an autoimmune disorder of the central nervous system, characterized by stiffness of the axial muscles with painful spasms. Affected people usually have high titers of anti-GAD and approximately one third to one half will develop type 1 diabetes [60].

Anti-insulin receptor antibodies can cause diabetes by binding to the insulin receptor thereby reducing the binding of insulin to target tissues [61]. However, these antibodies can also act as an insulin agonist after binding to the receptor and can thereby cause hypoglycemia [62]. Anti-insulin receptor antibodies are occasionally found in patients with systemic lupus erythematosus and other autoimmune diseases [63].

Other genetic syndromes associated with diabetes

Many genetic syndromes are accompanied by an increased incidence of diabetes mellitus. These include the chromosomal abnormalities of Down syndrome, Klinefelter syndrome, and Turner syndrome. These and other similar disorders are listed in Table 1.4.

Diabetes is commonly observed in cystic fibrosis patients. While it shares features of type 1 and type 2 diabetes, cystic fibrosis-related diabetes (CFRD) is a distinct clinical entity. It is primarily caused by insulin insufficiency, although fluctuating levels of insulin resistance related to acute and chronic illness and medications such as bronchodilators and glucocorticoids also play a role [64]. Since blood glucose levels within the IGT range appear to have an adverse effect on lung function, it has been suggested that diagnostic criteria for CFRD should be lower than that for other forms of diabetes, but data are currently inadequate to make this change [64]. CFRD is not associated with atherosclerotic vascular disease, despite the fact that individuals with cystic fibrosis nowadays can have a lifespan well into the 50s and 60s.

There are several distinct clinically defined subgroups of diabetes where an etiology has not yet been defined. In recognition of this, during the most recent WHO consultation, it was recommended that a category of “unclassified” or “nonclassical phenotype” be available.

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