Euglycemic clamp study in clozapine-induced diabetic ketoacidosis

OBJECTIVE: To describe the fifth case of clozapine-induced diabetic ketoaci dosis (DKA) with complete resolution of abnormal glucose metabolism after d iscontinuation of clozapine as assessed by oral glucose tolerance testing ( OGTT) and the first to be serially studied with markers of pancreatic autoi mmunity; to demonstrate insulin resistance using the euglycemic clamp study and reduced pancreatic insulin reserve using intravenous glucose tolerance testing (IVGTT) in clozapine-induced diabetes mellitus and DKA, when the O GTT was normal; and to systematically review the previously described cases of clozapine-induced diabetes mellitus and DKA. CASE SUMMARY: A 33-year-old white man without past or family history of dia betes mellitus presented with DKA after eight months of clozapine therapy ( 50 mg twice daily). After treatment of DKA and discontinuation of clozapine , glucose tolerance and concurrent serum insulin concentrations reverted to normal as measured by two OGTT performed 60 and 320 days after resolution of DKA. DISCUSSION: Antiislet-cell antibodies, antiglutamic acid decarboxylase anti bodies, and human insulin antibody were negative on two separate occasions. Euglycemic clamp study demonstrated insulin resistance manifested by a glu cose disposal rate of approximately 55% of mean normal values. IVGTT demons trated a low rate of glucose disappearance (K-G = 0.95) and diminished firs t-phase insulin response when OGTT was normal, indicating impairment in ins ulin sensitivity and reduction in beta cell function 323 days after discont inuance of clozapine. This adverse reaction is considered probable accordin g to the Naranjo probability scale. CONCLUSIONS: The occurrence of cases of DKA and new or worsening diabetes m ellitus in patients using clozapine suggests a causal relationship. We hypo thesize that the mechanism by which clozapine may produce glucose intoleran ce may require a preexisting latent defect in insulin secretion and insulin action. With the administration of clozapine, some of these patients may d evelop worsening insulin resistance and may fail to mount an appropriate co mpensatory beta cell insulin secretion for the degree of insulin resistance . As a consequence, hyperglycemia develops and its persistence results in g lucose toxicity, further suppressing beta cell insulin secretion. Such comb ined defects in insulin secretion and sensitivity are known to be synergist ic, leading to the development of abnormal glucose tolerance, which can be clinically manifested as a spectrum ranging from impaired glucose tolerance through sever hyperglycemia to DKA. Patients being started on clozapine sh ould be carefully followed for the development or worsening of diabetes mel litus, regardless of the dose of the drug.