A 40-year-old woman has experienced chest pain on exertion for the past 2 months. A month ago, she had pneumonia with Streptococcus pneumoniae cultured from her sputum. On physical examination, she has a body mass index of 35. A random blood glucose value is 132 mg/dL. The next day, fasting blood glucose is 120 mg/dL, followed by a value of 122 mg/ dL on the following day. She is given an oral glucose tolerance test, and her blood glucose is 240 mg/dL 2 hours after receiving the standard 75-g glucose dose. On the basis of these findings, she is prescribed an oral thiazolidinedione (TZD) drug. After 2 months of therapy, her fasting blood glucose is 90 mg/ dL. The beneficial effect of TZD in this patient is most likely related to which of the following processes?
Correct Answer: Activation of PPARg nuclear receptor in adipocytes
Description: The clinical features of obesity with angina and glucose intolerance in this patient strongly suggest type 2 diabetes mellitus. This is confirmed by the oral glucose tolerance test (>200 mg/dL at 2 hours), useful in this case because her fasting blood glucose levels of 120 mg/dL and 122 mg/dL did not quite reach the diagnostic criterion of 126 mg/dL. The fundamental abnormality in type 2 diabetes mellitus is insulin resistance. Several adipocyte-derived molecules, such as adiponectin and resistin, have been implicated in the causation of insulin resistance, establishing the link between obesity and type 2 diabetes mellitus. The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARg) has emerged as a key molecule in the regulation of insulin resistance through its actions on adipocyte hormones. TZDs bind to and activate PPARg in adipocytes, and increase the levels of the insulin-sensitizing hormone adiponectin and reduce the levels of free fatty acids and resistin, both of which increase insulin resistance. Insulin autoantibodies are seen with type 1 diabetes mellitus. Beta-cell loss and density of insulin receptors are not major factors in the pathogenesis of type 2 diabetes mellitus. TZDs do not affect the metabolism of insulin. Glucagon excess worsens diabetes, but TZDs do not affect its secretion. Beta cells do not regenerate, but many antidiabetogenic drugs in type 2 diabetes mellitus are designed to work with the beta cells that are left.
Category:
Pathology
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