A 43-year-old woman volunteers for a clinical trial testing a medication for type 2 diabetes mellitus. She was diagnosed with diabetes mellitus 5 years ago, and her blood sugar has recently been uncontrolled despite taking the maximum tolerated dose of metformin. The subject's medical history is otherwise unremarkable, and she takes no concurrent medications that would disqualify her from enrolling in the trial. Initial laboratory studies show a fasting glucose of 155 mg/dL and hemoglobin A1c of 8.2%. A urine pregnancy test is negative, and other screening tests are normal. The study drug activates peroxisome proliferator-activated receptor gamma, a nuclear receptor and transcription factor. Activation of this receptor would most likely result in which of the following metabolic changes?

Question

A 43-year-old woman volunteers for a clinical trial testing a medication for type 2 diabetes mellitus.  She was diagnosed with diabetes mellitus 5 years ago, and her blood sugar has recently been uncontrolled despite taking the maximum tolerated dose of metformin.  The subject's medical history is otherwise unremarkable, and she takes no concurrent medications that would disqualify her from enrolling in the trial.  Initial laboratory studies show a fasting glucose of 155 mg/dL and hemoglobin A1c of 8.2%.  A urine pregnancy test is negative, and other screening tests are normal.  The study drug activates peroxisome proliferator-activated receptor gamma, a nuclear receptor and transcription factor.  Activation of this receptor would most likely result in which of the following metabolic changes?

Quizplus · Accepted Answer

11ec160b_3bb0_1798_9249_8b516a501c8e_MD0001_00 This clinical trial is studying a thiazolidinedione (TZD), a class of medications that decrease insulin resistance. TZDs (eg, pioglitazone) bind to peroxisome proliferator-activated receptor gamma (PPAR-γ), a transcriptional regulator of genes involved in glucose and lipid metabolism. The activated complex then binds to the transcriptional regulatory sequence of target genes; important genes upregulated by TZDs include: TZDs are functionally similar to fibrate medications (eg, fenofibrate, gemfibrozil), which bind PPAR-α and are effective in lowering blood triglyceride levels. The PPAR family of transcriptional regulators also plays a significant role in the pathogenesis of metabolic syndrome (obesity, hypertension, dyslipidemia, and insulin resistance). (Choice C) PPAR-γ activation leads to an increase in fat mass secondary to the increased differentiation of preadipocytes into mature adipocytes. The increased movement of free fatty acids into fat cells, along with increased fatty acid oxidation (adiponectin effect), causes circulating free fatty acid levels to decrease. (Choice D) TZDs do not stimulate insulin secretion; rather, as insulin resistance diminishes, circulating levels of insulin tend to decrease over time. (Choice E) Leptin is a hormone secreted by fat cells that acts on the hypothalamus to decrease appetite. Although PPAR-γ activation increases fat cell mass, circulating leptin levels remain unchanged or decrease due to the inhibiting effect of PPAR-γ on leptin gene transcription. Educational objective: Thiazolidinediones (TZDs) lower blood glucose by decreasing insulin resistance. TZDs activate peroxisome proliferator-activated receptor gamma, a nuclear receptor that alters the transcription of genes involved in glucose and lipid metabolism. __________ References: Minireview: challenges and opportunities in development of PPAR agonists. (http://www.ncbi.nlm.nih.gov/pubmed/25148456) The roles of peroxisome proliferator-activated receptors in the metabolic syndrome. (http://www.ncbi.nlm.nih.gov/pubmed/24373239)

A 43-Year-Old Woman Volunteers for a Clinical Trial Testing a Medication