A 50-year-old woman comes to the office to discuss weight gain. She has gained about 13.6 kg (30 lb) over the last 2 years, which she attributes to excessive eating and not exercising. The patient is otherwise feeling well, and her past medical history is unremarkable. However, she has a strong family history of type 2 diabetes mellitus. Blood pressure is 150/90 mm Hg and pulse is 75/min. BMI is 30.3 kg/m². Hyperpigmentation in skinfolds is noted at the neck as shown in the image below. Laboratory testing shows a fasting blood glucose of 150 mg/dL and HbA1c of 8.0%. Elevated serum levels of which of the following substances are most likely contributing to this patient's disease process?

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11ec160b_3ac5_b6d4_9249_1998e2c6bde8_MD0001_00 This patient has new-onset type 2 diabetes mellitus (T2DM), which results from a combination of insulin resistance and relative insulin deficiency. The early course of T2DM is characterized by increased insulin production and decreased sensitivity of target organs to the effects of insulin, although insulin levels may later decline as the disease progresses. In addition, this patient has acanthosis nigricans, which is another sign of insulin resistance. Insulin resistance in adipose cells hinders the antilipolytic effects of insulin, leading to lipolysis and release of free fatty acids. In turn, chronically elevated free fatty acid levels contribute to insulin resistance by impairing insulin-dependent glucose uptake and increasing hepatic gluconeogenesis. Other factors that contribute to insulin resistance include obesity and a sedentary lifestyle. (Choice A) Absolute insulin deficiency in type 1 diabetes mellitus leads to increased gluconeogenesis and conversion of fatty acids to ketone bodies (eg, beta-hydroxybutyrate). Very high levels of ketone bodies are seen in diabetic ketoacidosis but are not typical in T2DM and do not interfere with the production or actions of insulin. (Choice B) C-peptide is secreted with insulin in equimolar amounts from pancreatic beta cells. Patients with insulin resistance will have increased production of both insulin and C-peptide, but C-peptide does not cause insulin resistance. (Choices D and E) The "metabolic syndrome" is a common collection of clinical features that includes elevated triglycerides, low HDL cholesterol, central obesity, hypertension, and elevated glucose. These patients typically have significant insulin resistance. However, elevated LDL and HDL levels do not contribute to insulin resistance or acanthosis nigricans. Educational objective: Type 2 diabetes mellitus is due to insulin resistance and relative insulin deficiency. Chronically elevated free fatty acid levels contribute to insulin resistance by impairing insulin-dependent glucose uptake and increasing hepatic gluconeogenesis. __________ References: Free fatty acids and skeletal muscle insulin resistance. (http://www.ncbi.nlm.nih.gov/pubmed/24373240) Obesity, insulin resistance and free fatty acids. (http://www.ncbi.nlm.nih.gov/pubmed/21297467) Low-density-lipoprotein cholesterol concentrations and risk of incident diabetes: epidemiological and genetic insights from the Framingham Heart Study. (http://www.ncbi.nlm.nih.gov/pubmed/26409460)

A 50-Year-Old Woman Comes to the Office to Discuss Weight