Faculty Bibliography

BACKGROUND:The adoption of low-carbohydrate diets can lead to weight loss in many patients. However, these now widespread diets also have the potential to exacerbate hypercholesterolemia. OBJECTIVE:The objective of this study is to display the potentially harmful effects of the ketogenic diet on cholesterol levels in patients with or without underlying hyperlipidemia. METHODS:We describe 5 patients who developed marked increases in plasma cholesterol on ketogenic diets and assessed whether they had a well-described underlying genetic hyperlipidemia. RESULTS:Three out of 5 patients had extraordinary increases of blood cholesterol levels to over 500 mg/dL. The other 2 patients more than doubled their low-density lipoprotein cholesterol levels on a ketogenic diet. One patient had an APOE E2/E2 genotype. A higher burden of common genetic polymorphisms was found in 2 patients, with no major mutations found. No potential genetic cause was seen in a fourth patient, and the fifth patient had no genetic testing. Three patients, including the one who was most hypercholesterolemic, had a marked reduction in cholesterol after reverting to a more liberal diet. One refused to change his diet but had a satisfactory low-density lipoprotein cholesterol reduction on ezetimibe. CONCLUSION/CONCLUSIONS:These cases should serve as a caution that high-fat low-carbohydrate diets have the potential to exacerbate or cause hypercholesterolemia in patients with or without underlying genetic hyperlipidemia.

CONTEXT: Distinguishing between pituitary [Cushing's disease (CD)] and ectopic causes [ectopic ACTH syndrome (EAS)] of ACTH-dependent Cushing's syndrome can be challenging. Inferior petrosal sinus sampling (IPSS) best discriminates between CD and occult EAS but is a specialized procedure that is not widely available. Identifying adjunctive diagnostic tests may prove useful. In EAS, abnormal processing of the ACTH precursor proopiomelanocortin (POMC) and the accumulation of POMC-derived peptides might be expected and abnormal levels of other neuropeptides may be detected. OBJECTIVE: The objective of the study was to evaluate the diagnostic utility of POMC measurements for distinguishing between CD and occult EAS in patients referred for IPSS. Another objective of the study was to evaluate in parallel the diagnostic utility of another neuropeptide, agouti-related protein (AgRP), because we have observed a 10-fold elevation of AgRP in plasma in a patient with EAS from small-cell lung cancer. DESIGN AND PARTICIPANTS: Plasma POMC and AgRP were measured in 38 Cushing's syndrome patients presenting for IPSS, with either no pituitary lesion or a microadenoma on magnetic resonance imaging, and in 38 healthy controls. RESULTS: Twenty-seven of 38 patients had CD; 11 of 38 had EAS. The mean POMC was higher in EAS vs CD [54.5 +/- 13.0 (SEM) vs 17.2 +/- 1.5 fmol/mL; P < .05]. Mean AgRP was higher in EAS vs CD (280 +/- 76 vs 120 +/- 16 pg/mL; P = .01). Although there was an overlap in POMC and AgRP levels between the groups, the POMC levels greater than 36 fmol/mL (n = 7) and AgRP levels greater than 280 pg/mL (n = 3) were specific for EAS. When used together, POMC greater than 36 fmol/mL and/or AgRP greater than 280 pg/mL detected 9 of 11 cases of EAS, indicating that elevations in these peptides have a high positive predictive value for occult EAS. CONCLUSIONS: Expanding upon previous observations of high POMC in EAS, this study specifically demonstrates elevated POMC levels can identify occult ectopic tumors. Elevations in AgRP also favor the diagnosis of EAS, suggesting AgRP should be further evaluated as a potential neuroendocrine tumor marker.

BACKGROUND: Moderate alcohol consumption is associated with a decreased risk of type 2 diabetes in the general population, but little is known about the effects in individuals at high risk of diabetes. OBJECTIVES: The objectives were to determine associations between alcohol consumption and diabetes risk factors and whether alcohol consumption was a predictor of incident diabetes in individuals enrolled in the Diabetes Prevention Program (DPP). DESIGN: DPP participants (n = 3175) had impaired glucose tolerance (2-h glucose: 7.8-11.1 mmol/L), elevated fasting glucose (5.3-7.0 mmol/L), and a body mass index (in kg/m(2)) > or =24. Participants were randomly assigned to placebo, metformin, or lifestyle modification and were followed for a mean of 3.2 y. Alcohol intake was assessed at baseline and year 1 by using a semiquantitative food-frequency questionnaire. Diabetes was diagnosed by annual oral-glucose-tolerance testing and semiannual fasting plasma glucose measurement. RESULTS: Participants who reported higher alcohol consumption tended to be male, older, white, and less obese and to have a higher calorie intake and a higher HDL-cholesterol concentration. Higher alcohol consumption was associated with lower insulin secretion at any level of insulin sensitivity. We found lower incidence rates of diabetes with higher alcohol consumption in the metformin (P < 0.01 for trend) and lifestyle modification (P = 0.02 for trend) groups, which remained significant after adjustment for multiple baseline covariates. No similar association was observed in the placebo group. CONCLUSIONS: Despite overall low rates of alcohol consumption, there was a reduced risk of incident diabetes in those who reported modest daily alcohol intake and were assigned to metformin or lifestyle modification. Moderate daily alcohol intake is associated with lower insulin secretion-an effect that warrants further investigation. This trial was registered at clinicaltrials.gov as NCT00038727.