Exploring residual risk for diabetes and microvascular disease in the Diabetes Prevention Program Outcomes Study (DPPOS).

AIM: Approximately half of the participants in the Diabetes Prevention Outcomes Study (DPPOS) had diabetes after 15 years of follow-up, whereas nearly all the others remained with pre-diabetes. We examined whether formerly unexplored factors in the DPPOS coexisted with known risk factors that posed additional risk for, or protection from, diabetes as well as microvascular disease. METHODS: Cox proportional hazard models were used to examine predictors of diabetes. Sequential modelling procedures considered known and formerly unexplored factors. We also constructed models to determine whether the same unexplored factors that associated with progression to diabetes also predicted the prevalence of microvascular disease. Hazard ratios (HR) are per standard deviation change in the variable. RESULTS: In models adjusted for demographics and known diabetes risk factors, two formerly unknown factors were associated with risk for both diabetes and microvascular disease: number of medications taken (HR = 1.07, 95% confidence intervals (95% CI) 1.03 to 1.12 for diabetes; odds ratio (OR) = 1.10, 95% CI 1.04 to 1.16 for microvascular disease) and variability in HbA1c (HR = 1.02, 95% CI 1.01 to 1.03 for diabetes; OR = 1.06, 95% CI 1.04 to 1.09 for microvascular disease per sd). Total comorbidities increased risk for diabetes (HR = 1.10, 95% CI 1.04 to 1.16), whereas higher systolic (OR = 1.22, 95% CI 1.13 to 1.31) and diastolic (OR = 1.14, 95% CI 1.05 to 1.22) blood pressure, as well as the use of anti-hypertensives (OR = 1.41, 95% CI 1.23 to 1.62), increased risk of microvascular disease. CONCLUSIONS: Several formerly unexplored factors in the DPPOS predicted additional risk for diabetes and/or microvascular disease - particularly hypertension and the use of anti-hypertensive medications - helping to explain some of the residual disease risk in participants of the DPPOS.

Combination of Recreational Soccer and Caloric Restricted Diet Reduces Markers of Protein Catabolism and Cardiovascular Risk in Patients with Type 2 Diabetes.

BACKGROUND: Moderate calorie-restricted diets and exercise training prevent loss of lean mass and cardiovascular risk. Because adherence to routine exercise recommendation is generally poor, we utilized recreational soccer training as a novel therapeutic exercise intervention in type 2 diabetes (T2D) patients. OBJECTIVE: We compared the effects of acute and chronic soccer training plus calorie-restricted diet on protein catabolism and cardiovascular risk markers in T2D. DESIGN, SETTING AND SUBJECTS: Fifty-one T2D patients (61.1±6.4 years, 29 females: 22 males) were randomly allocated to the soccer+diet-group (SDG) or to the diet-group (DG). The 40-min soccer sessions were held 3 times per week for 12 weeks. RESULTS: Nineteen participants attended 100% of scheduled soccer sessions, and none suffered any injuries. The SDG group showed higher levels of growth hormone (GH), free fatty acids and ammonia compared with DG. After 12 weeks, insulin-like growth factor binding protein (IGFPB)-3 and glucose levels were lower in SDG, whereas insulin-like growth factor (IGF)-1/ IGFBP-3 ratio increased in both groups. After the last training session, an increase in IGF-1/IGFBP-3 and attenuation in ammonia levels were suggestive of lower muscle protein catabolism. CONCLUSIONS: Recreational soccer training was popular and safe, and was associated with decreased plasma glucose and IGFBP-3 levels, decreased ammoniagenesis, and increased lipolytic activity and IGF-1/IGFBP-3 ratio, all indicative of attenuated catabolism.

Predicting, managing and preventing new-onset diabetes after transplantation.

New-onset diabetes after transplantation (NODAT) or posttransplant diabetes mellitus is a frequent metabolic complication of organ transplantation. Diabetes incidence rates among transplant recipients are higher than in the general population. The estimated rates are 9-18% after kidney, 20-33% after liver, 26-40% after lung, and 29% after heart transplants, respectively. In retrospective studies, NODAT was associated with higher costs of posttransplant care and increased risks of graft failure, infection, cardiovascular disease, and death. The incidence of NODAT is influenced by both traditional risk factors for type 2 diabetes (age, family history, obesity, hepatitis C infection, and ethnicity) and transplant-specific risk factors. Managing NODAT is challenging because posttransplant care is complex and characterized by multiple variables including immunosuppressive regimens, choice of antidiabetes agents, and optimal use of insulin therapy. Therefore, predicting and preventing NODAT would be a compelling objective for improving care of posttransplant patients. During the pretransplant period, lifestyle modifications in patients at risk for NODAT should be considered, recognizing that no randomized controlled trials exist to inform specific modalities or cost-effectiveness of such an approach. After hospital discharge, close monitoring of blood glucose during the first month, and every 3 months thereafter for the first year, is recommended for those without prior history of diabetes mellitus. Future areas of investigation include clinical validation of NODAT risk score engines, validation of interventions for primary prevention of NODAT, the development of immunosuppressive regimens with minimal diabetogenic effects, and prospective determination of the role of glycemic control on graft survival and cardiovascular outcomes.

Metabolic syndrome, prediabetes and the science of primary prevention.

This review provides an update on the metabolic syndrome and prediabetes. Compared to the downstream disorders, namely type 2 diabetes and cardiovascular disease (including coronary artery disease, cerebrovascular disease and peripheral vascular disease), prediabetes and the metabolic syndrome represent intermediate cardiometabolic states. The generally accepted working definitions, epidemiology, pathophysiology and clinical relevance of these intermediate conditions are discussed. Importantly, the review focuses on evidence-based strategies for preventing the cardiometabolic sequelae associated with prediabetes and the metabolic syndrome. The importance of lifestyle modification in the primary prevention of the metabolic syndrome and prediabetes is emphasized, and the interaction between genetics and lifestyle intervention in predicting outcomes is presented. In addition to discussing the evidence from landmark clinical trials, we identify methods for translating the success achieved in clinical trials to the community with regard to the prevention of diabetes and cardiometabolic risk. Future research needs are also highlighted. The overall goal is to foster an increased understanding of the prominent role of primary prevention in stemming the tide of cardiometabolic disorders in the society.

Comparison of vildagliptin and thiazolidinedione as add-on therapy in patients inadequately controlled with metformin: results of the GALIANT trial--a primary care, type 2 diabetes study.

AIM: To assess the efficacy and tolerability of vildagliptin compared with thiazolidinediones (TZDs) as an add on to metformin treatment in a primary care patient population with type 2 diabetes. METHODS: This was a randomized, 12-week, open-label study comparing vildagliptin (100 mg, n = 1653) and TZD (agent and dose at the investigators' discretion, n = 825) add-on therapy in patients inadequately controlled [haemoglobin A(1C) (HbA(1c)): 7-10%] on a stable dose of metformin (> or =1000 mg/day). The primary objective was to test non-inferiority of vildagliptin to TZDs for the difference in change in HbA(1c) from baseline [established if the upper limit of the two-sided 95% confidence intervals (CI) did not exceed 0.4%]. RESULTS: Mean (+/- s.e.) change in HbA(1c) from baseline to study endpoint was -0.68 +/- 0.02% in the vildagliptin group and -0.57 +/- 0.03% in the TZD group. The difference between groups was -0.11% (95% CI: -0.17% and -0.04%), establishing the non-inferiority of vildagliptin (p = 0.001) after 3 months of treatment. Vildagliptin was non-inferior to TZDs for subgroups of race, age and body mass index. Body weight increased in the TZD group (0.33 +/- 0.11 kg) and decreased in the vildagliptin group (mean: -0.58 +/- 0.09 kg; p < 0.001 for difference). Adverse events occurred in similar proportions of patients in both groups (vildagliptin: 39.5% and TZD: 36.3%) Hypoglycaemia and abnormal changes in liver enzymes were uncommon. CONCLUSIONS: This short-term study suggests that vildagliptin is as effective as TZDs after 3-month treatment as an add-on to metformin in a primary care population that included diverse patient subgroups.

Multiple drug targets in the management of type 2 diabetes.

Diabetes mellitus (DM) is being diagnosed at an alarming rate around the world. More than 90% of the estimated 200 million affected persons with diabetes worldwide have type 2 DM, an often clinically silent disorder. In the United States, nearly half of the estimated 16 million persons with diabetes remain undiagnosed. Type 2 diabetes is preceded by a long period of impaired glucose tolerance (IGT), a potentially reversible metabolic state associated with increased risk for macrovascular complications. At the time of diagnosis more than one-third of patients have already developed long-term complications of diabetes. Genetic and acquired factors contribute to the pathogenesis of type 2 diabetes. The pathophysiological hallmarks consist of progressive insulin resistance, pancreatic beta-cell dysfunction, and excessive hepatic glucose production. The ideal treatment for type 2 diabetes should correct insulin resistance, beta-cell dysfunction, and normalize hepatic glucose output, as well as prevent, delay, or reverse diabetic complications. Emerging targets for therapy of type 2 diabetes include inhibition of gluconeogenesis, lipolysis, and fatty acid oxidation, as well as stimulation of beta3-adrenergic receptors. Drug intervention for obesity is a legitimate adjunct to diabetes management. Additional drug targets include interventions to prevent or delay the progression of specific complications. Finally, primary prevention of type 2 diabetes is an important emerging strategy. The specific pharmacological agents acting at the various targets are discussed in this review. A targeted approach to the multiple underlying pathophysiologic processes offers the best chance of controlling diabetes and complications.

Human leptin regulation and promise in pharmacotherapy.

In rodents leptin inhibits food intake, stimulates energy expenditure, reverses obesity, ameliorates insulin resistance, and accelerates sexual maturation. These potent and diverse effects have stimulated interest in exploring a role for leptin in the treatment of human metabolic disorders. However, the significance of leptin in human (patho)physiology is still being investigated. The present review summarizes current knowledge of leptin regulation, provides a critical assessment of initial experience with leptin therapy, and discusses potential targets for recombinant leptin therapy in humans. The results of numerous studies indicate that leptin is indeed a regulated human hormone: The physiological factors that influence leptin secretion include gender, adiposity, physical exercise, feeding, and caloric restriction. Several hormones, including insulin, glucocorticoids, estradiol, growth hormone, testosterone, somatostatin, and insulin-like growth factor-I also modulate leptin secretion. The results of initial trials of leptin therapy in humans have become available. Treatment with recombinant human leptin (0.028 mg/kg) induced a progressive weight loss (without evidence of tachyphylaxis) in a morbidly obese patient with congenital leptin deficiency. The weight loss averaged 1-2 kg/month, was associated with preservation of lean muscle mass, and was almost exclusively accounted for by depletion of body fat. Administration ofrecombinant leptin (0.01-0.3 mg/kg) also resultedin a dose-dependentweight loss among lean and obese humans with presumably normal leptin genotype. Thus leptin may have a therapeutic role in humans, but its physiological functions and regulation first need to be fully unravelled.

Impaired leptin response to glucocorticoid as a chronic complication of diabetes.

Leptin has anorectic, anti-obesity, and insulin-sensitizing properties. We recently reported subnormal responses to the leptin secretagogue dexamethasone in diabetes (DM). To determine whether this defect precedes or follows the occurrence of diabetes, we have studied 37 adults: 11 with type 2 DM diagnosed within 6 months prior to study, 16 with chronic (> or =20 years) DM, and 10 healthy controls. After baseline measurements, subjects ingested dexamethasone (4 mg), followed by blood sampling 16 and 40 h later. Nadir plasma cortisol levels (<2.5 mg/dl) occurred 16 h after dexamethasone ingestion in all study groups; this period of maximal biological action of dexamethasone was associated with peak plasma leptin levels. The peak dexamethasone-stimulated plasma leptin responses (% baseline, +/-SEM) were 188+/-18.7% among healthy controls, 180+/-13.8% among new DM patients, and 127+/-10.5% (P<0.01) in chronic DM patients. Following dexamethasone ingestion, plasma glucose remained stable in the control and new DM groups but increased by 240% in the chronic DM patients; in contrast, plasma insulin increased significantly in controls and new DM patients but not in patients with chronic DM. These results indicate that plasma leptin responses to secretagogue are preserved in newly diagnosed diabetes patients but markedly attenuated in patients with long-standing diabetes, who also were unable to augment insulin secretion during glucocorticoid treatment. Thus, defective glucocorticoid augmentation of plasma leptin, probably related to beta-cell failure, may be a novel chronic complication of diabetes. Theoretically, such a defect could contribute to the obesity and insulin resistance associated with diabetes.

Hormonal regulation of human leptin in vivo: effects of hydrocortisone and insulin.

OBJECTIVE: To investigate the effects of continuous i.v. infusion of hydrocortisone or insulin on leptin secretion in humans. SUBJECTS: Six, nonfasting healthy adults (four women, two men), aged (mean +/- s.e.m.) 36.6 +/- 1.7 y; body mass index (BMI) 27.6 +/- 0.9 kg/m2. DESIGN: Randomized, placebo-controlled, cross-over study, with a 2-week 'wash-out' period. INTERVENTIONS: Intravenous infusion of hydrocortisone (3.3 microg/(kg min)), insulin (1 mU/(kg min)) or normal saline (placebo) for 24 h. MEASUREMENTS: Blood sampling every 1-2 h for measurement of glucose, insulin, cortisol and leptin; subcutaneous abdominal fat biopsy for determination of leptin mRNA expression. RESULTS: Plasma cortisol increased to 50.0 +/- 0.4 microg/dl during hydrocortisone infusion, but was unaltered during saline or insulin infusion. The plasma insulin levels were: 28.5 +/- 4.7 microU/ml (placebo), 40.8 +/- 9.2 microU/ml (hydrocortisone, P=0.214), and 243 +/- 23.0 microU/ml (insulin, P=0.0002). Peak hyperleptinemia occurred after 16h of insulin and 20h of hydrocortisone infusion; peak/baseline plasma leptin levels (ng/ml) were 18.2 +/- 4.2/15.1 +/- 3.3 (placebo, P=0.056), 42.1 +/- 7.0/16.0 +/- 3.8 (hydrocortisone, + 163%, P= 0.008) and 30.2 +/- 4.3/16.6 +/- 2.7 (insulin, +83%, P= 0.024). Adipocyte leptin mRNA increased by 350% after the hydrocortisone infusion. CONCLUSION: Hydrocortisone, a natural glucocorticoid, induces hyperleptinemia in vivo, with a potency greater than that of insulin. The interaction between glucocorticoids and leptin may be of metabolic significance in humans.

Physiological responses during hypoglycaemia induced by regular human insulin or a novel human analogue, insulin glargine.

AIM: Glargine, a product of recombinant technology, has different structural and physicochemical properties compared with native human insulin. We determined whether such differences are associated with alterations in the responses to hypoglycaemia induced by glargine. METHODS: Nineteen adults (six healthy and 13 with type 1 diabetes) underwent a 5-h hyperinsulinaemic (2 mU/kg/min(-1)) stepped hypoglycaemic clamps (hourly targets of 4.7, 4.2, 3.6, 3.1 and 2.5 mmol/l, respectively) on two occasions using intravenous infusion of regular human insulin or glargine, in random sequence. Hypoglycaemic symptoms, counter-regulatory hormones and glucose disposal rates were assessed at intervals throughout the clamps. A 1-week 'wash out' period was observed between studies. RESULTS: The peak total symptoms scores (mean +/- s.e.m.) at nadir blood glucose (2.5 mmol/1) were 18.83 +/- 2.68 (healthy) and 17.46 +/- 3.62 (diabetic) during regular insulin, and 18.50 +/- 3.20 (healthy) and 19.08 +/- 3.83 (diabetic) during glargine infusion. The peak epinephrine levels during hypoglycaemia were 767.8 +/- 140.4 pg/ml (regular insulin) and 608.8 +/- 129.9 pg/ml (glargine) among healthy subjects, and 332.5 +/- 54.8 pg/ml (regular insulin) and 321.8 +/- 67.4 pg/ml (glargine) in diabetic patients. Diabetic patients had blunted glucagon responses during hypoglycaemia with either insulin. Both insulins also elicited similar rates of glucose disposal. CONCLUSIONS: We conclude that insulin glargine and regular human insulin elicit comparable symptomatic and counter-regulatory hormonal responses during hypoglycaemia in healthy or diabetic subjects, and induce similar rates of glucose disposal. Since glargine is designed for subcutaneous (s.c.) use, it is possible (though unlikely) that our findings obtained using an intravenous protocol could differ from responses to hypoglycaemia induced by the s.c. route.

Thyroid function during pregnancy.

BACKGROUND: This Case Conference reviews the normal changes in thyroid activity that occur during pregnancy and the proper use of laboratory tests for the diagnosis of thyroid dysfunction in the pregnant patient. CASE: A woman in the 18th week of pregnancy presented with tachycardia, increased blood pressure, severe vomiting, increased total and free thyroid hormone concentrations, a thyroid-stimulating hormone (TSH) concentration within the reference interval, and an increased human chorionic gonadotropin (hCG) beta-subunit concentration. ISSUES: During pregnancy, normal thyroid activity undergoes significant changes, including a two- to threefold increase in thyroxine-binding globulin concentrations, a 30-100% increase in total triiodothyronine and thyroxine concentrations, increased serum thyroglobulin, and increased renal iodide clearance. Furthermore, hCG has mild thyroid stimulating activity. Pregnancy produces an overall increase in thyroid activity, which allows the healthy individual to remain in a net euthyroid state. However, both hyper- and hypothyroidism can occur in pregnant patients. In addition, two pregnancy-specific conditions, hyperemesis gravidarum and gestational trophoblastic disease, can lead to clinical hyperthyroidism. The normal changes in thyroid activity and the association of pregnancy with conditions that can cause hyperthyroidism necessitates careful interpretation of thyroid function tests during pregnancy. CONCLUSION: Assessment of thyroid function during pregnancy should be done with a careful clinical evaluation of the patient's symptoms as well as measurement of TSH and free, not total, thyroid hormones. Measurement of thyroid autoantibodies may also be useful in selected cases to detect maternal Graves disease or Hashimoto thyroiditis and to assess risk of fetal or neonatal consequences of maternal thyroid dysfunction.

Basal and stimulated plasma leptin in diabetic subjects.

OBJECTIVE: To determine whether leptin secretion is impaired in diabetes, we compared basal and stimulated plasma leptin levels in diabetic subjects and healthy controls. RESEARCH METHODS AND PROCEDURES: Blood samples for assay of leptin and other hormones were obtained at baseline in 54 diabetic patients and 65 controls, and 8 hours, 16 hours, and 40 hours following ingestion of dexamethasone (4 mg) in 6 healthy and 12 controls. C-peptide status was defined as "negative" if < or =0.1 ng/mL or "positive" if > or =0.3 ng/mL, in fasting plasma. RESULTS: Basal plasma leptin levels were 19.7+/-2.2 ng/mL in nondiabetic subjects, 13.4+/-1.5 ng/ml in C-peptide negative (n = 28) and 26.1+/-3.7 ng/mL in C-peptide positive (n = 26, p = 0.001) diabetic patients. Dexamethasone increased leptin levels of controls (n = 6) to 145+/-17% of baseline values at 8 hours (p = 0.03), 224+/-18% at 16 hours (p = 0.01), and 134+/-18% at 40 hours (p=0.05). The corresponding changes were 108+/-13%, 126+/-23%, and 98+/-16% in C-peptide negative (n=6), and 121+/-10%, 144+/-16% (p=0.03), and 147+/-23% (p=0.11) in C-peptide positive (n = 6) diabetic patients, respectively. The peak stimulated leptin levels were lower in the diabetic patients, compared with controls. Plasma insulin increased (p = 0.02) in controls, but not in the diabetic patients, following dexamethasone. DISCUSSION: Although diabetic patients have normal plasma leptin levels under basal conditions, their leptin responses to glucocorticoid are impaired, probably because of the concomitant insulin secretory defect. A subnormal leptin secretory response could worsen obesity and insulin resistance in diabetes.

Insulin resistance in HIV protease inhibitor-associated diabetes.

BACKGROUND: Fasting hyperglycemia has been associated with HIV protease inhibitor (PI) therapy. OBJECTIVE: To determine whether absolute insulin deficiency or insulin resistance with relative insulin deficiency and an elevated body mass index (BMI) contribute to HIV PI-associated diabetes. DESIGN: Cross-sectional evaluation. PATIENTS: 8 healthy seronegative men, 10 nondiabetic HIV-positive patients naive to PI, 15 nondiabetic HIV-positive patients receiving PI (BMI = 26 kg/m2), 6 nondiabetic HIV-positive patients receiving PI (BMI = 31 kg/m2), and 8 HIV-positive patients with diabetes receiving PI (BMI = 34 kg/m2). All patients on PI received indinavir. MEASUREMENTS: Fasting concentrations of glucoregulatory hormones. Direct effects of indinavir (20 microM) on rat pancreatic beta-cell function in vitro. RESULTS: In hyperglycemic HIV-positive subjects, circulating concentrations of insulin, C-peptide, proinsulin, glucagon, and the proinsulin/insulin ratio were increased when compared with those of the other 4 groups (p < .05). Morning fasting serum cortisol concentrations were not different among the 5 groups. Glutamic acid decarboxylase (GAD) antibody titers were uncommon in all groups. High BMI was not always associated with diabetes. In vitro, indinavir did not inhibit proinsulin to insulin conversion or impair glucose-induced secretion of insulin and C-peptide from rat beta-cells. CONCLUSIONS: The pathogenesis of HIV PI-associated diabetes involves peripheral insulin resistance with insulin deficiency relative to hyperglucagonemia and a high BMI. Pancreatic beta-cell function was not impaired by indinavir. HIV PI-associated diabetes mirrors that of non-insulin-dependent diabetes mellitus and impaired insulin action in the periphery.

Leptin elimination in hyperleptinaemic peritoneal dialysis patients.

BACKGROUND: Elevated plasma concentrations of leptin, a hormone thought to regulate body composition by influencing food intake/metabolic rate, are prevalent in renal failure patients. The mechanism for these increases is not known, but evidence suggests that simple accumulation due to decreased elimination is insufficient explanation. METHODS: We studied the incidence of hyperleptinaemia in 28 end-stage renal disease patients treated with continuous ambulatory peritoneal dialysis (CAPD), compared with body-mass-index-and sex-matched controls. Results were separated by gender because women have higher leptin concentrations than men. Excretion of leptin and other substances in dialysis fluid was also studied. RESULTS: Hyperleptinaemia was prevalent in women CAPD subjects, but not in men. Plasma leptin concentrations correlated strongly with the daily excretion of leptin in dialysis fluid. Clearance of leptin in dialysis fluid was greater in men than women CAPD subjects. Single regression analysis found that fasting insulin, glucose content of dialysis fluid, plasma albumin, C-reactive protein, erythropoietin dose, urinary creatinine clearance and plasma beta2-microglobulin were not determinants of plasma leptin concentrations. Stepwise forward multiple regression, examining the dependence of plasma leptin on body mass index, renal creatinine clearance, plasma albumin, daily dialysis fluid glucose load, daily leptin in dialysis fluid, erythropoietin dose and plasma C-reactive protein found only erythropoietin dose as a consistent negative predictor of plasma leptin concentrations. CONCLUSIONS: The results suggest that hyperleptinaemia of CAPD was due to predisposing loss of renal elimination capacity combined with increased production due to obesity (more prevalent in women subjects of this study) and potentially female gender.

Reproducibility of fasting plasma leptin concentration in lean and obese humans.

We determined the reproducibility of plasma leptin levels in 20 healthy subjects (10 men, 10 women; 10 lean, 10 obese) at stable body weight. Blood samples were obtained, after an overnight fast, between 0700 and 0800 on days 1, 2, 3, 4, 5, 12, 19, and 26. Body weights were recorded on the same days. Plasma leptin was measured using a specific radioimmunoassay. The mean +/- SE baseline body weights (kg) were 65.8 +/- 3.6 (lean) and 96.4 +/- 7.1 (obese). The body mass indices (BMI) were 22.9 +/- 2.8 kg/m2 (lean) and 32.7 +/- 2.2 kg/m2 (obese). The mean daily fasting plasma glucose level was 98.7 +/- 3.7 mg/dl. Baseline plasma leptin levels (ng/ml) were 5.3 +/- 0.75 in lean men, 14.9 +/- 4.6 in obese men, 11.2 +/- 2.8 in lean women, and 27.1 +/- 8.4 in obese women. Fasting leptin levels on days 2 to 26 were highly correlated with the baseline levels on day 1 (r2 = 0.9, P<0.0001). Body weights remained within 98%-102% of baseline, whereas intra-individual leptin levels fluctuated between 80% and 120% of baseline values, throughout the 26 days of study. We conclude that fasting plasma leptin levels are reproducible, with a maximum day-to-day variation of approximately 20%, in healthy, free-living, lean and obese persons who maintain a stable body weight.

Tumor-grade hyperprolactinemia induced by multiple medications in the setting of renal failure.

OBJECTIVE: To describe a patient with galactorrhea and severe hyperprolactinemia in whom workup revealed a nontumoral mechanism. METHODS: We present the medical history of a woman with long-standing diabetes in whom bilateral galactorrhea and hyperprolactinemia developed. In addition, the details of her clinical course and management are reviewed. RESULTS: A 33-year-old woman with diabetes, end-stage renal disease, and gastroparesis was admitted to the hospital because of intractable nausea and vomiting. Several months before admission, she had been noted to have galactorrhea and irregular menses. Routine medications included captopril, verapamil, furosemide, prochlorperazine, metoclopramide, cisapride, and Ortho-Novum. Laboratory evaluation showed normal thyroid function, increased serum prolactin levels (up to 1,197 ng/mL), and normal findings on magnetic resonance imaging of the pituitary. Electrophoresis of the patient's serum on a protein A Sepharose column showed no evidence of macro-prolactinemia. Orally administered medications were discontinued, and the patient was given total parenteral nutrition. These measures resulted in a decrease of 300 ng/mL in serum prolactin levels in 4 days. The prolactin levels eventually normalized after withdrawal of verapamil, prochlorperazine, and metoclopramide. CONCLUSION: A modest increase in serum prolactin level often can be produced by a variety of medications, but gross hyperprolactinemia of 200 ng/mL or higher usually raises suspicion of an underlying prolactin-secreting tumor. This case report demonstrates that conventional limits for nontumoral hyperprolactinemia can be exceeded by concurrent exposure to multiple lactotropic medications in the setting of renal failure.

High-flux dialysis lowers plasma leptin concentration in chronic dialysis patients.

Leptin is a protein produced by fat cells and involved in body weight regulation. Plasma leptin is significantly higher in some hemodialysis (HD) patients than in normal controls. We examined the influence of dialyzer membrane biocompatibility and flux on elevated plasma leptin concentrations in hemodialysis patients. Employing a crossover design, leptin and tumor necrosis factor-alpha (TNF-alpha) levels were serially determined in eight chronic dialysis patients. Patients were dialyzed sequentially on low-flux cellulosic (TAF) dialyzers, low-flux (F8) polysulfone, high-flux (F80B) polysulfone, then low-flux polysulfone and cellulosic dialyzers again. Mean leptin concentrations were similar when low-flux polysulfone or cellulosic dialyzers were employed (141.9+/-24.2 microg/L versus 137.8+/-18.4 microg/L, respectively (P=NS). In contrast, leptin fell significantly on the high-flux polysulfone dialyzer (99.4+/-16.2 microg/L) compared with cellulosic (P < 0.005), and low-flux polysulfone dialyzers (P < 0.02). Leptin clearance by the high-flux polysulfone dialyzer was significantly higher than the low-flux dialyzers (50.4+/-21.5 v -9.6+/-10.3 mL/min; P=0.043), but did not account fully for the 30% decline in plasma leptin during the high-flux arm of the study. Concentrations of TNF-alpha were lower when high-flux polysulfone dialyzers were employed, but there was no correlation of individual TNF-alpha levels with leptin concentrations. High-flux dialysis lowers plasma leptin concentrations an average of 30%, but biocompatibility does not influence leptin levels. The decrease in plasma leptin on high-flux dialysis cannot be explained solely by enhanced clearance.

Dose-dependent cortisol-induced increases in plasma leptin concentration in healthy humans.

BACKGROUND: Leptin is a hormone that regulates fat metabolism and appetite. The secretion of leptin is regulated by adiposity and, in the rodent, by factors such as insulin, beta-adrenergic agonists, and glucocorticoids (GCs). Increased secretion of the endogenous human GC, cortisol, occurs during stress and in disorders such as major depression. Pharmacological GCs can robustly increase plasma leptin concentrations in humans, leading us to hypothesize that cortisol may serve as a physiological regulator of human leptin secretion. METHODS: A randomized double-blind placebo-controlled comparison of 2 fixed oral dosages of cortisol (40 mg/d and 160 mg/d), given for 4 days to matched groups of healthy subjects (n=47). Low-dose treatment approximated GC output during mild stress, while high-dose treatment approximated GC output during maximal stress, spanning a range of GC secretion relevant to physiological stress. RESULTS: Cortisol produced dose-dependent and time-dependent increases in plasma leptin concentrations (time x treatment condition x body mass index; F6,123=10.73; P<.001). Initial treatment-induced increases in plasma leptin concentration returned toward baseline values during 4 treatment days, suggesting tolerance to this GC effect in these healthy subjects. CONCLUSIONS: The results indicate an important role for GCs in the short-term regulation of human leptin secretion. Glucocorticoid-induced increases in leptin secretion suggest a mechanism that may contribute to anorexia and weight loss during stress and disease states such as major depression, if these conditions are associated with sustained increases in plasma leptin concentrations.