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Patients who undergo solid organ transplantation may have preexisting diabetes mellitus (DM), develop new-onset DM after transplantation (NODAT), or have postoperative hyperglycemia that resolves shortly after surgery. Although insulin is usually used to control hyperglycemia in the hospital, following discharge most of the usual diabetes oral and parenteral medications can be used in treatment. However, when there are comorbidities such as impaired kidney or hepatic function, or heart disease, special precautions may be necessary. In addition, drug-drug interactions, such as drugs interacting with CYP3A4 enzyme pathway, require additional consideration because of possible interaction with immunosuppressive drug metabolism.

OBJECTIVE A portion of patients with diabetes are repeatedly hospitalized for diabetic ketoacidosis (DKA), termed recurrent DKA, which is associated with poorer clinical outcomes. This study evaluated recurrent DKA, fragmentation of care, and mortality throughout six institutions in the Chicago area. RESEARCH DESIGN AND METHODS A deidentified Health Insurance Portability and Accountability Act–compliant data set from six institutions (HealthLNK) was used to identify 3,615 patients with DKA (ICD-9 250.1x) from 2006 to 2012, representing 5,591 inpatient admissions for DKA. Demographic and clinical data were queried. Recurrence was defined as more than one DKA episode, and fragmentation of health care was defined as admission at more than one site. RESULTS Of the 3,615 patients, 780 (21.6%) had recurrent DKA. Patients with four or more DKAs (n = 211) represented 5.8% of the total DKA group but accounted for 26.3% (n = 1,470) of the encounters. Of the 780 recurrent patients, 125 (16%) were hospitalized at more than one hospital. These patients were more likely to recur (odds ratio [OR] 2.96; 95% CI 1.99, 4.39; P < 0.0001) and had an average of 1.88-times the encounters than nonfragmented patients. Although only 13.6% of patients died of any cause during the study period, odds of death increased with age (OR 1.06; 95% CI 1.05, 1.07; P < 0.001) and number of DKA encounters (OR 1.28; 95% CI 1.04, 1.58; P = 0.02) after adjustment for age, sex, insurance, race, fragmentation, and DKA visit count. This study was limited by lack of medical record–level data, including comorbidities without ICD-9 codes. CONCLUSIONS Recurrent DKA was common and associated with increased fragmentation of health care and increased mortality. Further research is needed on potential interventions in this unique population.

In trials of people with type 2 diabetes, albuminuria reduction with renin-angiotensin system inhibitors is associated with lower risks of cardiovascular events and CKD progression. We tested whether progression or remission of microalbuminuria is associated with cardiovascular and renal risk in a well characterized cohort of type 1 diabetes.We studied 1441 participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. Albumin excretion rate (AER) was quantified annually or biennially for up to 30 years. For each participant, albuminuria status was defined over time as normoalbuminuria (AER continuously30 mg/d), sustained microalbuminuria (AER, 30-299 mg/d on two consecutive visits), macroalbuminuria (AER≥300 mg/d), or remitted microalbuminuria (transition from sustained microalbuminuria to AER30 mg/d on two consecutive visits). We tested associations of time-updated albuminuria status with adjudicated clinical cardiovascular events, the development of reduced GFR (60 ml/min per 1.73 mAt least one cardiovascular event occurred in 184 participants, and 98 participants developed reduced eGFR. Compared with normoalbuminuria, sustained microalbuminuria, remitted microalbuminuria, and macroalbuminuria were each associated with higher risk of cardiovascular events (adjusted hazard ratios [HRs] and 95% confidence intervals [95% CIs]: 1.79 [1.13 to 2.85], 2.62 [1.68 to 4.07], and 2.65 [1.68 to 4.19], respectively) and reduced eGFR (adjusted HRs [95% CIs], 5.26 [2.43 to 11.41], 4.36 [1.80 to 10.57], and 54.35 [30.79 to 95.94], respectively). Compared with sustained microalbuminuria, remission to normoalbuminuria was not associated with reduced risk of cardiovascular events (adjusted HR, 1.33; 95% CI, 0.68 to 2.59) or reduced eGFR (adjusted HR, 1.75; 95% CI, 0.56 to 5.49). Compared with normoalbuminuria, sustained microalbuminuria, remitted microalbuminuria, and macroalbuminuria were associated with greater carotid intima-media thickness, and macroalbuminuria was associated with a greater degree of coronary artery calcification.In type 1 diabetes, microalbuminuria and macroalbuminuria are associated with higher risks of cardiovascular disease and reduced eGFR, but achieving a remission of established microalbuminuria to normoalbuminuria does not appear to improve outcomes.

Serum testosterone concentrations decrease as men age, but benefits of raising testosterone levels in older men have not been established.We assigned 790 men 65 years of age or older with a serum testosterone concentration of less than 275 ng per deciliter and symptoms suggesting hypoandrogenism to receive either testosterone gel or placebo gel for 1 year. Each man participated in one or more of three trials--the Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. The primary outcome of each of the individual trials was also evaluated in all participants.Testosterone treatment increased serum testosterone levels to the mid-normal range for men 19 to 40 years of age. The increase in testosterone levels was associated with significantly increased sexual activity, as assessed by the Psychosexual Daily Questionnaire (P0.001), as well as significantly increased sexual desire and erectile function. The percentage of men who had an increase of at least 50 m in the 6-minute walking distance did not differ significantly between the two study groups in the Physical Function Trial but did differ significantly when men in all three trials were included (20.5% of men who received testosterone vs. 12.6% of men who received placebo, P=0.003). Testosterone had no significant benefit with respect to vitality, as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue scale, but men who received testosterone reported slightly better mood and lower severity of depressive symptoms than those who received placebo. The rates of adverse events were similar in the two groups.In symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. The number of participants was too few to draw conclusions about the risks of testosterone treatment. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00799617.).

The 2012 update of the Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical Practice Guideline for Diabetes and Chronic Kidney Disease (CKD) is intended to assist the practitioner caring for patients with diabetes and CKD. Substantial high-quality new evidence has emerged since the original 2007 KDOQI guideline that could significantly change recommendations for clinical practice. As such, revisions of prior guidelines are offered that specifically address hemoglobin A(1c) (HbA(1c)) targets, treatments to lower low-density lipoprotein cholesterol (LDL-C) levels, and use of angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin receptor blocker (ARB) treatment in diabetic patients with and without albuminuria. Treatment approaches are addressed in each section and the stated guideline recommendations are based on systematic reviews of relevant trials. Appraisal of the quality of the evidence and the strength of recommendations followed the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Limitations of the evidence are discussed and specific suggestions are provided for future research.

AimsProgression of chronic kidney disease (CKD) in patients with diabetes is a growing problem. Diabetes is associated with elevated endothelin-1 (ET-1) and enhanced renal expression of the endothelin A receptor (ETAR). Atrasentan, a highly selective ETAR antagonist, reduces albuminuria in patients with DN.Key methodsThis was a randomized, double-blind trial of subjects with type 2 diabetes on renin–angiotensin system (RAS) inhibitors having eGFR >20ml/min, and urine albumin-to-creatinine ratio (UACR) of 100–3000mg/g, who were allocated to placebo, 0.25, 0.75 or 1.75mg atrasentan.Key findingsUACR was reduced in the 0.75mg and 1.75mg groups (42% and 35% vs placebo, P

Clinically nonfunctioning pituitary adenomas range from those causing significant hypothalamic/pituitary dysfunction and visual field compromise to those being completely asymptomatic, detected either at autopsy or as incidental findings on imaging scans performed for other reasons (often referred to as pituitary incidentalomas). Growth of nonfunctioning pituitary adenomas without treatment occurs in about 10% of microadenomas and 24% of macroadenomas. In the absence of hypersecretion, hypopituitarism, or visual-field defects, periodic screening by magnetic resonance imaging may detect enlargement. Potential indications for surgery are growth of a pituitary incidentaloma, the development of visual-field defects, or the development of hypopituitarism.

OBJECTIVE Renal insufficiency may increase the risk of hypoglycemia in hospitalized patients with diabetes who are treated with insulin. We randomized inpatients with type 2 diabetes and chronic renal failure to treatment with two different dose levels of insulin glargine and glulisine and studied control of hyperglycemia and the frequency of hypoglycemia. RESEARCH DESIGN AND METHODS We conducted a multicenter, prospective, randomized trial to compare the efficacy of once-daily glargine and three-times daily glulisine at 0.5 vs. 0.25 units/kg/day. A total of 107 subjects had type 2 diabetes for >1 year, had a glomerular filtration rate 180 mg/dL. Doses were adjusted based on four-times daily BG measurements for 6 days. RESULTS Mean BG on the first day was 196 ± 71 mg/dL in the group receiving 0.5 units/kg (0.5 group) and 197 ± 55 mg/dL in the group receiving 0.25 units/kg (0.25 group; P = 0.94). On days 2 to 6, mean BG was 174 ± 52 mg/dL in the 0.5 group and 174 ± 46 mg/dL in the 0.25 group (P = 0.96). There were no significant differences between groups in the percentage of BG values within the target range of 100 to 180 mg/dL on any of the 6 study days. In the 0.5 group, 30% experienced hypoglycemia (BG CONCLUSIONS Reduction of initial glargine/glulisine insulin weight-based dosing in hospitalized patients with diabetes and renal insufficiency reduced the frequency of hypoglycemia by 50% without compromising the control of hyperglycemia.

To demonstrate that drug-induced agranulocytosis can occur after a very prolonged period of low-dose treatment with antithyroid medications.We present the history and long-term follow-up of a patient with Graves disease, including clinical and laboratory findings, and provide a brief review of the related literature.A 53-year-old woman with a history of Graves disease presented with an absolute neutrophil count of zero, body temperature of 38.7°C, and symptoms of an upper respiratory tract infection. She had been treated continuously with low doses of antithyroid drugs for the preceding 11 years-propylthiouracil (100 to 150 mg daily) from February 1998 until July 2003 and methimazole (5 to 30 mg daily) from July 2003 until her presentation with severe neutropenia in March 2009. The daily dose of methimazole had been stable at 15 mg for 1 year before the current presentation. A thorough hematologic evaluation, including bone marrow biopsy, did not reveal an alternative cause for the agranulocytosis. After discontinuation of methimazole treatment and a short course of granulocyte colony-stimulating factor, she responded successfully with clinical improvement of her symptoms and resolved neutropenia.Although this case is atypical, it reinforces the importance of remaining vigilant for signs of agranulocytosis throughout the course of treatment with antithyroid drugs, even at low doses and after years of continuous administration.

Cushing's syndrome (CS) is a disorder associated with significant morbidity and mortality due to prolonged exposure to high cortisol concentrations.Our objective was to evaluate the safety and efficacy of mifepristone, a glucocorticoid receptor antagonist, in endogenous CS.We conducted a 24-wk multicenter, open-label trial after failed multimodality therapy at 14 U.S. academic medical centers and three private research centers.Participants included 50 adults with endogenous CS associated with type 2 diabetes mellitus/impaired glucose tolerance (C-DM) or a diagnosis of hypertension alone (C-HT).Mifepristone was administered at doses of 300-1200 mg daily.We evaluated change in area under the curve for glucose on 2-h oral glucose test for C-DM and change in diastolic blood pressure from baseline to wk 24 for C-HT.In the C-DM cohort, an area under the curve for glucose (AUC(glucose)) response was seen in 60% of patients (P0.0001). Mean ± sd glycated hemoglobin (HbA1c) decreased from 7.43 ± 1.52% to 6.29 ± 0.99% (P0.001); fasting plasma glucose decreased from 149.0 ± 75.7 mg/dl (8.3 ± 4.1 mmol/liter) to 104.7 ± 37.5 mg/dl (5.8 ± 2.1 mmol/liter, P0.03). In C-HT cohort, a diastolic blood pressure response was seen in 38% of patients (P0.05). Mean weight change was -5.7 ± 7.4% (P0.001) with waist circumference decrease of -6.78 ± 5.8 cm (P0.001) in women and -8.44 ± 5.9 cm (P0.001) in men. Overall, 87% (P0.0001) had significant improvement in clinical status. Insulin resistance, depression, cognition, and quality of life also improved. Common adverse events were fatigue, nausea, headache, low potassium, arthralgia, vomiting, edema, and endometrial thickening in women.Mifepristone produced significant clinical and metabolic improvement in patients with CS with an acceptable risk-benefit profile during 6 months of treatment.

A 50-year-old man was evaluated for a 5-month history of blurry vision. He had been diagnosed with the metabolic syndrome many years previously but has not seen his physician in years. He reported no current use of medications. On examination, he had a body mass index of 30.6 and a blood pressure of 160/102 mmHg. A dilated examination of the retina is shown in the Figure. Quiz at jama.com Figure. Left, Fundus photograph of the right eye. Right, Fundus photograph of the left eye.

Prolactinomas commonly cause infertility and treatment usually restores ovulation and fertility. The dopamine agonists are the preferred mode of treatment, with cabergoline generally being preferred to bromocriptine because of its higher therapeutic ratio. Experience with both drugs shows no increase in spontaneous abortions, preterm deliveries, multiple births, or congenital malformations, compared to what is expected in the normal population but the experience with bromocriptine is approximately 10-fold greater than with cabergoline. Clinically significant tumor growth may occur in 2.7% of those with microadenomas, 22.9% in those with macroadenomas without prior ablative treatment and 4.8% of those with macroadenomas with prior ablative treatment. Patients with macroadenomas should have visual fields assessed periodically during gestation. Should symptomatic tumor growth occur, reinstitution of the dopamine agonist is usually successful in shrinking the tumor but delivery if the pregnancy is sufficiently advanced is also an option and transsphenoidal debulking is rarely necessary.

This study compared the efficacy, safety, device satisfaction, and quality of life (QOL) in people with diabetes using an insulin bolus-patch versus current devices (pen/syringe) to deliver mealtime insulin.Thirty-eight subjects with diabetes (26 with type 1 and 12 with type 2) were randomized to bolus-patch or current injection device (55% pen and 45% syringe) to deliver mealtime insulin in a multicenter, 6-week crossover study. Efficacy was assessed by equivalence in mean daily seven-point blood glucose (MDBG). Safety assessments included severe hypoglycemia episodes, adverse device effects (ADEs), and adverse events (AEs). Device satisfaction was determined by the validated Insulin Delivery System Rating Questionnaire (IDSRQ) and QOL by the validated Diabetes Specific QOL Scale (DSQOLS).Using bolus-patch, MDBG (mean±SE) was equivalent to that using pen/syringe (8.61±0.28 vs. 9.02±0.26 mmol/L; P=0.098). SD of the seven-point blood glucose measurements was lower using bolus-patch (3.18±0.18 vs. 3.63±0.17 mmol/L; P=0.004), as was the coefficient of variation (CV) (37.2±1.7 vs. 40.3±1.7%; P=0.046). Hemoglobin A1c, 1,5-anhydroglucitol, fructosamine, and insulin use were similar between groups. There were no severe hypoglycemia episodes or serious ADEs. Between-device AEs were comparable. Subjects scored better on six of seven subscales on the DSQOLS and five of six subscales on the IDSRQ while using bolus-patch versus pen/syringe. At study completion, 76% of subjects would choose to switch to bolus-patch (P=0.001).Delivery of mealtime insulin with bolus-patch compared with pen/syringe resulted in equivalent MDBG, lower SD and CV of seven-point blood glucose measurements, good safety, significant device satisfaction, and improved QOL.

Background. Posttransplant hyperglycemia has been associated with increased risks of transplant rejection, infections, length of stay, and mortality. Methods. To establish a predictive model to identify nondiabetic recipients at risk for developing postliver transplant (LT) hyperglycemia, we performed this secondary, retrospective data analysis of a single-center, prospective, randomized, controlled trial of glycemic control among 107 adult LT recipients in the inpatient period. Hyperglycemia was defined as a posttransplant glucose level greater than 200 mg/dL after initial discharge up to 1 month following surgery. Candidate variables with P less than 0.10 in univariate analyses were used to build a multivariable logistic regression model using forward stepwise selection. The final model chosen was based on statistical significance and additive contribution to the model based on the Bayesian Information Criteria. Results. Forty-three (40.2%) patients had at least 1 episode of hyperglycemia after transplant after the resolution of the initial postoperative hyperglycemia. Variables selected for inclusion in the model (using model optimization strategies) included length of hospital stay (odds ratio [OR], 0.83; P < 0.001), use of glucose-lowering medications at discharge (OR, 3.76; P = 0.03), donor female sex (OR, 3.18; P = 0.02) and donor white race (OR, 3.62; P = 0.01). The model had good calibration (Hosmer-Lemeshow goodness-of-fit test statistic = 9.74, P = 0.28) and discrimination (C-statistic = 0.78; 95% confidence interval, 0.65-0.81, bias-corrected C-statistic = 0.78). Conclusions. Shorter hospital stay, use of glucose-lowering medications at discharge, donor female sex and donor white race are important determinants in predicting hyperglycemia in nondiabetic recipients after hospital discharge up to 1 month after liver transplantation.

We describe baseline renal function and albumin excretion rate in patients enrolled in Bypass Angioplasty Revascularization Investigation 2 Diabetes, a randomized clinical trial comparing the impact of revascularization and medical therapy with medical therapy alone and deferred or no revascularization and the impact of glycemic control with either insulin-providing or insulin-sensitizing drugs, on 5-year mortality.Study participants had type 2 diabetes mellitus, documented coronary artery disease, and creatinine2 mg/dL. Albuminuria status (albumin/creatinine ratio [ACR]) and estimated glomerular filtration rate (eGFR), using the abbreviated Modified Diet in Renal Disease equation, were determined at baseline. Univariate and multivariate relationships between baseline clinical characteristics and the presence of albuminuria and reduced eGFR rate were estimated.Two thousand one hundred forty-six subjects were included in the analysis. Forty-three percent of the cohort had evidence of kidney dysfunction at baseline: 23% had an eGFRor =60 mL/min/1.73 m with either microalbuminuria (30 ACR; 17%) or macroalbuminuria (300 ACR; 6%). Twenty-one percent had a reduced eGFR60 mL/min/1.73 m; 52% with reduced eGFR had no albuminuria; 28% had microalbuminuria, and 20% had macroalbuminuria. Race, smoking status, duration of diabetes, hypertension, hemoglobin A1c, triglycerides, vascular disease, abnormal ejection fraction, and reduced eGFR were associated with greater albuminuria. Age, sex, duration of diabetes, ACR, hemoglobin A1c, high density lipoprotein, and number of hypertensive medications were associated with reduced eGFR.Kidney dysfunction is common in older patients with type 2 diabetes mellitus and coronary artery disease; Albuminuria was present in 33%. Reduced eGFR was present in 21%, and half the patients with reduced eGFR had no evidence of albuminuria.

Surgical resection is often not curative in patients with acromegaly and long-acting somatostatin analogues (lanreotide or octreotide) are often needed. This study assessed the efficacy and safety of self- or partner-administration of lanreotide in patients with acromegaly. This was a six-month, single-arm, open-label study conducted at 13 endocrinology clinics. Fifty-nine patients received deep subcutaneous lanreotide injections every 28 days. Twelve patients started on 120 mg lanreotide and forty-seven started on 90 mg lanreotide. At week 16, the dose was adjusted to 60, 90 or 120 mg based on insulin-like growth factor-1 (IGF-1) levels at week 12. Fifty-nine patients with acromegaly either switched from long-acting octreotide (switch; n = 33) or were somatostatin analogue treatment-naïve or not currently taking long-acting octreotide (“other”; n = 26). The key endpoints included the percentage of patients/partners able to self- or partner-inject lanreotide and those with normal IGF-1 or growth hormone (GH) levels at week 24/early termination. 100% of patients/partners correctly self- (n = 41) or partner-injected (n = 18) lanreotide by week 4. By week 24/early termination, IGF-1 levels were controlled in 93.7% of switch and 46.2% of “other” patients, while GH levels were controlled in 76.9% and 39.1% of patients, respectively. Both IGF-1 and GH were controlled in 73.1% of switch and 30.4% of “other” patients. Most switch patients (81%) reported they preferred lanreotide over long-acting octreotide for future use (P = 0.0001). Self- or partner-administration of lanreotide is generally well tolerated and associated with IGF-1 and GH control in many lanreotide-naïve patients with acromegaly.

Incidental pituitary masses are commonly found during CT and MR imaging performed for a variety of reasons. Screening for hormone oversecretion by these tumors seems to be warranted. Patients with lesions greater than 1 cm should be screened for hypopituitarism. In the absence of visual field abnormalities or hypothalamic/stalk compression, it may be appropriate to observe such patients carefully with repeated MR imaging scans. A limited amount of data suggest that significant tumor enlargement occurs in less than 5% of patients with lesions smaller than 1 cm in diameter. However, all macroadenomas must start out as microadenomas, and thus periodic follow-up is indicated to assess for this possibility. Lesions larger than 1 cm in diameter by their very existence at the time of detection have already indicated a propensity for growth. Significant tumor growth occurs in just over one-quarter of such patients. Hemorrhage into such tumors is uncommon, but anticoagulation may predispose to this complication. When there is no evidence of visual field deficits, an attempt at medical therapy with a dopamine agonist or octreotide is reasonable, realizing that only 10% of such patients will respond with a decrease in tumor size. Alternatively, careful periodic observation without intervention may determine that the lesion is not growing. Surgery is indicated with evidence of tumor enlargement, especially when such growth is accompanied by compression of the optic chiasm, cavernous sinus invasion, or the development of pituitary hormone deficiencies.

The use of the combined GHRH and arginine (GHRH-ARG) test has gained increasing acceptance in the United States as a reliable alternative test to the insulin tolerance test (ITT) for diagnosing adult GH deficiency (GHD). In July 2008, the only manufacturer of recombinant GHRH in the United States, EMD Serono, Inc., announced the discontinuation of Geref, thus raising the question of which reliable alternative GH stimulation test should practicing endocrinologists be considering in place of the GHRH-ARG test. In this article, we review the existing published data and consensus guidelines and provide recommendations for alternative stimulation tests to the GHRH-ARG test.The major source of data acquisition included PubMed search strategies and personal experience of the authors from clinical experience.Previous consensus guidelines and previous data assessing the reliability and discriminatory value of the GHRH-ARG, glucagon, ARG, and GH secretagogues on assessing GH reserve are discussed. Our recommendations for performing the glucagon stimulation test, potential drawbacks in conducting this test, and caveats in interpreting this test are also discussed.The ITT should remain the test of choice in diagnosing adult GHD. However, when the ITT is not desirable and recombinant GHRH remains unavailable in the United States, we recommend the alternative to the GHRH-ARG test to be the glucagon stimulation test, based on its reliability and availability. Nevertheless, further studies into alternative GH stimulation tests that are available in the United States, comparable, and simpler to perform than the ITT in diagnosing adult GHD are still needed.

Optimal treatment for patients with both type 2 diabetes mellitus and stable ischemic heart disease has not been established.We randomly assigned 2368 patients with both type 2 diabetes and heart disease to undergo either prompt revascularization with intensive medical therapy or intensive medical therapy alone and to undergo either insulin-sensitization or insulin-provision therapy. Primary end points were the rate of death and a composite of death, myocardial infarction, or stroke (major cardiovascular events). Randomization was stratified according to the choice of percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) as the more appropriate intervention.At 5 years, rates of survival did not differ significantly between the revascularization group (88.3%) and the medical-therapy group (87.8%, P=0.97) or between the insulin-sensitization group (88.2%) and the insulin-provision group (87.9%, P=0.89). The rates of freedom from major cardiovascular events also did not differ significantly among the groups: 77.2% in the revascularization group and 75.9% in the medical-treatment group (P=0.70) and 77.7% in the insulin-sensitization group and 75.4% in the insulin-provision group (P=0.13). In the PCI stratum, there was no significant difference in primary end points between the revascularization group and the medical-therapy group. In the CABG stratum, the rate of major cardiovascular events was significantly lower in the revascularization group (22.4%) than in the medical-therapy group (30.5%, P=0.01; P=0.002 for interaction between stratum and study group). Adverse events and serious adverse events were generally similar among the groups, although severe hypoglycemia was more frequent in the insulin-provision group (9.2%) than in the insulin-sensitization group (5.9%, P=0.003).Overall, there was no significant difference in the rates of death and major cardiovascular events between patients undergoing prompt revascularization and those undergoing medical therapy or between strategies of insulin sensitization and insulin provision. (ClinicalTrials.gov number, NCT00006305.)

Reversal of new-onset diabetes secondary to thiazide diuretic use remains questionable. STAR-LET was a 6-month extension of the Study of Trandolapril/Verapamil SR and Insulin Resistance (STAR), which assessed the effects of a fixed-dose renin-angiotensin system inhibitor (RASI)/hydrochlorothiazide (HCTZ) combination on changes in 2-hour oral glucose tolerance test (OGTT) results. STAR-LET explored whether the glycemic impact of HCTZ could be reversed by conversion to a RASI/verapamil combination. The primary outcome was change in 2-hour OGTT results. Fifty-one percent of the STAR patients were enrolled in STAR-LET. The 2-hour OGTT value (mmol/L) was unchanged from STAR baseline in the RASI/verapamil group (7.7+/-2.4 vs 8.1+/-3.3; P=.18) and improved in those who were switched from RASI/HCTZ to RASI/verapamil (8.5+/-3.0 vs 7.2+/-2.3; P

To assess insulin resistance postoperatively in patients with (DM) and without (nonDM) a prior diagnosis of diabetes.Following cardiac surgery, 122 nonDM and 33 DM were treated with insulin infusions to obtain glucose levels110 mg dl(-1). Glucose levels, insulin infusion rates, and insulin infusion rate/glucose ratios were calculated to assess insulin resistance.The average blood glucose at insulin drip initiation (209 vs. 173 mg dl(-1); P.001) and during the first 12 h (146 vs. 135 mg dl(-1); P.05) was higher in DM, but during Hours 12-24 glucose levels were not different. The peak (5.7 vs. 4.1 U h(-1); P.001) and average insulin drip rates (3.7 vs. 2.9 U h(-1); P.01) were higher in DM. Insulin resistance (insulin drip rate/glucose ratio) was higher in DM during Hours 1-12 (0.029 vs. 0.022 U h(-1) mg(-1) dl(-1); P.001), but not during Hours 12-24 (P=.57). To eliminate glucotoxicity as a cause of the insulin resistance, 23 DM patients were pair matched with 23 nonDM patients based first on glucose levels at drip initiation then by body mass index (BMI) and then catecholamine use to maintain blood pressure. The average blood glucose levels, insulin drip rates, and insulin resistance ratios were not significantly different between the pair-matched groups at all time points.When matched for initial glucose levels, insulin resistance is not different between DM and nonDM following cardiac surgery, likely due to the overwhelming stress response. Insulin drip protocols used postoperatively do not have to be modified for those with a prior diagnosis of diabetes.

Objective To review approved treatment options for secondary hyperparathyroidism (SHPT) in patients with stages 3 and 4 chronic kidney disease (CKD). Methods Recently published data on the diagnosis and treatment of SHPT in patients with CKD were critically assessed. Results Early detection of SHPT is critical for effective treatment. Approximately 40% of patients with stage 3 CKD and 80% of patients with stage 4 have SHPT due to low serum 1,25-dihydroxyvitamin D levels. Appropriate treatment involves suppression of parathyroid hormone (PTH) to normal levels with active vitamin D therapy and phosphate binders. Ergocalciferol or cholecalciferol should be used to correct 25-hydroxyvitamin D levels either before or during active vitamin D therapy. Active vitamin D analogues include calcitriol, doxercalciferol, and paricalcitol. Calcitriol is effective, but has a narrow therapeutic window at higher doses because of hypercalcemia and hyperphosphatemia, which require frequent monitoring. Doxercalciferol is also effective, but has been associated with significant elevations in serum phosphorus requiring greater use of oral phosphate binders. Paricalcitol effectively suppresses PTH with minimal impact on serum calcium and phosphorus. Limited data exist on the use of cinacalcet in treating SHPT in stages 3 and 4 CKD, and it is only approved for use in patients receiving dialysis. Conclusion SHPT is an early and major complication of CKD. Treatment involves suppression of PTH to prevent metabolic bone disease, bone loss, and metabolic complications that may result in marked morbidity and mortality. Early detection of elevated PTH levels with appropriate intervention using active vitamin D therapy, even in the absence of elevated serum phosphorus and reduced serum calcium, is critical. (Endocr Pract. 2008;14:18-27)

Background:Lymphocytic hypophysitis is a disorder of the pituitary gland that presents as a sellar mass lesion and/or hypopituitarism. It causes pituicyte destruction and hypopituitarism and is speculated to have an autoimmune basis. Diagnosis: Lymphocytic hypophysitis should be considered in the differential diagnosis of pituitary masses and/or hypopituitarism in females who are pregnant or in the early postpartum period, especially in cases associated with other autoimmune diseases or unusual patterns of hormone deficiencies. A definitive diagnosis requires tissue biopsy. A presumptive clinical diagnosis can be made based on a history of gestational or postpartum hypopituitarism, a contrast-enhancing sellar mass with imaging features characteristic of lymphocytic hypophysitis, a pattern of pituitary hormone deficiency with early loss of adrenocorticotrophic hormone and thyroid-stimulating hormone unlike that typically found with macroadenomas, relatively rapid development of hypopituitarism and a degree of pituitary failure disproportionate to the size of the mass.Symptoms resulting from partial or panhypopituitarism occur in approximately 80% of cases and multiple deficiencies are found in approximately 75% of cases. Management:Appropriate management remains controversial. Corticosteroid therapy has been advocated as a means of attenuating inflammation, but given the uncertainty of its efficacy and the known adverse effects, such therapy does not seem justified for most patients. The optimal surgical strategy involves partial resection of the mass to decompress the surrounding structures. All patients with lymphocytic hypophysitis require appropriate replacement therapy for deficient hormones. Long-term follow-up is mandatory to monitor for the development of other hormonal deficits.

Introduction: Cardiac autonomic neuropathy (CAN) is a complication of diabetes mellitus (DM) that is associated with increased mortality. The severity of CAN may be related to type and duration of DM. Methods: 16 subjects with type 1 DM (age 32.9±10.1 years), 18 subjects with type 2 DM (55.4±8.0 years) and 30 controls (44.0±11.6 years) underwent exercise-based assessment of CAN. Two 16-minute submaximal bicycle tests were performed followed by 45 minutes of recovery. Continuous 12-lead electrocardiography was performed. On the 2nd test, atropine (0.04 mg/kg) was administered at peak exercise so that all of recovery occurred under parasympathetic blockade. Plasma epinephrine and norepinephrine levels were measured at rest, during exercise, and during recovery. For each subject and at each time point in recovery, parasympathetic effect on the RR interval was defined as the difference of the RR interval at baseline without atropine and the RR interval after parasympathetic blockade with atropine. Results: There were no differences in resting or peak exercise heart rates in the 3 groups. Parasympathetic effect on RR intervals during recovery (p Conclusions: Both type 1 and type 2 DM exhibit subtle abnormalities in autonomic function, but differentially affect the parasympathetic and sympathetic limbs of the autonomic nervous system. This is the first report of variable pathophysiology for CAN in type 1 versus type 2 DM.

When I was a medical student in the 1960s, about one-third of patients with type 1 diabetes developed end-stage renal disease (ESRD) by ∼30 years’ duration of diabetes (1), and there wasn’t anything that could be done for them. Medicare only started paying for treatment of ESRD (dialysis/transplantation) in the United States in 1973. So, most of those patients died. Recently, the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study showed that the cumulative incidences of ESRD were only 1% in the initial DCCT intensive therapy group and 2% in the initial conventional therapy group in subjects who had a mean diabetes duration of 28 years (2). Now, that’s a difference! Comparable numbers for type 2 diabetes are more difficult to interpret because of the very high competing risk of death from cardiovascular disease (CVD) in such patients and the various interventions that may differentially affect chronic kidney disease (CKD) versus CVD progression in this population. However, it is clear from analyses of the U.S. Renal Data System that the overall proportion of diabetic patients developing ESRD has decreased progressively and substantially since 1996 (3). Nonetheless, the absolute number of diabetic patients developing ESRD and the percentage of patients whose ESRD is the result of diabetes continue to increase because of the overall increase in the incidence of diabetes itself in the …

Purpose Hyperglycemia increases risks of kidney and liver transplant rejection. To determine whether perioperative and subsequent glycemic control was associated with increased risk of heart transplant rejection over the year after transplantation, we performed a retrospective analysis of glycemic control and rejection rates in heart transplantation patients. Methods Perioperative glucose levels were analyzed in 157 patients undergoing transplantation at Northwestern Memorial Hospital from June 2005 to December 2012 and compared in patients with and without rejection found on routine follow-up biopsy specimens. Results Grade ≤1R rejection on biopsy was observed in 116 patients and grade ≥2R rejection (grade requiring increased anti-rejection treatment) in 41 patients. Although no significant differences in the preoperative fasting or inpatient mean glucose levels were found, the mean glucose levels from discharge to 1 year trended higher in those with grade ≥2R compared to grade ≤1R (128.8 ± 40.9 versus 142.2 ± 46.6 mg/dL, P = .084). In a multivariable logistic regression model, neither the lowest nor highest quartile of glucose levels had significantly different odds ratios (ORs) for the development of ≥2R compared to the middle 50% glucose levels. Older age (OR 0.96, P = .020) and higher body mass index levels (OR 0.86, P = .004) were significantly associated with lower odds of developing grade ≥2R. Conclusions Although the glucose trend regarding rejection was not statistically significant, we cannot exclude the possibility that much higher glucose levels would influence rejection rates.

Glycemic control is essential to delay or prevent the onset of diabetic kidney disease. There are a number of glucose-lowering medications available but only a fraction of them can be used safely in chronic kidney disease and many of them need an adjustment in dosing. The ideal target hemoglobin A1c is approximately 7 % but this target is adjusted based on the needs of the patient. Diabetes control should be optimized for each individual patient, with measures to reduce diabetes-related complications and minimize adverse events. Overall care of diabetes necessitates attention to multiple aspects, including reducing the risk of cardiovascular disease, and often, multidisciplinary care is needed.

Significant advances are needed to improve the diagnosis, prognosis, and management of persons with CKD. Discovery of new biomarkers and improvements in currently available biomarkers for CKD hold great promise to achieve these necessary advances. Interest in identification and evaluation of biomarkers for CKD has increased substantially over the past decade. In 2009, the National Institute of Diabetes and Digestive and Kidney Diseases established the CKD Biomarkers Consortium (http://www.ckdbiomarkersconsortium.org/), a multidisciplinary, collaborative study group located at over a dozen academic medical centers. The main objective of the consortium was to evaluate new biomarkers for purposes related to CKD in established prospective cohorts, including those enriched for CKD. During the first 5 years of the consortium, many insights into collaborative biomarker research were gained that may be useful to other investigators involved in biomarkers research. These lessons learned are outlined in this Special Feature and include a wide range of issues related to biospecimen collection, storage, and retrieval, and the internal and external quality assessment of laboratories that performed the assays. The authors propose that investigations involving biomarker discovery and validation are greatly enhanced by establishing and following explicit quality control metrics, including the use of blind replicate and proficiency samples, by carefully considering the conditions under which specimens are collected, handled, and stored, and by conducting pilot and feasibility studies when there are concerns about the condition of the specimens or the accuracy or reproducibility of the assays.

Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.

Background.Research has shown less aggressive treatment and poorer control of cardiovascular disease (CVD) risk factors in women than men.Methods.We analyzed sex differences in pharmacotherapy strategies and attainment of goals for hemoglobin A1c (HbA1c), blood pressure (BP), and low density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes and established coronary artery disease enrolled into the BARI 2D trial.Results.Similar numbers of drugs were prescribed in both women and men. Women were less frequent on metformin or sulfonylurea and more likely to take insulin and to be on higher doses of hydroxymethylglutaryl-CoA reductase inhibitors (statins) than men. After adjusting for baseline differences and treatment prescribed, women were less likely to achieve goals for HbA1c (OR = 0.71, 95% CI 0.57, 0.88) and LDL-C (OR = 0.64, 95% CI 0.53, 0.78). More antihypertensives were prescribed to women, and yet BP ≤ 130/80 mmHg did not differ by sex.Conclusions.Women entering the BARI 2D trial were as aggressively treated with drugs as men. Despite equivalent treatment, women less frequently met targets for HbA1c and LDL-C. Our findings suggest that there may be sex differences in response to drug therapies used to treat diabetes, hypertension, and hyperlipidemia.

OBJECTIVE—We sought to test the hypothesis that a fixed-dose combination of trandolapril/verapamil-SR (T/V) is superior to a fixed-dose combination of losartan/hydrochlorothiazide (L/H) on glucose tolerance in hypertensive patients with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS—A prospective, randomized, open-label, blinded–end points design was used to assess the effects of a T/V versus L/H combination in patients with IGT and hypertension (n = 240) followed for up to 1 year. Doses were titrated to a systolic blood pressure RESULTS—Changes at study end were noted in 2-h OGTT glucose (T/V −0.21 ± 0.36 vs. L/H +1.44 ± 0.36 mmol/l; P < 0.001) and insulin level (−30.13 ± 38.38 vs. +84.86 ± 38.33 pmol/l, respectively; P = 0.025). Worsening of insulin resistance occurred by week 12 (T/V 0.000 ± 0.001 vs. L/H −0.005 ± 0.001; P = 0.016). A higher incidence of new-onset diabetes (T/V 11.0 vs. L/H 26.6%; P = 0.002) and HbA1c >7% (2.6 vs. 9.6%, respectively; P = 0.05) occurred at study end. CONCLUSIONS—In patients with IGT, normal kidney function, and hypertension, the fixed-dose combination of T/V reduces the risk of new-onset diabetes compared with an L/H-based therapy.

Prolactinomas are a common cause of reproductive/sexual dysfunction. Once other causes of hyperprolactinemia have been excluded with a careful history and physical examination, routine chemistries, a pregnancy test and a thyroid-stimulating hormone, imaging with magnetic resonance imaging or computed tomography will delineate the size and extent of the tumor. Medical therapy with cabergoline or bromocriptine is the initial treatment of choice. When infertility is the primary indication for treatment, bromocriptine use has an extensive safety experience and is preferred by some clinicians. However, for other indications, cabergoline appears to be more efficacious and better tolerated. Transsphenoidal surgery remains an option, especially for patients with microadenomas, when medical therapy is ineffective or not tolerated.

Objective: To describe a novel method of safe and effective intensive management of inpatient hyperglycemia with use of cost-effective protocols directed by a glucose management service (GMS). Methods: An intravenous insulin protocol was designed to achieve a glycemic target of 80 to 110 mg/dL. When stable inpatients were transferred from the intravenous protocol to a subcutaneous insulin protocol, which consisted of basal long-acting and prandial and supplemental rapid-acting insulins, the blood glucose target was 80 to 150 mg/dL. Glucose levels were reviewed by the GMS at least daily for protocol adjustments, when necessary. Results: The intravenous insulin protocol was used in 276 patients, and 4,058 capillary blood glucose levels were recorded. Glycemic target levels (80 to 110 mg/dL) were achieved, on average, 10.6 ± 5.2 hours after initiation of insulin drip therapy. The mean capillary blood glucose level during the study interval was 135.3 ± 49.9 mg/dL. Hypoglycemia (″60 mg/dL) was recorded in 1.5% of glucose values, and hyperglycemia (≥400 mg/dL) was recorded in only 0.06%. The subcutaneous insulin protocol was used in 922 patients, and 18,067 capillary glucose levels were documented. The mean blood glucose level was 145.6 ± 55.8 mg/dL during the study period. The blood glucose target of 80 to 150 mg/dL was achieved in 58.6%, whereas 74.3% of glycemic values were in the clinically acceptable range (80 to 180 mg/dL). Hypoglycemia (″60 mg/dL) occurred in 1.3% of capillary blood glucose values, and hyperglycemia (≥400 mg/dL) occurred in 0.4% of values. Conclusion: Validated protocols dedicated to the achievement of strict glycemic goals were implemented by a GMS and resulted in substantial improvements in glycemic control on the surgical inpatient services, with a reduced frequency of hypoglycemia. The protocols and the GMS have been well received by the inpatient nursing and surgical staff members, and all of this has been done in a cost-effective manner. (Endocr Pract. 2006;12:491505)

OBJECTIVE—To evaluate barriers to and strategies for medication adherence and predictors of adherence and the primary outcome in the Diabetes Prevention Program (DPP). RESEARCH DESIGN AND METHODS—Within a randomized, controlled primary prevention study for type 2 diabetes, we collected data on study medication adherence, its predictors, and health outcomes in 27 clinical centers across mainland U.S. and Hawaii. Medication arm participants included 2,155 adults with impaired glucose tolerance randomly assigned to either metformin or matched placebo treatment arms. Structured interviews were used to promote medication adherence and to collect data regarding adherence. Adherence was measured by pill count. The primary DPP outcome of type 2 diabetes was assessed by fasting plasma glucose and oral glucose tolerance test. RESULTS—Older age-groups were more adherent than the youngest group (P = 0.01) in the metformin group. The most frequently reported barrier to adherence was “forgetting” (22%). Women reported more adverse effects of metformin (15 vs. 10%, P = 0.002) in the metformin group. Odds of nonadherence increased as participants reported more than one barrier (odds ratio 19.1, P < 0.001). Odds of adherence increased as participants reported multiple strategies to take medication (2.69, P < 0.0001). There was a 38.2% risk reduction for developing diabetes for those adherent to metformin compared with those adherent to placebo (P < 0.0003). CONCLUSIONS—DPP medication adherence results are unique in primary prevention for a chronic disease in a large multiethnic sample. Our finding that adherence was associated with risk reduction for diabetes supports the development of brief interventions in clinical settings where medication adherence is a challenge.

The prevalence of sexual dysfunction, low vitality, and poor physical function increases with aging, as does the prevalence of low total and free testosterone (TT and FT) levels. However, the relationship between sex hormones and age-related alterations in older men is not clear.To test the hypotheses that baseline serum TT, FT, estradiol (E2), and sex hormone-binding globulin (SHBG) levels are independently associated with sexual function, vitality, and physical function in older symptomatic men with low testosterone levels participating in the Testosterone Trials (TTrials).Cross-sectional study of baseline measures in the TTrials.The study was conducted at 12 sites in the United States.The 788 TTrials participants were ≥ 65 years and had evidence of sexual dysfunction, diminished vitality, and/or mobility disability, and an average of two TT275 ng/dL.None.Question 4 of Psychosocial Daily Questionnaire (PDQ-Q4), the FACIT-Fatigue Scale, and the 6-minute walk test.Baseline serum TT and FT, but not E2 or SHBG levels had small, but statistically significant associations with validated measures of sexual desire, erectile function, and sexual activity. None of these hormones was significantly associated within or across trials with FACIT-Fatigue, PHQ-9 Depression or Physical Function-10 scores, or gait speed.FT and TT levels were consistently, independently, and positively associated, albeit to a small degree, with measures of sexual desire, erectile function, and sexual activity, but not with measures of vitality or physical function in symptomatic older men with low T who qualified for the TTrials.

Ke yW ords. sellar mass, parasellar mass, pituitary adenoma, cystic sellar lesions, sellar neoplasms Several types of lesions may present within the sella turcica and in parasellar areas, of which the most common are pituitary adenomas. Less commonly, sellar lesions are of non-pituitary origin with a broad range of potential etiologies including neoplastic, non-neoplastic cystic lesions, inflammatory and infectious lesions, vascular lesions and pituitary hyperplasia [1]. Differentiating among these various causes may be difficult, as they share similar clinical and radiographic features and easily mimic each other and pituitary adenomas. Making the correct preoperative diagnosis is of clinical relevance since the treatment of choice for many of these non-pituitary sellar masses differs from that of a pituitary adenoma. An overview of the clinical and radiographic features of the more common lesions as well as their management is provided in this article.

Pharmacologic resistance to dopamine agonists is defined here as failure to normalize PRL levels and failure to decrease macroprolactinoma size byor=50%. Failure to normalize PRL levels is found in about one-quarter of patients treated with bromocriptine and 10-15% of those treated with pergolide or cabergoline. Failure to achieve at least a 50% reduction in tumor size occurs in about one-third of those treated with bromocriptine and 10-15% of those treated with pergolide or cabergoline. The cause of dopamine resistance is primarily a decrease in D(2) receptors but the receptors have normal affinity for dopamine. Treatment approaches for patients resistant to dopamine agonists include changing to another dopamine agonist and increasing the dose of the drug as long as there is continued response to the dose increases and no adverse effects with higher doses. Transsphenoidal surgery is also an option. Clomiphene, gonadotropins, and GnRH can be used if fertility is desired. For those not desiring fertility, estrogen replacement may be used unless there is a macroadenoma, in which case control of tumor growth is also an issue and dopamine agonists are generally necessary. In many patients modest or even no reduction in tumor size may be acceptable as long as there is not tumor growth. Hormone replacement (estrogen or testosterone) may cause a decrease in efficacy of the dopamine agonist so that it must be carried out cautiously. Reduction of endogenous estrogen, use of selective estrogen receptor modulators, and aromatase inhibitors are potential experimental approaches.

Tumors vary in how they affect pregnancy depending upon the hormone secreted. Some hormone oversecretion syndromes must be controlled to allow pregnancy to proceed without undue maternal and fetal morbidity (Cushing's disease and hyperthyroidism) whereas treatment during pregnancy for other tumors is not necessary. Surveillance for tumor growth during pregnancy is necessary primarily for prolactinomas. A literature search was conducted to identify the effects of pregnancy on pre-existing pituitary tumors and the effects on the outcome of pregnancy due to hormone oversecretion by pituitary tumors. Results show that hyperprolactinemia and Cushing's disease may interfere with fertility and usually need to be controlled to allow for conception. Cushing's syndrome, acromegaly and hyperthyroidism secondary to hypersecretion of thyroid-stimulating hormone (TSH) may increase maternal morbidity (gestational diabetes, hypertension) and fetal morbidity and mortality. Intervention is warranted to remove a tumor that secretes adrenocorticotropic hormone (ACTH) during pregnancy to reduce the risk of fetal loss and to control hyperthyroidism. In contrast, surgery or medical therapy for adenomas that secrete growth hormone (GH) and for clinically nonfunctioning adenomas is not indicated during pregnancy. Pregnancy may cause an increase in the size of tumors that secrete prolactin (PRL), especially macroadenomas, so close surveillance is indicated and re-institution of bromocriptine therapy may be necessary to treat such an increase in tumor size. An increase in the size of other types of tumors during pregnancy is very rare.

Pregnancy may occur in the setting of endocrine diseases or be the first time these diseases manifest clinically. Management of pregnancy in these circumstances is challenging and requires a high degree of vigilance on the part of the treating physicians. The best outcome is achieved by a multidisciplinary approach consisting of endocrinology, obstetrics, anesthesiology, and endocrine surgery.

Epigenetic and genetic analysis of p16 in dermal fibroblasts from type 1 diabetic patients with nephropathy. Background Several studies have shown that cultured skin fibroblasts from patients with diabetic nephropathy (DN) exhibit a hyperplastic growth phenotype. Increased DNA synthesis in cells from patients with DN may ultimately involve alterations in cell cycle regulatory proteins. p16 protein is a member of INK4 family of cyclin-dependent kinase inhibitors, which plays an important role in cell cycle regulation. In this study, we examined the correlation between p16 protein expression in cultured dermal fibroblasts from type 1 diabetic patients and the presence of DN. Method Western blot analysis was performed to compare p16 protein expression in skin fibroblasts from patients with DN as compared to control subjects, diabetic patients without DN, and nondiabetic patients with nephropathy. Transcriptional regulation of the p16 gene was assessed using competitive reverse transcription-polymerase chain reaction (RT-PCR). Methylation status of the promoter region of p16 was examined using methylation-specific PCR, and we used single-stranded conformational polymorphism (SSCP)-PCR to assess p16 single-nucleotide polymorphism. Results Cells from diabetic patients with DN had nondetectable to significantly lower protein expression of p16. Similarly, mRNA expression of p16 was significantly lower in diabetic patients with DN. No hypermethylation of p16 gene was detected, and no abnormal migrating bands were noticed on SSCP-PCR analysis in cells from patients with DN. Conclusion Our data indicate that cells from patients with DN exhibit significantly lower protein and mRNA expression of p16. This study could have not only important implications for the understanding of the pathogenesis of DN, but also the absence of p16 may ultimately serve as an early marker for DN.

Men with acquired hypogonadotropic hypogonadism treated with testosterone are generally assumed to be infertile. The finding of two such patients with unexpected fertility and normal sperm counts prompted an evaluation of spermatogenesis in additional men with this condition. Case records were initially searched and one similar case with fertility was found. Subsequently, 12 consecutive men with acquired hypogonadotropic hypogonadism were evaluated for gonadal function and sperm production while receiving testosterone. In five of the cases with proven spermatogenesis, exon 10 of the FSH receptor was sequenced to look for activating mutations. The original three cases and four of the subsequent 12 men had sperm concentrations > or = 15 million/ml. Two additional men had concentrations of 1 million/ml and six were azoospermic. Residual LH and FSH levels were slightly higher in those with maintained spermatogenesis prior to testosterone replacement. No activating mutations were found in exon 10 of the FSH receptor in the five cases studied. We conclude that men with acquired hypogonadotropic hypogonadism being treated with testosterone should not be assumed to be sterile, as we have found that more than half have been shown to have persistent spermatogenesis with more than one-third having sperm concentrations > or = 15 million/ml. This may be related to fact that gonadotropin levels in such patients are present, albeit low. Semen analyses in such men should be routinely carried out so that they can be appropriately counseled regarding potential fertility.

Resistance to dopamine agonists can be defined with respect to failure to normalize PRL levels and failure to decrease tumor size by ≥50%. Using these definitions, failure to normalize PRL levels is seen in 24% of those treated with bromocriptine, 13% of those treated with pergolide and 11% of those treated with cabergoline. Failure to achieve at least a 50% reduction in tumor size occurs in about one-third of those treated with bromocriptine and 10–15% of those treated with pergolide or cabergoline. Studies of in vitro cell preparations show that the D2 receptors of resistant tumors are decreased in number but have normal affinity.

The association of insulin resistance and hyperinsulinemia to blood pressure has remained controversial. We examined the association of insulinemia to hypertension and blood pressure using baseline measurements for participants of the Diabetes Prevention Program (DPP). The DPP is a multicenter randomized controlled trial of 3819 participants with impaired glucose tolerance, and is designed to evaluate interventions for the delay or prevention of type 2 diabetes. The relationship between hypertension and insulinemia is described overall and by ethnicity. The effects of demographics (age and gender), adiposity, and glucose on the relationship are also presented. Asian Americans and African Americans had a similarly high prevalence of hypertension as did whites; American Indians had a lower prevalence of hypertension. Among participants not on antihypertensive medications, systolic blood pressure was significantly (but weakly) correlated with fasting insulin ( r =0.12), homeostasis model assessment of insulin resistance (HOMA IR; r =0.13), and fasting proinsulin ( r =0.10) when adjusted for age and gender (all, P r =0.06, P =0.002; DBP: r =0.06, P