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© 2014 Lazure et al.; licensee BioMed Central Ltd.Background: The Theoretical Domains Framework (TDF) is a set of 14 domains of behavior change that provide a framework for the critical issues and factors influencing optimal knowledge translation. Consider

Objective: Autonomic nervous system dysfunction, a correlate of obesity and poor cardiorespiratory fitness, is associated with the development of diabetes. We tested whether estimates of autonomic nervous system function improved in the intensive lifestyle versus metformin or placebo arms of the Diabetes Prevention Program (DPP) and whether baseline or a change in autonomic nervous system function was associated with the development of diabetes over 3.2 years.Research Design and Methods: In 2,980 DPP participants, 12-lead electrocardiograms were measured at baseline and annually. Heart rate, heart rate variability (HRV), and QT duration were used to estimate fitness and autonomic nervous system function.Results: In the lifestyle arm, heart rate and QT indexes decreased, and HRV increased over time. The magnitude of decline in heart rate and QT duration was substantially smaller in the other arms, whereas HRV did not increase. Baseline heart rate was the only index significantly (P < 0.05) associated with incident diabetes after adjustment for demographics and weight change (hazard ratio for lifestyle and metformin arms = 1.19 and 1.17 per 10.6 beats/min, respectively). Decreases in heart rate and QT indexes and increases in HRV over time were associated with a lower risk of developing diabetes. The protective association between decreased heart rate and incident diabetes in the lifestyle arm remained significant after accounting for change in weight and physical activity.Conclusions: Indexes that reflect autonomic function and fitness improved (i.e., heart rate decreased and HRV increased) in the lifestyle modification arm of the DPP. Improvements in these indexes are inversely associated with the development of diabetes independent of weight change. [ABSTRACT FROM AUTHOR]

Medication use is a common cause of hyperprolactinemia, and it is important to differentiate this cause from pathologic causes, such as prolactinomas. To ascertain the frequency of this clinical problem and to develop treatment guidelines, the medical literature was searched by using PubMed and the reference lists of other articles dealing with hyperprolactinemia due to specific types of medications. The medications that most commonly cause hyperprolactinemia are antipsychotic agents; however, some newer atypical antipsychotics do not cause this condition. Other classes of medications that cause hyperprolactinemia include antidepressants, antihypertensive agents, and drugs that increase bowel motility. Hyperprolactinemia caused by medications is commonly symptomatic, causing galactorrhea, menstrual disturbance, and impotence. It is Important to ensure that hyperprolactinemia in an Individual patient is due to medication and not to a structural lesion in the hypothalamic/pituitary area; this can be accomplished by (1) stopping the medication temporarily to determine whether prolactin levels return to normal, (2) switching to a medication that does not cause hyperprolactinemia (in consultation with the patient's psychiatrist for psychoactive medications), or (3) performing magnetic resonance imaging or computed tomography of the hypothalamic/pituitary area. If the patient's hyperprolactinemia is symptomatic, treatment strategies include switching to an alternative medication that does not cause hyperprolactinemia, using estrogen or testosterone replacement, or, rarely, cautiously adding a dopamine agonist. [ABSTRACT FROM AUTHOR]

Introduction: Tubular biomarkers may shed insight into progression of kidney tubulointerstitial pathology complementary to traditional measures of glomerular function and damage., Methods: We examined trajectories of tubular biomarkers in the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC Study) of type 1 diabetes (T1D). Biomarkers were measured in a subset of 220 participants across 7 time points over 26 years. Measurements included the following: kidney injury molecule 1 (KIM-1), soluble tumor necrosis factor 1 (sTNFR1) in serum or plasma, epidermal growth factor (EGF), monocyte chemoattractant protein-1 (MCP1) in timed urine, and a composite tubular secretion score. We described biomarker trajectories and examined how these were affected by intensive glucose-lowering therapy and glycemia., Results: At baseline, participants had a mean age of 28 years, 45% were women, and 50% were assigned to intensive glucose-lowering therapy. The mean estimated glomerular filtration rate (eGFR) was 125 ml/min per 1.73 m 2 and 90% of participants had a urinary albumin excretion rate (AER) <30 mg/24h. Mean changes in biomarkers over time (percent/decade) were: KIM-1: 27.3% (95% confidence interval [CI]: 21.4-33.5), sTNFR1: 16.9% (14.5-19.3), MCP1: 18.4% (8.9-28.8), EGF: -13.5% (-16.7 to -10.1), EGF-MCP1 ratio: -26.9% (-32.2 to -21.3), and tubular secretion score -0.9% (-1.8 to 0.0), versus -12.0% (CI: -12.9 to -11.1) for eGFR and 10.9% (2.5-20.1) for AER. Intensive versus conventional glucose-lowering therapy was associated with slower increase in sTNFR1 (relative difference in change: 0.94 [0.90-0.98]). Higher HbA1c was associated with faster increases in sTNFR1 (relative difference in change: 1.06 per 1% higher HbA1c [1.05-1.08]) and KIM-1 (1.09 [1.05-1.14])., Conclusion: Among participants with T1D and normal eGFR at baseline, kidney tubular biomarkers changed significantly over long-term follow-up. Hyperglycemia was associated with larger increases in serum or plasma sTNFR1 and KIM-1, when followed-up longitudinally., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Objective: To describe the relationships between the cumulative incidences of long-term complications in individuals with type 1 diabetes (T1D) and assess whether observed associations are independent of age, duration of diabetes, and glycemic levels., Methods: Proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), reduced estimated glomerular filtration rate (eGFR), amputations, cardiovascular disease (CVD), and mortality were assessed in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study over ∼30 years., Research Design and Results: The cumulative incidence of complications ranged from 3% (amputations) to 37% (CSME). There were large differences in the cumulative incidence of PDR between participants with versus without prior CSME (66% vs. 15%), reduced eGFR (59% vs. 29%), and amputation (68% vs. 32%); reduced eGFR with or without prior PDR (25% vs. 9%), amputation (48% vs. 13%), and CVD (30% vs. 11%); CVD with or without prior reduced eGFR (37% vs. 14%) and amputation (50% vs. 16%); and mortality with or without prior reduced eGFR (22% vs. 9%), amputation (35% vs. 8%), and CVD (25% vs. 8%). Adjusted for age, duration of T1D, and mean updated HbA1c, the complications and associations with higher risk included PDR with CSME (hazard ratio [HR] 1.88; 95% CI 1.42, 2.50), reduced eGFR (HR 1.41; 95% CI 1.01, 1.97), and CVD (HR 1.43; 95% CI 1.06, 1.92); CSME with higher risk of PDR (HR 3.94; 95% CI 3.18 4.89), reduced eGFR (HR 1.49; 95% CI 1.10, 2.01), and CVD (HR 1.35; 95% CI 1.03, 1.78); reduced eGFR with higher risk of CVD (HR 2.09; 95% CI 1.44, 3.03), and death (HR 3.40; 95% CI 2.35, 4.92); amputation(s) with death (HR 2.97; 95% CI 1.70, 2.90); and CVD with reduced eGFR (HR 1.59; 95% CI 1.08, 2.34) and death (HR 1.95; 95% CI 1.32, 2.90)., Conclusions: Long-term micro- and macrovascular complications and mortality are highly correlated. Age, diabetes duration, and glycemic levels do not completely explain these associations., (© 2023 by the American Diabetes Association.)

Introduction: Angiotensinogen (AOG) is the precursor of peptides of the renin angiotensin system (RAS). Because insulin up-regulates transcriptional factors that normally repress kidney AOG synthesis, we evaluated urinary AOG (uAOG) in patients with type 1 diabetes (T1D) and microalbuminuria who are receiving either intensive or conventional insulin therapy., Methods: Urine samples from participants of the Diabetes Control and Complications Trial (DCCT) were used for the following: (i) uAOG/creatinine measurements in 103 patients with microalbuminuria and 103 patients with normoalbuminuria, matched for age, gender, disease duration, and allocation to insulin therapy; and (ii) uAOG/creatinine measurements from patients with microalbuminuria allocated to intensive insulin therapy ( n  = 58) or conventional insulin therapy ( n  = 41) after 3 years on each modality., Results: uAOG was higher in patients who started with microalbuminuria than in those with normoalbuminuria (6.65 vs. 4.0 ng/mg creatinine, P  < 0.01). uAOG was higher in females than in males with microalbuminuria (11.7 vs. 5.4 ng/mg creatinine, P  = 0.015). uAOG was lower in patients with microalbuminuria allocated to intensive insulin therapy than in conventional insulin therapy (3.98 vs. 7.42 ng/mg creatinine, P  < 0.01). These differences in uAOG were observed though albumin excretion rate (AER) was not significantly different., Conclusion: In patients with T1D and microalbuminuria, uAOG is increased and varies with gender and the type of insulin therapy independently of AER. This suggests that AOG production is increased in females and it is decreased by intensive insulin therapy. The reduction in uAOG with intensive insulin therapy, by kidney RAS downregulation, may contribute to the known renoprotective action associated with intensive insulin and improved glycemic control., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Objective: CeQur Simplicity™ (CeQur, Marlborough, MA) is a 3-day insulin delivery patch designed to meet mealtime insulin requirements. A recently reported 48-week, randomized, multicenter, interventional trial compared efficacy, safety and self-reported outcomes in 278 adults with type 2 diabetes (T2D) on basal insulin therapy who initiated and managed mealtime insulin therapy with a patch pump versus insulin pen. We assessed changes in key glycemic metrics among a subset of patients who wore a continuous glucose monitoring (CGM) device., Methods: Study participants (patch, n = 49; pen, n = 48) wore a CGM device in masked setting during the baseline period and prior to week 24. Glycemic control was assessed using international consensus guidelines for percentage of Time In Range (%TIR: >70% at 70-180 mg/dL), Time Below Range (%TBR: <4% at <70 mg/dL; <1% at <54 mg/dL), and Time Above Range (%TAR: <25% at >180 mg/dL; <5% at >250 mg/dL)., Results: Both the patch and pen groups achieved recommended targets in %TIR (74.1% ± 18.7%, 75.2 ± 16.1%, respectively) and marked reductions in %TAR >180 mg/dL (21.1% ± 19.9%, 19.7% ± 17.5%, respectively) but with increased %TBR <70 mg/dL (4.7% ± 5.2%, 5.1 ± 5.8, respectively), all P < .0001. No significant between-group differences in glycemic improvements or adverse events were observed., Conclusions: CGM confirmed that the patch or pen can be used to safely initiate and optimize basal-bolus therapy using a simple insulin adjustment algorithm with SMBG. Preference data suggest that use of the patch vs pen may enhance treatment adherence.

Objective: Rapid loss of estimated glomerular filtration rate (eGFR) within its normal range has been proposed as a strong predictor of future kidney disease. We investigated this association of eGFR slope early in the course of type 1 diabetes with long-term incidence of kidney and cardiovascular complications., Research Design and Methods: The annual percentage change in eGFR (slope) was calculated during the Diabetes Control and Complications Trial (DCCT) for each of 1,441 participants over a mean of 6.5 years and dichotomized by the presence or absence of early rapid eGFR loss (slope ≤-3% per year) as the exposure of interest. Outcomes were incident reduced eGFR (eGFR <60 mL/min/1.73 m2), composite cardiovascular events, or major adverse cardiovascular events (MACE) during the subsequent 24 years post-DCCT closeout follow-up., Results: At DCCT closeout (the baseline for this analysis), diabetes duration was 12 ± 4.8 years, most participants (85.9%) had normoalbuminuria, mean eGFR was 117.0 ± 13.4 mL/min/1.73 m2, and 149 (10.4%) had experienced early rapid eGFR loss over the preceding trial phase. Over the 24-year subsequent follow-up, there were 187 reduced eGFR (6.3 per 1,000 person-years) and 113 MACE (3.6 per 1,000 person-years) events. Early rapid eGFR loss was associated with risk of reduced eGFR (hazard ratio [HR] 1.81, 95% CI 1.18-2.79, P = 0.0064), but not after adjustment for baseline eGFR level (HR 0.94, 95% CI 0.53-1.66, P = 0.84). There was no association with composite cardiovascular events or MACE., Conclusions: In people with type 1 diabetes primarily with normal eGFR and normoalbuminuria, the preceding slope of eGFR confers no additional association with kidney or cardiovascular outcomes beyond knowledge of an individual's current level., (© 2022 by the American Diabetes Association.)

Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio >300 mg/g, and estimated glomerular filtration rate of 30 to <90 mL/min/1.73 m 2 To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions in order to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications., (© 2020 by the American Diabetes Association and the National Kidney Foundation.)

Context: Prostate-specific antigen (PSA) changes during testosterone treatment of older hypogonadal men have not been rigorously evaluated., Design: Double-blinded, placebo-controlled trial., Setting: Twelve US academic medical centers., Participants: Seven hundred ninety hypogonadal men ≥65 years of age with average testosterone levels ≤275 ng/dL. Men at high risk for prostate cancer were excluded., Interventions: Testosterone or placebo gel for 12 months., Main Outcomes: Percentile changes in PSA during testosterone treatment of 12 months., Results: Testosterone treatment that increased testosterone levels from 232 ± 63 ng/dL to midnormal was associated with a small but substantially greater increase (P < 0.001) in PSA levels than placebo treatment. Serum PSA levels increased from 1.14 ± 0.86 ng/mL (mean ± SD) at baseline by 0.47 ± 1.1 ng/mL at 12 months in the testosterone group and from 1.25 ± 0.86 ng/mL by 0.06 ± 0.72 ng/mL in the placebo group. Five percent of men treated with testosterone had an increase ≥1.7 ng/mL and 2.5% of men had an increase of ≥3.4 ng/mL. A confirmed absolute PSA >4.0 ng/mL at 12 months was observed in 1.9% of men in the testosterone group and 0.3% in the placebo group. Four men were diagnosed with prostate cancer; two were Gleason 8., Conclusions: When hypogonadal older men with normal baseline PSA are treated with testosterone, 5% had an increase in PSA ≥1.7 ng/mL, and 2.5% had an increase ≥3.4 ng/mL., (Copyright © 2019 Endocrine Society.)

Objective: Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early Renal Loss in Diabetes (PERL) evaluates whether lowering SUA with allopurinol slows glomerular filtration rate (GFR) loss in people with type 1 diabetes (T1D) and mild to moderate DKD. We present the PERL rationale, design, and baseline characteristics., Research Design and Methods: This double-blind, placebo-controlled, multicenter trial randomized 530 participants with T1D, estimated GFR (eGFR) of 40-99.9 mL/min/1.73 m 2 , SUA ≥4.5 m/dL, and micro- to macroalbuminuric DKD or normoalbuminuria with declining kidney function (NDKF) (defined as historical eGFR decline ≥3 mL/min/1.73 m 2 /year) to allopurinol or placebo. The primary outcome is baseline-adjusted iohexol GFR (iGFR) after 3 years of treatment plus a 2-month washout period., Results: Participants are 66% male and 84% white. At baseline, median age was 52 years and diabetes duration was 35 years, 93% of participants had hypertension, and 90% were treated with renin-angiotensin system inhibitors (median blood pressure 127/71 mmHg). Median HbA 1c was 8%, SUA 5.9 mg/dL, iGFR 68 mL/min/1.73 m 2 , and historical eGFR slope -3.5 mL/min/1.73 m 2 /year. Compared with participants with albuminuria ( n = 419), those with NDKF ( n = 94) were significantly older (56 vs. 52 years), had lower HbA 1c (7.7 vs. 8.1%) and SUA (5.4 vs. 6.0 mg/dL), and had higher eGFR (82 vs. 74 mL/min/1.73 m 2 ) and historical eGFR loss (-4.7 vs. -2.5 mL/min/1.73 m 2 /year). These differences persisted when comparing groups with similar rates of historical eGFR loss., Conclusions: PERL will determine the effect of allopurinol on mild to moderate DKD in T1D, with or without albuminuria. Participants with normoalbuminuria and rapid GFR loss manifested many DKD risk factors of those with albuminuria, but with less severity., (© 2019 by the American Diabetes Association.)

Background and Objectives: Glomerular hyperfiltration has been considered to be a contributing factor to the development of diabetic kidney disease (DKD). To address this issue, we analyzed GFR follow-up data on participants with type 1 diabetes undergoing 125 I-iothalamate clearance on entry into the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications study., Design, Setting, Participants, & Measurements: This was a cohort study of DCCT participants with type 1 diabetes who underwent an 125 I-iothalamate clearance (iGFR) at DCCT baseline. Presence of hyperfiltration was defined as iGFR levels ≥140 ml/min per 1.73 m 2 , with secondary thresholds of 130 or 150 ml/min per 1.73 m 2 . Cox proportional hazards models assessed the association between the baseline hyperfiltration status and the subsequent risk of reaching an eGFR <60 ml/min per 1.73 m 2 ., Results: Of the 446 participants, 106 (24%) had hyperfiltration (iGFR levels ≥140 ml/min per 1.73 m 2 ) at baseline. Over a median follow-up of 28 (interquartile range, 23, 33) years, 53 developed an eGFR <60 ml/min per 1.73 m 2 . The cumulative incidence of eGFR <60 ml/min per 1.73 m 2 at 28 years of follow-up was 11.0% among participants with hyperfiltration at baseline, compared with 12.8% among participants with baseline GFR <140 ml/min per 1.73 m 2 . Hyperfiltration was not significantly associated with subsequent risk of developing an eGFR <60 ml/min per 1.73 m 2 in an unadjusted Cox proportional hazards model (hazard ratio, 0.83; 95% confidence interval, 0.43 to 1.62) nor in an adjusted model (hazard ratio, 0.77; 95% confidence interval, 0.38 to 1.54). Application of alternate thresholds to define hyperfiltration (130 or 150 ml/min per 1.73 m 2 ) showed similar findings., Conclusions: Early hyperfiltration in patients with type 1 diabetes was not associated with a higher long-term risk of decreased GFR. Although glomerular hypertension may be a mechanism of kidney injury in DKD, higher total GFR does not appear to be a risk factor for advanced DKD., (Copyright © 2019 by the American Society of Nephrology.)

Objective: The objective is to formulate clinical practice guidelines for the treatment of diabetes in older adults., Conclusions: Diabetes, particularly type 2, is becoming more prevalent in the general population, especially in individuals over the age of 65 years. The underlying pathophysiology of the disease in these patients is exacerbated by the direct effects of aging on metabolic regulation. Similarly, aging effects interact with diabetes to accelerate the progression of many common diabetes complications. Each section in this guideline covers all aspects of the etiology and available evidence, primarily from controlled trials, on therapeutic options and outcomes in this population. The goal is to give guidance to practicing health care providers that will benefit patients with diabetes (both type 1 and type 2), paying particular attention to avoiding unnecessary and/or harmful adverse effects., (Copyright © 2019 Endocrine Society.)

Objective: To characterize the types of hyperglycemia that occur up to 1 year following liver transplant and to clarify the nomenclature for posttransplant hyperglycemia., Design: We analyzed 1-year glycemic follow-up data in 164 patients who underwent liver transplant and who had been enrolled in a randomized controlled trial comparing moderate to intensive insulin therapy to determine if patients had preexisting known diabetes, transient hyperglycemia, persistent hyperglycemia, or new-onset diabetes after transplantation (NODAT)., Results: Of 119 patients with posttransplant hyperglycemia following hospital discharge, 49 had preexisting diabetes, 5 had insufficient data for analysis, 48 had transient hyperglycemia (16 resolved within 30 days and 32 resolved between 30 days and 1 year), 13 remained persistently hyperglycemic out to 1 year and most likely had preexisting diabetes that had not been diagnosed or insulin resistance/insulinopenia prior to transplant, and 4 had NODAT ( i.e. , patients with transient hyperglycemia after transplant that resolved but then later truly developed sustained hyperglycemia, meeting criteria for diabetes)., Conclusions: Distinct categories of patients with hyperglycemia following organ transplant include known preexisting diabetes, persistent hyperglycemia (most likely unknown preexisting diabetes or insulin resistance/insulinopenia), transient hyperglycemia, and NODAT. Those with preexisting diabetes for many years prior to transplant may well have very different long-term outcomes compared with those with true NODAT. Therefore, it would be prudent to classify patients more carefully. Long-term outcome studies are needed to determine if patients with true NODAT have the same poor prognosis as patients with preexisting diabetes (diagnosed and undiagnosed) undergoing transplant.

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.

The Testosterone Trials (TTrials) were a coordinated set of seven placebo-controlled, double-blind trials in 788 men with a mean age of 72 years to determine the efficacy of increasing the testosterone levels of older men with low testosterone. Testosterone treatment increased the median testosterone level from unequivocally low at baseline to midnormal for young men after 3 months and maintained that level until month 12. In the Sexual Function Trial, testosterone increased sexual activity, sexual desire, and erectile function. In the Physical Function Trial, testosterone did not increase the distance walked in 6 minutes in men whose walk speed was slow; however, in all TTrial participants, testosterone did increase the distance walked. In the Vitality Trial, testosterone did not increase energy but slightly improved mood and depressive symptoms. In the Cognitive Function Trial, testosterone did not improve cognitive function. In the Anemia Trial, testosterone increased hemoglobin in both men who had anemia of a known cause and in men with unexplained anemia. In the Bone Trial, testosterone increased volumetric bone mineral density and the estimated strength of the spine and hip. In the Cardiovascular Trial, testosterone increased the coronary artery noncalcified plaque volume as assessed using computed tomographic angiography. Although testosterone was not associated with more cardiovascular or prostate adverse events than placebo, a trial of a much larger number of men for a much longer period would be necessary to determine whether testosterone increases cardiovascular or prostate risk.

Context: Studies of the possible cardiovascular risk of testosterone treatment are inconclusive., Objective: To determine the effect of testosterone treatment on cardiovascular biomarkers in older men with low testosterone., Design: Double-blind, placebo-controlled trial., Setting: Twelve academic medical centers in the United States., Participants: In all, 788 men ≥65 years old with an average of two serum testosterone levels <275 ng/dL who were enrolled in The Testosterone Trials., Intervention: Testosterone gel, the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months., Main Outcome Measures: Serum markers of cardiovascular risk, including lipids and markers of glucose metabolism, fibrinolysis, inflammation, and myocardial damage., Results: Compared with placebo, testosterone treatment significantly decreased total cholesterol (adjusted mean difference, -6.1 mg/dL; P < 0.001), high-density lipoprotein cholesterol (adjusted mean difference, -2.0 mg/dL; P < 0.001), and low-density lipoprotein cholesterol (adjusted mean difference, -2.3 mg/dL; P = 0.051) from baseline to month 12. Testosterone also slightly but significantly decreased fasting insulin (adjusted mean difference, -1.7 µIU/mL; P = 0.02) and homeostatic model assessment‒insulin resistance (adjusted mean difference, -0.6; P = 0.03). Testosterone did not change triglycerides, d-dimer, C-reactive protein, interleukin 6, troponin, glucose, or hemoglobin A1c levels more than placebo., Conclusions and Relevance: Testosterone treatment of 1 year in older men with low testosterone was associated with small reductions in cholesterol and insulin but not with other glucose markers, markers of inflammation or fibrinolysis, or troponin. The clinical importance of these findings is unclear and requires a larger trial of clinical outcomes., (Copyright © 2017 Endocrine Society)

Objective: To evaluate biomarkers of renal tubulointerstitial damage and function in type 1 diabetes with and without diabetic kidney disease., Research Design and Methods: Cross-sectional case-control study of Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study participants. Cases (N=43) had incident persistent estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 with urinary albumin excretion >300 mg/24 hour. Controls (N=43) had persistent eGFR >90 mL/min/1.73 m 2 and urinary albumin excretion <30 mg/24 hour. Urinary and plasma biomarkers reflecting tubular injury, inflammation, fibrosis, secretion, and synthetic function were measured from stored specimens collected at the first study visit with reduced eGFR (for case participants) or the corresponding study year (for control participants)., Results: Mean (SD) age was 51 (9) and 50 (8) years for case and control participants, and mean (SD) duration of diabetes was 30 (6) and 30 (5) years, respectively. Mean (SD) eGFR was 39 (14) and 103 (9) mL/min/1.73 m 2 for case and control participants, and mean (SD) albumin excretion rate was 1978 (2914) and 10 (7) mg/day, respectively. Comparing cases with controls, significant differences were observed in each measured biomarker, including urine epidermal growth factor (mean 5.3 vs 21.2 μg/g creatinine for case vs control participants, respectively), urine monocyte chemoattractant protein-1 (596 vs 123 ng/g creatinine), urine galectin-3 (168 vs 52 μg/g creatinine), plasma soluble tubular necrosis factor receptor-1 (3695 vs 1022 pg/mL), plasma galectin-3 (21.3 vs 11.0 ng/mL), urinary clearances of hippurate (70 vs 167 mL/min) and cinnamoylglycine (77 vs 317 mL/min), and plasma arginine-citrulline ratio (5.6 vs 7.7 μg/μg), each P<0.001., Conclusions: Marked abnormalities in biomarkers of kidney tubular injury, inflammation, fibrosis, secretion, and synthetic function accompany reduced eGFR and albuminuria in type 1 diabetes., Trial Registration Number: NCT00360893, NCT00360815., Competing Interests: Competing interests: IHdeB consulted for Boehringer-Ingelheim and Ironwood and received research equipment and supplies from Medtronic and Abbott. BAP has consulted for Neurometrix, Boehringer-Ingelheim, Abbott and Insulet. He has received speaker fees for medical education events from Medtronic, Novo Nordisk, Abbott, Insulet and Janssen. His institution has received support on his behalf for research funded by Boehringer-Ingelheim and Novo Nordisk.

The largest and longest clinical trial of metformin for the prevention of diabetes is the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study (DPP/DPPOS). In this review, we summarise data from the DPP/DPPOS, focusing on metformin for diabetes prevention, as well as its long-term glycaemic and cardiometabolic effects and safety in people at high-risk of developing diabetes. The DPP (1996-2001) was a RCT of 3234 adults who, at baseline, were at high-risk of developing diabetes. Participants were assigned to masked placebo (n = 1082) or metformin (n = 1073) 850 mg twice daily, or intensive lifestyle intervention (n = 1079). The masked metformin/placebo intervention phase ended approximately 1 year ahead of schedule because of demonstrated efficacy. Primary outcome was reported at 2.8 years. At the end of the DPP, all participants were offered lifestyle education and 88% (n = 2776) of the surviving DPP cohort continued follow-up in the DPPOS. Participants originally assigned to metformin continued to receive metformin, unmasked. The DPP/DPPOS cohort has now been followed for over 15 years with prospective assessment of glycaemic, cardiometabolic, health economic and safety outcomes. After an average follow-up of 2.8 years, metformin reduced the incidence of diabetes by 31% compared with placebo, with a greater effect in those who were more obese, had a higher fasting glucose or a history of gestational diabetes. The DPPOS addressed the longer-term effects of metformin, showing a risk reduction of 18% over 10 and 15 years post-randomisation. Metformin treatment for diabetes prevention was estimated to be cost-saving. At 15 years, lack of progression to diabetes was associated with a 28% lower risk of microvascular complications across treatment arms, a reduction that was no different among treatment groups. Recent findings suggest metformin may reduce atherosclerosis development in men. Originally used for the treatment of type 2 diabetes, metformin, now proven to prevent or delay diabetes, may serve as an important tool in battling the growing diabetes epidemic. Long-term follow-up, currently underway in the DPP/DPPOS, is now evaluating metformin's potential role, when started early in the spectrum of dysglycaemia, on later-stage comorbidities, including cardiovascular disease and cancer., Trial Registration: ClinicalTrials.gov NCT00038727 and NCT00004992.

Context: Previous studies have shown a relationship between glycemic control and posttransplant morbidity., Objective: We conducted a prospective randomized controlled trial in postliver transplant patients to evaluate intensive inpatient glycemic control and effects on outcomes to 1 year., Research Design and Intervention: A total of 164 patients [blood glucose (BG) >180 mg/dL] were randomized into 2 target groups: 82 with a BG of 140 mg/dL and 82 with a BG of 180 mg/dL. Continuous insulin infusions were initiated and then converted to subcutaneous basal bolus insulin therapy by our glucose management service., Results: The inpatient mean BG level was significantly different (140 group, 151.4 ± 19.5 mg/dL vs 180 group, 172.6 ± 27.9 mg/dL; P < 0.001). Any infection within 1 year occurred in 35 of the 82 patients (42.7%) in the 140 group and 54 of 82 (65.9%) in the 180 group (P = 0.0046). In a time-to-first infection analysis, being in the 140 group resulted in a hazard ratio of 0.54 (95% confidence interval, 0.35 to 0.83; P = 0.004); the difference between the 2 groups was statistically significant at 1 month (P = 0.008). The number with adjudicated transplant rejection was similar between the 2 groups [17 of 82 (20.7%) and 20 of 82 (24.3%) in the 140 and 180 groups, respectively; P = not significant]. Severe hypoglycemia (BG ≤40 mg/dL) occurred in 3 patients (2 in the 140 group and 1 in the 180 group). However, more patients had moderate hypoglycemia (BG, 41 to 70 mg/dL) in the 140 group [27 of 82 (32.9%) vs 10 of 82 (12.2%) in the 180 group; P = 0.003]. Insulin-related hypoglycemia was not associated with the incidence of severe adverse outcomes., Conclusions: Glycemic control of 140 mg/dL safely resulted in a reduced incidence of infection after transplantation compared with 180 mg/dL, but with an increase in moderate hypoglycemia., (Copyright © 2017 by the Endocrine Society)

Background and Objectives: 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., Design, Setting, Participants, & Measurements: 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 continuously <30 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 AER<30 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 m 2 on two consecutive visits), and subclinical cardiovascular disease., Results: At 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., Conclusions: 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., (Copyright © 2016 by the American Society of Nephrology.)

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., (© 2016 by the American Diabetes Association.)

Context: The Testosterone Trials are a coordinated set of seven trials to determine the efficacy of T in symptomatic men ≥65 years old with unequivocally low T levels. Initial results of the Sexual Function Trial showed that T improved sexual activity, sexual desire, and erectile function., Objective: To assess the responsiveness of specific sexual activities to T treatment; to relate hormone changes to changes in sexual function; and to determine predictive baseline characteristics and T threshold for sexual outcomes., Design: A placebo-controlled trial., Setting: Twelve academic medical centers in the United States., Participants: A total of 470 men ≥65 years of age with low libido, average T <275 ng/dL, and a partner willing to have sexual intercourse at least twice a month., Methods: Men were assigned to take T gel or placebo for 1 year. Sexual function was assessed by three questionnaires every 3 months: the Psychosexual Daily Questionnaire, the Derogatis Interview for Sexual Function, and the International Index of Erectile Function., Results: Compared with placebo, T administration significantly improved 10 of 12 measures of sexual activity. Incremental increases in total and free T and estradiol levels were associated with improvements in sexual activity and desire, but not erectile function. No threshold T level was observed for any outcome, and none of the 27 baseline characteristics predicted responsiveness to T., Conclusions: In older men with low libido and low T levels, improvements in sexual desire and activity in response to T treatment were related to the magnitude of increases in T and estradiol levels, but there was no clear evidence of a threshold effect.

Metformin is and has been considered as first-line therapy for type 2 diabetes for over a quarter of a century. Like other biguanides, metformin can cause a lactic acidosis that is exceptionally rare but fatal. The likelihood of metformin-associated lactic acidosis is substantially higher in patients with kidney impairment and also among those with seemingly normal kidney function who are at risk of acute kidney injury (AKI). Hence, regulatory agencies in many industrialized nations have maintained strict renal restrictions surrounding metformin. However, there have been millions of people exposed to metformin for many years, many of them with serum creatinine values at or close to 1.5 mg/dL with estimated glomerular filtration rates (eGFRs) much below 60 mL/min/1.73 m(2) who have not developed lactic acidosis. Thus, there clearly remains controversy in this area, and there has been heightened pressure to remove the renal restrictions of metformin. To provide a discussion on the pros and cons of relaxing the renal restrictions for metformin use, we provide a Point-Counterpoint. In the preceding point narrative, Drs. Kalantar-Zadeh and Kovesdy provide their argument that although there is little evidence of the potential benefits of metformin in kidney disease, just considering the sheer numbers of metformin users and the high fatality rate of its associated lactic acidosis, the most appropriate practice is to avoid metformin use in people with eGFR <45 mL/min/1.73 m(2) or in those who are at high risk of AKI irrespective of underlying eGFR. In the counterpoint narrative below, Drs. Bakris and Molitch argue that the data from a very large analysis demonstrate clearly that serum creatinine should be supplanted with eGFR as the criteria for metformin use and that the incidence of lactic acidosis is only elevated in those with a reduced eGFR who become dehydrated for various reasons or in those exposed to some toxin resulting in AKI. Otherwise the data clearly support the use of metformin under normal circumstances down to eGFR >30 mL/min/1.73 m(2)-William T. CefaluEditor in Chief, Diabetes Care., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

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., (Copyright © 2015 by the American Society of Nephrology.)

Context: 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., Objective: 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)., Design: Cross-sectional study of baseline measures in the TTrials., Setting: The study was conducted at 12 sites in the United States., Participants: The 788 TTrials participants were ≥ 65 years and had evidence of sexual dysfunction, diminished vitality, and/or mobility disability, and an average of two TT < 275 ng/dL., Interventions: None., Main Outcome Measures: Question 4 of Psychosocial Daily Questionnaire (PDQ-Q4), the FACIT-Fatigue Scale, and the 6-minute walk test., Results: 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., Conclusions: 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.

Objective: To compare perioperative glycemic and long-term surgical outcomes in patients undergoing cardiac surgery before and after the recommended 2009 changes in inpatient glycemic targets., Research Design and Methods: We performed a retrospective review of patients who underwent cardiac surgery between 4 September 2007 and 30 April 2011. Comparison was made of blood glucose (BG) outcomes 3 days after surgery, and 30-day cardiac outcomes before and after a change in insulin protocol that took place on 1 September 2009, which consisted of raising the glycemic targets during intravenous insulin infusions from 80-110 mg/dL (80-110 group) to 110-140 mg/dL (110-140 group)., Results: When compared with the 80-110 group (n = 667), the 110-140 group (n = 658) had higher mean postoperative BG levels during the intravenous insulin infusion (141 ± 15 vs. 121 ± 15 mg/dL, P < 0.001) and the subcutaneous insulin period (134 ± 24 vs. 130 ± 23 mg/dL, P < 0.001), and for 3 days postoperatively (141 ± 17 vs. 127 ± 15 mg/dL, P < 0.001). Fewer patients in the 110-140 mg/dL group experienced moderate hypoglycemia (BG <70 mg/dL) (177 vs. 73, P = 0.04). Severe hypoglycemia (BG <40 mg/dL) occurred in only one patient in the 80-110 group and three patients in the 110-140 group. There were no significant differences in mortality or surgical complication rates (with the exception of reintubation) between the groups., Conclusions: The higher glycemic target of 110-140 mg/dL resulted in similar mean glucose values, with significantly less hypoglycemia and no significant differences in mortality/morbidity compared with the more strict target of 80-110 mg/dL., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: The aim was to formulate clinical practice guidelines for acromegaly., Participants: The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), five experts in the field, and a methodologist. The authors received no corporate funding or remuneration. This guideline is cosponsored by the European Society of Endocrinology., Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews., Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society and the European Society of Endocrinology reviewed drafts of the guidelines., Conclusions: Using an evidence-based approach, this acromegaly guideline addresses important clinical issues regarding the evaluation and management of acromegaly, including the appropriate biochemical assessment, a therapeutic algorithm, including use of medical monotherapy or combination therapy, and management during pregnancy.

The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50% of cases in the developed world. Although incidence rates for ESRD attributable to DKD have recently stabilized, these rates continue to rise in high-risk groups such as middle-aged African Americans, Native Americans, and Hispanics. The costs of care for people with DKD are extraordinarily high. In the Medicare population alone, DKD-related expenditures among this mostly older group were nearly $25 billion in 2011. Due to the high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association in collaboration with the American Society of Nephrology and the National Kidney Foundation to appraise issues regarding patient management, highlighting current practices and new directions. Major topic areas in DKD included 1) identification and monitoring, 2) cardiovascular disease and management of dyslipidemia, 3) hypertension and use of renin-angiotensin-aldosterone system blockade and mineralocorticoid receptor blockade, 4) glycemia measurement, hypoglycemia, and drug therapies, 5) nutrition and general care in advanced-stage chronic kidney disease, 6) children and adolescents, and 7) multidisciplinary approaches and medical home models for health care delivery. This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Macroalbuminuria, defined as urine albumin excretion rate (AER)≥300 mg/d, has long been considered a stage of irreversible kidney damage that leads reliably to GFR loss. We examined the long-term renal outcomes of persons with type 1 diabetes who developed incident macroalbuminuria during the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. One hundred fifty-nine participants developed incident macroalbuminuria and were subsequently followed for a median duration of 9 years (maximum of 25 years). At the time of macroalbuminuria diagnosis, mean (SD) age was 37 (9) years, mean (SD) duration of diabetes was 17 (5) years, median AER was 524 mg/d, and mean (SD) eGFR was 108 (20) ml/min per 1.73 m(2). Ten years after macroalbuminuria diagnosis, the cumulative incidence of a sustained reduction in AER to <300 mg/d was 52%, mostly but not entirely under treatment with renin-angiotensin system inhibitors. The cumulative incidence of impaired GFR (sustained eGFR<60 ml/min per 1.73 m(2)) 10 years after macroalbuminuria diagnosis was 32%, including 16% who developed ESRD. Lower hemoglobin A1c and BP and regression to AER<300 mg/d were associated with reduced risk of developing impaired GFR. In conclusion, people with type 1 diabetes who develop macroalbuminuria are at high risk of progressive kidney disease. However, through at least 10 years of follow-up, AER could often be controlled, and GFR frequently remained in the normal range., (Copyright © 2014 by the American Society of Nephrology.)

Context: It is unknown whether the hyperglycemia that follows cardiac arrest and during therapeutic hypothermia (TH) is due to the arrest or the TH, whether it is associated with adverse outcomes, or whether its treatment affects outcomes., Objective: The objective of the study was to determine the effects of TH on the blood glucose (BG) levels in postcardiac arrest patients and the effects of hyperglycemia on mortality., Design: This was a chart review of 62 patients undergoing TH after cardiac arrest between September 2005 and April 2008. BG levels from 72 hours before the arrest to 48 hours after TH and iv insulin infusion rates were analyzed and correlated with survival to discharge from hospital., Setting: The study was conducted at a tertiary, university referral center., Patients: PATIENTS undergoing TH after cardiac arrest participated in the study., Interventions: TH consisted of cooling as rapidly as possible to 33°C, holding that temperature for 24 hours, and then controlled rewarming to 37°C over 8 or 16 hours. Hyperglycemia was managed with iv insulin drip protocols., Main Outcome Measure: The relationship of cardiac arrest and hypothermia to hyperglycemia, with a key secondary outcome being the relationship of hyperglycemia to survival to discharge, was measured., Results: Analysis of glucose patterns showed no independent effect of TH on BG levels. Mean BG levels between cardiac arrest and the initiation of hypothermia were higher in nonsurvivors (253 ± 112 mg/dL, n = 48) than in survivors (192 ± 69 mg/dL, n = 24, P = .016). BG, insulin infusion rates, and insulin resistance during hypothermia, during rewarming, and 24-48 hours after hypothermia were not significantly different between the 2 groups., Conclusions: In patients treated with TH, the TH had no independent effect on BG levels. Mortality was associated with increased BG levels after cardiac arrest but before initiation of TH or an insulin drip. Likely, it is the severity of stress from the cardiac arrest that causes the hyperglycemia in these patients.

Background: The Theoretical Domains Framework (TDF) is a set of 14 domains of behavior change that provide a framework for the critical issues and factors influencing optimal knowledge translation. Considering that a previous study has identified optimal knowledge translation techniques for each TDF domain, it was hypothesized that the TDF could be used to contextualize and interpret findings from a behavioral and educational needs assessment. To illustrate this hypothesis, findings and recommendations drawn from a 2012 national behavioral and educational needs assessment conducted with healthcare providers who treat and manage Growth and Growth Hormone Disorders, will be discussed using the TDF., Methods: This needs assessment utilized a mixed-methods research approach that included a combination of: [a] data sources (Endocrinologists (n:120), Pediatric Endocrinologists (n:53), Pediatricians (n:52)), [b] data collection methods (focus groups, interviews, online survey), [c] analysis methodologies (qualitative - analyzed through thematic analysis, quantitative - analyzed using frequencies, cross-tabulations, and gap analysis). Triangulation was used to generate trustworthy findings on the clinical practice gaps of endocrinologists, pediatric endocrinologists, and general pediatricians in their provision of care to adult patients with adult growth hormone deficiency or acromegaly, or children/teenagers with pediatric growth disorders. The identified gaps were then broken into key underlying determinants, categorized according to the TDF domains, and linked to optimal behavioral change techniques., Results: The needs assessment identified 13 gaps, each with one or more underlying determinant(s). Overall, these determinants were mapped to 9 of the 14 TDF domains. The Beliefs about Consequences domain was identified as a contributing determinant to 7 of the 13 challenges. Five of the gaps could be related to the Skills domain, while three were linked to the Knowledge domain., Conclusions: The TDF categorization of the needs assessment findings allowed recommendation of appropriate behavior change techniques for each underlying determinant, and facilitated communication and understanding of the identified issues to a broader audience. This approach provides a means for health education researchers to categorize gaps and challenges identified through educational needs assessments, and facilitates the application of these findings by educators and knowledge translators, by linking the gaps to recommended behavioral change techniques.

Estimation of GFR from serum concentrations of creatinine and cystatin C has been refined using cross-sectional data from large numbers of people. However, the ability of the improved estimating equations to identify changes in GFR within individuals over time has not been rigorously evaluated, particularly within the normal range of GFR. In cross-sectional and longitudinal analyses of 1441 participants in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study with type 1 diabetes, we compared GFR estimated from creatinine (eGFR(Cr)), cystatin C (eGFR(Cys)), or both (eGFR(Cr+Cys)) with iothalamate GFR (iGFR), including changes in each over time. Mean (SD) iGFR was 122.7 (21.0) ml/min per 1.73 m(2). In cross-sectional analyses, eGFR(Cr+Cys) estimated iGFR with the highest correlation (r=0.48 versus 0.39-0.42), precision, and accuracy. In longitudinal analyses, change in eGFR(Cr+Cys) best estimated change in iGFR; however, differences between estimates were small, and no estimate accurately classified change in iGFR. Over a median 23 years of follow-up, mean rate of change in eGFR was similar across estimates of eGFR(Cr), eGFR(Cys), and eGFR(Cr+Cys) (-1.37, -1.11, and -1.29 ml/min per 1.73 m(2) per year, respectively). Associations of BP and hemoglobin A1c with change in eGFR were strongest for eGFR(Cys) and eGFR(Cr+Cys). Together, these results suggest that the addition of cystatin C to creatinine to estimate GFR may improve identification of the causes and consequences of GFR loss in type 1 diabetes, but may not meaningfully improve the tracking of GFR in clinical care.

Objective: People with type 1 diabetes are at high risk of premature atherosclerosis. Existing evidence suggests that impaired vitamin D metabolism may contribute to the development of atherosclerosis. We tested associations of circulating vitamin D metabolite concentrations with subclinical atherosclerosis among 1,193 participants with type 1 diabetes in the DCCT/EDIC study., Research Design and Methods: We measured plasma concentrations of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D, and 24,25-dihydroxyvitamin D by mass spectrometry at the end of the DCCT. In a staggered cross-sectional design, we tested associations with coronary artery calcium (CAC), measured by computed tomography a median of 10 years later, and with common and internal carotid intima-media thickness (IMT), measured by B-mode ultrasonography on two occasions a median of 4 years later and a median of 10 years later. We hypothesized that lower concentrations of each vitamin D metabolite would be associated with increased risk of CAC and greater carotid IMT. RESULTS At the time metabolites were measured, mean age was 32.4 years and mean duration of diabetes was 7.5 years. The prevalence and severity of CAC tended to be lower-not higher-with lower concentrations of each vitamin D metabolite. For instance, in a fully adjusted multinomial logistic model, a 25 nmol/L lower 25-hydroxyvitamin D was associated with a 0.8-fold decrease in the odds of having higher CAC (95% CI 0.68-0.96, P = 0.01). No vitamin D metabolite was associated with either common or internal mean IMT., Conclusions: We did not find evidence linking impaired vitamin D metabolism with increased subclinical atherosclerosis in type 1 diabetes.

Type 2 diabetes mellitus (T2DM) and its associated comorbidities are a major public health issue in the United States. Although a sizable pharmacotherapeutic armamentarium exists to combat this disease and several sources have published evidence-based management guidelines, the management of patients with T2DM remains complex and suboptimal. Currently available medications target various organs in an attempt to normalize hyperglycemia; however, newer agents targeting additional organ systems are in development. Among these, a class of medications that inhibit the sodium glucose cotransporter 2 (SGLT2) in the kidney show promise in their ability to decrease glucose reabsorption and increase glucose excretion. In particular, one of these compounds, canagliflozin, recently was approved by the US Food and Drug Administration. Despite such advances, the natural course of T2DM often eventually leads to the initiation of insulin therapy. A working knowledge of management guidelines, particularly concerning when and how to initiate monotherapies, combination therapies, and complex insulin regimens, is essential for optimal patient management. Insulin therapies should mimic normal physiologic levels of insulin through the use of both basal and bolus insulin analogues. Recognition of the various factors influencing therapeutic choices is also critical for improved patient management.

Context: In the absence of panhypopituitarism and low serum IGF-I levels, the diagnosis of adult GH deficiency (AGHD) requires confirmation with a GH stimulation test. Macimorelin is a novel, orally active ghrelin mimetic that stimulates GH secretion., Objective: The objective of the study was to determine the diagnostic efficacy and safety of macimorelin in AGHD., Design: This was a multicenter open-label study comparing the diagnostic accuracy of oral macimorelin with that of arginine+GHRH in AGHD patients and healthy, matched controls. After 43 AGHD patients and 10 controls were tested, the GHRH analog Geref Diagnostic [GHRH(1-29)NH2] became unavailable in the United States. The study was completed by testing 10 additional AGHD patients and 38 controls with macimorelin alone., Main Outcome Measure: Peak GH area under the receiver operating characteristic curve after macimorelin was measured., Results: Fifty AGHD subjects and 48 controls were evaluated. Peak GH levels in AGHD patients and controls after macimorelin were 2.36 ± 5.69 and 17.71 ± 19.11 ng/mL, respectively (P < .0001). With macimorelin, the receiver operating characteristic analysis yielded an optimal GH cut point of 2.7 ng/mL, with 82% sensitivity, 92% specificity, and 13% misclassification rate. For subjects receiving both tests, macimorelin showed discrimination comparable with arginine+GHRH (area under the receiver operating characteristic curve 0.99 vs 0.94, respectively, P = .29). Obesity (body mass index > 30 kg/m(2)) was present in 58% of subjects, and peak GH levels were inversely associated with body mass index in controls (r = -0.37, P = .01). Using the separate cut points of 6.8 ng/mL for nonobese and 2.7 for obese subjects reduced the misclassification rate to 11%. Only 1 drug-related serious adverse event, an asymptomatic QT interval prolongation on the electrocardiogram, was reported., Conclusion: Oral macimorelin is safe, convenient, and effective in diagnosing AGHD with accuracy comparable with the arginine+GHRH test.

Context: Impaired vitamin D metabolism may contribute to the development and progression of diabetic kidney disease., Objective: The aim of the study was to test associations of circulating vitamin D metabolites with risks of incident microalbuminuria, impaired glomerular filtration rate (GFR), and hypertension in type 1 diabetes., Design: We performed a cohort study of 1193 participants in the Diabetes Control and Complications Trial (DCCT), a randomized clinical trial of intensive diabetes therapy, and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. We measured plasma concentrations of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D, and 24,25-dihydroxyvitamin D by mass spectrometry at the end of the DCCT and tested associations with incident microalbuminuria, impaired GFR, and hypertension over up to 16 yr of EDIC follow-up., Results: At the time metabolites were measured, mean age was 32.4 yr; mean duration of diabetes, 7.5 yr; mean iothalamate GFR, 132.9 ml/min/1.73 m(2); and geometric mean albumin excretion rate, 11.8 mg/24 h. Over follow-up, 166 cases of microalbuminuria, 54 cases of impaired GFR, and 541 cases of hypertension were observed. Compared with 25(OH)D of at least 30 ng/ml, 25(OH)D below 20 ng/ml was associated with a 65% higher risk of microalbuminuria (95% confidence interval, 7 to 154%) in adjusted analyses. Low concentrations of 24,25-dihydroxyvitamin D, but not 1,25-dihydroxyvitamin D, were also associated with increased risk of microalbuminuria. No circulating vitamin D metabolite was associated with risk of impaired GFR or hypertension., Conclusions: Low plasma concentrations of 25(OH)D and 24,25-dihydroxyvitamin D are associated with increased risk of microalbuminuria in type 1 diabetes. In contrast, we did not find evidence linking impaired vitamin D metabolism to early GFR loss or the development of hypertension.

Context: Cushing's syndrome (CS) is a disorder associated with significant morbidity and mortality due to prolonged exposure to high cortisol concentrations., Objective: Our objective was to evaluate the safety and efficacy of mifepristone, a glucocorticoid receptor antagonist, in endogenous CS., Design and Setting: 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: 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)., Intervention: Mifepristone was administered at doses of 300-1200 mg daily., Main Outcome Measures: 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., Results: In the C-DM cohort, an area under the curve for glucose (AUC(glucose)) response was seen in 60% of patients (P < 0.0001). Mean ± sd glycated hemoglobin (HbA1c) decreased from 7.43 ± 1.52% to 6.29 ± 0.99% (P < 0.001); 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, P < 0.03). In C-HT cohort, a diastolic blood pressure response was seen in 38% of patients (P < 0.05). Mean weight change was -5.7 ± 7.4% (P < 0.001) with waist circumference decrease of -6.78 ± 5.8 cm (P < 0.001) in women and -8.44 ± 5.9 cm (P < 0.001) in men. Overall, 87% (P < 0.0001) 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., Conclusions: Mifepristone produced significant clinical and metabolic improvement in patients with CS with an acceptable risk-benefit profile during 6 months of treatment.

Galactorrhea is commonly caused by hyperprolactinemia, especially when it is associated with amenorrhea. Hyperprolactinemia is most often induced by medication or associated with pituitary adenomas or other sellar or suprasellar lesions. Less common causes of galactorrhea include hypothyroidism, renal insufficiency, pregnancy, and nipple stimulation. After pathologic nipple discharge is ruled out, patients with galactorrhea should be evaluated by measurement of their prolactin level. Those with hyperprolactinemia should have pregnancy ruled out, and thyroid and renal function assessed. Brain magnetic resonance imaging should be performed if no other cause of hyperprolactinemia is found. Patients with prolactinomas are usually treated with dopamine agonists (bromocriptine or cabergoline); surgery or radiation therapy is rarely required. Medications causing hyperprolactinemia should be discontinued or replaced with a medication from a similar class with lower potential for causing hyperprolactinemia. Normoprolactinemic patients with idiopathic, nonbothersome galactorrhea can be reassured and do not need treatment; however, those with bothersome galactorrhea usually respond to a short course of a low-dose dopamine agonist.

Objective: The aim was to update The Endocrine Society Clinical Practice Guideline on Evaluation and Treatment of Adult Growth Hormone Deficiency (GHD) previously published in 2006., Consensus Process: Consensus was guided by systematic reviews of evidence and discussions through a series of conference calls and e-mails. An initial draft was prepared by the Task Force, with the help of a medical writer, and reviewed and commented on by members of The Endocrine Society. A second draft was reviewed and approved by The Endocrine Society Council. At each stage of review, the Task Force received written comments and incorporated substantive changes., Conclusions: GHD can persist from childhood or be newly acquired. Confirmation through stimulation testing is usually required unless there is a proven genetic/structural lesion persistent from childhood. GH therapy offers benefits in body composition, exercise capacity, skeletal integrity, and quality of life measures and is most likely to benefit those patients who have more severe GHD. The risks associated with GH treatment are low. GH dosing regimens should be individualized. The final decision to treat adults with GHD requires thoughtful clinical judgment with a careful evaluation of the benefits and risks specific to the individual.