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With the increase in cannabis use due to policy changes and areas of decriminalization, it is important to recognize the potential impact of these substances on endocrine processes. Cannabinoids have many effects by activating the endocannabinoid system. This system plays a role in the normal functioning of nearly every organ and consists of the body’s natural endocannabinoids, the cannabinoid receptors, and the enzymes and processes that regulate endocannabinoids. Exogenous cannabinoids such as Δ9-tetrahydrocannabinol (THC) are known to act through cannabinoid type 1 and 2 receptors, and have been shown to mimic endocannabinoid signaling and affect receptor expression. This review summarizes the known impacts of cannabis on thyroid, adrenal, and gonadal function in addition to glucose control, lipids, and bone metabolism, including: reduced female fertility, increased risk of adverse pregnancy outcomes, reduced sperm counts and function, lower thyroid hormone levels with acute use, blunting of stress response with chronic use, increased risk of prediabetes but lower risk of diabetes, suggested improvement of high density lipoproteins and triglycerides, and modest increase in fracture risk. The known properties of endocannabinoids, animal data, population data, and the possible benefits and concerns of cannabinoid use on hormonal function are discussed. The interconnectivity of the endocrine and endocannabinoid systems suggests opportunities for future therapeutic modalities which are an area of active investigation.

BACKGROUND: We previously reported that a median of 5.6 years of intensive as compared with standard glucose lowering in 1791 military veterans with type 2 diabetes resulted in a risk of major cardiovascular events that was significantly lower (by 17%) after a total of 10 years of combined intervention and observational follow-up. We now report the full 15-year follow-up. METHODS: We observationally followed enrolled participants (complete cohort) after the conclusion of the original clinical trial by using central databases to identify cardiovascular events, hospitalizations, and deaths. Participants were asked whether they would be willing to provide additional data by means of surveys and chart reviews (survey cohort). The prespecified primary outcome was a composite of major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, and death from cardiovascular causes. Death from any cause was a prespecified secondary outcome. RESULTS: There were 1655 participants in the complete cohort and 1391 in the survey cohort. During the trial (which originally enrolled 1791 participants), the separation of the glycated hemoglobin curves between the intensive-therapy group (892 participants) and the standard-therapy group (899 participants) averaged 1.5 percentage points, and this difference declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a period of 15 years of follow-up (active treatment plus post-trial observation), the risks of major cardiovascular events or death were not lower in the intensive-therapy group than in the standard-therapy group (hazard ratio for primary outcome, 0.91; 95% confidence interval [CI], 0.78 to 1.06; P = 0.23; hazard ratio for death, 1.02; 95% CI, 0.88 to 1.18). The risk of major cardiovascular disease outcomes was reduced, however, during an extended interval of separation of the glycated hemoglobin curves (hazard ratio, 0.83; 95% CI, 0.70 to 0.99), but this benefit did not continue after equalization of the glycated hemoglobin levels (hazard ratio, 1.26; 95% CI, 0.90 to 1.75). CONCLUSIONS: Participants with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had a lower risk of cardiovascular events than those who received standard therapy only during the prolonged period in which the glycated hemoglobin curves were separated. There was no evidence of a legacy effect or a mortality benefit with intensive glucose control. (Funded by the VA Cooperative Studies Program; VADT ClinicalTrials.gov number, .)

IntroductionDiabetic kidney disease (DKD) is the most frequent cause of end-stage renal disease (ESRD) in the USA and worldwide. Recent experimental and clinical data suggest that the non-specific phosphodiesterase inhibitor pentoxifylline (PTX) may decrease progression of chronic kidney disease. However, a large-scale randomised clinical trial is needed to determine whether PTX can reduce ESRD and death in DKD.Methods and analysisVeterans Affairs (VA) PTXRx is a pragmatic, randomised, placebo-controlled multicentre VA Cooperative Study to test the hypothesis that PTX, when added to usual care, leads to a reduction in the time to ESRD or death in patients with type 2 diabetes with DKD when compared with usual care plus placebo. The study aims to enrol 2510 patients over a 4-year period with an additional up to 5-year follow-up to generate a total of 646 primary events. The primary objective of this study is to compare the time until ESRD or death (all-cause mortality) between participants randomised to PTX or placebo. Secondary endpoints will be: (1) health-related quality of life, (2) time to doubling of serum creatinine, (3) incidence of hospitalisations for congestive heart failure, (4) incidence of a three-point major adverse cardiovascular events composite (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), (5) incidence of peripheral vascular disease, (6) change in urinary albumin-to-creatinine ratio from baseline to 6 months and (7) rate of annual change in estimated glomerular filtration rate (eGFR) during the study period.Ethics and disseminationThis study was approved by the VA Central Institutional Review Board (cIRB/18-36) and will be conducted in compliance with the Declaration of Helsinki and the Guidelines for Good Clinical Practice. The Hines Cooperative Studies Programme will finalise the study results, which will be published in accordance with the Consolidated Standards of Reporting Trials statement in a peer-reviewed scientific journal.Trial registration numberNCT03625648.

PURPOSE: Machine learning is an attractive tool for identifying heterogeneous treatment effects (HTE) of interventions but generalizability of machine learning derived HTE remains unclear. We examined generalizability of HTE detected using causal forests in two similarly designed randomized trials in type 2 diabetes patients. METHODS: We evaluated published HTE of intensive versus standard glycemic control on all-cause mortality from the Action to Control Cardiovascular Risk in Diabetes study (ACCORD) in a second trial, the Veterans Affairs Diabetes Trial (VADT). We then applied causal forests to VADT, ACCORD, and pooled data from both studies and compared variable importance and subgroup effects across samples. RESULTS: HTE in ACCORD did not replicate in similar subgroups in VADT, but variable importance was correlated between VADT and ACCORD (Kendall’s tau-b 0.75). Applying causal forests to pooled individual-level data yielded seven subgroups with similar HTE across both studies, ranging from risk difference of all-cause mortality of −3.9% (95% CI −7.0, −0.8) to 4.7% (95% CI 1.8, 7.5). CONCLUSION: Machine learning detection of HTE subgroups from randomized trials may not generalize across study samples even when variable importance is correlated. Pooling individual-level data may overcome differences in study populations and/or differences in interventions that limit HTE generalizability.

Objective: The objective of this study was to assess the long-term role of intensive glycemic control (INT) on accumulated eye procedures in patients with advanced diabetes compared with those receiving standard glycemic control (STD). Research design and Methodology: We compared the effect of treatment assignment on the accumulated number of eye procedures during the intervention period of Veteran Affairs Diabetes Trial (VADT) (2000-2008), median follow-up of 5.6 years), the interim VADT-Follow-up (2000-2013) and the full 17 years of VADT follow-up (2000-2017). We further analyzed data using various cardiovascular markers in 2 models; model I included total cholesterol, HDL-cholesterol (HDL-C), LDL -cholesterol (LDL-C), triglycerides, systolic and diastolic blood pressure, and BMI. Model II included the above covariates plus age and DR severity scores at baseline of the original trial. Results: The final analysis of the data (detailed in Results section) showed a mild but nonsignificant increase in number of procedures, retinal or retinal plus cataract surgery during the three periods of the study (Table 3,4). Conclusions: We found no significant benefit of INT during the original trial period in eye related procedures such as various procedures for DR and cataract surgery during the 17 years follow up. Yet, after adjusting data for some known vascular markers, the increase in number of eye procedures in INT becomes more prevalent. This finding indicates that INT might not have a protective role on events that requires surgery in individual with advance DM.

As SARS-CoV-2 (COVID-19) overtakes the world, causing moderate to severe disease in about 15% of infected patients, COVID-19 is also found to have widespread effects throughout the body with a myriad of clinical manifestations including the endocrine system. This manuscript reviews what is known about the impact of COVID-19 on the pathophysiology and management of diabetes (both outpatient and inpatient) as well as pituitary, adrenal, thyroid, bone, and gonadal function. Findings in this area are evolving, and long-term effects of infection remain an active area of further research.

OBJECTIVE SBP variability may be a target for mitigating end-organ damage associated with vascular disease. We evaluated the relationship between increased SBP variability and risk of incident diabetic foot ulceration. METHODS Using a nested case-control design, we followed patients diagnosed with diabetes and treated within the US Department of Veterans Affairs Healthcare system for development of a diabetic foot ulcer (event) between 2006 and 2010. Each case was randomly matched to up to five controls based on age, sex, race/ethnicity, and calendar time. SBP variability was computed using at least three blood pressure measurements from the year preceding the event. The association between SBP variability and foot ulceration was examined using conditional logistic regression. Potential protective effects of calcium channel blockers, which blunt SBP variability, were also explored. RESULTS The study sample included 51 111 cases and 129 247 controls. Compared with those in quartile 1 (lowest variability), patients in quartiles 2-4 had higher adjusted odds ratios for diabetic foot ulcer development: 1.11 (95% CI 1.07-1.16), 1.20 (95% CI 1.15-1.25), 1.29 (95% CI 1.24-1.34) (P for trend

OBJECTIVE To determine the risk factors for severe hypoglycemia and the association between severe hypoglycemia and serious cardiovascular adverse events and cardiovascular and all-cause mortality in the Veterans Affairs Diabetes Trial (VADT). RESEARCH DESIGN AND METHODS This post hoc analysis of data from the VADT included 1,791 military veterans (age 60.5 ± 9.0 years) with suboptimally controlled type 2 diabetes (HbA1c 9.4 ± 2.0%) of 11.5 ± 7.5 years disease duration with or without known cardiovascular disease and additional cardiovascular risk factors. Participants were randomized to intensive (HbA1c RESULTS The rate of severe hypoglycemia in the intensive treatment group was 10.3 per 100 patient-years compared with 3.7 per 100 patient-years in the standard treatment group (P < 0.001). In multivariable analysis, insulin use at baseline (P = 0.02), proteinuria (P = 0.009), and autonomic neuropathy (P = 0.01) were independent risk factors for severe hypoglycemia, and higher BMI was protective (P = 0.017). Severe hypoglycemia within the past 3 months was associated with an increased risk of serious cardiovascular events (P = 0.032), cardiovascular mortality (P = 0.012), and total mortality (P = 0.024). However, there was a relatively greater increased risk for total mortality in the standard group compared with the intensive group (P = 0.019). The association between severe hypoglycemia and cardiovascular events increased significantly as overall cardiovascular risk increased (P = 0.012). CONCLUSIONS Severe hypoglycemic episodes within the previous 3 months were associated with increased risk for major cardiovascular events and cardiovascular and all-cause mortality regardless of glycemic treatment group assignment. Standard therapy further increased the risk for all-cause mortality after severe hypoglycemia.

Aims To examine the relationship between systolic blood pressure (SBP) variability and the risk of microvascular complications in a non-elderly diabetic population. Methods This is a retrospective cohort study of individuals aged ≤60years treated for diabetes in 2003 in the US Department of Veterans Affairs healthcare system. Individuals were followed for five years for any new diagnosis of diabetic nephropathy, retinopathy, or neuropathy. In each year of follow-up, individuals were classified into quartiles based on their SBP variability. Results We identified 208,338 patients with diabetes without diabetic nephropathy, retinopathy, or neuropathy at baseline. Compared to individuals with the least SBP variability (Quartile 1), those with most variability (Quartile 4) had 81% (OR=1.81; 95% CI, 1.72–1.91), 17% (OR=1.17; 95% CI, 1.13–1.21), 30% (OR=1.30; 95% CI, 1.25–1.35), and 19% (OR=1.19; 95% CI, 1.15–1.23) higher incidence of nephropathy, retinopathy, neuropathy, and any complication, respectively, after adjusting for mean SBP, demographic and clinical factors. Conclusions We found a significant graded relationship between SBP variability and the incidence of each complication and of any combined endpoint. This is the first study showing a significant association between SBP variability and the risk of diabetic retinopathy and neuropathy.

Hypophosphatasia (HPP) is a rare, inherited form of rickets or osteomalacia due to reduced activity of tissue non-specific alkaline phosphatase (TNSALP) caused by a loss of function mutation in the TNSALP gene marked by a low serum alkaline phosphatase. The ratio of PPi to Pi is crucial in the mineralization process. This process is regulated by the interaction of three phosphatases present in matrix vesicles: the mineralization promotors TNSALP and phosphatase orphan 1 (PHOSPHO1) and the mineralization inhibitor nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1). HPP is seen worldwide affecting all races. The broad-ranging clinical severity of HPP is correlated to the pattern of inheritance and degree of TNSALP activity, with lower levels of activity seen in the more severe autosomal recessive forms. HPP is marked by compromise of phase 2 hydroxyapatite crystal formation beyond the matrix vesicle resulting in skeletal hypomineralization, spontaneous fractures, tooth loss, and chondrocalcinosis. The major forms in declining order of severity include the following: perinatal, infantile, childhood, and adult HPP in addition to OdontoHPP and benign prenatal HPP. Biochemistry typically reveals a low serum alkaline phosphatase and elevated alkaline substrates such as pyridoxal-5′-phosphate (PLP) and phosphoethanolamine (PEA). Asfotase alfa, a recent novel enzyme replacement therapy for the treatment of HPP, has transformed this once lethal disease to one that is less severe.

Background and objectives The benefit of dual blockade of the renin-angiotensin system is limited by adverse effects. We performed a secondary analysis of the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) Study to describe the effect of increased intensity of renin-angiotensin system blockade on the incidence, risk factors, and outcomes of AKI. Design, setting, participants, & measurements In the VA NEPHRON-D Study, we randomized 1148 veterans receiving outpatient care with type 2 diabetes mellitus, eGFR of between 30 and 89.9 ml/min per 1.73 m 2 , and urinary albumin excretion of at least 300 μ g/mg creatinine (or a urinary total protein of at least 0.5 mg/mg creatinine) to either combination therapy with losartan and lisinopril or monotherapy with losartan. We identified hospitalized AKI events and their outcomes during a median follow-up of 2.2 years through systematic reporting of serious adverse events. Results The incidence of AKI was 12.2 (95% confidence interval, 10.5 to 14.0) versus 6.7 (95% confidence interval, 5.6 to 8.2) per 100 patient-years in the combination arm versus monotherapy arms ( P P P =0.04), lower 30-day mortality (4.7% versus 15.0%; P Conclusions Dual renin-angiotensin system blockade was associated with an increased risk of AKI compared with monotherapy, but AKI in the setting of monotherapy was associated with lower rates of recovery of kidney function, higher mortality, and higher risk of progression of kidney disease.

Systolic blood pressure (SBP) variability is emerging as a new risk factor for cardiovascular diseases, diabetic nephropathy, and other atherosclerotic conditions. Our objective is to examine whether it has any prognostic value for lower-extremity amputations.This is a nested case-control study of a cohort of patients with diabetes aged60 years and treated in the US Department of Veterans Healthcare system in 2003. They were followed over five years for any above-ankle (major) amputations. For each case with a major amputation (event), we randomly selected up to five matched controls based on age, sex, race/ethnicity, and calendar time. SBP variability was computed using three or more blood pressure measures taken during the one-year period before the event. Patients were classified into quartiles according to their SBP variability.The study sample included 1038 cases and 2932 controls. Compared to Quartile 1 (lowest variability), Quartile 2 had 1.4 times (OR=1.44, 95% CI=1.00-2.07) and Quartiles 3 and 4 (highest) had 2.5 times (OR for Quartile 3=2.62, 95% CI=1.85-3.72; OR for Quartile 4=2.50, 95% CI=1.74-3.59) higher risk of major amputation (P for trend0.001). This gradient relationship held in both normotensive and hypertensive groups as well as for individuals without prior peripheral vascular disease.This is the first study to show a significant graded relationship between SBP variability and risk of major amputation among non-elderly persons with diabetes.

Paget’s disease is a common disease of the bone, second in prevalence to osteoporosis. We review the epidemiology and prevalence of this disease, focusing on regional and temporal differences. The pathogenesis and genetic aspects are discussed. Clinical features are enumerated. Diagnosis is outlined. Therapy is reviewed.

Geographic variation in the use of prescription drugs, particularly those deemed harmful by the FDA, may lead to variation in patient exposure to adverse drug events. One such drug is the glucose-lowering drug rosiglitazone, for which the FDA issued a safety alert on May 21, 2007, following the publication of a meta-analysis that suggested a 43% increase in the risk of myocardial infarction with the use of rosiglitazone. This alert was followed by a black box warning on August 14, 2007, that was updated 3 months later. While large declines have been documented in rosiglitazone use in clinical practice, little is known about how the use of rosiglitazone and other glucose-lowering drugs varied within the Department of Veterans Affairs (VA), surrounding the FDA alerts. Understanding this variation within integrated health care systems is essential to formulating policies that enhance patient protection and quality of care.To document variation in the use of rosiglitazone and other glucose- lowering drugs across 21 Veterans Integrated Service Networks (VISNs).We conducted a retrospective analysis of drug use patterns for all major diabetes drugs in a national cohort of 550,550 veterans with diabetes from 2003 to 2008. This included the time periods when rosiglitazone was added to (November 2003) and removed from (October 2007) the VA national formulary (VANF). We employed multivariable logistic regression models to statistically estimate the association between a patient's location and the patient's odds of using rosiglitazone.Aggregate rosiglitazone use increased monotonically from 7.7%, in the quarter it was added to the VANF (November 4, 2003), to a peak of 15.3% in the quarter when the FDA issued the safety alert. Rosiglitazone use decreased sharply afterwards, reaching 3.4% by the end of the study period (September 30, 2008). The use of pioglitazone, another glucose-lowering drug in the same class as rosiglitazone, was low when the FDA issued the safety alert (0.4%) but increased sharply afterwards, reaching 3.6% by the end of the study period. Insulin use increased monotonically; metformin use remained relatively flat; and sulfonylurea use exhibited a general declining trend throughout the study period. Statistically significant geographic variation was observed in rosiglitazone use throughout the study period. The prevalence range, defined as the range of minimum to maximum use across VISNs was 3.7%-12.4% in the first quarter (January 1 to March 31, 2003); 1.0%-5.5% in the last quarter of study period (July 1 to September 30, 2008); and reached a peak of 9.6%-25.5% in the quarter when the FDA safety alert was issued (April 1 to March 31, 2007). In 5 VISNs, peak rosiglitazone use occurred before the FDA issued the safety alert. The odds ratio of using rosiglitazone in a given VISN varied from 0.55 (95% CI = 0.52-0.59; VISN 10) to 1.58 (95% CI = 1.50-1.66; VISN 15), with VISN 1 being the reference region. The variation was higher in the periods after the FDA issued the safety alert. Much less variation was observed in the use of pioglitazone, metformin, sulfonylurea, and insulin.Our results show statistically significant variation in the way VISNs within the VA responded to the FDA alerts, suggesting a need for mechanisms that disseminate information and guidelines for drug use in a consistent and reliable manner. Further study of regions that adopted ideal practices earlier may provide lessons for regional leadership and practice culture within integrated health care systems.

Objective: Selective hypoaldosteronism (SH) is a condition manifested by hyperkalemia due to low aldosterone secretion with normal cortisol. One of the obstacles in diagnosis is the awareness of the condition itself. The objective of this review is to highlight what is known about the epidemiology, pathophysiology, etiology, presentation, diagnosis, and treatment of SH. Methods: Literature search was performed on PubMed and Ovid Medline for articles which contained hypoaldosteronism as a major topic. Results: The recent literature on this topic is surprisingly limited. Few recent review articles were found, none of which were in English and less than 5 years old. Case reports and genetic literature were also included in this review, as they contain the most recent reports of SH in the literature. Conclusion: Awareness about SH will hopefully help physicians to identify patients at risk as well as decide on treatment if any therapy is required. Abbreviations: ACTH = adrenocorticotropic hormone AD = autosomal dominant AR = autosomal recessive ECF = extracellular fluid ICU = intensive care unit PHA II = pseudohypoaldosteronism type II PHA I = pseudohypoaldosteronism type I RTA = renal tubular acidosis SH = selective hypoaldosteronism ZG = zona glomerulosa

BackgroundThe Veterans Affairs Diabetes Trial previously showed that intensive glucose lowering, as compared with standard therapy, did not significantly reduce the rate of major cardiovascular events among 1791 military veterans (median follow-up, 5.6 years). We report the extended follow-up of the study participants. MethodsAfter the conclusion of the clinical trial, we followed participants, using central databases to identify procedures, hospitalizations, and deaths (complete cohort, with follow-up data for 92.4% of participants). Most participants agreed to additional data collection by means of annual surveys and periodic chart reviews (survey cohort, with 77.7% follow-up). The primary outcome was the time to the first major cardiovascular event (heart attack, stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, or cardiovascular-related death). Secondary outcomes were cardiovascular mortality and all-cause mortality. ResultsThe difference in glycated hemoglobin level...

Cathepsins are a diverse group of proteases that are increasingly being recognized for their role in various disease states. The focus of this article is to review the data regarding the activity of cathepsin K and cathepsin S in adipocyte differentiation and function as well as glucose metabolism. Data from animal and human studies have shown up-regulation of cathepsin K expression in white adipose tissue of overweight/obese mice and humans. Cathepsin K appears to affect adipocyte differentiation as well as weight gain. Data from studies using cathepsin K blocking agents suggest that by blocking cathepsin K, there is reduction in adipocyte differentiation and weight gain. Cathepsin K also may play a role in glucose metabolism with higher cathepsin K levels being associated with insulin resistance. Cathepsin S is also overexpressed in adipose tissue of overweight/obese subjects. Both murine and human models have been studied to further investigate its role in adipocytes and obesity. Cathepsin S appears to be involved in glucose dysregulation as well as pathogenesis of diabetes mellitus. Further studies are necessary to better characterize the role of cathepsin K and S and to examine whether there is potential for targeted therapy for prevention and treatment of obesity as well as diabetes mellitus.

To examine the effect of intensive glycemic control on cardiovascular disease events (CVD) among the major race/ethnic groups in a post-hoc analysis of the VADT.Participants included 1111 non-Hispanic Whites, 307 Hispanics and 306 non-Hispanic Blacks randomized to intensive or standard glucose treatment in VADT. Multivariable Cox proportional hazards models were constructed to assess the effect of intensive glucose treatment on CVD events among race/ethnic groups.Mean age was 60.4 years and median follow-up was 5.6 years. By design, modifiable risk factors were managed equally well in both treatment arms and only differed modestly between race/ethnic groups. HbA(1c) decreased significantly from baseline with intensive glucose treatment in each race/ethnic group, with a trend for a greater response in Hispanics (P=0.02 for overall comparison between groups). Intensive glucose treatment was associated with reduced risk of CVD events for Hispanics but not for others (hazard ratios ranged from 0.54 to 0.75 for Hispanics whereas they were consistently close to 1 for others). Sensitivity analyses with different definitions of race/ethnicity or limited to individuals free of previous known CVD yielded similar results.The results of these analyses support the hypothesis that race/ethnicity is worthy of consideration when tailoring intensive treatment for individuals with long-standing type 2 diabetes. However, additional studies are needed to confirm the findings of this post-hoc analysis.

Objective: The objectives of this report are to review the mechanisms of biotin interference with streptavidin/biotin-based immunoassays, identify automated immunoassay systems vulnerable to biotin interference, describe how to estimate and minimize the risk of biotin interference in vulnerable assays, and review the literature pertaining to biotin interference in endocrine function tests. Methods: The data in the manufacturer's “Instructions for Use” for each of the methods utilized by seven immunoassay system were evaluated. We also conducted a systematic search of PubMed/MEDLINE for articles containing terms associated with biotin interference. Available original reports and case series were reviewed. Abstracts from recent scientific meetings were also identified and reviewed. Results: The recent, marked, increase in the use of over-the-counter, high-dose biotin supplements has been accompanied by a steady increase in the number of reports of analytical interference by exogenous biotin in the immunoassays used to evaluate endocrine function. Since immunoassay methods of similar design are also used for the diagnosis and management of anemia, malignancies, autoimmune and infectious diseases, cardiac damage, etc., biotin-related analytical interference is a problem that touches every area of internal medicine. Conclusion: It is important for healthcare personnel to become more aware of immunoassay methods that are vulnerable to biotin interference and to consider biotin supplements as potential sources of falsely increased or decreased test results, especially in cases where a lab result does not correlate with the clinical scenario. Abbreviations: FDA = U.S. Food & Drug Administration FT3 = free tri-iodothyronine FT4 = free thyroxine IFUs = instructions for use LH = luteinizing hormone PTH = parathyroid hormone SA/B = streptavidin/biotin TFT = thyroid function test TSH = thyroid-stimulating hormone

Objective To analyze the relationship between glycemic control after renal transplantation and subsequent graft function and complications. Methods We conducted a retrospective chart review of 202 consecutive patients undergoing kidney transplantation to analyze the association between perioperative and chronic glycemic control and clinical outcomes of rejection, infection, and hospital readmission during the first year after kidney transplantation. Results Mean in-hospital blood glucose (BG) was 157 ± 34.5 mg/dL. Mean hemoglobin A1c (HbA1c) during the first 12 months posttransplantation was 6.84 ± 1.46%. Fiftyfour patients (27%) were treated for acute or chronic rejection, 88 (44%) for infection, and 149 (74%) patients were readmitted at least once within the first year after transplantation. There were no significant differences in the risks for rejection, infection, or readmission across the 5 mean initial inpatient BG or subsequent HbA1c quintiles. In addition, there was no significant relationship between the percentage of BG measurements that fell in the “tight control” range of 80 to 110 mg/dL for each patient and any of the outcomes. Conclusion We did not find an association between glycemic control (perioperative or chronic) and the outcomes of graft rejection, infection, or hospital readmission in the first 12 months after renal transplantation. Our results suggest that “near normal” glycemic targets are not necessary for managing hyperglycemia after renal transplantation. (Endocr Pract. 2014;20:894-900)

Background Combination therapy with angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m 2 of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥30 ml per minute per 1.73 m 2 if the initial estimated GFR was ≥60 ml per minute per 1.73 m 2 or a decline of ≥50% if the initial estimated GFR was

Aims: Cognitive decline disproportionately affects older adult type 2 diabetes. We tested whether randomized intensive glucose-lowering reduces the rate(s) of cognitive decline in adults with advanced type 2 diabetes (mean: age, 60 years; diabetes duration, 11 years) from the Veterans Affairs Diabetes Trial. Methods: A battery of neuropsychological tests (digit span, digit symbol substitution (DSym), and Trails-making Part B (TMT-B)) was administered at baseline in ~1700 participants and repeated at year 5. Thirty-six risk factors were evaluated as predictors of cognitive decline in multivariable regression analyses.Results: The mean age-adjusted, DSym or TMT-B declined significantly in all study participants (P < 0.001). Randomized intensive glucose-lowering did not significantly alter the rate of cognitive decline. The final model of risk factors associated with 5-year decline in age-adjusted TMT-B included as significant predictors: longer baseline diabetes duration (beta = -0.028; P = 0.0057), lower baseline diastolic blood pressure (beta = 0.028; P < 0.001), and baseline calcium channel blocker medication use (beta = -0.639; P < 0.001). Higher baseline pulse pressure was significantly associated with decline in age-adjusted TMT-B suggesting a role for both higher systolic and lower diastolic blood pressure. Baseline thiazide diuretic use (beta= -0.549; P =0.015) was an additional significant predictor of 5-year decline in age-adjusted digit symbol score. Post-baseline systolic blood pressure-lowering was significantly associated (P < 0.001) with decline in TMT-B performance. There was a significant inverse association between post-baseline plasma triglyceride- lowering (P = 0.045) and decline in digit symbol substitution task performance.Conclusions: A five-year period of randomized intensive glucose-lowering did not significantly reduce the rate of cognitive decline in older-aged adults with type 2 diabetes. Systolic and diastolic blood pressure as well as plasma triglycerides were modifiable risk factors of the rate of cognitive decline in older adult type 2 diabetes.

We thank the authors of the letter to the editor for the information provided regarding the article we recently published in Postgraduate Medicine [1].We are grateful to have received the insightfu...

The common insulin concentration in most preparations of insulin is 100 units per mL or U-100. Human regular U-500 insulin was the first concentrated insulin introduced and it has been available in the United States since the 1950s. Humulin R is the only human regular U-500 available on the market. Human regular U-500 is five times more concentrated than U-100 and because of its pharmacodynamic properties, works as both a basal and a bolus insulin. Human regular U500 allows for delivery of a larger insulin dose with a smaller volume leading to better absorption compared to U-100 and has traditionally been used in patients with moderate to severe insulin resistance. More recently other forms of concentrated insulin have become available and the newer concentrated insulin preparations can be used in diabetic patients with or without insulin resistance. Our intent is to provide primary care physicians with a review of the pharmacology and current literature on concentrated insulins as well as recommendations for patient selection, dose initiation, and dose adjustment.

OBJECTIVE The Veterans Affairs Diabetes Trial (VADT) was a randomized, prospective, controlled trial of 1,791 patients with type 2 diabetes to determine whether intensive glycemic control would reduce cardiovascular events compared with standard control. The effect of intensive glycemic control and selected baseline variables on renal outcomes is reported. RESEARCH DESIGN AND METHODS Baseline mean age was 60.4 years, mean duration of diabetes was 11.5 years, HbA1c was 9.4%, and blood pressure was 132/76 mmHg. The renal exclusion was serum creatinine >1.6 mg/dL. Renal outcomes were sustained worsening of the urine albumin-to-creatinine ratio (ACR) and sustained worsening by one or more stages in the estimated glomerular filtration rate (eGFR). RESULTS Intensive glycemic control did not independently reduce ACR progression but was associated with a significant attenuation in the progression of ACR in those who had baseline photocoagulation, cataract surgery, or both. The beneficial effect of intensive glycemic control increased with increasing BMI and with decreasing diastolic blood pressure (DBP). Intensive glycemic control was associated with less worsening of eGFR with increasing baseline ACR and insulin use. Baseline systolic blood pressure, triglycerides, and photocoagulation were associated with worsening of eGFR. CONCLUSIONS Intensive glycemic control had no significant effect on the progression of renal disease in the whole cohort but was associated with some protection against increasing ACR in those with more advanced microvascular disease, lower baseline DBP, or higher baseline BMI and on worsening of eGFR in those with high baseline ACR.

Burn injury is a significant and severe representation of critical illness. Nearly, 50% of patients admitted to hospitals for burn injuries have detectable levels of ethanol in their circulations and these patients have poorer clinical outcomes than burned individuals without measurable circulating ethanol. We report here data on a clinically relevant form of hepatic injury, the development of microvesicular steatosis, in a murine model wherein animals were either given ethanol or saline, and were subjected to burn or sham injury. Because better glycemic control with insulin has been shown in clinical studies to impart major clinical benefit, an additional group of burn ethanol animals were treated with insulin. Insulin significantly reduced blood glucose in injured animals to levels no different from those seen in animals that were neither ethanol exposed nor burned. A single intraperitoneal injection of ethanol was insufficient to raise blood alanine aminotransferase (ALT), measured as an index of liver injury. However, burn injury led to significant increases in ALT at 24 and 48 hours, which had returned to preinjury levels by 7 days. This ALT rise was completely prevented with insulin treatment. A single injection of ethanol did not evoke increased microvesicular steatosis but did potentiate the ability of burn to do so at 24 hours after injury. The burn induced increase in microvesicular steatosis was also seen at 48 hours, but had subsided by 7 days. The increased microvesicular steatosis was prevented by insulin therapy. Thus, ethanol potentiates the ability of burn to cause acute liver injury, which is completely preventable by insulin therapy. These findings may have substantial clinical significance and suggest this model may be useful for the study of the mechanisms of hepatic injury as well as the mechanisms, probably multiple, of insulin action in this setting.

Proteinuric diabetic kidney disease frequently progresses to ESRD. Control of BP delays progression, but the optimal BP to improve outcomes remains unclear. The objective of this analysis was to evaluate the relationship between BP and renal outcomes in proteinuric diabetic kidney disease.BP data from all 1448 randomized participants in the Veterans Affairs Nephropathy in Diabetes Trial were included in a post hoc analysis. The associations of mean on-treatment BP with the primary end point (decline in eGFR, ESRD, or death), renal end point (decline in eGFR or ESRD), rate of eGFR decline, and mortality were measured.The median (25th, 75th percentile) follow-up time was 2.2 (1.2, 3.0) years. There were 284 primary end points. In univariate analyses, both mean systolic and mean diastolic BPs were strongly associated (P0.001) with the primary end point. After multivariate adjustment, the hazard of developing the primary end point became progressively higher as mean systolic BP rose from120 to ≥ 150 mmHg (P=0.02), with a significantly higher hazard ratio for 140-149 versus 120-129 mmHg (1.51 [1.06, 2.15]; P=0.02). There was also a significant association of mean diastolic BP with the hazard of developing the primary end point (P0.01), with a significantly higher hazard ratio when mean diastolic BP was 80-89 versus 70-79 mmHg (1.54 [1.05, 2.25]; P=0.03); there was also a strong trend when mean diastolic BP was60 mmHg. Associations between BP and both renal end point and rate of eGFR decline were similar to those with the primary end point. No association of BP with mortality was observed, possibly because of the limited number of mortality events.In patients with proteinuric diabetic kidney disease, mean systolic BP ≥ 140 mmHg and mean diastolic BP ≥ 80 mmHg were associated with worse renal outcomes.

OBJECTIVE—The Veterans Affairs Diabetes Trial (VADT) cohort is enriched with ∼20% Hispanics and 20% African Americans, affording a unique opportunity to study ethnic differences in retinopathy. RESEARCH DESIGN AND METHODS—Cross-sectional analyses on the baseline seven-field stereo fundus photos of 1,283 patients are reported here. Diabetic retinopathy scores are grouped into four classes of increasing severity: none (10–14), minimal nonproliferative diabetic retinopathy (NPDR) (15–39), moderate to severe NPDR (40–59), and proliferative diabetic retinopathy (60+). These four groups have also been dichotomized to none or minimal (10–39) and moderate to severe diabetic retinopathy (40+). RESULTS—The prevalence of diabetic retinopathy scores >40 was higher for Hispanics (36%) and African Americans (29%) than for non-Hispanic whites (22%). The difference between Hispanics and non-Hispanic whites was significant (P < 0.05). Similarly, the prevalence of diabetic retinopathy scores >40 was significantly higher in African Americans than in non-Hispanic whites (P < 0.05). These differences could not be accounted for by an imbalance in traditional risk factors such as age, duration of diagnosed diabetes, HbA1c (A1C), and blood pressure. Diabetic retinopathy severity scores were also significantly associated with increasing years of disease duration, A1C, systolic and diastolic blood pressure, the degree of microalbuminuria, fibrinogen, and the percentage of patients with amputations. There was no relationship between retinopathy severity and the percentage of people who had strokes or cardiac revascularization procedures. There was an inverse relationship between retinopathy severity and total cholesterol, triglycerides, and plasminogen activator inhibitor-1 as well as with smoking history. Diabetic retinopathy scores were not associated with age. CONCLUSIONS—In addition to many well-known associations with retinopathy, a higher frequency of severe diabetic retinopathy was found in the Hispanic and African-American patients at entry into the VADT that is not accounted for by traditional risk factors for diabetic retinopathy, and these substantial ethnic differences remain to be explained.

K.D., a 20-year-old white female college student was brought by her parents for evaluation of hypoglycemia. She had experienced multiple episodes of palpitations, blurred vision, and left facial paresthesias for a year, progressively worsening and occurring more frequently in the 2 months just before her appointment. Usually the episodes occurred between 3:00 and 7:30 p.m. The symptoms occurred without regard to meals and were relieved with food or juice. Her most severe witnessed episode, which occurred while she was at college, happened a few days before the consultation, while K.D. was working, 2 hours postprandially. Observers reported that she appeared confused, agitated, and diaphoretic. Her glucose via fingerstick by paramedics was 35 mg/dl. She received intravenous dextrose, and subsequently her glucose rose to 217 mg/dl with resolution of her symptoms. She had several episodes with neuroglycopenic symptoms and glucose levels of 35-45 mg/dl. There was no history indicating diabetic medications in her home. She also complained of a 25-lb weight gain during the past year. A year before her visit, K.D. was diagnosed with diabetes by oral glucose tolerance test (OGTT). The results were: View this table: At that time, she had a normal hemoglobin A1c, and she was instructed in diet and exercise. No antidiabetic medications had been prescribed. K.D. had a psychiatric evaluation, was diagnosed with depression, and was started on sertraline. In the month before the consultation, she also had a neurological work-up with negative computed tomography scans of the head and normal electroencephalogram. Her family history was significant only for diabetes of a maternal aunt. She denied allergies or use of cigarettes, alcohol, or illicit drugs. She was taking sertraline, 50 mg daily for the past year; ethinyl estradiol/norgestimate, one daily for the past 2 years; and oxcarbazepine, 175 mg twice daily for the …

A number of patients with poor glycemic control receive the diagnosis of type 2 diabetes despite the fact that they do not exhibit some of the traditional characteristics of the disease, such as obesity. A more accurate diagnosis for many of these patients is latent autoimmune diabetes of adulthood (LADA). In this article, Dr Nabhan and coauthors describe features that LADA has in common with type 1 and type 2 diabetes, as well as those that distinguish LADA from these more widely recognized forms of diabetes. The authors also describe the pathogenesis of the disease, potential complications, and treatment options.

Chronic exposure of pubertal male rats to ethanol results in a decline in serum testosterone and decreased or inappropriately normal serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels suggesting a functional defect in the pituitary. The molecular mechanisms behind this disorder are undefined. A role for ethanol-induced oxidative damage in the pathophysiology is supported by studies in liver, muscle, and heart of experimental animals, but there is limited evidence in the pituitary. We examined markers of oxidative damage to lipids and proteins in pituitaries from rats consuming ethanol for 5, 10, 20, 30, and 60 days in addition to markers of damage to nucleic acids in pituitaries after 60 days of ethanol exposure. There were increases in 8-oxo-deoxyguanosine immunoreactivity, a marker of oxidative damage to nucleic acids, and an overall increase in malondialdehyde and 4-hydroxynonenal, markers of lipid peroxidation. Protein carbonylation and protein nitrotyrosination, markers of protein oxidation, were significantly increased after 30 days and 60 days of ethanol consumption, respectively. After 60 days of ethanol exposure, TUNEL assay revealed that cell death in the ethanol-treated pituitaries was not significantly different from that in the pair-fed controls at the time of examination. We also measured serum testosterone, FSH, and LH after ethanol consumption for 5, 10, 20, 30, and 60 days. Through 5 to 60 days of ethanol exposure, testosterone levels were consistently lower whereas LH and FSH were inappropriately unchanged, suggesting pituitary malfunction. These results provide evidence for ethanol-induced oxidative damage at the pituitary level, which may contribute to pituitary dysfunction.

Chronic exposure of pubertal male rats to ethanol results in a decline in serum testosterone, increased gonadotropins, pituitary luteinizing hormone (LH) and follicle stimulating hormone (FSH) content, and decreased or inappropriately normal serum LH and FSH levels, suggesting impaired secretory release of gonadotropins. The molecular mechanisms behind this disorder are undefined, but a disruption of vesicle-mediated secretory processes is possible because intracellular protein trafficking pathways are involved in secretion of glycoproteins such as FSH and LH. Because small GTP-binding proteins of Rab family have been implicated as key regulators of membrane and protein trafficking in mammalian cells, this study was designed to test if ethanol-impaired pituitary FSH and LH secretion is associated with changes in Rab proteins, particularly Rab1B, Rab3B, Rab6, and Rab11. Male Sprague-Dawley rats 35 days old were pair-fed a Lieber-DeCarli diet with ethanol or without ethanol for 5 to 60 days. After ethanol exposure, serum testosterone levels decreased while LH and FSH were inappropriately unchanged. Immunohistochemical staining showed decreased Rab1B, Rab3B, and Rab11 protein levels in ethanol-treated pituitaries. Immunoblotting showed that ethanol induced a transient reduction in Rab6 after 5 days of ethanol exposure, whereas Rab3B decreased after 20 days, Rab11 after 30 days, and Rab1B after 60 days. Despite these changes in Rab proteins, mRNA levels were unaffected by ethanol exposure. We concluded that reductions in key Rab proteins may lead to altered vesicle trafficking and may play a role in disruption of pituitary FSH and LH secretion caused by ethanol.

We and others have investigated the effects of acute and chronic ethanol (EtOH) administration on function of the hypothalamic-pituitary-gonadal (HPG) axis in female rats, consistently finding EtOH to be detrimental. There are now substantial data that pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNFalpha) and interleukin 6 (IL-6), have anti-reproductive effects. If EtOH increased levels of these cytokines, such data would be consistent with, though not necessarily prove, a cytokine mediated mechanism for EtOH's deleterious effects on reproduction. Young adult female Sprague Dawley rats were used. In the experiment reported here, the Lieber DeCarli diet was used, with animals fed a 36% EtOH containing diet or pair fed an identical diet which contained dextrimaltose instead of EtOH. This was done for 4 to 6 weeks. TNFalpha and IL-6 were measured in the hypothalamus, pituitary, and ovary by ELISA. EtOH exposure resulted in significant increases in TNFalpha and IL-6 in hypothalami, pituitaries, and ovaries. The data reported here are the first to show consistent stimulatory effects of EtOH exposure on cytokines in the reproductive axis of female rats. Because the effects of these cytokines are generally anti-reproductive, these data provide a rational for more rigorous testing of the notion that part of EtOH's deleterious HPG effects may be due to such immuno-endocrine interactions.

Within seminiferous tubules, Sertoli cells form three types of actin-filament-containing cell junctions, viz., tight junctions, ectoplasmic specializations, and tubulobulbar complexes. These Sertoli cell junctions are involved in the formation of the blood-testis barrier, germ cell translocation, and the release of spermatozoa. Actin and actin-binding proteins are important for these functions. In the present study, a monoclonal antibody against human smooth-muscle-cell calponin detected a 38-kDa protein in a total protein extract of rat testis. The protein has a molecular weight identical to that of aorta calponin and binds calmodulin. Calponin mRNA was detected in the testis and cultured rat Sertoli cells by the reverse transcription/polymerase chain reaction method. Thus, the 38-kDa protein present in the testes is a basic isoform of calponin. In adult rats (70 days of age or older), calponin was detected within seminiferous tubules at sites of Sertoli cell junctions. Cultured Sertoli cells express calponin, whereas cultured spermatogonia do not. When rat testicular tissue was fractionated into cytosol, membrane, and cytoskeleton fractions, calponin was detected in all three fractions. Calcium, potassium, and okadaic acid reduced the amount of calponin associated with the cytoskeleton. These data suggest that Sertoli cells express calponin. The function of calponin within the testis is as yet unknown.

Introduction Long-term glycemic control trials in type 2 diabetes show as the main clinical benefit a difference in retinal photocoagulation (3/1000 in the UK Prospective Diabetes Study [UKPDS]), but no effect on visual acuity or renal failure. No intensive glycemic control trial has yet affected cardiovascular (CV) events, the main cause of morbidity and mortality. By contrast, modest blood pressure reduction has protective effects on visual acuity, renal function, CV events, and mortality. Optimal glycemic control goals are not established in elderly, obese persons with advanced complications, the most common patients in the Veterans Affairs (VA) system. The earlier feasibility trial in such patients (VA-CSDM) suggested potentially worse CV outcomes with lower attained hemoglobin A1c (HbA1c) levels. Objectives The primary objective of the Veterans Affairs Diabetes Trial (VADT) is the assessment of the effect of intensive glycemic treatment on CV events. Other objectives are effects on microangiopathy, quality of life, and cost effectiveness. Research Design and Methods The VADT, started in December 2000, is enrolling 1700 men and women previously uncontrolled on insulin or maximum doses of oral agents at 20 VA medical centers. Accrual is 2 years and follow-up is 5–7 years, with visits every 1.5 months. The study has a power of 86% to detect a 21% relative reduction in major CV events (CV death, myocardial infarction [MI], cerebrovascular accident [CVA], congestive heart failure [CHF], revascularization and amputation for ischemia). Subjects are randomized to an intensive arm aiming at normal HbA1c levels or to a standard arm with usual, improved glycemic control. An HbA1c separation of >1.5% is to be maintained (expected 2%). Both arms receive step therapy: glimepiride or metformin plus rosiglitazone and addition of insulin or other oral agents to achieve goals. Strict control of blood pressure and dyslipidemia, daily aspirin, diet, and education are identical in both arms. Plasma fibrinogen, plasminogen-activating inhibitor I (PAI-I), lipids, renal function parameters, and ECG are measured throughout. Stereo retinal photographs are obtained at entry and 5 years, eye examinations yearly, and intervention as needed to prevent visual deterioration. Recruitment is proceeding on schedule: the current mean HbA1c at entry is 9.4±1.6% and mean duration of diagnosed diabetes 11±8 years.

Reproductive function is intimately related to caloric consumption. During fasting states, the hormones regulating reproduction, those of the hypothalamic-pituitary-gonadal axis, in particular, are severely altered. With the exciting observations that the obese (ob) gene product leptin, may also modulate neuroendocrine functions, we examined leptin's ability to prevent the consequences of fasting on reproductive hormones. Two groups of male rats, aged 65 days old, were either fasted and saline-injected or fasted and leptin-treated for approximately three days. Another group was given free access to rat chow. Leptin was able to prevent the fasting-induced fall of serum testosterone. Similar to testosterones dependence on leptin, leptin concentrations were somewhat dependent on testosterone. Castration accelerated the normal, age-related increase in serum leptin. Leptin also prevented the fasting-induced fall in luteinizing hormone (LH). The increase of beta-LH mRNA seen in the fasting state was prevented by leptin. There were no differences noted in luteinizing hormone releasing hormone (LHRH) mRNA among any of the groups. While neither fasting nor fasting plus leptin caused changes in serum prolactin, the increase in prolactin mRNA seen in fasted animals was prevented by leptin treatment. These data support the hypothesis that leptin plays a specific role in mediating the response of reproductive hormones to the nutritional status of the organism.

Major clinical trials have shown that excellent glycemic control, sustained over time, can prevent or delay the microvascular complications of diabetes, including retinopathy, nephropathy, and neuropathy. No prospective trial has clearly shown that glycemic intervention can prevent the macrovascular complications of diabetes, such as myocardial infarction, cerebrovascular accident, and amputation. However, a number of landmark clinical trials have shown the efficacy of control of blood pressure and lipids and use of antiplatelet agents (mainly aspirin) in protecting the macrovasculature of individuals with diabetes. In this article, glycemic, blood pressure, lipid, and antiplatelet trials relevant to the treatment of people with type 2 diabetes are reviewed.

Albuminuria is a strong predictor of diabetic nephropathy chronic kidney disease outcomes. Yet, therapeutic albuminuria-lowering has not consistently translated into a reduction in clinical events suggesting the involvement of additional pathogenic factors. Our hypothesis is that anti-endothelial cell autoantibodies play a role in development and progression in diabetic nephropathy. We determined anti-endothelial cell antibody (AECA) bioactivity in protein A-elutes of baseline plasma in 305 participants in the VA NEPHRON-D study, a randomized trial of angiotensin receptor blocker (ARB) or dual ARB plus angiotensin-converting enzyme inhibitor therapy in type 2 diabetes with proteinuric nephropathy. Thirty-eight percent (117/305) of participants had significantly reduced endothelial cell survival ( ≤80%) in the IgG fraction of plasma. A VA NEPHRON-D primary endpoint [end-stage renal disease (ESRD), significant reduction in estimated glomerular filtration rate, or death] was experienced by 58 individuals. In adjusted Cox regression analysis, there was a significant interaction effect of baseline anti-endothelial cell-mediated cell survival and albuminuria on the hazard rate (HR) for primary composite endpoint (P = 0.017). Participants lacking strongly inhibitory antibodies with albuminuria ≥1 g/g creatinine had a significantly increased primary event hazard ratio, 3.41 – 95% confidence intervals (CI 1.84–6.33; P

OBJECTIVE Blood pressure (BP) control for renal protection is essential for patients with type 2 diabetes. Our objective in this analysis of Veterans Affairs Diabetes Trial (VADT) data was to learn whether on-study systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) affected renal outcomes measured as albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). RESEARCH DESIGN AND METHODS The VADT was a prospective, randomized study of 1,791 veterans with type 2 diabetes to determine whether intensive glucose control prevented major cardiovascular events. In this post hoc study, time-varying covariate survival analyses and hazard ratios (HR) were used to determine worsening of renal outcomes. RESULTS Compared with SBP 105–129 mmHg, the risk of ACR worsening increased significantly for SBP 130–139 mmHg (HR 1.88 [95% CI 1.28–2.77]; P = 0.001) and for SBP ≥140 mmHg (2.51 [1.66–3.78]; P < 0.0001). Compared with a PP range of 40–49 mmHg, PP CONCLUSIONS SBP ≥130 mmHg and PP >60 mmHg were associated with worsening ACR. The results suggest that treatment of SBP to

Neuropathy as a complication of diabetes is common and presents in a wide variety of clinical scenarios. Often the work-up is one of exclusion tempered with monitoring the response of symptoms to treatment options. The collaboration of a neurologist is often crucial to determining the best course of action for the patient. This review will address proposed pathogenic mechanisms and potential therapeutic interventions, both pharmacologic and nonpharmacologic.

Background : Ethanol exposure impairs mammalian reproductive function. However, the mechanisms are not fully understood. Methods: Adult female rats were given an ethanol or a calorically matched control diet. A third group was given a liquid nonethanol diet. Half the animals were killed at 2 weeks (short chronic) and the other half at 2 months (long chronic), all on the day of proestrous on the basis of daily vaginal smears. Results: The major effect of ethanol feeding was disruption in the estrous cycle. Although all of the pair-fed animals continued to cycle, 40% of the ethanol rats in the short chronic study had disruption of their cycles. In the long chronic study, 83% of the ethanol animals had abnormal cycling, in contrast to 16% of the pair-fed controls. The nature of the cycle disruption was prolongation of diestrous, with an increased time interval between proestrous surges. In four ethanol-fed rats, there was complete cessation of the estrous cycle. However, ethanol did not decrease ovarian or uterine weight. Ethanol significantly increased serum estradiol in the short chronic but not long chronic study, whereas progesterone was unchanged. Ethanol did cause a significant reduction in circulating insulin-like growth factor. Conclusions: The major effect of both short chronic and long chronic ethanol exposure was disruption of the estrous regularity, leading to a decreased number of proestrous surges. Part of the mechanism of this disruption might be a transient estrogen increase or a decrease in circulating insulin-like growth factor.

The well-characterized suppression of the male reproductive unit after ethanol (EtOH) exposure has been speculated to be partially due to activation of the hypothalamic-pituitary-adrenal (HPA) axis. The subsequent corticosterone elevation could result in hypogonadism via suppression of hypothalamic LHRH, pituitary LH, or a direct gonadal effect. To directly examine this possibility, adult male Sprague Dawley rats were either adrenalectomized (ADX) or sham ADX. The ADX animals were given low dose corticosterone via replacement pellet, resulting in a steady level of serum corticosterone. The sham ADX (adrenal intact) animals were implanted with placebo pellets. Half of both groups were then exposed to EtOH by I.P. injection on two consecutive days to mimic an acute binge-drinking model. The other half was given saline I.P., serving as controls. In the adrenal intact animals, EtOH caused the expected rise in corticosterone, and fall in luteinizing hormone (LH) and testosterone. In the ADX animals, where constant levels of corticosterone were maintained by pellet implantation, EtOH resulted in similar LH and testosterone reduction. These results suggest that suppression of the reproductive axis is independent of the activation of the HPA unit.

Background: Chronic ethanol abuse causes testicular atrophy and male infertility in alcoholic men. It is well known that ethanol exposure disrupts the hypothalamic-pituitary-gonadal axis, adversely affects the secretory function of Sertoli cells, and produces oxidative stress within the testes. It is still not clear what cellular mechanisms are responsible for the morphologic alteration of the testes that results in a reduction of testicular mass as a consequence of ethanol exposure. The hypothesis tested was that ethanol enhances apoptosis of testicular germ cells. Methods: In the experiments of chronic ethanol exposure, male Sprague Dawley® rats (Harlan Sprague Dawley, Inc., Indianapolis, IN) were fed Liber-Decarlie liquid diet for 9 weeks. In the experiments of acute ethanol exposure, a small volume of 20% ethanol solution was administered by intratesticular injection. Both 3′-end labeling of isolated testicular deoxyribonucleic acid (DNA) and labeling of apoptotic cells in situ by the terminal deoxynucleotidyl transferase-mediated deoxyuridine 5′-triphosphate nick end-labeling method were used to determine apoptosis rates within the testes. The expression of proteins involved in apoptosis was assessed by reverse transcription-polymerase chain reaction and by Western blotting. Results: The testes of rats that were fed an ethanol-containing liquid diet had more testicular DNA fragmentation than did those of animals that were fed an isocaloric control diet. Ethanol increased the number of apoptotic spermatogonia as well as spermatocytes. Direct intratesticular injections of ethanol solution enhanced testicular DNA fragmentation, suggesting an increase in apoptosis. Moreover, Fas ligand levels were increased within the testes of rats that were chronically fed ethanol. In vitro, ethanol treatment of cultured Sertoli cells enhanced the production of Fas ligand. In addition, testicular levels of p53 messenger ribonucleic acid were increased in rats that were chronically fed ethanol. Conclusions: All of these observations suggest that ethanol enhances testicular germ cell apoptosis.

OBJECTIVE: Microalbuminuria can reflect the progress of microvascular complications and may be predictive of macrovascular disease in type 2 diabetes. The effect of intensive glycemic control on microalbuminuria in patients in the U.S. who have had type 2 diabetes for several years has not previously been evaluated. RESEARCH DESIGN AND METHODS: We randomly assigned 153 male patients to either intensive treatment (INT) (goal HbA(1c) 7.1%) or to standard treatment (ST) (goal HbA(1c) 9.1%; P = 0.001), and data were obtained during a 2-year period. Mean duration of known diabetes was 8 years, mean age of the patients was 60 years, and patients were well matched at baseline. We obtained 3-h urine samples for each patient at baseline and annually and defined microalbuminuria as an albumin:creatinine ratio of 0.03-0.30. All patients were treated with insulin and received instructions regarding diet and exercise. Hypertension and dyslipidemia were treated with similar goals in each group. RESULTS: A total of 38% of patients had microalbuminuria at entry and were evenly assigned to both treatment groups. INT retarded the progression of microalbuminuria during the 2-year period: the changes in albumin:creatinine ratio from baseline to 2 years of INT versus ST were 0.045 vs. 0.141, respectively (P = 0.046). Retardation of progressive urinary albumin excretion was most pronounced in those patients who entered the study with microalbuminuria and were randomized to INT. Patients entering with microalbuminuria had a deterioration in creatinine clearance at 2 years regardless of the intensity of glycemic control. In the group entering without microalbuminuria, the subgroup receiving ST had a lower percentage of patients with a macrovascular event (17%) than the subgroup receiving INT (36%) (P = 0.03). Use of ACE inhibitors or calcium-channel blockers was similarly distributed among the groups. CONCLUSIONS: Intensive glycemic control retards microalbuminuria in patients who have had type 2 diabetes for several years but may not lessen the progressive deterioration of glomerular function. Increases in macrovascular event rates in the subgroup entering without albuminuria who received INT remain unexplained but could reflect early worsening, as observed with microvascular disease in the Diabetes Control and Complications Trial.

Background: Oxidative stress contributes to the development of liver injury after chronic alcohol intake. Women exhibit greater sensitivity to alcohol-induced liver disease than do men. The aim of the study was to determine the relationship between the sex hormone status of male and female rats and the degree of alcohol-induced oxidative stress in the liver. Methods: Male and female rats were pair-fed a liquid diet that contained 36% of their total daily calories as ethanol (EtOH group) or maltose (control group). Blood and liver samples were collected at the end of 8 weeks of diet. Results: Male EtOH rats experienced a reduction in plasma testosterone (T) and an increase in estradiol (E2) levels, with an increase in their calculated E2/T ratio with respect to their controls. Malonaldehyde (MDA) levels, an index of lipid peroxidation, and protein carbonyl content, an index of protein oxidation, in the liver were greater among the EtOH groups in females than in males. In males, an inverse correlation was found between hepatic MDA and circulating T levels, and a direct correlation was disclosed between MDA and estradiol levels. In addition, the hepatic histopathological score correlated inversely with the plasma T levels and directly with the calculated E2/T ratio, an index of feminization. Conclusions: Alcohol-induced oxidative injury, which contributes to hepatic injury in both male and female rats, is enhanced in females compared with males. A role for plasma T levels in protecting male rat liver from ethanol-induced oxidative injury can be hypothesized.

OBJECTIVE: The Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus (VA CSDM) was a multicenter randomized prospective study of 153 male type 2 diabetic patients to assess the ability to sustain clinically significant glycemic separation between intensive and standard treatment arms. A trend toward an excess of combined cardiovascular events in the intensive treatment arm of this trial was reported earlier. The present analysis was done to evaluate the effect of 2 years of intensive glycemic control on the left ventricular (LV) function. RESEARCH DESIGN AND METHODS: The patients were randomized to intensive step treatment with insulin alone or with sulfonylurea (intensive treatment arm [INT], n = 75) or to standard once-daily insulin injection (standard treatment arm [STD], n = 78) treatment. A total of 136 patients (standard treatment arm [STD], n = 70; INT, n = 66) had radionuclide ventriculography at entry and at 24 months for the assessment of LV function. RESULTS: There was no difference in the mean LV ejection fraction (at entry: STD 57.1+/-9.51%; INT 58.1+/-8.7%; at 24 months: STD 57.3+/-10.8%, INT 59.5+/-10.7%), peak filling rate (at entry: STD 2.6+/-0.7 end diastolic volume per second, INT 2.4+/-0.8 end diastolic volume per second; at 24 months: STD 2.7+/-1.0 end diastolic volume per second, INT 2.5+/-0.7 end diastolic volume per second), or time to peak filling rate (at entry: STD 195.3+/-69.5 ms, INT 185.6 +/-62.4 ms; at 24 months: STD 182.6+/-64.8 ms, INT 179.2+/-61.2 ms) between the 2 treatment arms. A subgroup analysis of 104 patients (STD, n = 53; INT, n = 51) that omitted individuals with intervening cardiac events/revascularization or a change in cardioactive medications also showed no difference in the LV function at entry and at 24 months between the 2 groups. Abnormal LV ejection fraction at baseline predicted cardiac events (interval between cardiac beats [RR] = 2.5). CONCLUSIONS: Two years of intensive glycemic control does not affect the LV systolic or diastolic function in patients with type 2 diabetes.

Background: The effect of chronic alcohol ingestion on bone formation is mediated through its direct actions on osteoblasts. The affected population of mature osteoblasts declines in both number and function resulting in decreased cancellous bone volume and cortical bone strength. Although the mechanism of action on osteoblasts is unknown, alcohol alters osteoblast gene expression and matrix synthesis. Methods: Male rats consuming alcohol (EtOH) daily for 60 days from 35 days of age until 95 days of age (unrecovered group) were compared to rats switched to a regular diet of rat chow without EtOH for an additional 90 days (recovered group). The effects of chronic dietary EtOH on skeletal development during adolescence were examined in the unrecovered and recovered rats by hormonal analysis, bone mineral density determination, bone histomorphometry, metaphyseal gene expression for osteoblast-specific proteins, and biomechanical analysis. Results: The unrecovered EtOH imbibing rats weighed less than their paired isocaloric-fed and ad libitum mates. Statistically significant reductions occurred in femur lengths in the unrecovered EtOH-fed group compared to controls. Serum testosterone levels were significantly decreased by EtOH consumption but returned to higher normal levels during the recovery period. Serum insulin-like growth factor-1 (IGF-1) levels were unaffected by EtOH. Serum osteocalcin levels in the unrecovered EtOH-fed group were higher than those in the recovered group but EtOH intake did not elevate the unrecovered levels compared to isocaloric or ad libitum control rats. Quantitative computed tomography (QCT) determination of bone mineral density (BMD) revealed a statistically significant reduction only in the distal femur metaphysis in the unrecovered EtOH-fed rats. BMD increased during recovery in the distal femur metaphysis and femur mid-cortex. Image analysis of midsagittal sections of the proximal tibial metaphysis of unrecovered rats revealed reductions in cancellous area, trabecular cellularity and thickness, and increased trabecular separation. Cortical widths were significantly reduced by chronic EtOH consumption. These changes remained statistically significant at the end of the recovery period. Four-point biomechanical testing of femurs from EtOH-fed and control unrecovered groups revealed significant reductions in cortical strength, energy-to-failure, and stiffness. These cortical characteristics returned to normal values with abstinence. Tibial metaphyseal alpha-1 type I collagen and osteocalcin mRNA expression levels were significantly elevated above the paired isocaloric control levels after 60 days of EtOH consumption. Metaphyseal alkaline phosphatase mRNA levels remained unaltered by EtOH consumption in the unrecovered group. After 90 days of abstinence alpha-1 type I collagen and alkaline phosphatase gene expression levels remained significantly elevated over the isocaloric and ad libitum control levels (collagen) and the isocaloric control value (alkaline phosphatase). However, metaphyseal osteocalcin mRNA levels declined to normal levels during abstinence. Conclusions: Chronic consumption of EtOH during the peripubertal period of skeletal growth leads directly to decreased metaphyseal and cortical bone mediated through effects on osteoblasts. Removal of EtOH from the diet is accompanied by incomplete restoration of normal bone metabolism during skeletal growth.

The effects of ethanol (EtOH) and nitric oxide (NO) are well known in the adult male rat reproductive axis. In the present study, we investigate the effects of EtOH, NO, and their interaction on key genes and reproductive hormone levels in mid- (45-day) and late pubertal (55-day) male rats. Using three different NO synthase blockers--N'omega-nitro-L-arginine methyl ester (L-NAME), N'omega-nitro-L-arginine (L-NA), and 7-nitroindazole--we show that it is possible to block, in part, some of the disruptive effects of EtOH. L-NAME totally prevented the EtOH-induced fall in serum testosterone in both 45- and 55-day-old rats (p < 0.05 and p < 0.001, respectively). On the other hand, the D-NAME, an inactive isomer of L-NAME, did not protect testosterone from suppression caused by EtOH. Similarly, L-NA and 7-nitroindazole prevented the suppression of testosterone caused by EtOH in 55-day-old animals (p < 0.001 L-NA and p < 0.05 for 7-nitroindazole), but not in the 45-day-old rats. Serum luteinizing hormone (LH) was significantly reduced by EtOH in all the studies in both age groups. L-NAME (but not D-NAME) and L-NA prevented this inhibition in 55-day-old animals (p < 0.001 for L-NAME and p < 0.01 for L-NA). However, only L-NA was able to prevent the effects of EtOH on LH in the 45-day-old rats. 7-Nitroindazole was unable to prevent the decrease in LH in either age group. Despite changes in the other reproductive hormones, there were no consistent changes in hypothalamic concentrations of either LH releasing hormone (LHRH) or its precursor, pro-LHRH. No treatment caused any change in steady-state levels of beta-LH mRNA. There were no consistent changes in pro-LHRH mRNA; but, interestingly, in 45-day-old rats, L-NA given with or without EtOH lead to a significant fall in LHRH gene expression. Our findings indicate that the acute suppressive effects of EtOH on the hypothalamic-pituitary-gonadal axis of the pubertal male rat can be at least partially prevented by NO synthase blockade.