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Introduction Type 2 diabetes mellitus (T2DM) is a powerful risk factor for cardiovascular disease (CVD), conferring a greater relative risk in women than men. We sought to examine sex differences in cardiometabolic risk factors and management in the contemporary cohort represented by the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).Research design and methods GRADE enrolled 5047 participants (1837 women, 3210 men) with T2DM on metformin monotherapy at baseline. The current report is a cross-sectional analysis of baseline data collected July 2013 to August 2017.Results Compared with men, women had a higher mean body mass index (BMI), greater prevalence of severe obesity (BMI≥40 kg/m2), higher mean LDL cholesterol, greater prevalence of low HDL cholesterol, and were less likely to receive statin treatment and achieve target LDL, with a generally greater prevalence of these risk factors in younger women. Women with hypertension were equally likely to achieve blood pressure targets as men; however, women were less likely to receive ACE inhibitors or angiotensin receptor blockers. Women were more likely to be divorced, separated or widowed, and had fewer years of education and lower incomes.Conclusions This contemporary cohort demonstrates that women with T2DM continue to have a greater burden of cardiometabolic and socioeconomic risk factors than men, particularly younger women. Attention to these persisting disparities is needed to reduce the burden of CVD in women.Trial registration number ClinicalTrials.gov (NCT01794143)

Introduction The shape of the glucose curve during an oral glucose tolerance test (OGTT) reflects β-cell function in populations without diabetes but has not been as well studied in those with diabetes. A monophasic shape has been associated with higher risk of diabetes, while a biphasic pattern has been associated with lower risk. We sought to determine if phenotypic or metabolic characteristics were associated with glucose response curve shape in adults with type 2 diabetes treated with metformin alone.Research design and methods This is a cross-sectional analysis of 3108 metformin-treated adults with type 2 diabetes diagnosed

Introduction: Type 2 diabetes mellitus (T2DM) has affected many people worldwide. One population that is greatly affected by T2DM is the Asian Indian population. The relative effects of genetics and environment on the development of diabetes in adults are not completely understood., Objectives: We conducted an analysis to determine if location, through the environment and different diets, affects T2DM inheritance in Asian Indians. We hypothesised that the prevalence of T2DM depended on location., Materials and Methods: We analysed previously collected data on T2DM in the individual states of India and the U.S. and used this information to compare the prevalence of T2DM in Asian Indians living in these two countries., Results: A total of 1,117,465,226 individuals were surveyed in India. Of these, 108,295,674 individuals had T2DM. Similarly, of the 1,704,846 individuals in the US, 298,107 had T2DM. The prevalence of T2DM was 17.49% in Asian Indians living in the US compared to 9.69% for Indians living in India ( P < 0.00001). In individuals with similar genetic backgrounds, environmental factors significantly influence the development of T2DM., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Indian Journal of Endocrinology and Metabolism.)

Objective: To assess the landscape of digital health resources in the United States, better understand the impact of the digital health on shared decision-making, and identify potential barriers and opportunities for progress in the care of persons with diabetes., Methods: The study consisted of two phases: A qualitative phase in which one-on-one interviews were conducted virtually with 34 physicians (endocrinologists {Endos}: n = 15; primary care physicians {PCPs}: n = 19) between February 11, 2021 and February 18, 2021, and a quantitative phase in which two online, email-based surveys in the English language were conducted between April 16, 2021 and May 17, 2021: one with healthcare professionals (HCP) (n = 403: n = 200 Endos and n = 203 PCPs), and one with persons with diabetes (n = 517: patients with type 1 diabetes, n = 257; patients with type 2 diabetes, n = 260)., Results: Diabetes digital health tools were found to be helpful in shared decision-making, but leading barriers include cost, coverage, and lack of time by healthcare professionals. Among diabetes digital health tools, continuous glucose monitoring (CGM) systems were used most commonly and viewed as most effective in improving quality of life and facilitating shared decision-making. Strategies for increasing use of diabetes digital health resources included lower cost, integration into electronic health records, and increased simplicity of tools., Conclusion: This study revealed that both Endos and PCPs feel that diabetes digital health tools have an overall positive impact. Integration with telemedicine and simpler, lower cost tools with increased patient access can further facilitate shared decision-making and improved diabetes care and quality of life., Competing Interests: Disclosure CCL reports receiving research funding from Jaeb Center for Health Research by Dexcom Inc. FM reports no conflicts of interest to disclose. AS reports no conflicts of interest to disclose. AAM reports no conflicts of interest to disclose. VS reports no conflicts of interest to disclose., (Copyright © 2023 AACE. Published by Elsevier Inc. All rights reserved.)

Aims: Patients with diabetic foot ulcers are instructed to be non-weight bearing on the affected limb to promote healing. Therefore, the aim of this study was to investigate the effect of different assistive devices on whole foot plantar loading, peak forefoot force, ankle range of motion, and locomotion speed during gait in patients with Type 2 Diabetes Mellitus., Methods: Participants walked normally, with crutches, a walker, and a wheeled knee walker (WKW) in randomized order. Force sensitive insoles and 3D motion capture were used to record plantar normal force and ankle kinematics. Force sensitive pads were wrapped around handles of the crutches and walker to measure bodyweight offloaded onto the assistive device. An instrumented WKW was used to measure bodyweight offloaded onto the handlebars and knee cushion., Results: Locomotion with the WKW produced the lowest whole foot plantar loading and peak forefoot force in the propulsive limb, while also producing the greatest ankle range of motion and locomotion speed amongst assistive devices., Conclusions: This pre-clinical study found that the WKW could be the preferred assistive device for total unilateral offloading of diabetic foot ulcers as it reduced propulsive limb whole foot and forefoot plantar loading while retaining ankle range of motion and locomotion speed., Competing Interests: Conflict of interest The authors disclose to have no financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Analysis of cytologically indeterminate thyroid nodules with Afirma Gene Expression Classifier (GEC) and Genomic Sequencing Classifier (GSC) can reduce surgical rate and increase malignancy rate of surgically resected indeterminate nodules., Methods: Retrospective cohort analysis of all adults with cytologically indeterminate thyroid nodules from January 2013 through December 2019. We compared surgical and malignancy rates of those without molecular testing to those with GEC or GSC, analyzed test performance between GEC and GSC, and identified variables associated with molecular testing., Results: 468 indeterminate thyroid nodules were included. No molecular testing was performed in 273, 71 had GEC, and 124 had GSC testing. Surgical rate was 68% in the group without molecular testing, 59% in GEC, and 40% in GSC. Malignancy rate was 20% with no molecular testing, 22% in GEC, and 39% in GSC ( P = 0.022). GEC benign call rate (BCR) was 46%; sensitivity, 100%; specificity, 61%; and positive predictive value (PPV), 28%. GSC BCR was 60%; sensitivity, 94%; specificity, 76%; and PPV, 41%. Those with no molecular testing had larger nodule size, preoperative growth of nodules, and constrictive symptoms and those who underwent surgery in the no molecular testing group had higher body mass index, constrictive symptoms, higher Thyroid Imaging Reporting and Data System and Bethesda classifications. Type of provider was also associated with the decision to undergo surgery., Conclusion: Implementation of GEC showed no effect on surgical or malignancy rate, but GSC resulted in significantly lower surgical and higher malignancy rates. This study provides insight into the factors that affect the real-world use of these molecular markers preoperatively in indeterminate thyroid nodules., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Management of post-transplant diabetes mellitus is challenging; there is a lack of prospective randomized controlled trials for safety and efficacy of antidiabetic medications in solid organ recipients. Glucagon-like peptide 1 receptor agonists (GLP-1RA) are a relatively new class of medications used to manage type 2 diabetes in the general population. They have several benefits besides glycemic control, including weight loss and improved cardiovascular risk. However, they have not been studied extensively in the post-transplant population for safety and efficacy., Methods: We conducted a retrospective study of patients who had received kidney, liver, or heart transplant, had diabetes either pre- or post-transplant, and were treated with GLP-1RA. We identified seven kidney, seven liver, and five heart transplant recipients who had received GLP-1RA. We assessed changes in immunosuppressant levels, rejection episodes, changes in hemoglobin A1c (HbA1c), weight, and body mass index (BMI) while on the GLP-1RA. We also looked at changes in insulin dose, other diabetes medications, heart rate, blood pressure, and renal function., Results: After a mean follow-up period of 12 months, there were no significant changes in tacrolimus (FK506) levels and renal function for the period of GLP-1RA use. At the end of 12 months, the mean drop in weight was 4.86 kg [95% CI - 7.79, - 1.93]. The BMI decreased by a mean of 1.63 kg/m 2 at the end of 12 months [95% CI - 2.53, - 0.73]. HbA1c decreased from baseline by 1.08% [95% CI - 1.65, - 0.51], 0.96% [95% CI - 1.68, - 0.25], and 0.75% [95% CI - 1.55, 0.05] at 3, 6, and 12 months, respectively., Conclusions: Our data suggest that GLP-1RA do not affect tacrolimus levels or transplant outcomes in solid organ transplant (SOT) recipients in the short term. GLP-1RA also seem to be as effective in SOT recipients for glycemic control and weight loss as in the non-transplant population with diabetes.

We previously reported that fish oil in combination with cyclooxygenase (COX) inhibitors exerts enhanced hypolipidemic and anti-inflammatory effects in mice. Here, we sought to determine the effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in combination with naproxen (NX), a COX inhibitor, on dyslipidemia and gene expression in adipose tissue (AT) in humans. Obese dyslipidemic patients were randomly assigned to one of these interventions for 12 wk: 1) Standard nutrition counseling (control), 2) ω-3 PUFAs (2 g twice daily), 3) NX (220 mg twice daily), and 4) ω-3 PUFAs (2 g twice daily) + NX (220 mg twice daily). The serum triglycerides showed a trend towards a reduction and a significant reduction (P<0.05) in ω-3 and ω3 + NX-treated subjects, respectively, compared to control. The mRNA expression of vascular cell adhesion molecule-1 (Vcam1), an inflammatory marker, increased significantly in AT of ω-3 PUFA-treated subjects but not in ω-3 PUFAs+NX-treated group. The plasma level of glycine-conjugated hyodeoxycholic acid, a secondary bile acid with hypolipidemic property, increased significantly in ω-3 PUFAs + NX-treated group. Our data suggest that combining NX with ω-3 PUFAs increases their effectiveness in reducing serum TG and favorably altering AT gene expression and plasma bile acid profile., (Published by Elsevier Inc.)

This study investigates spatiotemporal gait adjustments that occur while stepping over virtual obstacles during treadmill walking in people with/without diabetic peripheral neuropathy (DPN). Eleven adults with Type 2 diabetes mellitus, ten DPN, and 11 age-matched healthy adults (HTY) participated in this study. They stepped over forthcoming virtual obstacles during treadmill walking. Outcomes such as success rate, spatiotemporal gait characteristics during obstacle crossing, and correlations between these variables were evaluated. The results partially supported our hypotheses that when comparing with HTY and DM, people with DPN adopted a crossing strategy which decreased obstacle crossing success rate and maximal toe elevation, and increased stride time and stance time during virtual obstacle crossing. This might be due to the compromised somatosensory functions of their lower extremity which may increase the risk of falling. This study also found an inter-leg relationship which may be applied to future stepping or obstacle crossing training that incorporates both legs as a means for improving outcomes of the trailing leg during daily obstacle negotiation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Post-transplant diabetes mellitus (PTDM) is common after most types of solid organ transplantation, though the actual incidence is as yet unknown because of the use of different diagnostic criteria. PTDM is the result of individual risk factors as well as risk factors associated with the transplant itself, particularly immunosuppressants. Previously called New Onset Diabetes, in many cases inadequate screening for diabetes before transplant cannot assure that the diabetes is new after transplant. The most recent international consensus guidelines suggest diagnosis should be delayed until the patient is taking maintenance doses of immunosuppressants even if they require treatment in the immediate hospitalization. Criteria for diagnosis follow those of the American Diabetes Association and the World Health Organization, although hemoglobin A1C should not be used as the only screening test at least until one year after transplant because of its insensitivity for significant glucose intolerance in the transplant patient and setting. Management of PTDM is best done in a team setting, with an emphasis on glycemic control, dyslipidemia, and hypertension, and taking into consideration immunosuppressant regimens and potential drug side effects and interactions. While PTDM has been associated with changes in outcomes, these have and may continue to improve with improved diabetes care in and out of the hospital, and other changes in post-transplant care.

Aims: The aim of this study was to compare the changes in the total daily dose (TDD) of insulin of patients on U-500 insulin; before hospitalization, during hospitalization and six weeks after discharge., Methods: A retrospective chart review of veterans with type 2 diabetes receiving U-500 insulin in the ambulatory setting and who were admitted between 2012 and 2015 was performed. During hospitalization, patients were transitioned to receive U-100 insulin (detemir or glargine for basal and aspart for bolus). Paired t-tests were conducted to compare TDD of insulin during hospitalization to prior to admission and at six week of follow-up., Results: The average hemoglobin A1 c at the time of hospital admission was 8.3±1.5% (n=20). The average TDD of insulin during hospitalization (124±67units) was significantly less than prior to admission (295±123units) and at six week follow-up (310±105units). The average glucose during hospitalization was 180±36mg/dL. Hypoglycemia was less than 0.5%., Conclusion: We showed that patients received significantly less total daily insulin while hospitalized compared to their insulin doses in the ambulatory setting, and we demonstrate that patients receiving U-500 insulin can be safely transitioned to U-100 insulin while hospitalized, with minimal hypoglycemia., (Published by Elsevier Inc.)

The dramatic rise in the prevalence of obesity and diabetes is associated with increased morbidity, mortality, and public health care costs worldwide. The need for new, effective, and long-lasting drugs is urgent. Recent research has focused on the role of the inhibitors of sodium- glucose co-transporter 2 (SGLT-2). Clinical trials have shown that SGLT-2 inhibitors have glycemic efficacy and weight-lowering potential. Dual drug therapy is a recommended therapy for patients with new-onset type 2 diabetes who need significant glycemic control. Fixed-dose combination therapy represents a particularly attractive option as it may reduce pill burden and improve adherence. The combination of metformin and empagliflozin was approved by the US Food and Drug Administration in 2014 and represents a safe and effective means to combat glycemic control and weight gain. The purpose of this systematic review is to summarize the background of the SGLT-2 inhibitors, particularly empagliflozin, and focus on the safety and efficacy of the fixed-dose combination of empagliflozin and metformin., Competing Interests: The authors report no conflicts of interest in this work.

Post-transplant diabetes mellitus (PTDM) is a frequent consequence of solid organ transplantation. PTDM has been associated with greater mortality and increased infections in different transplant groups using different diagnostic criteria. An international consensus panel recommended a consistent set of guidelines in 2003 based on American Diabetes Association glucose criteria but did not exclude the immediate post-transplant hospitalization when many patients receive large doses of corticosteroids. Greater glucose monitoring during all hospitalizations has revealed significant glucose intolerance in the majority of recipients immediately after transplant. As a result, the international consensus panel reviewed its earlier guidelines and recommended delaying screening and diagnosis of PTDM until the recipient is on stable doses of immunosuppression after discharge from initial transplant hospitalization. The group cautioned that whereas hemoglobin A1C has been adopted as a diagnostic criterion by many, it is not reliable as the sole diabetes screening method during the first year after transplant. Risk factors for PTDM include many of the immunosuppressant medications themselves as well as those for type 2 diabetes. The provider managing diabetes and associated dyslipidemia and hypertension after transplant must be careful of the greater risk for drug-drug interactions and infections with immunosuppressant medications. Treatment goals and therapies must consider the greater risk for fluctuating and reduced kidney function, which can cause hypoglycemia. Research is actively focused on strategies to prevent PTDM, but until strategies are found, it is imperative that immunosuppression regimens are chosen based on their evidence to prolong graft survival, not to avoid PTDM.

A rare cause for rapid adrenal enlargement is adrenal oncocytoma of uncertain malignant potential. A full biochemical evaluation is warranted to screen secreting adrenal adenomas as well as to evaluate adrenal cortical carcinoma. Careful pathologic evaluation is required as the diagnosis of AOC cannot be made by imaging.

Significant hyperglycemia is commonly observed immediately after solid organ and bone marrow transplant as well as with subsequent hospitalizations. Surgery and procedures are well known to cause pain and stress leading to secretion of cytokines and other hormones known to aggravate insulin action. Immunosuppression required for transplant and preexisting risk are also major factors. Glucose control improves outcomes for all hospitalized patients, including transplant patients, but is often more challenging to achieve because of frequent and sometimes unpredictable changes in immunosuppression doses, renal function, and nutrition. As a result, risk of hypoglycemia can be greater in this patient group when trying to achieve glucose control goals for hospitalized patients. Key to successful management of hyperglycemia is regular communication between the members of the care team as well as anticipating and rapidly implementing a new treatment paradigm in response to changes in immunosuppression, nutrition, renal function, or evidence of changing insulin resistance.

Although the contribution of the immunosuppressants tacrolimus (TAC) and sirolimus (SIR) to the development of posttransplant diabetes mellitus (PTDM) are being increasingly recognized, the mechanisms of immunosuppressant-induced hyperglycemia are unclear. SIR induces insulin resistance predominantly, but is associated with β-cell dysfunction in rodents. TAC affects islet function but is associated with worsening insulin sensitivity in a few, and improvement in some, clinical studies. We sought to clarify the contributions of TAC and SIR to insulin resistance and islet function. Four groups of male and female Sprague-Dawley rats received TAC, SIR, TAC and SIR, or control for 2 weeks. All rats were administered an oral glucose challenge at the end of treatment. Half the groups were sacrificed 10 minutes after administration of regular insulin whereas the other half did not receive insulin before sacrifice. Liver, pancreas, fat, and muscle were harvested subsequently. Quantification of Western blots revealed that SIR and TAC plus SIR suppressed the phospho-Akt (pAkt)-to-Akt ratios in liver, muscle, and fat compared with control, regardless of sex. TAC alone did not impair the pAkt-to-Akt ratios in any of the tissues in male and female rats. β-Cell mass was reduced significantly after TAC treatment in male rats. SIR did not affect β-cell mass, regardless of sex. Our study demonstrated very clearly that SIR impairs insulin signaling, without any effect on β-cell mass, and TAC does not impair insulin signaling but reduces β-cell mass. Our efforts are key to understanding the mechanisms of immunosuppressant-induced hyperglycemia and to tailoring treatments for PTDM., (Published by Mosby, Inc.)

New-onset diabetes after transplantation (NODAT) is a common comorbidity after renal transplantation. Though metformin is the first-line agent for the treatment of type 2 diabetes, in renal transplant recipients, metformin is frequently avoided due to concerns about renal dysfunction and risk for lactic acidosis. Therefore, alternative first-line agents for the treatment of NODAT in renal transplant recipients are needed. Sitagliptin, a dipeptidyl-peptidase-4 (DPP-4) inhibitor, has a low incidence of hypoglycemia, is weight neutral, and, in a small study, did not affect immunosuppressant levels. However, long-term sitagliptin use for the treatment of NODAT in kidney transplant recipients has not been studied. We retrospectively analyzed renal transplant recipients diagnosed with NODAT and treated with sitagliptin to assess safety and efficacy. Twenty-two patients were started on sitagliptin alone. After 12 months of followup, 19/22 patients remained on sitagliptin alone with a significant improvement in hemoglobin A1c. Renal function and immunosuppressant levels remained stable. Analysis of long-term followup (32.5 ± 17.8 months) revealed that 17/22 patients remained on sitagliptin (mean hemoglobin A1c < 7%) with 9/17 patients remaining on sitagliptin alone. Transplant-specific adverse events were rare. Sitagliptin appears safe and efficacious for the treatment of NODAT in kidney transplant recipients.

Background: Immunosuppressants are an important cause of posttransplantation diabetes mellitus. We have shown that tacrolimus and sirolimus induce hyperglycemia and hyperinsulinemia in normal rats. We hypothesized that metformin, given concurrently with tacrolimus and/or sirolimus, prevents disturbances in glucose and insulin metabolism., Methods: Eight groups (n=6) of normal Sprague-Dawley rats were studied: four groups received tacrolimus, sirolimus, tacrolimus/sirolimus, or control for 14 days, and four more groups received similar treatments along with metformin. Daily glucoses were measured. All rats were administered an oral glucose challenge before sacrifice. Pancreata were analyzed by terminal deoxynucleotide tranferase-mediated dUTP nick-end labeling staining and immunohistochemistry., Results: Tacrolimus, sirolimus, and tacrolimus/sirolimus impaired glucose tolerance compared to control. Sirolimus and tacrolimus/sirolimus also increased random blood glucose levels. Sirolimus alone resulted in hyperinsulinemia after oral glucose challenge compared to control. In the sirolimus/metformin and tacrolimus/sirolimus/metformin groups, mean daily random glucose was no longer increased, although the response to glucose challenge was still impaired. Metformin decreased pancreatic exocrine and trended to decrease endocrine apoptosis in tacrolimus/sirolimus group and reduced islet insulin content in sirolimus group., Conclusions: This is the first study to show that metformin can improve immunosuppressant-induced hyperglycemia, when administered concurrently, and reduces exocrine apoptosis (reducing the impact on potential islet progenitor cells).

Aims: Obesity, which is at epidemic proportions in the USA, is associated with a higher risk of several co-morbid diseases including, cardiovascular disease, cancer and sleep apnea. Weight loss and weight maintenance programmmes are difficult to sustain for long term. Mental health problems such as apathy may be a major factor in patients unsuccessful in adhering to weight loss programmes. We propose that treating apathy will result in better weight loss in obese patients., Methods: This was a randomized prospective pilot study. Obese patients (n = 101) were randomized in a 1:2:2 ratio to either (i) standard nutrition counselling; or (ii) the Department of Veterans Affairs weight loss programme called 'motivate obese veterans everywhere ' (MOVE); or (iii) methylphenidate treatment plus the MOVE programme together. The intervention was for 6 months (26 weeks)., Results: For the within groups analysis, the absolute changes in weight (kg) are as follows, for MOVE (mean: -1.84; 95% confidence interval (CI): -4.56 to 0.87; p = 0.25), Methylphenidate (mean: -4.61; 95% CI: -7.90 to -1.33; p = 0.04), standard nutrition counselling (mean: -0.60; 95% CI: -2.59 to 1.39; p = 0.21), which indicates that although all three groups lost weight, only the methylphenidate group achieved statistical significance. The between group differences of the relative change in weight were not statistically different. The apathy evaluation score and the patient activation measure improved in all groups., Conclusion: Together these data suggest that treating apathy might be an important factor in the success of weight management programmes., (Published 2011. This article is a U.S. Government work and is in the public domain in the USA.)

Kidney transplantation is being performed more frequently for individuals with end stage renal disease (ESRD) due to improved survival and quality of life compared to long-term dialysis. Though rates decrease after transplant, cardiovascular disease (CVD) remains the most common cause of death after kidney transplant. New-onset diabetes after transplant (NODAT), a common complication following kidney transplantation, and pre-transplant diabetes both significantly increase the risk for CVD. Several other risk factors for CVD in kidney transplant recipients have been identified; however, optimal therapy for controlling the risk factors of CVD after kidney transplantation, including NODAT and pre-transplant diabetes, is not well defined. In the following review we will discuss the role of traditional and non-traditional risk factors in CVD after kidney transplant and the mechanisms involved therein. We will also examine the current literature regarding treatment of these risk factors for the prevention of CVD. Finally, we will review the current recommendations for pre- and post-transplant cardiovascular evaluation and management.

Background: Immunosuppression medications contribute to posttransplant diabetes mellitus in patients and can cause insulin resistance in male rats. Tacrolimus (TAC)-sirolimus (SIR) immunosuppression is also associated with appearance of ovarian cysts in transplant patients. Because insulin resistance is observed in patients with polycystic ovary syndrome, we hypothesized that TAC or SIR may induce reproductive abnormalities., Methods: We monitored estrus cycles of adult female rats treated daily with TAC, SIR, and combination of TAC-SIR, or diluent (control) for 4 weeks. Animals were then challenged with oral glucose to determine their glucose and insulin responses, killed, and their blood and tissues, including ovaries and uteri harvested., Results: TAC and TAC-SIR treatments increased mean random glucose concentrations (P<0.05). TAC, SIR, and TAC-SIR treatments also increased the glucose response to oral glucose challenge (P<0.05). The insulin response to glucose was significantly higher in rats treated with SIR compared with TAC (P<0.05). TAC, SIR and TAC-SIR treatments reduced number of estrus cycles (P<0.05). The ovaries were smaller after SIR and TAC-SIR treatment compared with controls. The TAC and TAC-SIR treatment groups had fewer preovulatory follicles. Corpora lutea were present in all groups. Ovarian aromatase expression was reduced in the SIR and TAC-SIR treatment groups. A significant (P<0.05) reduction in uterine size was observed in all treatment groups when compared with controls., Conclusion: In a model of immunosuppressant-induced hyperglycemia, both TAC and SIR induced reproductive abnormalities in adult female rats, likely through different mechanisms.

Post-transplant diabetes mellitus (PTDM) worsens outcomes after kidney transplantation, and immunosuppression agents contribute to PTDM. We have previously shown that tacrolimus (TAC) and sirolimus (SIR) cause hyperglycemia in normal rats. While there is little data on the mechanism for immunosuppressant-induced hyperglycemia, we hypothesized that the TAC and SIR-induced changes are reversible. To study this possibility, we compared normal rats treated for 2 weeks with either TAC, SIR, or a combination of TAC and SIR prior to evaluating their response to glucose challenge, with parallel groups also treated for 2 weeks after which treatment was stopped for 4 weeks, prior to studying their response to glucose challenge. Mean daily glucose and growth velocity was decreased in SIR, and TAC+SIR-treated animals compared to controls (P < 0.05). TAC, SIR, and TAC+SIR treatment also resulted in increased glucose response to glucose challenge, compared to controls (P < 0.05). SIR-treated animals also had elevated insulin concentrations in response to glucose challenge, compared to controls (P < 0.05). Insulin content was decreased in TAC and TAC+SIR, and islet apoptosis was also increased after TAC+SIR treatment (P < 0.05). Four weeks after treatments were stopped, all differences resolved between groups. In conclusion, TAC, SIR, and the combination of TAC+SIR-induced changes in glucose and insulin responses to glucose challenge that were accompanied by changes in islet apoptosis and insulin content. These changes were no longer present 4 weeks after cessation of therapy suggesting immunosuppressant-induced changes in glucose metabolism are likely reversible.

The increase in obesity and the aging of the population has lead to an increase in the incidence of type 2 diabetes. This has led to the development of new drugs such as thiazolidinediones (TZDs) which are Peroxisome Proliferator-Activated Receptor (PPARgamma) agonists, to treat type 2 diabetes. TZDs have recently been at the center of a controversy with regards to their cardiovascular safety. Pioglitazone is a TZD which has been shown to be effective in glycemic control by lowering insulin resistance. Pioglitazone also has beneficial effects on lipid metabolism and cardiovascular risk. The safety and efficacy of pioglitazone including its pleotropic effects are discussed at length in this article.

Ept1, Ept2, Ept6, and Ept9 are quantitative trait loci mapped in crosses between the ACI and Copenhagen (COP) rat strains as genetic determinants of responsiveness of the pituitary gland to estrogens. We have developed four congenic rat strains, each of which carries, on the genetic background of the ACI rat strain, alleles from the COP rat strain that span one of these quantitative trait loci. Relative to the female ACI rats, female ACI.COP-Ept1 rats exhibited reduced responsiveness to 17beta-estradiol (E2) in the pituitary gland, as evidenced by quantification of pituitary mass and circulating prolactin, and in the mammary gland, as evidenced by reduced susceptibility to E2-induced mammary cancer. The ACI.COP-Ept2 rat strain exhibited reduced responsiveness to E2 in the pituitary gland but did not differ from the ACI strain in regard to susceptibility to E2-induced mammary cancer. Interestingly, female Ept2 congenic rats exhibited increased responsiveness to E2 in the thymus, as evidenced by enhanced thymic atrophy. The ACI.COP-Ept6 rat strain exhibited increased responsiveness to E2 in the pituitary gland, which was associated with a qualitative phenotype suggestive of enhanced pituitary vascularization. The ACI.COP-Ept9 rat strain exhibited reduced responsiveness to E2 in the anterior pituitary gland, relative to the ACI rat strain. Neither Ept6 nor Ept9 impacted responsiveness to E2 in the mammary gland or thymus. These data indicate that each of these Ept genetic determinants of estrogen action is unique in regard to the tissues in which it exerts its effects and/or the direction of its effect on estrogen responsiveness.

Background: Patients with diabetes have been reported to have greater dyslipidemia after kidney transplant (KTX). Because postKTX management of diabetes has changed markedly since those reports, we hypothesized that lipids can be controlled as well in diabetic as in nondiabetic recipients., Methods: We compared lipid levels up to 2 years after KTX (n=192) between diabetic and nondiabetic recipients. The cohort was subdivided into nondiabetic (nonDM-K; n=123), type 2 (DM2-K; n=33), or type 1 diabetes after KTX (DM1-K; n=14), or type 1 after kidney-pancreas transplant (DM1-KP; n=22)., Results: Mean age and body mass index of DM2-K were greater than the others (P<0.01), and diabetes groups had a higher pretransplant A1C than nonDM-K (P<0.001). After KTX, lipid levels were not higher in diabetic than in nondiabetic recipients, and did not increase in any group. Total and low-density lipoprotein cholesterol levels decreased in DM1-K (P<0.001), high-density lipoprotein levels decreased in DM1-KP (P=0.02), and triglyceride levels were unchanged after KTX for all groups. A1C improved in DM1-K and DM1-KP (P<0.0001). There was less improvement in lipid levels with tacrolimus-sirolimus immunosuppression than with other steroid-containing regimens (P<0.05)., Conclusions: Multiple mechanisms may contribute to better lipid levels in both groups as well as the lack of difference between diabetic and nondiabetic recipients compared with what has been reported previously: greater use of and more effective lipid-lowering agents, no significant weight gain, no difference in renal function between groups, and better control of glucose in the diabetic group. Thus, overall, lipids can be controlled as well in diabetic as in nondiabetic KTX recipients.

Objective: Diabetes mellitus is a major public health problem with a prevalence of 6-7%. Self-care behaviors play a major role in the control of diabetes. Apathy is characterized by loss of initiative and motivation. Apathy may interfere with self-care behavior and glycemic control. The primary objective was to determine the prevalence of apathy in patients with diabetes. The secondary objective was to determine if there was an association between clinically significant apathy and factors that affect glycemic control., Research Design and Methods: We conducted a cross-sectional study of 100 patients with diabetes who were assessed with the Apathy Evaluation Scale-Clinician version (AES-C), the Hamilton Depression Scale (HAM-D), and the Self-Care Inventory (SCI). For this study we defined clinically significant apathy as AES-C score of >30. We excluded patients with a HAM-D score of >14 (n=19) to avoid confounding from depression. T-tests were used to compare clinical characteristics between subjects with and without apathy. Multiple linear regression modeling was used to investigate the association between clinically significant apathy and factors that affect glycemic control., Results: Fifty (61.7% of 81) patients had clinically significant apathy. Compared to the non-apathetic patients, those with apathy had a higher mean BMI (30.5 kg/m(2) versus 34.1 kg/m(2) (p=0.03)) and were less likely to adhere to an exercise plan (p=0.01) or insulin regimen (p=0.003). After adjustment for age, BMI, cholesterol, mild depression and the average Self-Care Index score, the mean HbA1C level was 0.66% greater for apathetic compared to non-apathetic subjects (P=0.08)., Conclusion: Apathy is highly prevalent in patients with diabetes without depression. Apathy may have a negative impact on self-care behaviors and diabetes control.

Phosphatidylserine (PS) efflux characterizes cytotrophoblast apoptosis and differentiation. To evaluate whether PS externalization and intercellular fusion were secondary to apoptosis, BeWo cells were induced to differentiate by forskolin or undergo apoptosis by staurosporine. PS externalization was measured by FITC-annexin V binding, and intercellular fusion was quantified by counting nuclei in syncytial cells. During forskolin treatment, vanadate decreased PS efflux by 78.0 per cent from 68.0 [5.3] (mean [SD]) to 15.0 [8.8] Lum (x10(3)) (P<0.001), whereas Z-VAD-fmk had no effect (66.5 [7.3]). Vanadate decreased intercellular fusion from 78.1 per cent [4.1] fusion in uninhibited cultures to 23.4 per cent [2.5], compared with 10.0 per cent [1.7] in media alone. Z-VAD-fmk did not affect fusion (80.4 per cent [6.8]). Staurosporine induced PS efflux was not affected by vanadate (69.6 [5.5] Lum x10(3)), but was inhibited 87.8 per cent by Z-VAD-fmk; from 71.5 [6.2] to 8.7 [3.6] Lum (x10(3)) (P<0.001). Apoptosis was measured by the TUNEL and COMET assays, lamin B fragmentation, activation of procaspase 3, mitochondrial membrane potential, and release of mitochondrial cytochrome c and apoptosis inducing factor. There was no indication of apoptosis associated with differentiation. Thus, PS efflux and intercellular fusion occurred through a vanadate-sensitive mechanism that was independent of apoptosis.

Addition of ferrous sulfate, but not ferric chloride, in micromolar concentrations to rat liver mitochondria induced high rates of consumption of oxygen. The oxygen consumed was several times in excess of the reducing capacity of ferrous-iron (O:Fe ratios 5-8). This occurred in the absence of NADPH or any exogenous oxidizable substrate. The reaction terminated on oxidation of ferrous ions. Malondialdehyde (MDA), measured as thiobarbituric acid-reacting material, was produced indicating peroxidation of lipids. The ratio of O2:MDA was about 4:1. Pretreatment of mitochondria with ferrous sulfate decreased the rate of oxidation (state 3) with glutamate (+ malate) as the substrate by about 40% but caused little damage to energy transduction process as represented by ratios of ADP:O and respiratory control, as well as calcium-stimulated oxygen uptake and energy-dependent uptake of [45Ca]-calcium. Addition of succinate or ubiquinone decreased ferrous iron-induced lipid peroxidation in intact mitochondria. In frozen-thawed mitochondria, addition of succinate enhanced lipid peroxidation whereas ubiquinone had little effect. These results suggest that ferrous-iron can cause peroxidation of mitochondrial lipids without affecting the energy transduction systems, and that succinate and ubiquinone can offer protection from damage due to such ferrous-iron released from the stores within the cells.

Cytochrome c, a "mobile electron carrier" of the mitochondrial respiratory chain, also occurs in detectable amounts in the cytosol, and can receive electrons from cytochromes present in endoplasmic reticulum and plasma membranes as well as from superoxide and ascorbate. The pigment was found to dissociate from mitochondrial membranes in liver and kidney when rats were subjected to heat exposure and starvation, respectively. Treating cytochrome c with hydroxylamine gives a partially deaminated product with altered redox properties; decreased stimulation of respiration by deficient mitochondria, increased reduction by superoxide, and complete loss of reducibility by plasma membranes. Mitochondria isolated from brown adipose tissue of cold-exposed rats are found to be sub-saturated with cytochrome c. The ability of cytochrome c to reactivate reduced ribonuclease is now reinterpreted as a molecular chaperone role for the hemoprotein.

Mitochondria isolated from the livers of rats administered with sodium meta-, ortho-, or polyvanadate, but not vanadyl sulphate, exhibited enhanced Ca2+ -stimulated respiration and uptake of calcium. These effects were shown also by mitochondria isolated from livers perfused with polyvanadate. The concentration of acid-soluble calcium decreased significantly in the mitochondrial fraction on vanadate treatment, while that in the cytosol showed a corresponding increase. Phenoxybenzamine, an antagonist to alpha-adrenergic receptors, effectively inhibited vanadate-induced Ca2+ mobilization, but surgical sympathectomy was without effect. This is the first demonstration of vanadate mimicking alpha-adrenergic agonists in vivo.

In partially hepatectomized rats, the activity of phenylalanine hydroxylase decreased in the regenerating liver but not in the kidneys. The concentration of corticosterone in the plasma of hepatectomized rats increased, and phenylalanine hydroxylase, despite being cortisol inducible, decreased in these as well as simultaneously adrenalectomized rats, showing lack of correlation between the changes of the steroid and the enzyme during the regeneration process. The decrease in the enzyme activity could be prevented by administering, during hepatic regeneration, only noradrenaline and adrenergic blocking agents, among the many hormones and phenyl compounds tested. A decrease in hepatic phenylalanine hydroxylase was also observed during two other conditions of hepatocyte cell proliferation obtained after giving chlorophenoxyisobutyrate and alpha-hexachlorocyclohexane.

Liver mitochondria isolated from vanadate-administered rats showed increased (20-25%) rates of oxidation of both NAD(+)-linked substrates and succinate. Respiratory control index and ADP/O were unaffected by the treatment. Dormant and uncoupler-stimulated ATPase activity also was not affected by vanadate administration. Membrane-bound, electron-transport-linked dehydrogenase activities (both NAD(+)- and succinate-dependent) increased by 15-20% on vanadate treatment. Mitochondrial alpha-glycerophosphate dehydrogenase activity increased by 50% on vanadate administration. The above effects of vanadate on oxidoreductase activities could be prevented by the prior administration of antagonists to alpha-adrenergic receptors. Substrate-dependent H2O2 generation by mitochondria also showed an increase on vanadate administration.

Exposure of rats to higher environmental temperature (36-37 degrees C) decreased the capacity of their kidney mitochondria to oxidize succinate. The decrease was corrected on the addition of exogenous cytochrome c. Kidney mitochondria of heat-exposed animals showed decreased rates of H2O2 generation when alpha-glycerophosphate, but not succinate, was used as electron donor. These mitochondria also showed decreased activity of alpha-glycerophosphate dehydrogenase but not of succinate dehydrogenase. The content of cytochrome c in kidney mitochondria of heat-exposed animals was low even though the concentration of the pigment in the whole tissue did not decrease. Starvation as well as administration of an antithyroid agent like propylthiouracil simulated some of the effects of heat exposure on kidney mitochondria, but the cytochrome c-dependent reversal of inhibition of oxidation was obtained only in heat exposure.