Margaret C. Lo

Relationship of vitamin D with insulin resistance and disease severity in non-alcoholic steatohepatitis.

BACKGROUND & AIMS The role of plasma vitamin D deficiency in the development of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) remains poorly understood. Previous studies have suggested a role for vitamin D deficiency in the pathogenesis of NAFLD/NASH, but they have been rather small, and/or NAFLD was diagnosed using only aminotransferases or liver ultrasound. This study aimed to assess the role of vitamin D deficiency in relationship to liver fat accumulation and severity of NASH. METHODS A total of 239 patients were recruited and state-of-the-art techniques were used to measure insulin resistance (euglycemic insulin clamp with 3-(3)H-glucose), liver fat accumulation (magnetic resonance spectroscopy or (1)H-MRS), total body fat (dual energy X-ray absorptiometry), and severity of liver disease (liver biopsy). RESULTS Patients were divided into 3 groups according to plasma 25-hydroxyvitamin D levels (normal: >30 ng/ml; insufficiency: 20-30 ng/ml; deficiency: <20 ng/ml). When well-matched for clinical parameters (BMI, total adiposity, or prevalence of prediabetes/type 2 diabetes), no significant differences were observed among groups in terms of skeletal muscle, hepatic, or adipose tissue insulin sensitivity, the amount of liver fat by (1)H-MRS, or the severity of histological inflammation, ballooning, or fibrosis. Patients were then divided according to liver histology into those with definite NASH and those without NASH. Although patients with NASH had higher insulin resistance, plasma vitamin D concentrations were similar between both groups. CONCLUSIONS Our results suggest that plasma vitamin D levels are not associated with insulin resistance, the amount of liver fat accumulation, or the severity of NASH.

Blockade of NADPH Oxidase Restores Vasoreparative Function in Diabetic CD34+ Cells

PURPOSE The vasodegenerative phase of diabetic retinopathy is likely caused by endothelial dysfunction and reduced endothelial repair. Migration of endothelial progenitor cells (EPCs) into areas of vascular injury is critical to vascular repair. This key function, often defective in diabetes, is largely mediated by nitric oxide (NO), which is known to be inactivated by superoxide produced by NADPH oxidase. The authors tested the hypothesis that either increasing eNOS expression or inhibiting NADPH oxidase would restore the reparative function in diabetic EPCs. METHODS Peripheral blood was obtained from healthy (n = 27) and diabetic (n = 31) persons, and CD34(+) cells were isolated. Expression and activation of eNOS and NADPH oxidase and intracellular levels of NO, superoxide, and peroxynitrite were evaluated. cGMP production and migration to SDF-1α were also determined. Reparative function was evaluated in a mouse model of retinal ischemia-reperfusion injury. RESULTS Diabetic EPCs demonstrate reduced eNOS expression and decreased NO bioavailability and migration in response to SDF-1α. Increasing eNOS expression in diabetic cells by AVE3085 resulted in increased peroxynitrite levels and, therefore, did not enhance NO-mediated functions in vitro and in vivo. Expression of Nox2, NADPH oxidase activity, and superoxide levels were higher in diabetic than in nondiabetic EPCs. Pretreatment with apocynin or gp91ds-tat increased NO bioavailability without increasing eNOS activity in response to SDF-1α. Ex vivo NADPH oxidase inhibition in diabetic cells restored migratory function in vitro and enhanced their homing to ischemic retinal vasculature in vivo. CONCLUSIONS The NADPH oxidase system is a promising target for correcting vasoreparative dysfunction in diabetic EPCs.

Metabolic Impact of Nonalcoholic Steatohepatitis in Obese Patients With Type 2 Diabetes

OBJECTIVE Nonalcoholic steatohepatitis (NASH) is increasingly common in obese patients. However, its metabolic consequences in patients with type 2 diabetes mellitus (T2DM) are unknown. RESEARCH DESIGN AND METHODS We studied 154 obese patients divided in four groups: 1) control (no T2DM or NAFLD), 2) T2DM without NAFLD, 3) T2DM with isolated steatosis, and 4) T2DM with NASH. We evaluated intrahepatic triglycerides by proton MRS (1H-MRS) and assessed insulin secretion/resistance during an oral glucose tolerance test and a euglycemic-hyperinsulinemic clamp with glucose turnover measurements. RESULTS No significant differences among groups were observed in sex, BMI, or total body fat. Metabolic parameters worsened progressively with the presence of T2DM and the development of hepatic steatosis, with worse hyperinsulinemia, insulin resistance, and dyslipidemia (hypertriglyceridemia and low HDL cholesterol) in those with NASH (P < 0.001). Compared with isolated steatosis, NASH was associated with more dysfunctional and insulin-resistant adipose tissue (either as insulin suppression of plasma FFA [33 ± 3 vs. 48 ± 6%] or adipose tissue insulin resistance index [9.8 ± 1.0 vs. 5.9 ± 0.8 mmol/L ⋅ µIU/mL]; both P < 0.03). Furthermore, insulin suppression of plasma FFA correlated well with hepatic steatosis (r = –0.62; P < 0.001) and severity of steatohepatitis (rs = −0.52; P < 0.001). Hepatic insulin sensitivity was also more significantly impaired among patients with T2DM and NASH, both fasting and with increasing insulin levels within the physiological range (10 to 140 µIU/mL), compared with other groups. CONCLUSIONS In obese patients with T2DM, the presence of NAFLD is associated with more severe hyperinsulinemia, dyslipidemia, and adipose tissue/hepatic insulin resistance compared with patients without NAFLD. The unfavorable metabolic profile linked to NAFLD should prompt strategies to identify and treat this population early on.

Carvedilol reduces aortic wave reflection and improves left ventricular/vascular coupling: a comparison with atenolol (CENTRAL Study).

J Clin Hypertens (Greenwich). 2011;13:917–924. ©2011 Wiley Periodicals, Inc.

Anti-Glycation and Anti-Albuminuric Effects of GLY-230 in Human Diabetes

Background/Aims: Inhibiting nonenzymatic glycation with GLY-230 lowers glycated albumin without affecting hyperglycemia and ameliorates renal dysfunction in the db/db mouse, but the effects of this compound in man have not been assessed. We report results from the first clinical trial in patients with diabetes of this new glycation inhibitor. Methods: 21 diabetic men were randomly assigned to receive a total dose of 250, 500 or 750 mg of GLY-230 or placebo (1:1:1:1.2 ratio) daily for 14 days to evaluate safety and the effect of drug on plasma concentrations of glycated albumin and on urinary albumin. Results: GLY-230 dose-responsively decreased glycated albumin in all participants, in whom HbA1c did not change. Among participants exhibiting microalbuminuria at baseline, mean albumin excretion significantly decreased in patients receiving GLY-230 (µg albumin/mg creatinine = 61.4 ± 15.8 and 29.8 ± 10.4 at baseline and completion, respectively; p = 0.001), but not placebo. There were no serious adverse events or laboratory abnormalities, and all safety parameters remained within normal limits. Conclusions: This first-in-diabetic man study indicates that GLY-230 lowers glycated albumin and that this decrease is associated with a reduction in urine albumin excretion in patients with preexisting microalbuminuria. These data encourage further evaluation of GLY-230 in diabetic renal dysfunction.

Improving residents' clinical approach to obesity: impact of a multidisciplinary didactic curriculum.

Background/Objectives Obesity has been declared a 21st century pandemic by WHO. Yet surveys reveal physicians-in-training are uncomfortable managing obesity. One major barrier is the lack of residency education on obesity management. This study incorporates an obesity-specific didactic curriculum into an internal medicine (IM) residency programme and assesses its impact on residents’ knowledge, attitudes, practice behaviours, and clinical outcomes in patients with obesity. Methods The intervention consisted of four, 1 h, obesity-specific lectures in the University of Florida Resident Noon Conference. Lectures were taught by multidisciplinary experts and offered to 75 IM residents every 2 weeks from 5 November 2010 to 17 December 2010. Impact on IM residents’ knowledge and attitudes was assessed by a pre- and post-intervention Obesity Awareness Questionnaire (OAQ). IM residents’ clinical performance was assessed by chart reviews of 238 patients with body mass index >25 kg/m2 in residents’ clinics 4 months pre- and 6 months post-intervention for three clinical outcomes and seven practice behaviours on obesity management. Pre- and post-intervention outcomes were compared via paired t tests (quantitative data) or McNemars test (binary data). Results Mean lecture attendance was 25/75 residents (33%) per lecture. Survey response was 67/75 residents (89%) pre-OAQ and 63/75 residents (84%) post-OAQ. While most attitudes remained unchanged, IM residents gained significant confidence in exercise counselling, safety of bariatric surgery, and patients’ weight loss potential; they were more likely to address obesity in the plan and referrals to bariatric surgery. Clinical outcomes and IM residents’ knowledge demonstrated no improvement. Conclusions Our brief lecture-based curriculum has the potential to improve IM residents’ attitudes and practice behaviours towards obesity. The lack of improvement in clinical outcomes and resident knowledge prompts the need for multimodal, longitudinal curricula with experiential application of obesity medicine.

Recent and emerging therapeutic medications in type 2 diabetes mellitus: incretin-based, Pramlintide, Colesevelam, SGLT2 Inhibitors, Tagatose, Succinobucol.

Nearly 285 million people worldwide, with 10% being Americans, suffer from diabetes mellitus and its associated comorbidities. This is projected to increase by 6.5% per year, with 439 million inflicted by year 2030. Both morbidity and mortality from diabetes stem from the consequences of microvascular and macrovascular complications. Of the 285 million with diabetes, over a quarter of a million die per year from related complications, making diabetes the fifth leading cause of death in high-income countries. These startling statistics illustrate the therapeutic failure of current diabetes drugs to retard the progression of diabetes. These statistics further illustrate the continual need for further research and development of alternative drugs with novel mechanisms to slow disease progression and disease complications. The treatment algorithm updated in 2008 by American Diabetes Association and the European Association for the Study of Diabetes currently recommends the traditional medications of metformin, either as monotherapy or in combination with sulfonylurea or insulin, as the preferred choice in the tier 1 option. The algorithm only suggests addition of alternative medications such as pioglitazone and incretin-based drugs as second-line agents in the tier 2 “less well-validated” option. However, these traditional medications have not proven to delay the progressive course of diabetes as evidence of increasing need over time for multiple drug therapy to maintain sufficient glycemic control. Because current diabetes medications have limited efficacy and untoward side effects, the development of diabetes mellitus drugs with newer mechanisms of action continues. This article will review the clinical data on the newly available incretin-based drugs on the market, including glucagon-like peptide agonists and of dipeptidyl peptidase type-4 inhibitors. It will also discuss 2 unique medications: pramlintide, which is indicated for both type and type-2 diabetes, and colesevelam, which is approved by the United States Food and Drug Administration for both type-2 diabetes and hyperlipidemia. It will further review the clinical data on the novel emerging agents of sodium–glucose cotransporter-2 inhibitors, tagatose, and succinobucol, all currently in phase III clinical trials. This review article can serve as an aid for clinicians to identify clinical indications in which these new agents can be applied in the treatment algorithm.

Unilateral lower extremity swelling as a rare presentation of non-Hodgkin's lymphoma

Lower extremity oedema is frequently encountered in clinical practice. The challenge is to correctly identify the aetiology of oedema, and hence correctly manage the cause. Oedema can be classified as venous oedema and lymphoedema. Lymphoedema of the lower extremities is usually bilateral. Unilateral leg lymphoedema may occur secondary to radiation, surgery, compression by a tumour or early filariasis infection. Unilateral lower extremity lymphoedema has been reported as a rare initial presentation for lymphoma, mostly in women, usually without B-symptoms, and often with inguinal lymphadenopathies or abdominal masses. In this paper, we report a rare case of unilateral lower extremity oedema in a healthy male presenting to the outpatient clinic following trauma; further work-up revealed non-Hodgkins lymphoma with bulky inguinal lymphadenopathy compressing the iliac veins.

Ambulatory Curriculum Design and Delivery for Internal Medicine Residents

This chapter guides ambulatory educators through the key educational principles, components, and steps needed for a robust ambulatory curriculum with a longitudinal design and a diverse delivery mechanism. Ambulatory medical education for residents is structured into three major curricula designs—ambulatory block rotations, longitudinal continuity clinics, and ambulatory long blocks. Embedded into these curricular designs is a core curricular thread comprised of high-yield ambulatory topics and delivered through various teaching pedagogies. Highlighted in this chapter are specific formal instructional strategies as well as resident-directed learning modalities. The chapter concludes with a step-by-step guide of the essential elements in developing an ambulatory curriculum. Sample implementation tools provide deliverables for educators to utilize in their own ambulatory teaching environment. These include needs assessment tools, mini-CEX forms, and a goal and objective template for resident continuity clinics.

Cor Triatriatum as an Uncommon Cause of Recurrent Syncope

A 48-year-old woman with recurrent syncope presented with acute left vision loss after another syncopal fall. She reported no prodromal symptoms and no prior syncope workup. Vital signs were normal. Ophthalmologic exam revealed left corneal ulcerations. Cardiopulmonary and neurologic examinations were unremarkable. Brain MRI, carotid ultrasound, serial troponins, telemetry, and EKG were normal. Transthoracic echocardiography uncovered a diagnosis of cor triatriatum, an obstructing patent membrane in a dilated, bisected left atrium (Fig. 1) with constricted blood flow and increased flow velocity across the restrictive orifice (Fig. 2). Cor triatriatum represents only 0.1–0.4% of congenital cardiac malformations and has several anatomic variants. Ventricular inflow obstruction results from abnormal septation within the left or right atrium, creating two atrial chambers subdivided by a thin membrane. Many remain asymptomatic until their thirties. Most cases in adulthood are discovered incidentally. Clinicians should suspect cor triatriatum in young healthy patients with clinical features mimicking mitral stenosis but no cardiovascular co-morbidities. Early and severe manifestations occur in smaller communicating orifices and higher obstruction between bisected atrial chambers. Late symptoms results from progressive increase in pulmonary artery pressure. Syncope, heart failure, and sudden cardiac arrest are well cited. Early diagnosis by echocardiography is important to expedite surgical cure.