O ptimal treatment of type 1 diabetes should achieve normoglycemia at all times, without risk of hypoglycemia. Such a treatment should dramatically reduce or prevent diabetes complications and significantly improve patients' quality of life. This goal may be accomplished through pancreatic or islet cell transplantation, but availability of these tissues is limited, survival and function are unpredictable, and longterm immunosuppressive therapy is required (1). The potential for an automated closed-loop system, or artificial ␤-cell, to achieve round-the-clock glycemic control, has not been fully explored.An artificial ␤-cell requires a glucose sensor, an insulindelivery pump, and an algorithm for calculating insulin delivery. Technological and scientific advances have made sensors and pumps available, but linking the two as a "closed loop" has been challenging (2). Lingering questions remain regarding the suitability of different glucosesensing sites (subcutaneous versus intravascular), insulindelivery sites (subcutaneous versus intravascular versus intraperitoneal), and sensor reliability. In addition, no one algorithm has been universally accepted as optimal for insulin delivery (3).Herein, we describe the feasibility of achieving glycemic control in patients with type 1 diabetes using a system comprised of a subcutaneous glucose sensor, an external insulin pump, and an algorithm emulating the ␤-cell's multiphasic glucose-induced insulin release (4 -6). ). Subjects had been treated with continuous subcutaneous insulin infusion (CSII) using Lispro insulin (Lilly, Indianapolis, IN) for at least 6 months before study enrollment and were required to have an HbA 1c Ͻ9%. Data from a previously published study (7) characterizing insulin secretion over a 24-h period in nondiabetic subjects are included for comparison of the glucose profiles (n ϭ 17) obtained with a similar diet. The study was approved by the University of California, Los Angeles Institutional Review Board, and all patients gave written informed consent. RESEARCH DESIGN AND METHODSGlycemic control under CSII therapy was characterized over a 3-day outpatient period using a continuous glucose monitoring system (CGMS) (Medtronic MiniMed, Northridge, CA). The CGMS records sensor current every 5 min and glucose profiles are obtained retrospectively (8). Patients were instructed to keep their daily routine but to take a minimum of seven fingerstick blood glucose readings per day (preprandial and 2-h postprandial and at bedtime) with their home glucose meters. Patients were also instructed to record meal carbohydrate content, physical activity, and any hypoglycemic episodes or supplemental carbohydrate in a logbook.To evaluate the closed-loop insulin delivery system, patients were admitted to the general clinical research center at ϳ5:00 P.M., and their insulin pump was replaced with a Medtronic 511 Paradigm Pump capable of communicating telemetrically with a laptop computer. Two subcutaneous glucose sensors were inserted in the abdominal area and connected to...

BACKGROUND The predictive value of ascending aortic distensibility (AAD) for mortality and hard cardiovascular disease (CVD) events is not fully established. OBJECTIVES We sought to assess the utility of AAD to predict mortality and incident CVD events beyond conventional risk factors in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS AAD was measured with magnetic resonance imaging at baseline in 3,675 MESA participants free of overt CVD. Cox proportional-hazards regression was used to evaluate risk of death, heart failure (HF), and incident CVD in relation to AAD, CVD risk factors, indices of subclinical atherosclerosis, and Framingham risk score. RESULTS There were 246 deaths and 171 hard CVD (myocardial infarction, resuscitated cardiac arrest, stroke and cardiovascular [CV] death) and 88 HF events over a median 8.5-year follow-up. Decreased AAD was associated with increased all-cause mortality with a hazard ratio (HR) for the first verus fifth quintile of AAD of 2.7 (p = 0.008) independent of age, sex, ethnicity, other CVD risk factors, and indices of subclinical atherosclerosis. Overall, subjects with lowest AAD had an independent 2-fold risk of hard CVD events. Decreased AAD was associated with CV events in low-to-intermediate CVD risk individuals with an HR for the first quintile of AAD of 5.3 (p = 0.03) as well as with incident HF but not after full adjustment. CONCLUSIONS Decreased proximal aorta distensibility significantly predicts all-cause mortality and hard CV events among individuals without overt CVD. AAD may help refine risk stratification, especially among asymptomatic, low-to-intermediate risk individuals.

Aims/hypothesis: Glucose sensors often measure s.c. interstitial fluid (ISF) glucose rather than blood or plasma glucose. Putative differences between plasma and ISF glucose include a protracted delay during the recovery from hypoglycaemia and an increased gradient during hyperinsulinaemia. These have often been investigated using sensor systems that have delays due to signal smoothing, or require long equilibration times. The aim of the present study was to define these relationships during hypoglycaemia in a well-equilibrated system with no smoothing. Methods: Hypoglycaemia was induced by i.v. insulin infusion (360 pmol·m −2 ·min −1 ) in ten non-diabetic subjects. Glucose was sequentially clamped at ∼5, 4.2 and 3

Purpose-To study the effectiveness of anti-CD20 (Rituximab, RTX, Rituxan®, Genentech Inc. USA) therapy in patients with severe, corticosteroid (CS)-resistant thyroid-associated ophthalmopathy (TAO). Design-Retrospective interventional case seriesParticipants-Six consecutive subjects with severe, progressive TAO unresponsive to CS.Methods-Electronic medical record review of consecutive patients receiving RTX during the previous 18 months. Responses to therapy were graded using standard clinical assessment and flowcytometric analysis of peripheral lymphocytes.Main outcome measures-Clinical activity score (CAS), proptosis, strabismus, treatment sideeffects, and quantification of regulatory T cells.Results-Six patients were studied. Systemic CS failed to alter clinical activity in all patients (CAS= 5.3 + 1.0 (mean + standard deviation) before vs 5.5 + 0.8 during therapy for 7.5+ 6.4 months,

The largest and longest clinical trial of metformin for the prevention of diabetes is the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study (DPP/DPPOS). In this review, we summarise data from the DPP/DPPOS, focusing on metformin for diabetes prevention, as well as its long-term glycaemic and cardiometabolic effects and safety in people at high-risk of developing diabetes. The DPP (1996–2001) was a RCT of 3234 adults who, at baseline, were at high-risk of developing diabetes. Participants were assigned to masked placebo (n = 1082) or metformin (n = 1073) 850 mg twice daily, or intensive lifestyle intervention (n = 1079). The masked metformin/placebo intervention phase lasted 3.2 years, with primary outcome of diabetes incidence reported early, at 2.8 years, because of demonstrated efficacy. At the end of the DPP, all participants were offered lifestyle education and 88 % (n = 2776) of the surviving DPP cohort continued follow-up in the DPPOS. Participants originally assigned to metformin continued to receive metformin, unmasked. The DPP/DPPOS cohort has now been followed for over 15 years with prospective assessment of glycaemic, cardiometabolic, health economic, and safety outcomes. After an average follow-up of 2.8 years, metformin reduced the incidence of diabetes by 31 % compared with placebo, with a greater effect in those who were more obese, had a higher fasting glucose or a history of gestational diabetes. The DPPOS addressed the longer-term effects of metformin, showing a risk reduction of 18 % over 10 and 15 years post-randomisation. Metformin treatment for diabetes prevention was estimated to be cost-saving. At 15 years, lack of progression to diabetes was associated with a 28 % lower risk of microvascular complications across treatment arms, a reduction that was no different among treatment groups. Recent findings suggest metformin may reduce atherosclerosis development in men. Originally used for the treatment of type 2 diabetes, metformin, now proven to prevent or delay diabetes, may serve as an important tool in battling the growing diabetes epidemic. Long-term follow-up, currently underway in the DPP/DPPOS, is now evaluating metformin’s potential role, when started early in the spectrum of dysglycaemia, on later-stage comorbidities, including cardiovascular disease and cancer.