original articleT h e ne w e ngl a nd jou r na l o f m e dic i ne n engl j med 355;13 www.nejm

OBJECTIVETo describe trends of primary efficacy and safety outcomes of islet transplantation in type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet Transplant Registry (CITR) from 1999 to 2010.RESEARCH DESIGN AND METHODSA total of 677 islet transplant-alone or islet-after-kidney recipients with type 1 diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999–2002), mid (2003–2006), or recent (2007–2010) transplant era based on annual follow-up to 5 years.RESULTSInsulin independence at 3 years after transplant improved from 27% in the early era (1999–2002, n = 214) to 37% in the mid (2003–2006, n = 255) and to 44% in the most recent era (2007–2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone). C-peptide ≥0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001). Reduction of HbA1c and resolution of severe hypoglycemia exhibited enduring long-term effects. Fasting blood glucose stabilization also showed improvements in the most recent era. There were also modest reductions in the occurrence of adverse events. The islet reinfusion rate was lower: 48% by 1 year in 2007–2010 vs. 60–65% in 1999–2006 (P < 0.01). Recipients that ever achieved insulin-independence experienced longer duration of islet graft function (P < 0.001).CONCLUSIONSThe CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007–2010 compared with those in 1999–2006, with fewer islet infusions and adverse events per recipient.

OBJECTIVE -We examined the association between depression, measured as either a continuous symptom severity score or a clinical disorder variable, with self-care behaviors in type 2 diabetes.RESEARCH DESIGN AND METHODS -We surveyed 879 type 2 diabetic patients from two primary care clinics using the Harvard Department of Psychiatry/National Depression Screening Day Scale (HANDS), the Summary of Diabetes Self-Care Activities, and self-reported medication adherence.RESULTS -Of the patients, 19% met the criteria for probable major depression (HANDS score Ն9), and an additional 66.5% reported at least some depressive symptoms. After controlling for covariates, patients with probable major depression reported significantly fewer days' adherent to diet, exercise, and glucose self-monitoring regimens (P Ͻ 0.01) and 2.3-fold increased odds of missing medication doses in the previous week (95% CI 1.5-3.6, P Ͻ 0.001) compared with all other respondents. Continuous depressive symptom severity scores were better predictors of nonadherence to diet, exercise, and medications than categorically defined probable major depression. Major depression was a better predictor of glucose monitoring. Among the two-thirds of patients not meeting the criteria for major depression (HANDS score Ͻ9, n ϭ 709), increasing HANDS scores were incrementally associated with poorer self-care behaviors (P Ͻ 0.01).CONCLUSIONS -These findings challenge the conceptualization of depression as a categorical risk factor for nonadherence and suggest that even low levels of depressive symptomatology are associated with nonadherence to important aspects of diabetes self-care. Interventions aimed at alleviating depressive symptoms, which are quite common, could result in significant improvements in diabetes self-care. Diabetes Care 30:2222-2227, 2007M ajor depression is a significant problem among patients with diabetes, with an estimated prevalence of 15-20%, compared with 2-9% in the general population (1). Among patients with type 2 diabetes, major depression is associated with a 2.3-fold increase in mortality, and minor or "subclinical" depression is associated with a 1.7-fold increase (2). Depression also increases the risk of poorer diabetes-specific outcomes such as hyperglycemia (3) and an increase in diabetes complications (4).The available literature suggests that clinically significant levels of depression are associated with a range of poorer selfcare behaviors including adherence to diet (5-8), exercise (6,7), and prescribed medications (5,7,9,10). However, although depression is clinically conceptualized as a discrete comorbid illness, few researchers have investigated the possibility of a dose-response relationship between symptoms of depression and poorer self-care, favoring instead a conceptualization of depression as a discrete comorbid illness when examining its relationship to diabetes self-care behaviors.The aim of the current study was to extend previous research by examining the relationships between depression and the full range of diab...

OBJECTIVE -Diabetes eliminates the protective effect of female sex on the risk of coronary heart disease (CHD). We assessed sex differences in the treatment of CHD risk factors among patients with diabetes. CONCLUSIONS -Women with diabetes received less treatment for many modifiable CHD risk factors than diabetic men. More aggressive treatment of CHD risk factors in this population offers a specific target for improvement in diabetes care. RESEARCH DESIGN AND METHODS Diabetes Care 28:514 -520, 2005D iabetes confers a markedly increased risk of coronary heart disease (CHD) events in both women and men (1) and eliminates the protective effect of female sex on the risk of CHD. In women with and without diagnosed heart disease, diabetes raises the relative risk of heart disease mortality 3-to 10-fold relative to that of women without diabetes (2-6). Despite declining CHD mortality over the last 30 years in the U.S. population overall and in men with diabetes, women with diabetes appear to have experienced an increase in age-adjusted CHD mortality (7).Several pathophysiological mechanisms may contribute to the increased risk of CHD mortality in men and women with diabetes. Patients with type 2 diabetes have an increased incidence of conventional and unconventional CHD risk factors (8,9). Women with diabetes may be subject to even more adverse changes in coagulation, vascular function, and CHD risk factor levels than diabetic men (10 -13).In addition to sex-based physiologic differences, there may also be differences in treatment of CHD risk factors that contribute to increased risk in women with diabetes. Several studies of patients without diabetes have demonstrated disparities in treatment of heart disease and CHD risk factors among women and men in primary care (14,15) and hospital settings (16,17). Treatment disparities have been shown to be related to differences in patient risk factors (18) and physician behavior (19). These differences may persist even after a problem is identified: when women receive treatment, they are often treated less aggressively (20).Treating modifiable CHD risk factors (such as blood pressure and lipids) and using ACE inhibitors and aspirin reduce mortality in diabetes (21-25), which is now considered a CHD equivalent (26). The Heart Protection Study showed an ϳ25% reduction in vascular event rates in all subgroups treated with simvastatin, including patients with diabetes and women, regardless of initial levels of LDL and HDL cholesterol (27). In 2000, the American Diabetes Association (ADA) recommended statin therapy for patients with LDL cholesterol Ͼ100 mg/dl if CHD or multiple risk factors were present, as well as prophylactic use of aspirin and blood pressure control with an ACE inhibitor to delay progression to microalbuminuria (28). Subsequent recommendations are more stringent (29). The American Heart Association, concordant with the latest ADA guidelines, has endorsed an HDL target of Ͼ50 mg/dl and recommends that statins be initiated in women with diabetes, even if LDL is Ͻ...

Aims/hypothesis: We assessed the impact of medical comorbidities, depression, and treatment intensity on quality of life in a large primary care cohort of patients with type 2 diabetes. Methods: We used the Health Utilities Index-III, an instrument that measures healthrelated quality of life based on community preferences in units of health utility (scaled from 0=death to 1.0=perfect health), in 909 primary care patients with type 2 diabetes. Demographic and clinical correlates of health-related quality of life were assessed. Results: The median health utility score for this population was 0.70 (interquartile range 0.39-0.88). In univariate analyses, older age, female sex, low socioeconomic status, cardiovascular disease, microvascular complications, congestive heart failure, peripheral vascular disease, chronic lung disease, depression, insulin use and number of medications correlated with decreased quality of life, while obesity, hypertension and hypercholesterolaemia did not. In multiple regression analyses, microvascular complications, heart failure and depression were most strongly related to decreased healthrelated quality of life, independently of duration of diabetes; in these models, diabetes patients with depression had a utility of 0.59, while patients without symptomatic comorbidities did not have a significantly reduced quality of life. Treatment intensity remained a significant negative correlate of quality of life in multivariable models. Conclusions/interpretation: Patients with type 2 diabetes have a substantially decreased quality of life in association with symptomatic complications. The data suggest that treatment of depression and prevention of complications have the greatest potential to improve health-related quality of life in type 2 diabetes.

To identify events and mechanisms that might contribute to the poor reversibility of diabetic complications, we examined whether diabetes or high glucose induces changes in gene expression and whether such changes outlast the presence of the metabolic abnormalities. The study focused on fibronectin because the increased amounts of this glycoprotein found in diabetic tissues and thickened basement membranes are as yet unexplained. In streptozotocin-induced diabetic rats, fibronectin mRNA levels were increased to 304 ± 295% of control (mean ± SD) in the kidney cortex (P < 0.02), and to 271 ± 273% of control in the heart (P < 0.02), while actin mRNA levels remained unchanged. Elevation of fibronectin mRNA persisted for weeks after restoration of nearnormoglycemia. In cultured human endothelial cells, high glucose-induced overexpression of fibronectin and collagen IV remained detectable after replating and multiple cell divisions in the absence of high glucose. Cells shifted to normal-glucose medium after prolonged exposure to high glucose also exhibited a proliferative advantage over cells chronically maintained in normal glucose. Thus, diabetes increases fibronectin expression in tissues that are known targets of the complications, and the effect is not readily reversible. The in vitro studies suggest that hyperglycemia may be responsible for these events through induction of self-perpetuating changes in gene expression.As evidence is mounting that the metabolic abnormalities of diabetes are necessary, if not sufficient, to engender the lesions of diabetic microangiopathy (1-3), an issue with important therapeutic and prognostic implications is whether the progression of the vascular lesions can be halted or reversed by meticulous metabolic control. A definitive answer to this question must await completion of the Diabetes Control and Complications Trial (4), but data indicate that despite long-term near-normoglycemia achieved by intensive insulin treatment or pancreatic transplantation, characteristic features of microvascular disease such as background retinopathy and renal basement membrane thickening progress (5-7), persist (8-10), or show a remarkably inertial slowing of deterioration (6, 7).These observations suggest that events occurring during a finite period of metabolic derangement can leave long-lasting sequelae in the system. Such sequelae are not mediated solely by changes in tissue architecture since progression of retinopathy despite good metabolic control can occur from stages that are histologically normal (5). Processes that could conceivably propagate a "memory" of the diabetic state at these early stages are the hyperglycemia-induced irreversible modifications of long-lived extracellular matrix proteins (11) and/or self-perpetuating changes in cellular function. By using a combined in vivo/in vitro approach, we have sought to define whether there is a cellular component to the memory effect.To identify a discrete cellular event affected by diabetes and relevant to the known phenomenolog...

The results of the surveys, which were generally consistent, identified several remediable misconceptions regarding insulin therapy and suggest targets for educational interventions.

OBJECTIVETo test cognitive behavioral therapy for adherence and depression (CBT-AD) in type 2 diabetes. We hypothesized that CBT-AD would improve adherence; depression; and, secondarily, hemoglobin A1c (A1C).RESEARCH DESIGN AND METHODSEighty-seven adults with unipolar depression and uncontrolled type 2 diabetes received enhanced treatment as usual (ETAU), including medication adherence, self-monitoring of blood glucose (SMBG), and lifestyle counseling; a provider letter documented psychiatric diagnoses. Those randomized to the intervention arm also received 9–11 sessions of CBT-AD.RESULTSImmediately after acute treatment (4 months), adjusting for baseline, CBT-AD had 20.7 percentage points greater oral medication adherence on electronic pill cap (95% CI −31.14 to −10.22, P = 0.000); 30.2 percentage points greater SMBG adherence through glucometer downloads (95% CI −42.95 to −17.37, P = 0.000); 6.44 points lower depression scores on the Montgomery-Asberg Depression Rating Scale (95% CI 2.33–10.56, P = 0.002); 0.74 points lower on the Clinical Global Impression (95% CI 0.16–1.32, P = 0.01); and 0.72 units lower A1C (95% CI 0.29–1.15, P = 0.001) relative to ETAU. Analyses of 4-, 8-, and 12-month follow-up time points indicated that CBT-AD maintained 24.3 percentage points higher medication adherence (95% CI −38.2 to −10.3, P = 0.001); 16.9 percentage points greater SMBG adherence (95% CI −33.3 to −0.5, P = 0.043); and 0.63 units lower A1C (95% CI 0.06–1.2, P = 0.03) after acute treatment ended. For depression, there was some evidence of continued improvement posttreatment, but no between-group differences.CONCLUSIONSCBT-AD is an effective intervention for adherence, depression, and glycemic control, with enduring and clinically meaningful benefits for diabetes self-management and glycemic control in adults with type 2 diabetes and depression.