Enrico Cagliero

Improvement in Outcomes of Clinical Islet Transplantation: 1999–2010

OBJECTIVE To 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 METHODS A 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. RESULTS Insulin 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). CONCLUSIONS The 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.

Glucose Toxicity for Human Endothelial Cells in Culture: Delayed Replication, Disturbed Cell Cycle, and Accelerated Death

Functional and anatomical abnormalities of endothelium may represent a pathway to the increased vascular permeability and accelerated atherosclerosis characteristic of diabetes. To identify whether and how hyperglycemia may compromise the endothelial barrier, we have employed an in vitro system of human endothelial cells obtained from umbilical veins and cultured in elevated glucose concentrations (20 mM). Under these conditions, the achievement of saturation density was substantially delayed, with cell counts throughout most of the growth curve being 70–80% of control (P < 0.002). More profound suppression of cell number was present in cultures exposed to 40 mM glucose. Similar, albeit slightly lesser, effects were observed in cultures exposed to 20 mM mannitol, mimicking the hypertonicity of the high glucose media. The effect of elevated glucose and mannitol was primarily mediated by a decrease in overall rate of replication of the endothelium as documented by the lower mitotic index (P < 0.025). Analysis of the distribution of cells along phases of the cell cycle uncovered in the high glucose cultures a decreased proportion of cells in G0-G1 (70.5 ± 5% versus 73.2 ± 4% in controls, P < 0.05) and an increased proportion of cells in S phase (16.5 ± 2.7% versus 13.5 ± 2.2% in controls, P < 0.01), suggesting that the replicative delay is likely to occur between the phase of DNA synthesis and mitosis. Increased cellular death was specifically observed in the cultures exposed to elevated glucose concentrations (P < 0.05), but it could account for only a minor portion of the deficit in cell number. The mechanism(s) underlying the described ill effects of high glucose/hypertonicity on endothelium and the relevance of such abnormalities to diabetic angiopathy are currently under investigation.

Increased expression of basement membrane components in human endothelial cells cultured in high glucose.

Although the degree of hyperglycemia is a powerful and independent risk factor for diabetic microvascular disease, it has not been established if and how high glucose per se can induce the typical lesions of microangiopathy. We have investigated in human vascular endothelial cells the expression of messenger RNA (mRNA) for collagen type IV and fibronectin, the two glycoproteins characteristically increased in diabetic basement membranes. In 12 confluent primary cultures exposed for 11 +/- 1 d (mean +/- SD) to 30 mM glucose and exhibiting cell number and thymidine incorporation similar to control cultures, the levels of collagen IV and fibronectin mRNA were, respectively, 238 +/- 140 and 221 +/- 231 percent of control (P less than 0.01). The effects of high glucose were selective (the levels of collagen I and c-myc mRNA remained unchanged), independent of the proliferative activity of the cultures and of the plating substratum, and maintained throughout multiple passages. However, several days of exposure to high glucose were required before their appearance. These observations establish that high glucose is a perturbation sufficient to mimic the effects of diabetes on the regulation of basement membrane components and propose that modifications in gene expression may pertain to the chain of events leading to diabetic angiopathy.

Correlates of health-related quality of life in type 2 diabetes

Aims/hypothesisWe 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.MethodsWe used the Health Utilities Index-III, an instrument that measures health-related 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.ResultsThe 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 health-related 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/interpretationPatients 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.

Characteristics and Mechanisms of High-Glucose–Induced Overexpression of Basement Membrane Components in Cultured Human Endothelial Cells

Growing evidence that high glucose may be a causative agent of the thickened vascular basement membranes that characterize diabetic microangiopathy prompted this investigation of the underlying mechanisms. When exposed to 30 mM glucose, 70% of 52 primary cultures of human endothelial cells, each derived from a single umbilical vein, showed increased levels of fibronectin (median 181% of control, range 104–549%) and collagen IV mRNA (175% of control, range 101–807%). The response of the two transcripts to high glucose was concordant in 77% of the 52 cultures studied (P = 0.01), required 5 days of exposure, and was accompanied by proportionally increased synthesis of the respective protein. Laminin B1 expression was also upregulated by high glucose, concordantly with that of fibronectin and collagen IV. Increased fibronectin and collagen IV mRNA levels resulted from increased gene transcription (median 183 and 236% of control, respectively) without evidence of translational regulation, were not triggered by hypertonicity or signals originating from the matrix, and were also induced by hexoses with limited (D-galactose) or no (L-glucose) access to metabolic pathways but capable of inducing nonenzymatic glycosylation. There was no amplification of the overexpressed genes. Thus, high glucose upregulates in a coordinated fashion the transcription of genes coding for basement membrane components through effects exerted intracellularly or at the cell-matrix boundary and modulated by individual characteristics of the target cells.

Clinical inertia in the management of Type 2 diabetes metabolic risk factors.

Aims  Delays in the initiation and intensification of medical therapy may be one reason patients with diabetes do not reach evidence‐based goals for metabolic control. We assessed intensification of medical therapy over time, comparing the management of hyperglycaemia, hypertension, and hyperlipidaemia.

Association of diabetes‐related emotional distress with diabetes treatment in primary care patients with Type 2 diabetes

Aims  To characterize the determinants of diabetes‐related emotional distress by treatment modality (diet only, oral medication only, or insulin).

Symptoms of Depression Prospectively Predict Poorer Self-Care in Patients with Type 2 Diabetes

Aims  To examine prospectively the association of depression symptoms with subsequent self‐care and medication adherence in patients with Type 2 diabetes mellitus.

Pathobiology of Endothelial and Other Vascular Cells in Diabetes Mellitus: Call for Data

Because the pathogenetic understanding of diabetic vascular complications remains fragmentary, and even the best available interventions may prove insufficient to arrest the progression of certain lesions, new avenuses of investigation should be pursued. One of these should be the early in vivo investigation of the cells that endure the pathological process (pericytes and endothelial and mesangial cells), preferably in humans. The abnormal vascular architecture (i.e., capillary acellularity, microaneurysms, thickened basement membranes, and mesangial expansion) and the hemostatic and hemodynamic alterations observed in diabetes point to an adaptive/maladaptive replicative and biosynthetic program triggered by the metabolic perturbation, but positive documentation of cellular changes in vivo remains grossly insufficient. Critical review of current knowledge of microangiopathy permits elaboration of specific questions that, with the tools provided by the new molecular technology, may be posed about vascular cells in situ. Knowing whether and how the cell types involved in the vascular complications of diabetes modify their differentiated functions may offer novel targets for intervention and, most important, should provide a much needed “sounding board” against which to test the viability and refine the focus of pathogenetic hypotheses.

Measuring psychological insulin resistance: barriers to insulin use.

PURPOSE The purpose of this study is to explore the attitudes that contribute to psychological insulin resistance (PIR) in insulin-naive patients with type 2 diabetes and to identify predictors of PIR. METHODS A prospective study using 2 self-report surveys and incorporating demographic and health variables was conducted to determine the prevalence of PIR among a sample of 100 adult, insulin-naive patients with type 2 diabetes at an outpatient diabetes center in a university-affiliated teaching hospital. RESULTS Thirty-three percent of patients with type 2 diabetes were unwilling to take insulin. The most commonly expressed negative attitudes were concern regarding hypoglycemia, permanent need for insulin therapy, less flexibility, and feelings of failure. Less than 40% expressed fear of self-injection or thought that injections were painful. However, compared with willing subjects, unwilling subjects were more likely to fear injections and thought injections would be painful, life would be less flexible, and taking insulin meant health would deteriorate (P< .005 for all comparisons). Poorer general health and higher depression scores also correlated with PIR. CONCLUSIONS The results of the surveys, which were generally consistent, identified several remediable misconceptions regarding insulin therapy and suggest targets for educational interventions.