Cytomegalovirus infection and new-onset post-transplant diabetes mellitus.

We analyzed data from all consecutive kidney transplant patients at our institution between April 2003 and October 2006. We found 15 cases of late-onset cytomegalovirus (CMV) infection, two of which developed concurrent post-transplant diabetes mellitus (PTDM). In these two cases, PTDM was transient and normal glucose tolerance was achieved after an eight-wk therapeutic course of oral valganciclovir. These findings suggest that CMV infection after organ transplantation may be associated with concurrent PTDM. The distinct causative relationship is yet to be determined.

Potassium channel alterations mediate peripheral nerve hyperexcitability in a mouse model of type 2 diabetes mellitus

Diabetes mellitus (DM) is a major cause of peripheral neuropathy. More than 220 million people worldwide suffer from type 2 DM, which will, in approximately half of them, lead to the development of diabetic peripheral neuropathy. While of significant medical importance, the pathophysiological changes present in DPN are still poorly understood. To get more insight into DPN associated with type 2 DM, we decided to use the rodent model of this form of diabetes, the db/db mice. During the in-vivo conduction velocity studies on these animals, we observed the presence of multiple spiking followed by a single stimulation. This prompted us to evaluate the excitability properties of db/db peripheral nerves. Ex-vivo electrophysiological evaluation revealed a significant increase in the excitability of db/db sciatic nerves. While the shape and kinetics of the compound action potential of db/db nerves were the same as for control nerves, we observed an increase in the after-hyperpolarization phase (AHP) under diabetic conditions. Using pharmacological inhibitors we demonstrated that both the peripheral nerve hyperexcitability (PNH) and the increased AHP were mostly mediated by the decreased activity of Kv1-channels. Importantly, we corroborated these data at the molecular level. We observed a strong reduction of Kv1.2 channel presence in the juxtaparanodal regions of teased fibers in db/db mice as compared to control mice. Quantification of the amount of both Kv1.2 isoforms in DRG neurons and in the endoneurial compartment of peripheral nerve by Western blotting revealed that less mature Kv1.2 was integrated into the axonal membranes at the juxtaparanodes. Our observation that peripheral nerve hyperexcitability present in db/db mice is at least in part a consequence of changes in potassium channel distribution suggests that the same mechanism also mediates PNH in diabetic patients. ∗Current address: Department of Physiology, UCSF, San Francisco, CA, USA.

Regulated expression of GLUT2 in diabetes studied in transplanted pancreatic beta cells.

GLUT2 disappearance is a marker of the beta cell glucose-unresponsiveness associated with diabetes. Understanding the factor(s) leading to this dysfunction may shed light on pathogenesis of diabetes. Since the regulation of GLUT2 expression in diabetes can so far only be studied in in vivo experiments, we developed a novel experimental approach to study the genetic regulation of GLUT2 in diabetes. By encapsulating islets or cell lines in semi-permeable membranes, these cells can be exposed to the diabetic environment of rats or mice and can be retrieved for analysis of GLUT2 expression and for the change in the secretory response to glucose. Immunocytochemical analysis of transporter expression reveals changes in protein expression while transcriptional analysis of GLUT2 gene expression could be performed in cells transfected with promoter-reporter gene constructs. Using this last approach we hope to be able to characterize the promoter regions involved in the beta cell- and diabetes-specific regulation of GLUT2 expression and possibly to determine which factors are responsible for this regulation.

Allogeneic beta-islet cells correct diabetes and resist immune rejection.

Allogeneic MHC-incompatible organ or cell grafts are usually promptly rejected by immunocompetent hosts. Here we tested allogeneic beta-islet cell graft acceptance by immune or naive C57BL/6 mice rendered diabetic with streptozotocin (STZ). Fully MHC-mismatched insulin-producing growth-regulated beta-islet cells were transplanted under the kidney capsule or s.c. Although previously or simultaneously primed mice rejected grafts, STZ-treated diabetic mice accepted islet cell grafts, and hyperglycemia was corrected within 2-4 weeks in absence of conventional immunosuppression. Allogeneic grafts that controlled hyperglycemia expressed MHC antigens, were not rejected for >100 days, and resisted a challenge by allogeneic skin grafts or multiple injections of allogeneic cells. Importantly, the skin grafts were rejected in a primary fashion by the grafted and corrected host, indicating neither tolerization nor priming. Such strictly extralymphatic cell grafts that are immunologically largely ignored should be applicable clinically.

Syndrome métabolique, diabète sucré et vulnérabilité: une approche "syndémique" de la maladie chronique [Metabolic syndrome, diabetes mellitus and vulnerability: a syndemic approach of chronic diseases].

The pandemic metabolic syndrome is generally attributed to our lifestyle. The current therapeutic strategies are centered on the behavioral changes and pharmacotherapy. A deeply analysis reveals the importance of the socio-cultural determinants with a "dose-responses effect according to the socio-economic level. The "syndemic" theory, which puts at the same level the socio-cultural environment, the behaviors and biomedecine, suggests a more holistic approach. This theory suggests introducing other partners of care, such cultural-mediators and welfare workers trained in the care, to have finally an approach centered on the roots of the causes. The healthcare networks centered on the management of the costs of health should not forget the socio-cultural dimension, unless wanting to select the good cases.

Renal responses to three types of renin-angiotensin system blockers in patients with diabetes mellitus on a high-salt diet: a need for higher doses in diabetic patients?

Objective Activation of the renal renin-angiotensin system in patients with diabetes mellitus appears to contribute to the risk of nephropathy. Recently, it has been recognized than an elevation of prorenin in plasma also provides a strong indication of risk of nephropathy. This study was designed to examine renin-angiotensin system control mechanisms in the patient with diabetes mellitus.Methods We enrolled 43 individuals with type 2 diabetes mellitus. All individuals were on a high-salt diet to minimize the contribution of the systemic renin-angiotensin system. After an acute exposure to captopril (25 mg), they were randomized to treatment with either irbesartan (300 mg) or aliskiren (300 mg) for 2 weeks.Results All agents acutely lowered blood pressure and plasma aldosterone, and increased renal plasma flow and glomerular filtration rate. Yet, only captopril and aliskiren acutely increased plasma renin and decreased plasma angiotensin II, whereas irbesartan acutely affected neither renin nor angiotensin II. Plasma renin and angiotensin II subsequently did increase upon chronic irbesartan treatment. When given on day 14, irbesartan and aliskiren again induced the above hemodynamic, renal and adrenal effects, yet without significantly changing plasma renin. Irbesartan at that time did not affect plasma angiotensin II, whereas aliskiren lowered it to almost zero.Conclusion The relative resistance of the renal renin response to acute (irbesartan) and chronic (irbesartan and aliskiren) renin-angiotensin system blockade supports the concept of an activated renal renin-angiotensin system in diabetes, particularly at the level of the juxtaglomerular cell, and implies that diabetic patients might require higher doses of renin-angiotensin system blockers to fully suppress the renal renin-angiotensin system. J Hypertens 29: 2454-2461 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Causas específicas de mortalidad en una cohorte de pacientes con diabetes mellitus tipo 2

La diabetis mellitus és un trastorn metabòlic a causa del dèficit de secreció d'insulina i a un augment de la seva resistència perifèrica. En el present estudi es van determinar les causes específiques de mortalitat en pacients amb diabetis mellitus. Es va observar que la mortalitat cardiovascular segueix sent la principal causa de mort en pacients amb diabetis metllitus tipus 2, seguida de la mortalitat per neoplàsies. La mortalitat total i específica per patologia cardiovascular o per neoplàsies va ser significativament superior en els pacients homes.

Control glucémico y prevalencia de complicaciones a los 20 años de evolución en pacientes con diabetes mellitus tipo 1 sometidos a terapia intensiva desde el debut

Dels pacients amb DM1 diagnosticats entre 1985-1994 en el nostre centre, vàrem seleccionar 147 amb seguiment ininterromput des del debut i durant més de 10 anys. Vàrem revisar les dades registrades anualment relacionades amb el tractament, control glicèmic i risc cardiovascular, amb els objectius d'avaluar el Grau de control, l'existència de factors predictors, la prevalença de complicacions tardanes i la seva relació amb el control glucèmic. Vàrem objectivar que la insulinoteràpia intensiva permetia mantenir un control glucèmic adequat, i que el grau de control a l'any del diagnòstic predeia el control posterior. La prevalença de complicacions va ser inferior a la descrita prèviament.

Could moderate alcohol consumption help prevent the metabolic syndrome and diabetes mellitus ?

Aim and purpose: Moderate alcohol consumption has been associated with lower risk of diabetes mellitus, but few data exist on the metabolic syndrome and on the metabolic impact of heavy drinking. The aim of our study was to investigate the complex relationship between alcohol and the metabolic syndrome and diabetes mellitus in a population-based study in Switzerland with high mean alcohol consumption. Design and methods: In 6188 adults aged 35 to 75, alcohol consumption was categorized as 0, 1-6, 7-13, 14-20, 21-27, 28-34 and >= 35 drinks/week or as nondrinkers, moderate (1-13 drinks), high (14-34 drinks) and very high (>= 35 drinks) alcohol consumption. The metabolic syndrome was defined according to the ATP-III criteria and diabetes mellitus as fasting glycemia >= 7 mmol/l or self-reported medication.We used multivariate analysis adjusted for age, gender, smoking status, physical activity and education level to determine the prevalence of the conditions according to drinking categories. Results: 73% (n = 4502) of the participants consumed alcohol, 16% (n = 993) were high drinkers and 2% (n = 126) very high drinkers. In multivariate analysis, alcohol consumption had a U-shaped relationship with the metabolic syndrome and diabetes mellitus. The prevalence of the metabolic syndrome significantly differed between nondrinkers (24%), moderate (19%), high (20%) and very high drinkers (29%) (P<= 0.005). The prevalence of diabetes mellitus also significantly differed between nondrinkers (6.0%), moderate (3.6%), high (3.8%) and very high drinkers (6.7%) (P<= 0.05). These relationships did not differ according to beverage types. Conclusions: The prevalence of the metabolic syndrome and diabetes mellitus decrease with moderate alcohol consumption and increase with heavy drinking, without differences according to beverage types. Recommending to limit alcohol consumption to 1-2 drinks/day might help prevent these conditions in primary care Metabolic Syndrome and Diabetes Mellitus.

Current genetic data do not improve the prediction of type 2 diabetes mellitus: the CoLaus study.

CONTEXT: Several genetic risk scores to identify asymptomatic subjects at high risk of developing type 2 diabetes mellitus (T2DM) have been proposed, but it is unclear whether they add extra information to risk scores based on clinical and biological data. OBJECTIVE: The objective of the study was to assess the extra clinical value of genetic risk scores in predicting the occurrence of T2DM. DESIGN: This was a prospective study, with a mean follow-up time of 5 yr. SETTING AND SUBJECTS: The study included 2824 nondiabetic participants (1548 women, 52 ± 10 yr). MAIN OUTCOME MEASURE: Six genetic risk scores for T2DM were tested. Four were derived from the literature and two were created combining all (n = 24) or shared (n = 9) single-nucleotide polymorphisms of the previous scores. A previously validated clinic + biological risk score for T2DM was used as reference. RESULTS: Two hundred seven participants (7.3%) developed T2DM during follow-up. On bivariate analysis, no differences were found for all but one genetic score between nondiabetic and diabetic participants. After adjusting for the validated clinic + biological risk score, none of the genetic scores improved discrimination, as assessed by changes in the area under the receiver-operating characteristic curve (range -0.4 to -0.1%), sensitivity (-2.9 to -1.0%), specificity (0.0-0.1%), and positive (-6.6 to +0.7%) and negative (-0.2 to 0.0%) predictive values. Similarly, no improvement in T2DM risk prediction was found: net reclassification index ranging from -5.3 to -1.6% and nonsignificant (P ≥ 0.49) integrated discrimination improvement. CONCLUSIONS: In this study, adding genetic information to a previously validated clinic + biological score does not seem to improve the prediction of T2DM.

Altered distribution of juxtaparanodal kv1.2 subunits mediates peripheral nerve hyperexcitability in type 2 diabetes mellitus.

Peripheral nerve hyperexcitability (PNH) is one of the distal peripheral neuropathy phenotypes often present in patients affected by type 2 diabetes mellitus (T2DM). Through in vivo and ex vivo electrophysiological recordings in db/db mice, a model of T2DM, we observed that, in addition to reduced nerve conduction velocity, db/db mice also develop PNH. By using pharmacological inhibitors, we demonstrated that the PNH is mediated by the decreased activity of K(v)1-channels. In agreement with these data, we observed that the diabetic condition led to a reduced presence of the K(v)1.2-subunits in juxtaparanodal regions of peripheral nerves in db/db mice and in nerve biopsies from T2DM patients. Together, these observations indicate that the T2DM condition leads to potassium channel-mediated PNH, thus identifying them as a potential drug target to treat some of the DPN related symptoms.

Evaluation of the natural killer cytotoxicity and the levels of cytokines in rats with type I diabetes mellitus

Type I diabetes mellitus (insulin-dependent DM = IDDM) is a chronic disease characterized by specific destruction of pancreatic beta cells, resulting in an absolute lack of insulin. Immune mechanisms, genetic susceptibility, and environmental factors are all implicated in the pathogenesis of Type 1 diabetes. This study was aimed at determining the efficiency of cytokines, natural killer (NK) cells in the pathophysiology of IDDM. Therefore, we evaluated the plasma levels of cytokines by specific enzyme-linked immunosorbent assay (ELISA) and the cytotoxicity activity of NK cells by anti-candididal index in rats with type I diabetes. We found that the cytotoxicity activity of NK cells in IDDM groups significantly decreased compared to the control groups. The levels of interferon-g (IFN-g) in IDDM groups were slightly higher than in healthy controls. These results indicate that the changes of T H1 type cytokines such as IFN-g and NK cell activity can play a role in the etiology of IDDM. The data may provide new strategies for the treatment of IDDM.