Institute of Endocrinology and Diabetes

Petah Tikva, Israel

Institute of Endocrinology and Diabetes

Petah Tikva, Israel
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Zung A.,Hebrew University of Jerusalem | Blumenfeld O.,The Israel Center for Disease Control | Shehadeh N.,Meyer Childrens Hospital | Dally Gottfried O.,Rivka Ziv Hospital | And 40 more authors.
Pediatric Diabetes | Year: 2012

Background: Type 1 diabetes is an autoimmune disease occurring in genetically susceptible individuals. The precipitating cause is unclear. Recently, the Second Lebanon War exposed a large civilian population in northern Israel to significant psychological stress in the form of repeated barrages of missile attacks. Hypothesis: We hypothesized that trends in regional incidence of type 1 diabetes before and after the war would reflect an association with stress. Methods: All type 1 diabetes patients aged 0-17 yr who were reported to the Israel Juvenile Diabetes Register (n = 1822) in the four pre-war (2002-2005) and two post-war years (2006-2007) were included in the study. The patients were stratified by gender, age, ethnicity, family history of type 1 diabetes, season at diagnosis, and region of residency, namely, those who lived in the northern regions that were attacked and those in other regions. Results: The post-war incidence of type 1 diabetes was increased in the northern regions (rate ratio, RR = 1.27; p = 0.037), with no change in the other regions. This change was more prominent in males (RR = 1.55; p = 0.005) but similar in summer and winter, in different ages, and in different ethnic groups. There was no change in the proportion of new patients with a family history of the disease. Conclusions: For the first time in a large population, we found a positive association between the trauma of war and an increase in the incidence of type 1 diabetes in children and adolescents. The increase in incidence was not associated with genetic susceptibility to the disease. © 2011 John Wiley & Sons A/S.


Garnett S.P.,Institute of Endocrinology and Diabetes | Garnett S.P.,University of Sydney | Garnett S.P.,Childrens Hospital at Westmead | Gow M.,Institute of Endocrinology and Diabetes | And 16 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Prediabetes and clinical insulin resistance in adolescents are rapidly emerging clinical problems with serious health outcomes. Objective: The objective of this study was to determine the efficacy of 2 structured lifestyle interventions, both differing in diet macronutrient composition, on insulin sensitivity. Design: This study was a randomized controlled trial, known as Researching Effective Strategies to Improve Insulin Sensitivity in Children and Teenagers, in 2 hospitals in Sydney, Australia. Participants: Participants included overweight or obese 10- to 17-year-olds with either prediabetes and/or clinical features of insulin resistance. Intervention: At baseline adolescents were prescribed metformin and randomized to a structured diet, which was either high carbohydrate or moderate carbohydrate with increased protein. The program commenced with a 3-month dietary intervention, with the addition of an exercise intervention in the next 3 months. Outcomes: The outcomes included an insulin sensitivity, anthropometry, and cardiometabolic profile at 6 months. Results: One hundred eleven subjects (66 girls) were recruited and 98 subjects (58 girls) completed the 6-month intervention. After 3 months the mean insulin sensitivity index increased by 0.3 [95% confidence interval (CI) 0.2-0.4]. After 6 months the mean insulin (picomoles per liter) to glucose ratio (millimoles per liter) decreased by 7.2 [95% CI -12.0 to -2.3], body mass index, expressed as a percentage of the 95th centile, decreased by 9% (95% CI -3 to -15), but there was no significant change in the lipids. There were no significant differences in outcomes between the diet groups at any time point. Conclusions: These results are in contrast with our hypothesis that adolescents randomized to the increased protein diet would have better outcomes. Further strategies are required to better address prediabetes and clinical features of insulin resistance in adolescents. Copyright © 2013 by The Endocrine Society.


Abu-Saad K.,Gertner Institute for Epidemiology and Health Policy Research | Chetrit A.,Gertner Institute for Epidemiology and Health Policy Research | Eilat-Adar S.,Wingate Institute | Eilat-Adar S.,Tel Aviv University | And 8 more authors.
American Journal of Hypertension | Year: 2014

Background: Population-based studies about factors associated with blood pressure (BP) levels and hypertension awareness and control are lacking in Israel. We aimed to identify covariables of BP level (across the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) categories) and hypertension awareness and control. Methods: Participants (n = 763; aged 25-74 years) were randomly selected from the population registry and stratified by sex, age, and ethnicity (Arab or Jewish). Sociodemographic, lifestyle, chronic morbidity, drug therapy, and measured anthropometric and BP data were collected. Hypertension was defined as physician diagnosis, antihypertension drug therapy, or systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg. Results: Standardized hypertension prevalence was 32.5%. Age and body mass index were positively associated with being in a higher JNC-7 category. In multivariable analysis, the association between gender and JNC-7 category depended upon marital status. Of those with hypertension (n = 315), 66.0% were aware of their status, and 26.0% exhibited adequate BP control. Using "aware-and-controlled" as the outcome reference category, the odds ratio (OR) of being aware and uncontrolled was 1.9 (95% confidence interval (CI) = 1.3-2.9) for 10-year age increment. The OR of being unaware and uncontrolled was 5.6 (95% CI = 2.0-15.8) for Arabs vs. Jews, 5.6 (95% CI = 1.4-22.3) for single/divorced vs. married participants, 3.9 (95% CI = 1.7-9.2) for those with <3 visits to the family physician per year, and 0.1 (95% CI = 0.02-0.4) for those with self-reported cardiovascular disease. Conclusions: Sociodemographic factors and primary healthcare service utilization are associated with hypertension awareness and control. Specially focused outreach may be needed to improve hypertension awareness among Arabs, certain subgroups not traditionally considered to be at high risk, and those who have less contact with the healthcare system. © American Journal of Hypertension, Ltd 2014. All rights reserved.


Nair S.,Prince of Wales Hospital | Nair S.,University of New South Wales | Leung K.-C.,The Childrens Hospital at Westmead | Leung K.-C.,University of Sydney | And 7 more authors.
Journal of Medical Virology | Year: 2010

Despite evidence supporting an association between enterovirus (EV) infection and type 1 diabetes, the etiological mechanism(s) for EV-induced beta cell destruction is(are) not well understood. In this study, the effects of Coxsackievirus B (CVB) 1-6 on cell lysis and cytokine/chemokine expression in the insulinoma-1 (INS-1) beta cell line were investigated. Cytolysis was assessed using tissue culture infectious dose 50 (TCID50). Quantitative RT-PCR was used to measure viral RNA and mRNA of cytokines interferon (IFN)-α, IFN-β, IFN-γ, tumor necrosis factor (TNF)-α, and chemokine (C-X-C motif) ligand 10 (CXCL10), chemokine (C-C motif) ligand 2 (CCL2), and chemokine (C-C motif) ligand 5 (CCL5) in infected INS-1 cells. CVB2, 4, 5, and 6 lysed and replicated in INS-1 cells; TCID50 was lowest for CVB5 and highest for CVB6. IFN-γ, CXCL10, and CCL5 mRNA levels all increased significantly following infection with CVB2, 4, 5, and 6 (P<0.05). CCL2 mRNA increased with CVB2, 5, and 6 (P<0.05), IFN-α mRNA increased with CVB5 infection (P<0.05), while TNF-α mRNA and IFN-β mRNA (P<0.001) increased with CVB2 infection. Dose-dependent effects of infection on cytokine mRNA levels were observed for all (P<0.01) except IFN-γ. Following inoculation of INS-1 cells with CVB1 and 3, viral RNA was not detected and cytokine/chemokine mRNA levels were unchanged. In conclusion, CVB2, 4, 5, and 6 induce dose-dependent cytokine and chemokine mRNA production from INS-1 cells suggesting that pro-inflammatory cytokine and chemokine secretion by beta cells is a potential mechanism for EV-induced beta cell damage in type 1 diabetes. J. Med. Virol. 82:1950-1957, 2010. © 2010 Wiley-Liss, Inc.


Nimri R.,Institute of Endocrinology and Diabetes | Lebenthal Y.,Institute of Endocrinology and Diabetes | Lazar L.,Institute of Endocrinology and Diabetes | Lazar L.,Tel Aviv University | And 10 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: The G protein-coupled receptor 54 (GPR54), the kisspeptin receptor, is essential for stimulation of GnRH secretion and induction of puberty. Recently loss-of-function mutations of the GPR54 have been implicated as a cause of isolated idiopathic hypogonadotropic hypogonadism (IHH). Objective: The objective of the study was to identify the genetic cause of IHH in a consanguineous pedigree and to characterize the phenotypic features from infancy through early adulthood. Design: In six patients with normosmic IHH belonging to two families of Israeli Muslim-Arab origin highly related to one another, DNA was analyzed for mutations in the GnRHR and GPR54 genes, with functional analysis of the mutation found. The five males underwent comprehensive endocrine evaluation and were under longitudinal follow-up; the one female presented in early adulthood. Results: A new homozygous mutation (c.T815C) in GPR54 leading to a phenylalanine substitution by serine (p.F272S) was detected in all patients. Functional analysis showed an almost complete inhibition of kisspeptin-induced GPR54 signaling and a dramatic decrease of the mutated receptor expression at thecell surface. The males exhibited the same clinical features from infancy to adulthood, characterized by cryptorchidism, a relatively short penis, and no spontaneous pubertal development. The female patient presented at 18 yr with impuberism and primary amenorrhea. Repeated stimulation tests demonstrated complete gonadotropin deficiency throughout follow-up. Conclusion: A novel loss-of-function mutation (p.F272S) in the GPR54 gene is associated with familial normosmic IHH. Underdeveloped external genitalia and impuberism point to the major role of GPR54 in the activation of the gonadotropic axis from intrauterine life to adulthood. Copyright © 2011 by The Endocrine Society.


Shalitin S.,Institute of Endocrinology and Diabetes
International journal of clinical practice. Supplement | Year: 2011

Type 1 diabetes (T1D) is one of the most common chronic childhood diseases and its incidence has doubled during the last decade. The goals of intensive management of diabetes were established in 1993 by the Diabetes Control and Complications Trial (DCCT) (1). Children with T1D and their caregivers continue to face the challenge to maintain blood glucose levels in the near-normal range. It is important to prevent sustained hyperglycaemia which is associated with long-term microvascular and macrovascular complications and to avoid recurrent episodes of hypoglycaemia or hyperglycaemia, especially in young children, which may have adverse effects on cognitive function and impede efforts to achieve the recommended glycaemic targets. Advances in the use of technology that may help maintain the metabolic control goals for young people with T1D were centred on continuous subcutaneous insulin infusion (CSII) (2-4), continuous glucose monitoring (CGM) (5-7), and combining both technologies into a closed-loop system (8-10). The dilemma in paediatrics of patient selection for insulin pump therapy was found to be most successful in those with more frequent self-monitoring of blood glucose (SMBG) and younger age prior to pump initiation (2). Similarly, those who used a dual-wave bolus probably paid closer attention to their management and had lower HbA1c levels (3). The advantage of using a pre-meal bolus to improve postprandial glucose levels was shown to offer another potential method to improve glycaemic control (4). SMBG is an important component of therapy in patients with diabetes, especially in the paediatric age group. Standard use of glucose meters for SMBG provides only intermittent single blood glucose levels, without giving the 'whole picture' of glucose variability during the 24 h, and especially during the night, when blood glucose levels are seldom measured. Therefore, the use of a device such as real-time continuous glucose monitoring (RT-CGM) that provides continuous glucose measurements can help patients optimise glycaemic control. These devices may have the potential to increase the proportion of patients who are able to maintain target HbA1c values, to decrease glucose excursions and to decrease the risk of severe hypoglycaemia. Previous studies in paediatric T1D patients (11,12) have demonstrated that the frequency of CGM use was significantly associated with the effect of lowering HbA1c levels.


PubMed | Institute of Endocrinology and Diabetes
Type: | Journal: International journal of clinical practice. Supplement | Year: 2011

Type 1 diabetes (T1D) is one of the most common chronic childhood diseases and its incidence has doubled during the last decade. The goals of intensive management of diabetes were established in 1993 by the Diabetes Control and Complications Trial (DCCT) (1). Children with T1D and their caregivers continue to face the challenge to maintain blood glucose levels in the near-normal range. It is important to prevent sustained hyperglycaemia which is associated with long-term microvascular and macrovascular complications and to avoid recurrent episodes of hypoglycaemia or hyperglycaemia, especially in young children, which may have adverse effects on cognitive function and impede efforts to achieve the recommended glycaemic targets. Advances in the use of technology that may help maintain the metabolic control goals for young people with T1D were centred on continuous subcutaneous insulin infusion (CSII) (2-4), continuous glucose monitoring (CGM) (5-7), and combining both technologies into a closed-loop system (8-10). The dilemma in paediatrics of patient selection for insulin pump therapy was found to be most successful in those with more frequent self-monitoring of blood glucose (SMBG) and younger age prior to pump initiation (2). Similarly, those who used a dual-wave bolus probably paid closer attention to their management and had lower HbA1c levels (3). The advantage of using a pre-meal bolus to improve postprandial glucose levels was shown to offer another potential method to improve glycaemic control (4). SMBG is an important component of therapy in patients with diabetes, especially in the paediatric age group. Standard use of glucose meters for SMBG provides only intermittent single blood glucose levels, without giving the whole picture of glucose variability during the 24 h, and especially during the night, when blood glucose levels are seldom measured. Therefore, the use of a device such as real-time continuous glucose monitoring (RT-CGM) that provides continuous glucose measurements can help patients optimise glycaemic control. These devices may have the potential to increase the proportion of patients who are able to maintain target HbA1c values, to decrease glucose excursions and to decrease the risk of severe hypoglycaemia. Previous studies in paediatric T1D patients (11,12) have demonstrated that the frequency of CGM use was significantly associated with the effect of lowering HbA1c levels. The important STAR 3 study of 485 patients (156 children) with T1D showed the benefit of sensor-augmented pump therapy over remaining on multiple daily injections (MDI) (10). The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring (JDRF-CGM) studies were initially described in the 2009 Yearbook (13). Further reports of youths and adults in this study found that those with initial low HbA1c levels (< 7%) show a significant benefit from the use of CGM (5). Prolonged nocturnal hypoglycaemia was shown to continue to be a common occurrence in the entire cohort using CGM (7). Thus, there is an obvious need for closing the loop. Many patients with diabetes and especially parents of diabetic children dream about the invention of an artificial pancreas. CSII and RT-CGM can be combined to form closed-loop systems. Insulin is then delivered according to RT-CGM data, as directed by a control algorithm, rather than at pre-programmed rates. Few closed-loop prototypes have been developed with advanced control algorithms, such as those that are based on model predictive control (14). The group at Cambridge studied 19 young people in closed-loop systems and was able to demonstrate that exercise and diet variations could be aptly managed (9). It is expected that closed-loop studies in young people will continue to multiply in future years. T1D is characterised by immune-mediated pancreatic -cell destruction. Thus, a major goal in the treatment of T1D in youth will be in the area of prevention. The identification of increased levels of inflammatory markers in the SEARCH study of young people with T1D may provide an important clue (15). Most of the studies countered the diabetes process by immunomodulation and/or enhancement of -cell proliferation and regeneration (16). An initial pilot trial of a tumour necrosis factor (TNF-) binding agent, Entanercept, showed benefit in preserving C-peptide production in 18 young people with newly diagnosed T1D. HbA1c levels were also lower in the treatment group (5.9% 0.5% vs. 6.98% 1.2%; p < 0.05) (17). Similarly, -cell function was shown to be preserved in children receiving the lower of two doses of ingested human recombinant interferon- (hrINF-) in comparison with subjects who received placebo (18). A future larger trial of both of these agents will be of interest. In this review of the literature we have tried to select recent publications that offer some insight into these issues in paediatric patients with T1D.

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