Heterozygous coding mutations in the INS gene that encodes preproinsulin were recently shown to be an important cause of permanent neonatal diabetes. These dominantly acting mutations prevent normal folding of proinsulin, which leads to beta-cell death through endoplasmic reticulum stress and apoptosis. We now report 10 different recessive INS mutations in 15 probands with neonatal diabetes. Functional studies showed that recessive mutations resulted in diabetes because of decreased insulin biosynthesis through distinct mechanisms, including gene deletion, lack of the translation initiation signal, and altered mRNA stability because of the disruption of a polyadenylation signal. A subset of recessive mutations caused abnormal INS transcription, including the deletion of the C1 and E1 cis regulatory elements, or three different single base-pair substitutions in a CC dinucleotide sequence located between E1 and A1 elements. In keeping with an earlier and more severe beta-cell defect, patients with recessive INS mutations had a lower birth weight (−3.2 SD score vs. −2.0 SD score) and were diagnosed earlier (median 1 week vs. 10 weeks) compared to those with dominant INS mutations. Mutations in the insulin gene can therefore result in neonatal diabetes as a result of two contrasting pathogenic mechanisms. Moreover, the recessively inherited mutations provide a genetic demonstration of the essential role of multiple sequence elements that regulate the biosynthesis of insulin in man. (8-12). In contrast, abnormalities in chromosome 6q24 are the most common cause of TNDM (13), followed by mutations in the KCNJ11 and ABCC8 genes (14). Despite these advances, the etiology of neonatal diabetes is still not known in at least 30% of patients with PNDM, suggesting other genetic causes are still to be found (9).Insulin is secreted from islet beta cells of the pancreas. Insufficient secretion of insulin results in hyperglycemia and diabetes, whereas excessive secretion results in hypoglycemia. Insulin biosynthesis and secretion are therefore tightly regulated to maintain blood glucose levels within a narrow physiological range. Extensive studies have dissected an array of cis sequence elements in the INS promoter region and their cognate DNA binding factors, which together ensure the cellular specificity and rate of INS transcription (15)(16)(17)(18)(19)(20)(21)(22). In addition, insulin biosynthesis is strongly dependent on posttranscriptional regulatory mechanisms, including the modulation of translation and stability (23-25). The latter is largely mediated through sequences located in the untranslated regions of INS transcripts (26-28).

OBJECTIVE -Since the Diabetes Control and Complications Trial, diabetes management goals have changed. The aims of the present study were to assess complication rates, including nerve abnormalities, in adolescents from 1990 to 2002 and to investigate associated risk factors. RESEARCH DESIGN AND METHODS-Cross-sectional analysis of complications was assessed in three study periods (1990 -1994 [T1], 1995-1998 [T2], and 1999 -2002 [T3]) in adolescents matched for age and diabetes duration (n ϭ 878, median age 14.6 years, median duration 7.5 years). Retinopathy was assessed by seven-field stereoscopic fundal photography, albumin excretion rate (AER) from three consecutive timed overnight urine collections, peripheral nerve function by thermal and vibration thresholds, and autonomic nerve function by cardiovascular reflexes.RESULTS -Retinopathy declined significantly (T1, 49%; T2, 31%; and T3, 24%; P Ͻ 0.0001), early elevation of AER (Ն7.5 g/min) declined (38, 30, and 25%, respectively, P ϭ 0.022), and microalbuminuria (AER Ն20 g/min) declined (7, 3, and 3%, respectively; P ϭ 0.017, T1 vs. T2 and T3). Autonomic nerve abnormalities were unchanged (18, 21, and 18%, respectively; P ϭ 0.60), but peripheral nerve abnormalities increased (12, 19, and 24%, respectively; P ϭ 0.0017). More patients were treated with three or more injections per day (12, 46, and 67%, respectively; P Ͻ 0.0001) and insulin dose increased (1.08, 1.17, and 1.22 units ⅐ kg Ϫ1 ⅐ day Ϫ1 , respectively; P Ͻ 0.0001), but median HbA 1c (A1C) was unchanged (8.5, 8.5, and 8.4%, respectively). BMI and height SD score increased: BMI 0.46, 0.67, and 0.79, respectively (P Ͻ 0.0001), and height Ϫ0.09, 0.05, and 0.27, respectively (P Ͻ 0.0001).CONCLUSIONS -Retinopathy and microalbuminuria declined over time in this cohort, but the increased rate of peripheral nerve abnormalities is of concern. Despite intensified management (higher insulin dose and more injections), A1C has not changed and remains well above the recommended targets for adolescents. Recognition that screening is important to identify individuals who will benefit from interventions has led to screening programs for adolescents (2,3). Prevention of long-term chronic complications has now become one of the main goals of modern type 1 diabetes treatment in children and adolescents.In Australia, we initially reported a retinopathy rate of 42% in adolescents (4) and microalbuminuria has been found in 4 -20% of children, mostly after the age of 12-15 years (5-7). Although symptomatic neuropathy is uncommon in children with diabetes, previous studies have found a high prevalence of subclinical neurological abnormalities: nerve conduction abnormalities in 51% (8), cardiac autonomic abnormalities in 31% (9), and reduced sensory sensibility in 16% (10). A decline in the cumulative incidence of nephropathy was reported in Linkoping, Sweden, in 1994 in individuals diagnosed as children during 1961-1980 (11). This finding was considered by some to apply to only that geographical area because a similar study in...

Availability of good quality irrigation water is a big challenge in arid and semi arid regions of the world. Drought stress results in poor plant growth and low yield; however, the rhizobacteria, capable of producing 1-aminocyclopropane-1-carboxylate (ACC)-deaminase are likely to improve crop growth and productivity under drought stress. Similarly, biochar could also ameliorate the negative impacts of drought stress. Therefore, this pot experiment was conducted to evaluate the role of ACC-deaminase producing plant growth promoting rhizobacteria (PGPR) alone and in combinations with timber-waste biochar in improving maize growth under drought stress. The ACC-deaminase producing rhizobacteria, Pseudomonas aeruginosa, Enterobacter cloacae, Achromobacter xylosoxidans and Leclercia adecarboxylata were studied along with two rates (0.75 and 1.50% of the soil weight) of biochar under three moisture levels i.e., normal moisture, mild drought stress and severe drought stress. The E. cloacae in conjunction with higher rate of biochar produced a significant improvement i.e., up to 60, 73, 43, 69, 76 and 42% respectively, in grain yield plant -1 , photosynthetic rate, stomatal conductance, chlorophyll a, total chlorophyll and carotenoids contents of maize as compared to the control under mild drought stress. Similarly, A. xylosoxidans with higher rate of biochar also enhanced grain yield plant -1 , photosynthetic rate, stomatal conductance, chlorophyll a, total chlorophyll and carotenoids contents of maize up to 200, 213, 113, 152, 148 and 284%, respectively over control under severe drought stress. In conclusion, combination of ACC-deaminase containing PGPR, A. xylosoxidans and biochar (0.75%) proved an effective technique to improve maize growth and productivity under drought stress.

Introduction:Recent data show that the prevalence of diabetes among children and adolescents is increasing in some ethnic groups. The worldwide epidemic of childhood obesity has been accompanied by an increase in the incidence of type 2 diabetes (T2D) in youth.Methods:The aim of this study was to describe the baseline characteristics of children and adolescents diagnosed ≤18 years who had features of T2D and presented at Changing Diabetes in Children, Paediatric Diabetes Clinic at Bangladesh Institute of Research and Rehabilitation of Diabetes, Endocrine, and Metabolic Disorders. All patients who were newly diagnosed and came to the clinic from March 2011 to March 2015 were included.Results:Among 939 newly registered patients, 77 (8%) had a diagnosis of T2D. The age at diagnosis was 9–10 years in 11 patients (14%), 11–14 years in 46 (60%) and 15–17 years in other 20 patients (26%). Majority of the children had a positive family history of T2D (94%) and 58% were obese. Median fasting insulin (27.9 [17.3–99.3]) was high in 76% patients. Insulin was started initially along with metformin in 40 patients and could be stopped in six patients in 3 months.Conclusion:Our study reflects that T2D is emerging as a problem in children and adolescents in Bangladesh.

Background:Fasting (Sawm) during Ramadan, one of the five pillars of Islam is obligatory for all healthy adult and adolescent Muslims from the age of 12 years. Some children with diabetes, despite their exemption insist on fasting in Ramadan. We evaluated the safety of fasting among children with type 1 diabetes.Materials and Mathods:A prospective observational study was designed for diabetic children and adolescents who wish to fast during Ramadan 2012. Patients with their caregivers were given intensive education and instructions were provided by diabetic educators, dieticians and physicians on insulin adjustment, home blood glucose monitoring and dietary adjustments prior to Ramadan.Results:A total of 33 children and adolescents were included in this study. Of these, 16 were male and 17 were female. Majority (60.6%) of the patients could complete their fasting during the Ramadan. Patients were divided into two groups, those who completed fasting were considered as Group-I, whereas patients who broke the fast were in Group-ll. Blood glucose, hemoglobin A1c weight, and insulin dose before and after Ramadan in two groups showed no significant difference.Conclusion:Children older than 11 years of age with type 1 diabetes mellitus with conventional twice-a-day regimen can fast safely during Ramadan provided they have proper education and intensive follow-up during Ramadan.

Fasting during Ramadan, the holy month of Islam, is mandatory for all healthy adult Muslims. It is estimated that there are 1.1-1.5 billion Muslims worldwide, comprising 18-25% of the world population. About 62% of the world's Muslim population resides in Asia. Women comprise approximately 50% of this population. There is great religious fervor and enthusiasm in the majority of Muslims the world over for observing the religious fasting. Many of the Muslim women perhaps due to the family and societal pressures or lack of proper information hesitate and fail to avail themselves of the generous provisions of temporary or permanent exemptions from fasting available in Islam. It is therefore important that medical professionals as well as the general population be aware of potential risks that may be associated with fasting during Ramadan. This familiarity and knowledge is as important in South Asia and the Middle East as it is in Europe, North America, New Zealand, and Australia. There has not yet been any statement of consensus regarding women's health issues during Ramadan, namely menstruation, sexual obligations of married life, pregnancy, and lactation. This document aims to put forward some of the general guidelines for these issues especially for the South Asian Muslim women.

A retrospective study was done in the in-patient department of paediatrics, BIRDEM from January 2002 to November 2006 to determine the clinico-laboratory features, precipitating factors and outcome of diabetic ketoacidosis. Over the five year period, 344 diabetic patients were hospitalized. Among them, 54 (15.6%) had diabetic ketoacidosis (DKA). Among those, 50 were Type I, one was Fibrocalculous Pancreatic Diabetes (FCPD) and 3 were of other specific types. More than half (51.9%) of the patients were newly diagnosed. Amongst the precipitating factors, 28% had missed insulin and 48% had overt infection. Infections, particularly those of the respiratory tract, were the main precipitating cause for the DKA. There was h/o both infection and missed insulin injections in 11.5% patients. The mean age of patients with DKA was 11.2 ± 4.4 years. Those in the age range 10-14 yrs suffered most frequently (p<0.0001) from ketoacidosis (n= 38, 70.4%) compared with those aged 0-4 yrs (9%) and 5-9 yrs. (20%). There was a significant difference between those newly diagnosed (group I) and known diabetics (group II) (p<.029). The frequency of DKA was higher in girls than in boys (66.7% vs. 33.3%; p =.0001). The median duration of polyuria and/or polydipsia was variable between newly diagnosed and known diabetics (3.2 -25d) (p<.001). All patients presented with altered levels of consciousness and 35 (67.3%) were unconscious of different grades. Mean random blood glucose (RBG) and HbA1c were 27.6mmol/L and 13.4%. Complications noted were acute renal failure (n=2, 3.7%) and cerebral edema (n = 4, 7.5%). The outcome of treatment in the whole group was good, 46 (86.7%) patients recovered without complications, but 7 (13.4%) patients died.

Folate status has been associated with endothelial dysfunction in adolescents with type 1 diabetes, and elevated total plasma homoocyst(e)ine (tHcy) is a risk for vascular disease in the non-diabetic population. Polymorphisms in genes involved in folate and homocysteine metabolism are implicated in vascular disease. We aimed to determine whether polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genes are risk factors for early microvascular disease in a large group of adolescents with type 1 diabetes. Four hundred and eighty adolescents were screened annually for retinopathy and microalbuminuria for a median of 4 yr. Molecular analysis for the polymorphisms 677C-->T, 1298A-->C in MTHFR, and 66A-->G in MTRR was performed. The MTRR 66GG genotype reduced the risk for elevated albumin excretion rate (AER) (OR 0.47, CI 0.25, 0.88, p = 0.018) and showed a trend to reduced risk for microalbuminuria (OR 0.27, CI 0.06-1.21, p = 0.09). Survival without elevated AER was increased with the MTRR 66GG genotype (12.4 vs. 9.7 yr, p = 0.04) and with the MTHFR 1298CC genotype (15.2 vs. 10.2 yr, p = 0.007). Conversely, survival without retinopathy was reduced with the MTHFR 677TT and MTRR 66GG combined genotype (6.2 vs. 10.2 yr, p = 0.015). The MTRR 66GG and MTHFR 1298 CC genotypes may confer protection against early nephropathy, possibly because they are associated with lower tHcy. The MTHFR 677 TT was only related to earlier onset retinopathy in combination with MTRR 66GG.