The role for gut permeability in the pathogenesis of type 1 diabetes – a solid or leaky concept?

Increasing evidence, both functional and morphological, supports the concept of increased intestinal permeability as an intrinsic characteristic of type 1 diabetes (T1D) in both humans and animal models of the disease. Often referred to as a ‘leaky gut’, its mechanistic impact on the pathogenesis of T1D remains unclear. Hypotheses that this defect influences immune responses against antigens (both self and non‐self) predominate, yet others argue hyperglycemia and insulitis may contribute to increased gut permeability in T1D. To address these complicated issues, we herein review the many conceptual role(s) for a leaky gut in the pathogenesis of T1D and suggest ways that if true, therapeutic interventions aimed at the gut–pancreas axis may prove promising for future therapeutic interventions.     

The Scylla and Charybdis of glucose control in childhood type 1 diabetes?

Glucose control in childhood type 1 diabetes is difficult and often characterized by significant glucose variability, including periods of prolonged hyperglycemia and intermittent episodes of hypoglycemia that can be severe. The brain of the developing child is thought to be more susceptible to metabolic insults because of its relatively high demand for glucose to fuel neuronal growth and differentiation. In this review we consider the impact of glucose variability, especially when associated with recurrent hypoglycemia, on long‐term cognitive function in childhood type 1 diabetes. At present, this indicates a subtle effect of type 1 diabetes per se on a number of cognitive modalities. Within the population of children with type 1 diabetes, a history of severe hypoglycemia also appears to have an additional negative effect on cognitive function. However, interpretation of the literature is difficult in that the human studies draw largely from cross‐sectional observational epidemiology while more basic work has used models that do not translate well into human disease. Moreover, it is likely to be many years before we will be able to clearly document the effects of recurrent hypoglycemia or chronic hyperglycemia on cognitive function. In the meantime, it seems appropriate to advocate that minimizing glucose variability when achieving glycemic targets should be the therapeutic goal of clinicians involved in the management of childhood type 1 diabetes.     

Sweet dreams? – nocturnal hypoglycemia in children with type 1 diabetes

Abstract: Hypoglycemia is an inevitable consequence of the treatment of type 1 diabetes in childhood. Nocturnal hypoglycemia is often considered as merely the submerged part of this serious complication yet there are reasons to believe that hypoglycemia occurring during sleep may be different in physiological terms. Glucose homeostasis during fasting, delayed effects of exercise and alterations in sleep physiology, itself, may not only affect the risk of nocturnal hypoglycemia but may influence the ability to correct glucose concentration as it falls, leading to episodes of hypoglycemia which are both profound and prolonged. The etiology and potential repercussions are incompletely understood and the most appropriate defense remains unclear. A greater understanding of this enigmatic phenomenon is essential before appropriate methods for hypoglycemia avoidance can be developed.     

Preservation of C‐peptide secretion in subjects at high risk of developing type 1 diabetes mellitus – a new surrogate measure of non‐progression?

Individuals at high risk of developing type 1 diabetes mellitus can be identified using immunologic, genetic, and metabolic parameters. In the Diabetes Prevention Trial-1 (DPT-1), annual intravenous infusions of low doses of regular insulin, together with daily subcutaneous injection of a single low dose of Ultralente insulin at nighttime, failed to prevent or delay the onset of type 1 diabetes in high-risk non-diabetic relatives. In our study, we attempted to achieve beta-cell rest by administering higher doses of neutral protamine Hagedorn (NPH) insulin twice daily to high-risk non-diabetic subjects in an effort to prevent or delay the onset of the disease. The maximum tolerable dose was given with the dose reduced for any hypoglycemia (mean dose 0.33 +/- 0.15; range 0.09-0.66 units/kg/d). We treated 26 subjects who were confirmed to have islet cell antibodies (ICAs) and a low first-phase insulin response (FPIR) to intravenous glucose. Fourteen had normal glucose tolerance and 12 impaired glucose tolerance (IGT). The median duration of follow-up was 5.5 yr. Diabetes occurred in 10 of 12 subjects with IGT and five of 14 subjects with normal glucose tolerance. The cumulative incidence of diabetes was the same as with that seen in a matched, observation group (subjects followed prospectively as part of the University of Florida natural history studies) (age, sex, ICA, insulin autoantibodies, duration of ICA prior to enrollment, FPIR, and glucose intolerance; p = 0.39), as was the rate of progression (p = 0.79). There was a higher rate of progression to diabetes in the group with abnormal glucose tolerance at baseline than in those with normal baseline glucose tolerance (p = 0.003). Interestingly, in non-progressors, as opposed to progressors, there was no fall in C-peptide (peak and area under the curve) production regardless of the type of tolerance testing (mixed meal, oral or intravenous) over time (p < 0.001). In this study, in the dose and regimen of NPH insulin used, insulin did not delay or prevent the development of type 1 diabetes. However, preservation of C-peptide production in the prediabetic period appears to indicate non-progression to clinical disease and may serve as a new surrogate for determining response to preventative efforts.     

Varying clinical presentations at onset of type 1 diabetes mellitus in children – epidemiological evidence for different subtypes of the disease?

Abstract: Objective: On the basis of 2121 case observations between 1987 and 1997, we describe the clinical and laboratory characteristics of diabetes mellitus type 1 at its onset. Our objective is to analyze whether clinical presentation follows a uniform pattern or whether there is evidence for different subtypes. Research design and methods: Thirty‐one pediatric hospitals and one diabetes center in Baden‐Wuerttemberg (BW), Germany, participated in this study. The hospital records of 2121 children below 15 yr of age were examined retrospectively. Statistical analysis was done after logarithmic transformation into a normal distribution. Results: The average duration of symptoms was found to be 15.2 d (95% CI (Confidence Intervals) = 14.3–16.1) ranging between 2.0 and 180 d (95% central range). The most frequent symptoms were polyuria and polydipsia; 7.2% presented with altered level of consciousness. The mean blood glucose value was 407.9 mg/dL (95% CI = 400.0–416.0), corresponding to 23.3 mmol/L (95% CI = 22.8–23.8). The median pH value was 7.35 (95% CI = 7.34–7.36), and the median base excess was ?5 mmol/L (95% CI =?5 to ?4). The younger patients had a shorter duration of symptoms and suffered most frequently from ketoacidosis. Conclusions: Although the symptoms of diabetes at its onset follow a uniform pattern, the clinical presentation and duration of symptoms indicate that there may be various forms of type 1 diabetes.     

Toll-like receptors, the NLRP3 inflammasome, and interleukin-1β in the development and progression of type 1 diabetes

Traditionally, type 1 diabetes (T1D) has been thought of as a disease of cellular immunity, but there is increasing evidence that components of the innate immune system, controlled largely by Toll-like receptors (TLRs), play a significant role in T1D development. TLRs are pattern-recognition molecules on immune cells that recognize pathogens, leading to the production of cytokines such as interleukin-1β (IL1β, encoded by the IL1B gene). IL1β is increased in patients with newly diagnosed T1D and likely acts as an early inflammatory signal in T1D development. Because hyperglycemia is a hallmark of T1D, the effects of hyperglycemia on IL1β expression in peripheral blood mononuclear cells (PBMCs) and islet cells have been examined, but with inconsistent results, and the mechanisms leading to this increase remain unknown. Fatty acids stimulate IL1β expression and may promote inflammation, causing hyperglycemia and insulin resistance. The mechanisms by which IL1β is involved in T1D pathogenesis are controversial. Overall, studies in pancreatic β-cells suggest that IL1β-mediated damage to islet cells involves multiple downstream targets. Potential therapies to decrease the progression of T1D based on IL1β biology include pioglitazone, glyburide, IL1 receptor antagonists, and agents that remove IL1β from the circulation.     

What is the frequency of symptomatic mild hypoglycemia in type 1 diabetes in the young?: assessment by novel mobile phone technology and computer‐based interviewing

BACKGROUND: The prevalence of mild hypoglycemia is difficult to document, particularly, in young people with diabetes. The usual method is to ask for subject recall using written 'diaries'. OBJECTIVE: In 2004, we investigated if new technology could be used to ascertain an accurate prevalence of mild hypoglycemia, particularly self-treated. We compared the use of 'text messaging' and computer-based interviewing with the standard diary method. PARTICIPANTS: Thirty-seven participants, aged 7-18 yr, with type 1 diabetes (T1D) for >1-yr duration. METHOD: Open comparison of three systems to collect the data on frequency of hypos (all severity): diary, mobile phone and computer-based interview (CBI), with qualitative analysis of patient feedback. RESULTS: One hundred thirty-two hypos were found over 705 recorded days. All were graded mild or moderate and none severe. Calculated frequency was 5.2 hypos per month: 13.6% subjects had no recorded episode, 36.4% had 1-4, 31.8% 5-9 and 18.2% >10. Mean blood glucose level at the onset of hypoglycemia was 3.0 mmol/L (1.0-5.2). Response rate of occurrence of hypoglycemic episode recorded by three systems is as follows - diary: 24 (65%) of the 37 subjects reported episodes, mobile: 18 (95%) of 19 subjects and CBI: 16 (89%) of 18 subjects. Sixty-five percent of subjects preferred the mobile and 54% of subjects preferred CBI compared with the diary. Fifty-five percent and 30.8% of subjects found the mobile and the CBI, respectively, easiest to fit into their everyday life. CONCLUSIONS: Mobile phone text messaging and CBI are alternatives to written diaries as methods of data collection. Each has its own strengths and weaknesses, but both have the advantage of daily reminders, rapid response and quick data analysis. Using this technology, it was found that the frequency of hypoglycemia was higher (>3 times) than that previously recognized.     

Exploring self‐management characteristics in youths with type 1 diabetes mellitus: does membership in a glycemic control category matter?†

Kichler JC, Kaugars AS, Ellis J, Alemzadeh R. Exploring self‐management characteristics in youths with type 1 diabetes mellitus: does membership in a glycemic control category matter? Background: Hemoglobin A1c (HbA1c) levels have been shown to worsen in adolescence and be related to long‐term diabetes complications. Although categories of diabetes control (e.g., ideal, satisfactory, and poor) are routinely used in clinical practice, research has not fully explored whether these categories meaningfully distinguish between different self‐management characteristics. Objectives: This study examines potential differences in self‐management characteristics for youths and their caregivers for three different categories of diabetes control (e.g., ideal, satisfactory, and poor control). Methods: A total of 69 adolescents (35 M/34 F) with type 1 diabetes mellitus (T1DM) (aged 12–17 yr) and their caregivers completed questionnaires of readiness to change the balance of responsibility for diabetes tasks, family responsibility in diabetes management, and self‐efficacy for diabetes. A medical record review yielded demographic information, most recent HbA1c level, and health care utilization over the past year. Results: Youths in the three different categories of diabetes control demonstrated no significant differences on measures of self‐management characteristics. Maternal caregivers from the satisfactory control category and youths in the poor control category demonstrated the most consistent responses across various self‐management characteristics. Conclusions: Youths classified in different categories of glycemic control may not be as different in their self‐management characteristics as was presumed. Moreover, associations among self‐management characteristics were not universal across responders. Therefore, individual assessments of youths' and caregivers' self‐management characteristics need to occur independent of the youths' membership in a certain category of diabetes control.     

End‐stage renal disease due to ARPKD in the first months of life: Transplantation or dialysis? – Two case reports

Beil S, Drube J, Gluer S, Lehner F, Ehrich JHH, Pape L. End‐stage renal disease due to ARPKD in the first months of life: Transplantation or dialysis? – Two case reports.
Pediatr Transplantation 2010: 14:E75–E78. © 2009 John Wiley & Sons A/S. Abstract: ARPKD with renal insufficiency during the first months of life is a clinical challenge. We report on two children with ARPKD with massively enlarged kidneys requiring renal replacement therapy in early infancy. Patient 1 developed pulmonary insufficiency due to massively enlarged kidneys. At the age of six months the girl was listed for KT as “high urgency” on the Eurotransplant waiting list. A kidney from a deceased donor was pre‐emptively transplanted and simultaneous nephrectomy performed. No postoperative complications were observed, and the patient was discharged from in‐patient care 42 days after transplantation. Unexpectedly, she died at the age of one yr due to cerebral vascular spasms of unknown origin. Patient 2 was transferred at the age of three months to our clinic with life‐threatening pulmonary insufficiency. Pre‐emptive KT was not possible; therefore, bilateral nephrectomy was performed and PD begun. The boy is still doing well on PD one yr later. Pre‐emptive KT and bilateral nephrectomy followed by PD are two options for infants with ARPKD and excessive kidney enlargement. PD could be complicated and in some cases become impossible by peritoneal damage during nephrectomy. On the other hand, KT covers a high risk of infections caused by immunosuppression. The decision, which method to choose, should be driven by the individual situation of the patient and the expertise of the center.     

Executive functioning – a key construct for understanding developmental psychopathology or a ‘catch‐all’ term in need of some rethinking?

For the past few decades, the role of executive functions in developmental psychopathology has been the focus of considerable research and a feature of conceptual models for a range of conditions including, but not limited to, ADHD, autism, schizophrenia, bipolar disorder, learning disorders, and aggression/conduct problems. Consistent with its prominence throughout the field, executive functioning plays a central role in approximately a third of the papers in this issue of JCPP, and notably, with foci largely on different conditions. These papers, all of which make valuable contributions to the field, propose or test the possibility of a causal role for executive functions in the emergence of psychopathology.     

Prevalence of thyroid antibodies (TPO and ATG) at the onset of type 1 diabetes mellitus in children treated in two diabetes centres in Łódź and Kielce

Patients with autoimmune type 1 diabetes mellitus have often, besides immune diabetes markers, also other organ-specific antibodies, particularly thyroid autoantibodies (antithyreoglobulin antibodies - ATG and/or thyroid peroxidase antibodies - TPO). In many of these patients autoimmune thyroid diseases, i.e. Hashimoto thyroiditis and Grave's disease, with silent clinical course can be diagnosed. The aim of this study was to evaluate the prevalence of TPO and ATG antibodies in children with newly diagnosed type 1 diabetes treated in two diabetes centres, in Lodz and in Kielce. Elevated ATG and/or TPO antibodies were found in 17,8% (15/84) of children: in 19,2% (11/57) in Lodz centre and in 14,8% (4/27) in Kielce centre. Children with elevated thyroid autoantibodies were significantly older than those without thyroid autoantibodies. Daily insulin requirement did not differ between both groups.     

Regional differences in outcome for very low‐birthweight infants: Do they persist at 7–8 years of age?

OBJECTIVE: To determine whether regional differences in early neonatal morbidity in a national cohort of very low-birthweight (VLBW) infants persisted at 7-8 years of age. METHODS: Perinatal data collected prospectively from birth on all VLBW infants born in New Zealand in 1986 and admitted to a neonatal unit included the hospital principally caring for the infant: hospitals A-D being level III hospitals and 'Other' including the smallest level III and all level II hospitals. At 7-8 years of age, 298 surviving children (96% survivors living in New Zealand) were assessed at a home visit. Parents were given a comprehensive questionnaire to complete, the children underwent a visual examination and were tested with the Revised Wechsler Intelligence Scale for Children and the child's teacher was sent a questionnaire to complete. RESULTS: Neonatal survival was significantly greater in the two largest hospitals (A and B) and this difference in survival remained at 7-8 years of age after adjustment for perinatal factors (P < 0.05). There were no differences between hospitals in risks of long-term sensorineural disability and behavioural or educational outcomes. There were interhospital differences in rates of visual problems and, after adjustment for confounding factors, there remained a marginally significant (P = 0.06) increased risk of myopia in hospital D. CONCLUSIONS: Despite differences in early morbidity favouring larger hospitals, there were no substantive differences in long-term (7-8 years) outcomes across a range of measures in this national cohort of VLBW infants.     

Absence of breast-feeding is associated with the risk of type 1 diabetes: a case–control study in a population with rapidly increasing incidence

There are indications that the effect of environmental factors on the risk of type 1 diabetes mellitus (T1DM) is increasing over time. This can be documented by the rapid increase of T1DM incidence in genetically stable populations. Our aim was to study an association of T1DM with the variable factors of the perinatal period and of early infancy, using data from children born over a period of changing exposure to some of the studied factors. A case–control dataset was analysed, consisting of 868 diabetic children and 1,466 anonymous controls, mostly schoolmates of the children with T1DM. The data were collected using structured questionnaires completed by parents. After performing univariate analyses, the associations were analysed using multiple logistic regression adjusted for potential confounders, including the year of birth. The risk of T1DM decreased with increasing duration of breast-feeding, while no breast-feeding was associated with an increased T1DM risk, OR=1.93 [95% CI: 1.33–2.80], breast-feeding for more than 12 months was protective, OR=0.42 [95% CI: 0.22–0.81], both being relative to the reference category of breast-feeding for 1–3 months. A short duration of day-care attendance (none or less than 1 year) was weakly associated with the risk of T1DM, OR=1.65 [95% CI: 1.05–2.62]. No association was detected between T1DM and signs of prenatal infections, perinatal stress factors, birth size and weight, indicators of crowding or the presence of a domestic pet in the household. Short breast-feeding period and short attendance to day care is associated with the risk of T1DM in Czech children.