Yearbook of Pediatric Endocrinology 2013

K. Ong, Z. Hochberg

• Publisher: S. Karger
• Year: 2013
• ISBN:
  9783318025071
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

The body of knowledge in most medical specialties is rapidly expanding, making it virtually impossible to follow all advances in clinical and basic sciences that are relevant to a given field. This is particularly true in pediatric endocrinology, at the cross-road of pediatrics, endocrinology, development and genetics.

Type 1 Diabetes: Clinical and Experimental

M. Loredana Marcovecchio and Francesco Chiarelli

Department of Paediatrics, University of Chieti, Chieti, Italy

This 2013 chapter on type 1 diabetes (T1D) has the ambitious aim of summarizing the major breakthroughs in T1D basic and clinical research achieved during the last 12 months. Nineteen articles have been selected and commented on. As usual this selection has been difficult given the enormous amount of published papers, and the choice has been directed towards articles which in the authors’ opinion are of interest because they highlight new aspects or confirm/expand previous findings related to T1D pathogenesis, prevention, treatment and complications.

The chapter starts with experimental studies summarizing major progress made in the understanding of the pathogenesis of T1D and highlighting the role of the gut microbiome and its interplay with sex hormones, the role of the innate immune system with a complex interplay between neutrophils, B-1a cells and plasmacytoid dendritic cells. Experimental studies have also allowed a better understanding of mechanisms implicated in podocytopathy in the context of diabetes, and in particular the role of mTOR pathways in the pathogenesis of nephropathy.

Major discoveries in the genetics field are also highlighted in this chapter and these include a genetic defect in SIRT1 associated with a monogenic form of T1D and a recent meta-analysis of genome-wide association studies on diabetic nephropathy.

The chapter also includes studies assessing new genetic, immunological and metabolic markers of disease onset and progression, as well as new data on fertility in people with T1D and new findings on the physiology of hypoglycemia.

Several studies aiming at improving the field of islet transplantation have been published during the last year and for this chapter we have just picked one key article highlighting the role of α₁-antitrypsin in reducing inflammation and enhancing mouse pancreatic transplant survival. With regard to T1D prevention and treatment, important results on the artificial pancreas system are reported together with data on the potential key role of the combined insulin pump-continuous glucose monitoring system in managing patients with poor glycemic control. In addition, negative results from two immunotherapy trials are discussed.

The chapter ends with a systematic review on one of the most feared complications of diabetes, diabetic ketoacidosis, showing a large between-country variation in its frequency at first presentation of T1D.

We do hope you will enjoy reading this chapter and find some useful information for your clinical practice or new ideas for your research.

Mechanism of the year
Gut microbiome protects male mice from T1D

Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity

Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, von Bergen M, McCoy KD, Macpherson AJ, Danska JS

Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ont., Canada

[email protected]

Science 2013;339:1084-1088

Background: Microbial exposures and sex hormones exert strong effects on autoimmune diseases, which are often more prevalent in women.

Methods and Results: Early-life microbial exposures influenced sex hormone levels and modified progression to autoimmunity in the non-obese diabetic (NOD) mouse model of T1D. Colonization by commensal microbes increased serum testosterone and protected NOD males from developing T1D. Transfer of gut microbiota from adult males to immature females altered the recipient's microbiota and was associated with increased testosterone levels and metabolomic changes, decreased islet inflammation and autoantibody production, and protection from the development of T1D. These effects were strongly dependent on an intact androgen receptor activity.

Conclusions: Gut microbiome affects sex hormone levels and regulates T1D risk in mice with high genetic risk.

The gut microbiome is the central element assessed in the series of elegant and fascinating experiments performed by Markle and colleagues. Starting from the observation that autoimmunity presents a sex dimorphism with a higher incidence of some autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis, in females during the fertile age, the study proved that gut microbiome composition can explain gender differences in autoimmunity.

The experiments were performed in NOD mice which are genetically predisposed to develop T1D and in these mice there is a higher female frequency of diabetes. In the first part of the study it was shown that male NOD mice housed in specific pathogen-free (SPF) conditions were protected from T1D relative to females, whereas this was not the case in germ-free (GF) conditions, suggesting a role for the gut microbiome in the male protection from T1D.

Comparison of testosterone levels under SPF and GF conditions showed that levels in males were lower in GF than SPF conditions, whereas in females testosterone levels increased in GF conditions. These data suggested that commensal colonization regulates testosterone production and/or usage. Interestingly, the microbiome composition differences between sexes where evident only from the pubertal period onwards. Transfer of male microbiota, through gavage with cecal content, in female NOD weanlings altered gut microbiome and increased testosterone levels. These changes were prevented by treatment with flutamide, an androgen receptor antagonist. Further evidence for the role of the gut microbiome in modulating T1D risk emerged from the finding that the risk of developing T1D was significantly reduced in a cohort of female mice with modified microbiome followed longitudinally.

Overall, this study brilliantly shows that alterations in the gut microbiome composition in early life might suppress autoimmunity in animals at high risk for T1D, and highlights a strict bi-directionally interaction between the microbiome and sex hormones, in particular testosterone levels.

New mechanisms
The emerging role of innate immunity in T1D pathogenesis

Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes

Diana J, Simoni Y, Furio L, Beaudoin L, Agerberth B, Barrat F, Lehuen A

Institut National de Santé et de Recherche Médicale (INSERM), U986, Paris, France

[email protected]

Nat Med 2013;19:65-73

Background: Type 1 diabetes is characterized by the destruction of insulin-producing pancreatic β-cells by autoreactive T cells. Up to now, the role of innate cells in the initiation of this disease remains poorly understood.

Methods and Results: In young female non-obese diabetic mice, physiological β-cell death induced the recruitment and activation of B-1a cells, neutrophils and plasmacytoid dendritic cells (pDCs) to the pancreas. Activated B-1a cells secreted IgGs specific for double-stranded DNA. IgGs activated neutrophils to release DNA-binding cathelicidin-related antimicrobial peptide (CRAMP), which bound self DNA. Self DNA, DNA-specific IgG and CRAMP peptide in turn activated pDCs through the Toll-like receptor 9-myeloid differentiation factor 88 pathway, leading to interferon-α production in pancreatic islets. Depletion of pDCs, or blocking the Toll-like receptor pathways responsible for triggering IFN-α production by pDCs, confirmed that B-1a cells, neutrophils and IFN-α-producing pDCs are required for the initiation of the T-cell response and T1D onset.

Conclusions: These findings demonstrate that an innate immune cell crosstalk occurs in the pancreas of young NOD mice and leads to the initiation of T1D.

T1D is well known to be a T-cell-mediated autoimmune disease, where β-cell damage is associated with the appearance of specific autoantibodies. This recent study by Diana et al. sheds more light on the pathogenesis of the disease and introduces new players in its context, represented by neutrophils, pDC and innate-like B-1a cells. Results from experiments in the NOD mice suggest that an interplay between these cells is among the earliest events in the pathogenesis of T1D. These cells appear to cooperate to induce IFN-α and other pro-inflammatory cytokines and chemokines in the islets of T1D-susceptible mice. The physiological waves of β-cell apoptosis occurring during the first weeks of postnatal life, both in mice and humans, could be the starting point for the activation of the innate immunity through the release of self DNA. This DNA forms immune complexes with specific IgG secreted by B-1a cells. Neutrophils in turn produce DNA-binding peptides, which potentiate the immune complexes and lead to the production of IFN-α by pancreatic pDCs.

The importance of these new intriguing findings is related to their potential translation into preventive strategies targeting these new ‘actors’ of the early phase of T1D pathogenesis. In order to reach this aim, one key point, as the authors point out, is to develop new tools able to allow the detection of these early events. In addition, it is important to understand whether a similar crosstalk between the same cells is involved in the onset of T1D in humans.

New mechanisms
Understanding podocyte loss in diabetes

mTOR Regulates Nox4-Mediated Podocyte Depletion in Diabetic Renal Injury

Eid AA, Ford BM, Bhandary B, Cavagliery R, Block K, Barnes JL, Gorin Y, Choudhury GG, Abboud HE

Department of Medicine, South Texas Veterans Healthcare System and the University of Texas Health Science Center, San Antonio, TX, USA

[email protected]

Diabetes 2013 (E-pub ahead of print)

Background: Podocyte apoptosis is a key mechanism implicated in excessive loss of urinary albumin. Pharmacological doses of the mTOR inhibitor rapamycin reduce albuminuria in diabetes. The aim of this study was to test the hypothesis as to whether mTOR mediates podocyte damage in diabetes.

Methods and Results: High glucose (HG) induced apoptosis of podocytes, inhibited AMPK activation, inactivated tuberin and activated mTOR. HG also increased the levels of Nox4 and Nox1 and NADPH oxidase activity. Inhibition of mTOR by low-dose rapamycin decreases HG-induced Nox4 and Nox1, NADPH oxidase activity and podocyte apoptosis. Inhibition of mTOR had no effect on AMPK or tuberin phosphorylation indicating that mTOR is downstream of these signaling molecules. A similar decrease in the activation of AMPK and tuberin and activation of mTOR with increase in Nox4 and NADPH oxidase activity was detected in isolated glomeruli of OVE26 mice. mTOR inhibition by small dose of rapamycin reduced podocyte apoptosis, attenuated glomerular injury and albuminuria.

Conclusions: These results support a novel function of mTOR in Nox4-derived ROS generation and podocyte apoptosis that contributes to urinary albumin excretion in T1D. This suggests that mTOR and or NADPH oxidase inhibition may represent new treatment strategies for diabetic kidney disease.

The pathogenesis of albuminuria in people with T1D is complex and derives from the interplay of several metabolic and hemodynamic factors acting on glomerular components. Podocytes are key elements of the glomerular barrier and their apoptosis seems to be one of the key events leading to glomerular injury...