Diabetes Associated with Single Gene Defects and Chromosomal Abnormalities

F. Barbetti, L. Ghizzoni, F. Guaraldi, F., Barbetti, L., Ghizzoni, F., Guaraldi, Massimo Porta, Massimo, Porta

• Publisher: S. Karger
• Year: 2017
• Print ISBN: 9783318060249
• eBook ISBN: 9783318060256
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

This volume, written by renowned experts, provides complete coverage of the main genetic conditions associated with diabetes. Divided into five sections, it offers insights into genetic defects involving the pancreatic beta cell, extreme insulin resistance, ciliopathies, obesity and glucose metabolism, chromosomal defects, and other genetic conditions associated with increased susceptibility to diabetes. Other topics include the various subtypes of monogenic diabetes, such as the neonatal form and the Wolfram syndrome, as well as chromosomal defects leading to complex conditions affiliated with diabetes, like Trisomy 21 or Prader-Willi syndrome. There are also chapters dedicated to the poorly explored relationships between metabolism and neurodegenerative disorders like Friedreich's ataxia and muscular dystrophy. This book is a reference for every pediatric and adult endocrinologist and diabetologist, even experienced ones, with an interest in the intricacies and protean aspects of disorders of glucose metabolism secondary to genetic diseases.

Diabetes and Genetic Defects Prevalently Involving the Pancreatic Beta Cells

Barbetti F, Ghizzoni L, Guaraldi F (eds): Diabetes Associated with Single Gene Defects and Chromosomal Abnormalities. Front Diabetes. Basel, Karger, 2017, vol 25, pp 1-25 (DOI: 10.1159/000454748)

______________________

Neonatal Diabetes: Permanent Neonatal Diabetes and Transient Neonatal Diabetes

Fabrizio Barbetti^a-c · Corrado Mammì^d · Ming Liu^e · Valeria Grasso^b · Peter Arvan^f · Maria Remedi^g · Colin G. Nichols^h

^aDepartment of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, ^bBambino Gesù Children’s Hospital, Rome, ^cS. Pietro Hospital - Fatebenefratelli, Rome, and ^dMedical Genetics Unit, BMM Great Metropolitan Hospital, Reggio Calabria, Italy; ^eDivision of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China; ^fDivision of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, and Departments of ^gMedicine and ^hCell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA

______________________

Abstract

The concept of monogenic diabetes emerged 25 years ago with a paper reporting the glucokinase locus linkage to maturity-onset diabetes of the young, an autosomal dominant disorder of glucose metabolism. Since then a huge leap forward has been made with the discovery of other clinical forms of monogenic diabetes, such as neonatal diabetes mellitus (NDM), and the identification of literally tens of genes that cause diabetes, either in isolation or syndromic. Of note, NDM genetics not only shed light on several aspects of pancreatic β-cell biology, but revealed new and unexpected therapeutic options for patients carrying mutations in specific genes, such as oral hypoglycemic agents (mutations of KATP genes) or stem cell transplantation (IPEX). In this chapter, we describe the genetic defects leading to neonatal diabetes that recognize dominant, recessive, and X-linked modes of inheritance or the association with incorrect parental origins of chromosomes and disturbances of imprinting.

© 2017 S. Karger AG, Basel

Neonatal Diabetes Mellitus: An Introduction

Early reports of single patients with “congenital diabetes” or neonatal diabetes mellitus (NDM) can be found as far back as the mid-19th century, but the first thoroughly described, well-proven, cases of neonates with diabetes were published in the 1950s [1]. Interestingly, the notion that two clinical forms of NDM - permanent and transient - can be distinguished was already established at that time [1], along with the fact that most cases were sporadic. In addition, temporary subcutaneous insulin treatment with long-acting neutral protamine Hagedorn insulin had also been successfully used in patients with transient neonatal diabetes mellitus (TNDM) [1]. Nevertheless, further progress in understanding NDM had to wait another 40 years until the genetic discoveries that paternal uniparental isodisomy (UDP) of chromosome 6 (UDP6) is linked to TNDM [2], whilst homozygous, loss-of-function mutation of insulin promoter factor 1 (IPF1, now known as PDX1) causes pancreatic agenesis leading to permanent neonatal diabetes mellitus (PNDM) and exocrine pancreas deficiency [3].

Around the same time, the main clinical features of both recognized forms of NDM were (temporarily) established through an extensive review of the literature [4], in which Von Muhlendahl and Herkenhoff proposed the first comprehensive definition of NDM as: “hyperglycemia occurring within the first month of life that lasts for at least two weeks and requires insulin therapy.” These authors reported the variability of time between onset and remission of diabetes for patients with the transient form (17-1,914 days), together with the fact that in some TNDM cases, relapse subsequently occurs at a later age (range: 7-20 years) [4]. They also provided a crude estimate of the incidence of NDM in Germany (based on survey of cases with neonatal diabetes between 1977 and 1991) as 1 in 500,000 live births, and in conclusion, put forward the idea that NDM may generally have a genetic origin [4].

In 2000, the gene responsible for Wolcott-Rallison syndrome, a recessive condition that encompasses neonatal (or infancy-onset) diabetes, osteopenia, and liver dysfunction was identified [5], and 1 year later the first 2 cases of PNDM due to homozygous loss-of-function mutations of the glucokinase (GCK) gene were reported [6]. Of note, one of the patients described in that paper presented with isolated (i.e., nonsyndromic) diabetes (like all cases with biallelic, inactivating, GCK mutations subsequently reported in the literature), highlighting the key role of glucokinase in coupling glucose to insulin secretion from the pancreatic β-cell [6]. In the same year, the cause of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), presenting with X-linked neonatal autoimmune diabetes mellitus, autoimmune endocrinopathy and enthropathy was linked to mutations of the FOXP3 gene [7, 8]. Around the same time, Koster et al. [9] reported NDM in mice as a result of ATP-sensitive K⁺ (K_ATP) channel gain of function (GOF), although it would take another 4 years for the first reports that the same mechanism is the most prominent cause of human NDM (see below).

In 2002, Iafusco et al. [10] showed that patients with permanent diabetes with onset in the first 6 months have different clinical and laboratory features compared with patients with diabetes onset between 6 months and 1 year of life. While individuals belonging to the second group were often positive for type 1a diabetes (T1Da)-associated autoantibodies, and had normal birth weight, those in the first group had low birth weight, rarely carried HLA alleles predisposing to T1Da diabetes, and were almost invariably negative for T1Da autoantibodies. On the basis of these results, Iafusco et al. suggested that the cause of hyperglycemia in patients with diabetes onset in the first 6 months of birth was probably genetic, thus extending Von Muhlendahl’s pathophysiologic hypothesis of NDM well beyond the standard neonatal period of 1 month. This work established the value of systematic assessment of T1D autoantibodies in diabetes of very early onset, and paved the way for a new clinical definition of NDM [10].

In the following 5 years, three genes (KCNJ11, ABCC8, and INS; 2004, 2006, and 2007) were identified as causing most cases of PNDM in developed countries [11-14]. Of note, clinical records showed that patients carrying mutations in these three genes [11-14] typically present with diabetes within 6 months of birth, matching Iafusco’s prediction of a genetic origin of hyperglycemia in patients with diabetes onset within 6 months of birth and negative to T1D autoantibodies [10]. Perhaps not surprisingly, retrospective genetic analysis revealed that 19 out of 25 Italian patients with diabetes onset within 6 months of birth included in the original report of Iafusco et al., carry a mutation in either the KCNJ11, INS, ABCC8, or GCK gene [6, 14-16]. That patients with diabetes onset within 6 months of age do not carry HLA alleles associated with polygenic autoimmune diabetes (i.e., T1Da) was confirmed in 2006 [17]. Further analyses have led to the current diagnostic guidelines for and definition of NDM (i.e., diabetes with onset within 6 months of age instead of 1 month) such that molecular genetic screening is recommended for this condition, with an estimated incidence that is currently calculated at around 1:200,000 live births for the permanent form only [18, 19] and at 1:90,000 for both PNDM and TNDM [19]. This incidence is twice that estimated in previous investigations for Western countries [4, 20], but is lower than the incidence estimate for the Middle East, which is set between 1:48,000 and 1:21,000 [21, 22], due to the high recurrence of recessive forms of NDM.

In the last 10 years, many other genes responsible for very rare, usually syndromic, conditions that include permanent neonatal diabetes have been discovered. Most encode transcription factors important for embryonic development of endocrine pancreas and other organs [23, 24]. The clinical features of each syndromic subtype may be helpful in directing molecular genetic screening, even though with the advent of next-generation sequencing of genomic DNA, a selection based on clinical characteristics need not be an absolute requirement [25].

In this chapter we will place emphasis on the major genetic determinants of PNDM and TNDM (KCNJ11, ABCC8, INS, and defects of chromosome 6), while coverage of the less frequent causes will be left to a minimum.

Permanent Neonatal Diabetes Mellitus

K_ATP Channel Mutations as Cause of Human PNDM

The identification of K_ATP channels as key players in pancreatic β-cell physiology was a breakthrough in the understanding of the mechanism of glucose-stimulated insulin secretion. K_ATP channels, through regulated changes in their activity, couple membrane excitability to glucose-stimulated insulin secretion, and thereby maintain blood glucose within a narrow physiologic range [26]. After a meal, glucose metabolism leads to an increase in the intracellular [ATP]:[ADP] ratio, which closes β-cell K_ATP channels, inducing membrane depolarization and opening voltage-dependent Ca²⁺ channels (Fig. 1a). Ca²⁺ influx increases intracellular [Ca²⁺], which triggers insulin vesicle fusion to the membrane and insulin secretion [26]. Conversely, a decrease in the metabolic signal keeps K_ATP channels open, suppressing the electrical trigger of insulin secretion. This electrical pathway is also modulated by K_ATP-independent mechanisms, e.g. nutrient metabolites and incretins, which affect secretion at various stages downstream of K_ATP channels [26, 27]. However, the ability of selective K_ATP channel inhibitors, sulfonylureas (SUs), to directly trigger insulin secretion underscores the critical role of K_ATP-dependent regulation [28-30].

Any mechanism that results in ‘overactive’ K_ATP channels should decrease membrane excitability, thereby impairing glucose sensing by the β-cell and reducing insulin secretion. Activating mutations in both the Kir6.2 (KCNJ11) [11] and the SUR1 (ABCC8) [12] genes that encode the pancreatic K_ATP channel subunits have now been identified as the commonest cause of human NDM [31, 32], both TNDM (see below) and PNDM. In approximately one-third of PNDM cases, K_ATP mutations are also associated with developmental de...

Table of contents

• Cover Page
• Front Matter
• Diabetes and Genetic Defects Prevalently Involving the Pancreatic Beta Cells
• Extreme Insulin Resistance with Diabetes
• Ciliopathies, Obesity, and Glucose Metabolism
• Chromosomal Defects and Diabetes
• Other Genetic Conditions with Increased Susceptibility to Diabetes
• Author Index
• Subject Index
• Back Cover Page