Neonatal diabetes mellitus - PubMed (original) (raw)
Review
Neonatal diabetes mellitus
Lydia Aguilar-Bryan et al. Endocr Rev. 2008 May.
Abstract
An explosion of work over the last decade has produced insight into the multiple hereditary causes of a nonimmunological form of diabetes diagnosed most frequently within the first 6 months of life. These studies are providing increased understanding of genes involved in the entire chain of steps that control glucose homeostasis. Neonatal diabetes is now understood to arise from mutations in genes that play critical roles in the development of the pancreas, of beta-cell apoptosis and insulin processing, as well as the regulation of insulin release. For the basic researcher, this work is providing novel tools to explore fundamental molecular and cellular processes. For the clinician, these studies underscore the need to identify the genetic cause underlying each case. It is increasingly clear that the prognosis, therapeutic approach, and genetic counseling a physician provides must be tailored to a specific gene in order to provide the best medical care.
Figures
Figure 1
Birth weights of 45 patients with NDM. The percentiles are those for normal girls from the study by Weller and Jorch (275). The third percentile for boys is higher by 20 g at 24 wk gestation, 125 g at 34 wk, and 150 g at term. Closed symbols denote girls; open symbols, boys; circles, infants with TNDM; triangles, infants with TNDM with later recurrence; and squares, infants with PNDM. [Reproduced with permission from K. E. von Muhlendahl and H. Herkenhoff: N Engl J Med 333:704–708, 1995 (9). © Massachusetts Medical Society.]
Figure 2
Breakdown of the genetic causes of TNDM derived from studies on French, English, and Japanese cohorts. The data are from Metz et al. (20), Babenko et al. (21), Flanagan et al. (12), and Suzuki et al. (23).
Figure 3
Potential roles of ZAC in chromosome 6q24 anomalies. A, The state of ZAC expression in control and TNDM cases due to paternal UPD or loss of imprinting (LOI) at the maternal locus. B, Four potential mechanisms by which overexpression of ZAC could reduce cell proliferation or increase apoptosis.
Figure 4
Schematic representation of the central role of PDX1/IPF-1 within the network of transcription factors critical for pancreas differentiation and development. The accompanying table relates MODY classification with the affected protein. Glut2, Glucose transporter 2; L-PK, L-pyruvate kinase.
Figure 5
Schematic representation of a pancreatic β-cell illustrating the roles of GCK and KATP channels. The entry of glucose (G) is facilitated by a transporter (Glut) and converted to glucose-6-phosphate (G-6-P) by GCK. Glycolysis converts G-6-P to pyruvate, which enters mitochondria. Subsequent metabolism to CO2 and H2O generates the mitochondrial membrane potential used by ATP synthase to convert ADP to ATP. Mitochondrial creatine kinase at the inner mitochondrial membrane transfers the γ-phosphate of ATP to creatine and, with the adenine nucleotide translocase, recycles ADP back into the mitochondrial matrix. Cytosolic creatine kinase and adenylate kinase serve as a phosphotransferase shuttle to link ATP-producing with ATP-consuming sites, including KATP channels in the plasma membrane (see for example Refs. and 277). Increases in the ATP/ADP ratio close KATP channels producing membrane depolarization and activation of ‘L-type’ voltage-gated Ca2+ channels. The resulting influx of Ca2+ is required for insulin secretion.
Figure 6
Effect of the A378V GCK mutation on the β-cell glucose phosphorylation rate. The threshold for insulin release with wild-type GCK is approximately 5 m
m
glucose. The loss of GCK activity due to the A378V mutation in the heterozygous condition (dashed line) increases the threshold to approximately 8.5 m
m
producing MODY. In the homozygous condition (dotted line), there is a complete loss of GCK activity, and the threshold for insulin release is never achieved. The relative BGPR was simulated as described in Ref. .
Figure 7
MgATP Stimulation of WT and H1023Y KATP channels. A, Inhibition of KATP channels by ATP in the presence and absence of Mg2+. The lines are fits of the relative activity (channel activity with ATP/activity without ATP) to a modified Hill equation (as shown). B, The H1023Y mutant shows increased Mg2+-dependent stimulatory activity plotted here as (relative activity of H1023Y/relative activity of WT − 1). The line is a fit to a modified Hill equation (as shown), (S0.5 ∼230 μ
m
, MaxS ∼5.6-fold, h ∼1.07); the curve in the inset is the fit of a single site binding isotherm to the data (S0.5 ∼270 μ
m
, MaxS ∼5.7-fold). The data are taken from Babenko et al. (21).
Figure 8
Comparison of net Mg-dependent stimulation for three KATP channel mutants. A, An illustration of the inhibition of homozygous WT and mutant KATP channels by ATP with and without Mg2+ present. Both mutations have a reduced apparent affinity for inhibitory ATP and are stimulated by MgATP. B, Comparison of the net Mg-dependent stimulation for the H1023Y, R201H and Q52R NDM mutations. The data are for heterozygous channels; the net Mg-dependent stimulations (relative activity of mutant/relative activity of WT) in 1 m
m
MgATP are ∼2.5-, 14-, and 36-fold for the H1023Y, R201H, and Q52R mutations, respectively.
Figure 9
Summary of mutation-dependent stimulation for KCNJ11 and ABCC8 NDM mutations. The net stimulation values for control and mutant channels were estimated as outlined in Fig. 7 using published data (21,194,197,236,266,268,278,279,280,281,282,284,285,286). To approximate physiological conditions, the mutation-dependent net stimulation values for heterozygous channels in 1 m
m
MgATP are plotted vs. the clinical diagnosis (colored circles). The means ±
sd
(in black) are 5.6 ± 3.7, 7.3 ± 3.7, and 28.0 ± 8.7, respectively.
Figure 10
Approximate location of NDM mutations in KIR6.2 and SUR1. The KIR6.2 backbone is a homology model based on the structure of a chimeric protein (287). Two of the four subunits are shown with the locations of the mutations shown on both chains. The green residues are associated with TNDM, the blue with PNDM, and the red with the iDEND/DEND syndrome. The three light green spheres symbolize K+ ions in the pore. The ABC core was modeled using SAV1866 (PDB 2ONJ; Ref. 288) and MsbA (PDB 3B60; Ref. 289) as templates. The nucleotides in the ABC domain of SUR1 are AMPPNP. In all cases the wild-type residues are shown. Several residues give rise to more or less severe phenotypes; in these cases we have color coded all the phenotypes in the structures and a mixed marker in the TMD0-L0 domain. The mutations used to construct the figure are given in the table. The molecular graphics images were produced using the University of California San Francisco Chimera package (290) from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by National Institutes of Health Grant P41 RR-01081).
References
- Fosel S 1995 Transient and permanent neonatal diabetes. Eur J Pediatr 154:944–948 - PubMed
- Kitselle JF 1852 Kinderheilk 18:313 [Shield JP 2007 Neonatal diabetes. Horm Res 68(Suppl 5):32–36] - PubMed
- Attia N, Zahrani A, Saif R, Kattan HA, Sakati N, Al Ashwal A, Tamborlane WV 1998 Different faces of non-autoimmune diabetes of infancy. Acta Paediatr 87:95–97 - PubMed
- Shield JP 2000 Neonatal diabetes: new insights into aetiology and implications. Horm Res 53(Suppl 1):7–11 - PubMed
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