There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

It has become increasingly apparent over the last few years that the seemingly ubiquitous auto-immune aetiology to pre-pubertal diabetes does not apply to those diagnosed under 6 months of age. In this age group, disease appears, in the vast majority of cases, to be conferred by single gene disorders mainly related to pancreatic development. The unravelling of these disorders has resulted in a far greater understanding of pancreatic development and some startling changes in treatment, resulting in improved quality of life and diabetes control. The progress made in our scientific and clinical understanding of these extremely rare diseases is a perfect example of how studying seemingly rare illnesses can improve our overall knowledge of much more common conditions. Copyright (c) 2007 S. Karger AG, Basel.

Related collections

Most cited references 37

Record: found
Abstract: found
Article: not found

Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival.

Heather P. Harding, Huiqing Zeng, Yuhong Zhang … (2001)

The protein kinase PERK couples protein folding in the endoplasmic reticulum (ER) to polypeptide biosynthesis by phosphorylating the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha), attenuating translation initiation in response to ER stress. PERK is highly expressed in mouse pancreas, an organ active in protein secretion. Under physiological conditions, PERK was partially activated, accounting for much of the phosphorylated eIF2alpha in the pancreas. The exocrine and endocrine pancreas developed normally in Perk-/- mice. Postnatally, ER distention and activation of the ER stress transducer IRE1alpha accompanied increased cell death and led to progressive diabetes mellitus and exocrine pancreatic insufficiency. These findings suggest a special role for translational control in protecting secretory cells from ER stress.

0 comments Cited 291 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.

Anna L. Gloyn, Ewan Pearson, Jennifer F Antcliff … (2004)

Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes. We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene. Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K(ATP) channels was greatly reduced. Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas. Copyright 2004 Massachusetts Medical Society

0 comments Cited 272 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations.

Ewan Pearson, Isabelle Flechtner, Pål R. Njølstad … (2006)

Heterozygous activating mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel, cause 30 to 58 percent of cases of diabetes diagnosed in patients under six months of age. Patients present with ketoacidosis or severe hyperglycemia and are treated with insulin. Diabetes results from impaired insulin secretion caused by a failure of the beta-cell K(ATP) channel to close in response to increased intracellular ATP. Sulfonylureas close the K(ATP) channel by an ATP-independent route. We assessed glycemic control in 49 consecutive patients with Kir6.2 mutations who received appropriate doses of sulfonylureas and, in smaller subgroups, investigated the insulin secretory responses to intravenous and oral glucose, a mixed meal, and glucagon. The response of mutant K(ATP) channels to the sulfonylurea tolbutamide was assayed in xenopus oocytes. A total of 44 patients (90 percent) successfully discontinued insulin after receiving sulfonylureas. The extent of the tolbutamide blockade of K(ATP) channels in vitro reflected the response seen in patients. Glycated hemoglobin levels improved in all patients who switched to sulfonylurea therapy (from 8.1 percent before treatment to 6.4 percent after 12 weeks of treatment, P<0.001). Improved glycemic control was sustained at one year. Sulfonylurea treatment increased insulin secretion, which was more highly stimulated by oral glucose or a mixed meal than by intravenous glucose. Exogenous glucagon increased insulin secretion only in the presence of sulfonylureas. Sulfonylurea therapy is safe in the short term for patients with diabetes caused by KCNJ11 mutations and is probably more effective than insulin therapy. This pharmacogenetic response to sulfonylureas may result from the closing of mutant K(ATP) channels, thereby increasing insulin secretion in response to incretins and glucose metabolism. (ClinicalTrials.gov number, NCT00334711 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.

0 comments Cited 239 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

PubMed ID:: 17047341

DOI:: 10.1159/000096354

ScienceOpen disciplines: Chemistry

Keywords: Animals,Chromosomes, Human, Pair 6,genetics,Diabetes Mellitus, Type 1,drug therapy,Forkhead Transcription Factors,Glucokinase,Hepatocyte Nuclear Factor 1-beta,Homeodomain Proteins,Humans,Infant,Infant, Newborn,Infant, Newborn, Diseases,Insulin,therapeutic use,Insulin Infusion Systems,Pancreas,growth & development,Potassium Channels, Inwardly Rectifying,Trans-Activators,Transcription Factors,eIF-2 Kinase

Neonatal diabetes: how research unravelling the genetic puzzle has both widened our understanding of pancreatic development whilst improving children's quality of life.

Read this article at

Abstract

Related collections

Karger: Endocrinology

Most cited references 37

Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival.

Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.

Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations.

Author and article information

Journal

Comments

Comment on this article

Similar content 70

Cited by 3

Most referenced authors 1,260