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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The differential diagnosis for children with diabetes includes a group of monogenic diabetic disorders known as maturity-onset diabetes of the young (MODY). So far, six underlying gene defects have been identified. The most common subtypes are caused by mutations in the genes encoding the transcription factor HNF-1a (MODY 3) and the glycolytic enzyme glucokinase (GCK) (MODY 2). MODY 2 is the most benign form of diabetes as the threshold for glucose sensing is elevated resulting in mild, regulated hyperglycemia. MODY 2 may usually be treated with diet alone without risk of microvascular complications. Patients with MODY usually present as children or young adults. Genetic testing for MODY in diabetic subjects is often not performed because of the costs and its unavailability in Switzerland. We describe the impact of the genetic analysis for MODY 2 on diabetes management and treatment costs in a five-year-old girl. The patient and her diabetic mother were both found to have a heterozygous missense mutation (V203A) in the glucokinase gene. The five-year-old girl was started on insulin therapy for her diabetes but because her HbA1c remained between 5.8-6.4% (reference 4.1-5.7%) and her clinical presentation suggested MODY insulin was discontinued. She is now well controlled on a carbohydrate controlled diet regimen only. Omission of insulin treatment made regular blood glucose monitoring unnecessary and removed her risk of hypoglycemia. Costs for the genetic analysis were 500 Euro. At our centre costs for diabetes care of a patient with type 1 diabetes are approximately 2050 Euro/year compared to 410 Euro/year for the care of a patient with MODY 2. In addition, a diagnosis of MODY 2 may reassure patients and their families, as microvascular complications are uncommon. Thus there are both health and financial benefits in diagnosing MODY 2. We recommend genetic testing for MODY 2 in clinically selected patients even though this analysis is currently not available in Switzerland and costs are not necessarily covered by the health insurances.
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PMID:Genetic testing for glucokinase mutations in clinically selected patients with MODY: a worthwhile investment. 1605 90

Beside the clinical diagnosis of diabetes mellitus based on the measurement of blood glucose level, these days, the etiologic classification of the disease comes to the forefront. Genetic analysis (HLA typing, searching for glucokinase gene and mitochondrial gene mutations), immunologic examination (determination of islet specific autoantibodies) and measurement of the insulin secretory capacity help the etiologic classification. The most important result of classification is the discovery of the slowly progressive form of type 1 diabetes mellitus (formerly latent autoimmune diabetes in adults). Another direction of diagnostic procedures is the prediction of the disease in nondiabetic population. The prediction of type 1 diabetes is not specific enough at present, but that of type 2 diabetes can be done easily.
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PMID:[Diagnosis of diabetes mellitus]. 1689 84

Type 1 diabetes is a metabolic disorder caused by loss of insulin-producing pancreatic beta-cells. Expression of insulin in non-beta-cells to create beta-cell surrogates has been tried to treat type 1 diabetes. Enteroendocrine K cells have characteristics similar to pancreatic beta-cells, such as a glucose-sensing system and insulin-processing proteases. In this study, we genetically engineered an enteroendocrine cell line (STC-1) to express insulin under the control of the glucose-dependent insulinotropic polypeptide promoter. We screened clones and chose one, Gi-INS-7, based on its high production of insulin. Gi-INS-7 cells expressed glucose transporter 2 (GLUT2) and glucokinase (GK) and secreted insulin in response to elevated glucose levels in vitro. To determine whether Gi-INS-7 cells can control blood glucose levels in diabetic mice, we transplanted these cells under the kidney capsule of streptozotocin (STZ)-induced diabetic mice and found that blood glucose levels became normal within 2 weeks of transplantation. In addition, glucose tolerance tests in mice that became normoglycemic after transplantation with Gi-INS-7 cells showed that exogenous glucose was cleared appropriately. These results suggest that engineered K cells may be promising surrogate beta-cells for possible therapeutic use for the treatment of type 1 diabetes.
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PMID:Engineered enteroendocrine cells secrete insulin in response to glucose and reverse hyperglycemia in diabetic mice. 1729 98

The capacity for self-renewal and differentiation of human embryonic stem (ES) cells makes them a potential source for generation of pancreatic beta cells for treating type I diabetes mellitus. Here, we report a newly developed and effective method, carried out in a serum-free system, which induced human ES cells to differentiate into insulin-producing cells. Activin A was used in the initial stage to induce definitive endoderm differentiation from human ES cells, as detected by the expression of the definitive endoderm markers Sox17 and Brachyury. Further, all-trans retinoic acid (RA) was used to promote pancreatic differentiation, as indicated by the expression of the early pancreatic transcription factors pdx1 and hlxb9. After maturation in DMEM/F12 serum-free medium with bFGF and nicotinamide, the differentiated cells expressed islet specific markers such as C-peptide, insulin, glucagon and glut2. The percentage of C-peptide-positive cells exceeded 15%. The secretion of insulin and C-peptide by these cells corresponded to the variations in glucose levels. When transplanted into renal capsules of Streptozotocin (STZ)-treated nude mice, these differentiated human ES cells survived and maintained the expression of beta cell marker genes, including C-peptide, pdx1, glucokinase, nkx6.1, IAPP, pax6 and Tcf1. Thirty percent of the transplanted nude mice exhibited apparent restoration of stable euglycemia; and the corrected phenotype was sustained for more than six weeks. Our new method provides a promising in vitro differentiation model for studying the mechanisms of human pancreas development and illustrates the potential of using human ES cells for the treatment of type I diabetes mellitus.
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PMID:In vitro derivation of functional insulin-producing cells from human embryonic stem cells. 1742 93

Maturity onset diabetes of the young (MODY) is characterized by a primary defect in insulin secretion and hyperglycemia, nonketotic disease, monogenic autosomal dominant mode of inheritance, age at onset less than 25 years, and lack of auto-antibodies. It accounts for 2-5% of all cases of non-type 1 diabetes. The diagnosis may be made by careful clinical evaluation, but exact subtyping is possible only by genetic analysis. Several genetic factors have been identified as causative agents in MODY, each leading to a different type of the disease. These include the enzyme glucokinase, which causes MODY2, and the transcription factors HNF- 4 alpha, TCF1, I PF-1, TCF2, and NeuroD1, which cause MODY1, 3, 4, 5, and 6, respectively. The genetic findings have important clinical implications, allowing for proper genetic counseling, early diagnosis, and better care of patients.
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PMID:Maturity onset diabetes of the young--review. 1755 75

Alloxan is a classical diabetogen which is used to achieve beta-cell destruction and type 1 diabetes due to its selective cytotoxic effect on pancreatic beta-cells. Although alloxan-induced diabetes is widely used in the laboratory to mimic diabetic pathology and for screening antidiabetic drugs, there has not been any comprehensive research in vivo on its diabetogenicity. In our study, alloxan-induced diabetic mice were generated by a single intravenous injection of alloxan (100 mg/kg). Our data show that these mice possess hyperglycemia, hypoinsulinism and morphological characteristics of impaired pancreas that are consistent with the accepted diabetogenic effects of alloxan. Alloxan is believed to confer its diabetogenic effect by inhibiting pancreatic glucokinase activity, leading to pancreatic beta-cell death. We examined the effects of alloxon on the other major site of glucokinase expression, the liver. Our results show that alloxan treatment led to an 81% reduction in glucokinase immunoreactivity and a greater than 90% reduction in glucokinase enzymatic activity in the liver, suggesting that alloxan's toxicity is not specific to the pancreas. Given the important role of glucokinase as a glucose sensor, and our findings on the effects of alloxon on liver glucokinase activity we propose that the effects on the liver are the primary contributor to pathogenesis in alloxan-induced diabetes. Alloxan-induced diabetes is thus a multifactor-promoted diabetes model which still could be used to examine the antidiabetic effects of compounds prompting insulin secretion and increasing liver-specific glucokinase activity. Despite alloxan-induced diabetes being inconsistent with the natural pathogenesis of human diabetes, further research on the causes of decreased glucokinase activity will help us to unravel the pathogenesis of diabetes and its complications.
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PMID:Hepatic glucokinase activity is the primary defect in alloxan-induced diabetes of mice. 1776 29

Antecedent insulin-induced hypoglycemia (IIH) reduces adrenomedullary responses (AMR) to subsequent bouts of hypoglycemia. The ventromedial hypothalamus [VMH: arcuate (ARC) + ventromedial nuclei] contains glucosensing neurons, which are thought to be mediators of these AMR. Since type 1 diabetes mellitus often begins in childhood, we used juvenile (4- to 5-wk-old) rats to demonstrate that a single bout of IIH (5 U/kg sc) reduced plasma glucose by 24% and peak epinephrine by 59% 1 day later. This dampened AMR was associated with 46% higher mRNA for VMH glucokinase, a key mediator of neuronal glucosensing. Compared with neurons from saline-injected rats, ventromedial nucleus glucose-excited neurons from insulin-injected rats demonstrated a leftward shift in their glucose responsiveness (EC50 = 0.45 and 0.10 mmol/l for saline and insulin, respectively, P = 0.05) and a 31% higher maximal activation by glucose (P = 0.05), although this maximum occurred at a higher glucose concentration (saline, 0.7 vs. insulin, 1.5 mmol/l). Although EC50 values did not differ, ARC glucose-excited neurons had 19% higher maximal activation, which occurred at a lower glucose concentration in insulin- than saline-injected rats (saline, 2.5 vs. insulin, 1.5 mmol/l). In addition, ARC glucose-inhibited neurons from insulin-injected rats were maximally inhibited at a fivefold lower glucose concentration (saline, 2.5 vs. insulin, 0.5 mmol/l), although this inhibition declined at >0.5 mmol/l glucose. These data suggest that the increased VMH glucokinase after IIH may contribute to the increased responsiveness of VMH glucosensing neurons to glucose and the associated blunting of the AMR.
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PMID:Prior hypoglycemia enhances glucose responsiveness in some ventromedial hypothalamic glucosensing neurons. 1809 65

Pancreatic islet transplantation has demonstrated that long-term insulin independence may be achieved in patients suffering from diabetes mellitus type 1. However, limited availability of islet tissue means that new sources of insulin-producing cells that are responsive to glucose are required. Here, we show that human amnion epithelial cells (HAEC) can be induced to differentiate into functional insulin-producing cells in vitro. After induction of differentiation, HAEC expressed multiple pancreatic beta-cell genes, including insulin, pancreas duodenum homeobox-1, paired box gene 6, NK2 transcription factor-related locus 2, Islet 1, glucokinase, and glucose transporter-2, and released C-peptide in a glucose-regulated manner in response to other extracellular stimulations. The transplantation of induced HAEC into streptozotocin-induced diabetic C57 mice reversed hyperglycemia, restored body weight, and maintained euglycemia for 30 d. These findings indicated that HAEC may be a new source for cell replacement therapy in type 1 diabetes.
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PMID:Human amnion epithelial cells can be induced to differentiate into functional insulin-producing cells. 1877 96

Xenotransplantation of insulin-secreting cells from nonhuman sources is an alternative therapeutic approach to bypass the shortage of human pancreatic islet tissue for transplantation in order to treat insulin deficiency in type 1 diabetes mellitus. Therefore, we studied the suitability of pseudoislets generated from insulin-secreting MIN6 tissue culture cells to serve as a surrogate for replacement of pancreatic islets after encapsulation in a minicell, representing a prototype of a new bioartificial pancreas device. MIN6 pseudoislets showed an excellent insulin secretory responsiveness with a typical biphasic secretory pattern to glucose stimulation. When encapsulated in the minicell, insulin release from the pseudoislets in response to glucose stimulation was reduced. The initial first phase insulin secretory response was greatly attenuated. In contrast, the first phase insulin secretory response of the encapsulated pseudoislets was restored on stimulation with the sulfonylurea drug tolbutamide. Our results indicate that the reason for the attenuated first phase of release is the restricted permeability of the pores in the separating membrane in the minicell for the hydrophilic glucose molecule rather than a limited permeability for the secretion product insulin. The reduced release of insulin from the encapsulated pseudoislets could be compensated by overexpression of glucokinase in MIN6 cells, which resulted in an increased glucose responsiveness of the pseudoislets for stimulation with glucose. Thus, this minicell is a well-suited miniature test system for the evaluation of the feasibility of encapsulation of insulin-secreting cells and allows the testing of permeability properties of separating membranes in bioartificial pancreas devices.
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PMID:Kinetics of insulin secretion from MIN6 pseudoislets after encapsulation in a prototype device of a bioartificial pancreas. 1885 6

Autoimmune destruction of beta cells in the pancreas leads to type I, or insulin dependent diabetes mellitus (IDDM), through the loss of endogenous insulin production capacity. This paper describes an attempt to generate 'artificial'beta cells using the fibroblast cell line BHK21. Stable transfectants expressing the human preproinsulin (PPI) gene were isolated and characterised. The resulting clone selected for further analysis (BHK-PPI-C16) was capable of secreting 0.12 pmol proinsulin/hr/10(5) cells and maintained a steady cellular proinsulin content of 0.36 +/- 0.04 pmol l(-1). There was no processing of the proinsulin to mature insulin. The cells were unresponsive to glucose but there was increased proinsulin secretion in the presence of agents that stimulated formation of intracellular cAMP. Transfection of cDNAs for the key elements of the glucose sensing apparatus (GLUT2 and glucokinase) led to a subphysiological stimulation of secretion when glucokinase was transfected alone while there was a complete loss of insulin secretion when both components were overexpressed. The deleterious effect on proinsulin secretion observed upon co-expression of the glucose sensing genes may have implications for applications requiring multigene expression in BHK21 cells.
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PMID:Characterisation of BHK-21 cells engineered to secrete human insulin. 1900 58


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