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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The differential diagnosis of hyperglycemia in childhood and adolescence has to take into consideration early-onset non-insulin-dependent diabetes, defined as maturity onset diabetes of the young (MODY). To date, mutations in genes of five proteins have been shown to cause MODY: glucokinase (MODY2), hepatic nuclear factor-1 alpha (HNF-1 alpha) (MODY3), hepatic nuclear factor-4 alpha (HNF-4 alpha) (MODY1), insulin promoter factor 1 (IPF-1) (MODY4) and hepatic nuclear factor-1 beta (HNF-1 beta) (MODY5), but other MODY genes still await elucidation. Clinical and metabolic heterogeneity of these subtypes of type 2 diabetes need to be defined, as deficiency of each factor has its own phenotype. Pediatric diabetologists should be aware of the increasing importance of MODY as a possible cause of hyperglycemia in children and adolescents. This will allow for the early diagnosis of these metabolic conditions and for the appropriate follow-up and treatment.
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PMID:Maturity-onset diabetes of the young (MODY): a new challenge for pediatric diabetologists. 1041 64

Maturity onset diabetes of the young is characterized by early onset diabetes inherited in an autosomal dominant pattern. Classic MODY occurs predominantly in Caucasians and presents before age 25, is nonketotic, and is generally not insulin-requiring. Less than 5% of cases of childhood diabetes in Caucasians are caused by MODY. ADM is a subtype of MODY that occurs in approximately 10% of African-Americans with youth onset diabetes. In contrast to MODY in Caucasians, ADM presents clinically as acute onset diabetes often associated with weight loss, ketosis, and even diabetic ketoacidosis. Approximately 50% of patients with ADM are obese. Therefore, based strictly on clinical grounds, at onset, ADM cannot be distinguished from type 1 diabetes. Months to years following diagnosis, a non-insulin-dependent clinical course develops in patients with ADM that is clearly different from type 1 diabetes. Mutations in five genes can cause MODY. These genes encode hepatocyte nuclear factor-4 alpha (HNF-4 alpha, MODY1), glucokinase (MODY2), hepatocyte nuclear factor-1 alpha (HNF-1 alpha, MODY3), insulin promoter factor-1 (IPF-1, MODY4), and hepatocyte nuclear factor-1 beta (HNF-1 beta, MODY5). These monogenic forms of MODY have been used as model systems to investigate the inheritance and pathophysiology of type 2 diabetes. Clinicians, should be able to diagnose MODY. Type 1 diabetes, the most common form of diabetes in Caucasians, is always insulin-requiring for control and survival, whereas patients with MODY do not usually require long-term insulin for survival. Diagnostic confusion can lead to inappropriate management and patient expectations. Primary care physicians must be alert to avoid therapeutic confusion when patients with ADM enter into the non-insulin-dependent stage. An approach to the diagnosis of childhood diabetes is offered in Table 4. The majority of youth onset diabetes remains type 1; however, the frequency of type 2 diabetes is rising in obese children and adolescents and especially in obese minority youth. The diagnosis of MODY can be made through a careful review of the patient's clinical course, severity of hyperglycemia, and family history. The identification of islet autoantibodies is confirmatory evidence of autoimmune (type 1) diabetes. Because testing for MODY mutations is expensive and is performed at a select number of research laboratories only, routine molecular genetic studies to search for the various MODY mutations should be limited to research investigations. In the future, the availability of gene chip technology may allow rapid screening of mitochondrial and MODY mutations.
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PMID:Monogenic diabetes mellitus in youth. The MODY syndromes. 1060 19

Plasma insulin displays 5-10 min oscillations. In Type 2 diabetes the regularity of the oscillations disappears, which may lead to insulin receptor down-regulation and glucose intolerance and explain why pulsatile delivery of the hormone has a greater hypoglycemic effect than continuous delivery. The rhythm is intrinsic to the islet. Variations in metabolism, cytoplasmic Ca(2+) concentration ([Ca(2+)](i)), other hormones, neuronal signaling and possibly beta-cell insulin receptor expression have been implicated in the regulation of plasma insulin oscillations. Most of these factors are important for amplitude-regulation of the insulin pulses. Although evidence exists supporting a role of both metabolism and [Ca(2+)](i) as pacemakers of the pulses, metabolic oscillations probably have a primary role and [Ca(2+)](i) oscillations a permissive role. Results from islets from animal models of diabetes suggest that altered plasma insulin pattern could be due to lowering of pulse amplitude of insulin oscillations rather than alterations in their frequency. Supporting a role of metabolism, altered plasma insulin oscillations were found in MODY2, MIDD and glycogenosis Type VII, which are linked to alterations in glucokinase, mitochondrial tRNALeu(UUR) and phosphofructokinase. Plasma insulin oscillations require coordination of islet secretory activities in the pancreas. The intrapancreatic ganglia have been suggested as coordinators. The diabetes-associated neuropathy may contribute to the deranged pattern as indicated by glucose intolerance in chagasic patients. Continued investigation of the role and regulation of pulsatile insulin release will lead to better understanding of the pathophysiology of impaired pulsatile insulin release, which could lead to new approaches to restore normal plasma insulin oscillations in diabetes and related diseases.
Diabetes Metab Res Rev
PMID:Pathophysiology of impaired pulsatile insulin release. 1086 18

Maturity onset diabetes of youth (MODY) occurs in children, adolescents and young adults as a non-insulin-requiring form of diabetes mellitus that is inherited as an autosomal dominant trait. Maturity onset diabetes of youth in whites presents subtly similar to type 2 diabetes in adults. In contrast, a MODY variant that occurs in young blacks, termed atypical diabetes mellitus, presents as an acute-onset form of diabetes. Months to years after diagnosis, atypical diabetes mellitus reverts to a noninsulin requiring course similar to MODY in whites. Five molecular causes for MODY have been identified: mutations in four transcription factors and mutations in one enzyme (glucokinase). Transcription factors regulate gene expression within cells. Mutations in hepatocyte nuclear factor-4alpha, hepatocyte nuclear factor-1alpha, insulin promoter factor-1 and hepatocyte nuclear factor-1beta, respectively, cause MODY1, MODY3, MODY4, and MODY5. Glucokinase is the glucosensor of the beta cell. MODY2 is caused by glucokinase mutations. Although testing for MODY mutations is only available in research laboratories, a careful history and review of the patient's clinical course can often allow the clinician to diagnose MODY. The diagnosis of MODY has implications for the clinical management of the patient's diabetes.
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PMID:Molecular and genetic bases for maturity onset diabetes of youth. 1094 22

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset (<25 years) and pancreatic beta-cell dysfunction. MODY is genetically heterogeneous with five different genes identified to date: hepatocyte nuclear factor-4 alpha (HNF-4 alpha) [MODY1]; glucokinase [MODY2]; hepatocyte nuclear factor-1 alpha (HNF-1 alpha) [MODY3]; insulin promoter factor-1 (IPF-1) [MODY4]; and hepatocyte nuclear factor-1 beta (HNF-1 beta) [MODY5]. Mutations in the HNF-1 alpha gene represent a common cause of MODY in the majority of populations studied. Sixty-five different mutations have been described in a total of 116 families. The most common mutation is a C-insertion (P291fsinsC) in the polyC tract of exon 4, which has been reported in 22 families. The identification of an HNF-1 alpha gene mutation in a patient with type 2 diabetes confirms the diagnosis of MODY and has important implications for clinical management.
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PMID:Hepatocyte nuclear factor 1 alpha (HNF-1 alpha) mutations in maturity-onset diabetes of the young. 1105 94

The glucokinase gene is expressed not only in pancreatic B cells and in the liver, but also in pancreatic alpha cells, and in some cells of the central nervous system. A decreased glucokinase activity in the latter cell types may interfere with counterregulatory responses to hypoglycemia. In order to assess functional consequences of glucokinase mutations, counterregulatory hormones secretion and glucose production (6,6(- 2) H glucose) were monitored during an hyperinsulinemic clamp at about 2.4 pmol.kg(- 1).min(- 1) insulin with progressive hypoglycemia in 7 maturity onset diabetes of the young (MODY) type 2 patients, 5 patients with type 2 diabetes, and 13 healthy subjects. Basal glucose concentrations were significantly higher in MODY2 patients (7.6 +/- 0.4 mmol.l(- 1) ) and type 2 diabetic patients (12.4 +/- 2.3 mmol.l(- 1) ) than in healthy subjects (5.3 +/- 0.1 mmol.l(- 1), p<0.01) but counterregulatory hormones concentrations were identical. Insulin-mediated glucose disposal and suppression of endogenous glucose production at euglycemia were unchanged in MODY2 patients, but were blunted in type 2 diabetes. During progressive hypoglycemia, the glycemic thresholds of MODY2 patients for increasing glucose production (5.0 +/- 0.4 mmol.l(- 1) ) and for glucagon stimulation (4.5 +/- 0.4 mmol. l(- 1) ) were higher than those of healthy subjects and type 2 diabetic patients (3.9 +/- 0.1 and 4.1 +/- 0.1 mmol.l(- 1) respectively for glucose production and 3.7 +/- 0.1 and 3.5 +/- 0.1 mmol.l(- 1) for glucagon stimulation, p <0.02 in both cases). These results indicate that counterregulatory responses to hypoglycemia are activated at a higher plasma glucose concentration in MODY2 patients. This may be secondary to decreased glucokinase activity in hypothalamic neuronal cells, or to alterations of glucose sensing in pancreatic alpha cells and liver cells.
Diabetes Metab 2000 Nov
PMID:Counterregulatory responses to hypoglycemia in patients with glucokinase gene mutations. 1111 17

Type 2 diabetes is a complex disease and genetic as well as environmental factors play a role in its pathogenesis. Six different genes have been identified so far to be responsible for rare forms of autosomal dominant, early onset type 2 diabetes mellitus. All but one are transcription factors which influence expression of the other genes through the regulation of mRNA synthesis. These are hepatocyte nuclear factor (HNF)-4 alpha, HNF-1 alpha, insulin promoter factor (IPF)-1 and HNF-1 beta, which are associated with MODY1, 3, 4, 5 respectively. MODY1 is a relatively rare and usually severe form of diabetes. It is associated with progressive hyperglycemia and frequent chronic complications. The HNF-4 alpha gene is localized on chromosome 20q. Similar clinical characteristics apply to the MODY3 form, however the latter is much more frequent among early onset, autosomal dominant type 2 diabetes (20-40%). HNF-1 alpha gene is localized on chromosome 12q. HNF-1 beta (MODY5 locus on chromosome 17q) is a protein which forms heterodimers with HNF-1 alpha. This rare form of diabetes has a clinical picture similar to MODY1 and MODY3. It is sometimes accompanied by symptoms of early kidney damage which are independent from diabetes. The other two transcription factors responsible for the development of autosomal dominant type 2 diabetes are proteins which bind directly to the insulin promoter. MODY4 (IPF-1, chromosome 13q) is a rare form and of a typical middle and late onset type 2 diabetes. BETA 2/Neurod1 has been recently associated with MODY by Dr Krolewski's group from Joslin Diabetes Center, Boston, MA, USA. BETA 2 is responsible for about 2% of autosomal dominant type 2 diabetes. The clinical characteristics depend on the localization of the mutations in the specific functional domains of the protein. Mutations identified in the glucokinase gene are associated with the MODY2 form. Glucokinase is an enzyme involved in the first level of glucose metabolism in b-cells-enzymatic phosphorylation. MODY2 is a modest form of diabetes. It is characterized by mild hyper-glycemia, mainly fasting, and the chronic complications are very rare. Glucokinase gene is localized on chromosome 7p. It is expected that in the nearest future more type 2 susceptibility genes will be identified.
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PMID:[Molecular background and clinical characteristics of autosomal dominant type 2 diabetes mellitus]. 1129 29

Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both. Genetic factors contribute to the development of diabetes. Some forms such as the condition called maturity-onset diabetes of the young(MODY) result from mutations in a single gene. Other forms such as type 1 or type 2 diabetes are multifactorial in origin with different combinations of genes together with non-genetic factors contributing to the development of hyperglycemia. MODY has been a good model for studying the genetics and pathophysiology of diabetes. This form of diabetes can result from mutations in at least seven different genes: hepatocyte nuclear factor(HNF)-4 alpha/MODY1, glucokinase/MODY2, HNF-1 alpha/MODY3, insulin promoter factor(IPF-1)/MODY4, HNF-1 beta/MODY5, NeuroD1/MODY6 and Islet(Isl)-1/MODY7. Mutations in HNF-1 alpha/MODY3 are the most common cause of MODY in Japanese identified to date accounting for about 15% of cases of MODY. Mutations in the HNF-4 alpha/MODY1, glucokinase/MODY2, HNF-1 beta/MODY5 and Isl-1/MODY7 genes have also been found in Japanese; however, they are rare causes of MODY. Clinical studies indicate that patients with MODY are generally not obese and that all forms of MODY are characterized by pancreatic beta-cell dysfunction. Patients who have mutations in the HNF-1 beta/MODY5 gene have non-diabetic kidney dysfunction including renal cysts. Female carriers may also exhibit abnormalities in the upper vagina and uterus. Genetic approach for type 2 diabetes had done by using non-parameteric linkage analysis such as sibpair analysis which worked well and NIDDM1 and NIDDM2 have been identified to date. The responsible gene for NIDDM1 was recently identified to be Calpain 10, and SNP43 in this gene could explain all of the evidence for linkage in Mexican American type 2 diabetes.
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PMID:[Diabetes mellitus]. 1130 9

Maturity-onset diabetes of the young (MODY) exhibits an autosomal dominant pattern of inheritance and can be divided in at least five subtypes (MODY 1 to 5), each subtype being caused by mutations in a specific gene. The unambiguous molecular diagnosis of the specific MODY subtype facilitates an early diagnosis of diabetes and can help to reduce the development of diabetic complications. Furthermore, MODY2 patients generally have a milder clinical course and fewer complications than MODY3 patients, who consequently require a more aggressive therapeutic approach.
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PMID:[From gene to disease; 'maturity-onset diabetes of the young' (MODY), monogenetic inheritable forms of diabetes mellitus]. 1148 33

Maturity-onset diabetes of the young (MODY), an autosomal dominant, early-onset form of type-2 diabetes, is caused by mutations in five different genes all leading to defect(s) in the pancreatic beta cell. However, some patients with this form of diabetes do not bear a mutation in any of the known (MODY1-MODY5) loci, a notion prompting the search for new MODY genes. Clinical and genetic data point toward a defect in beta cell function in the majority of patients with MODY, and partners of the glucose-sensing device are reasonable functional candidates. The high-capacity glucose transporter GLUT2 has the ideal kinetic features for performing this task. However, complete GLUT2 deficiency in humans leads to hepato-renal glycogenosis (Fanconi-Bickel syndrome), and heterozygous GLUT2 mutations apparently behave in a recessive manner. Furthermore, in the human beta cell GLUT1 mRNA is predominant when compared to GLUT2 and glucose influx appears to be largely mediated by this low-Km transporter. Thus, we looked for the presence of sequence variants by polymerase chain reaction and single-strand conformation polymorphism (PCR-SSCP) within the GLUT1 gene in 90 Italian pedigrees negative at the search for mutations in glucokinase (MODY2) and hepatocyte nuclear factor-1alpha (MODY3), the two genes responsible for about 60% of MODY cases in Italian children. We found three already described silent mutations and a new single base deletion in position -173 of the 5' regulatory region. The -173de1A variant, which was detected in the heterozygous or homozygous state in 30.8% of MODY patients examined and is located in a Nuclear Factor Y binding sequence, is not associated with hyperglycemia in affected relatives of MODY probands. In conclusion, it appears from these results that the glucose transporter gene GLUT1 is unlikely to play a major role in the etiology of MODY diabetes.
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PMID:Single-strand conformation polymorphism analysis of the glucose transporter gene GLUT1 in maturity-onset diabetes of the young. 1148 13


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