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PubMed2005

Suppression of Pdx-1 perturbs proinsulin processing, insulin secretion and GLP-1 signalling in INS-1 cells.

AIMS/HYPOTHESIS: Mutations in genes encoding HNF-4alpha, HNF-1alpha and IPF-1/Pdx-1 are associated with, respectively, MODY subtypes-1, -3 and -4. Impaired glucose-stimulated insulin secretion is the common primary defect of these monogenic forms of diabetes. A regulatory circuit between these three transcription factors has also been suggested. We aimed to explore how Pdx-1 regulates beta cell function and gene expression patterns. METHODS: We studied two previously established INS-1 stable cell lines permitting inducible expression of, respectively, Pdx-1 and its dominant-negative mutant. We used HPLC for insulin processing, adenovirally encoded aequorin for cytosolic [Ca2+], and transient transfection of human growth hormone or patch-clamp capacitance recordings to monitor exocytosis. RESULTS: Induction of DN-Pdx-1 resulted in defective glucose-stimulated and K+-depolarisation-induced insulin secretion in INS-1 cells, while overexpression of Pdx-1 had no effect. We found that DN-Pdx-1 caused down-regulation of fibroblast growth factor receptor 1 (FGFR1), and consequently prohormone convertases (PC-1/3 and -2). As a result, DN-Pdx-1 severely impaired proinsulin processing. In addition, induction of Pdx-1 suppressed the expression of glucagon-like peptide 1 receptor (GLP-1R), which resulted in marked reduction of both basal and GLP-1 agonist exendin-4-stimulated cellular cAMP levels. Induction of DN-Pdx-1 did not affect glucokinase activity, glycolysis, mitochondrial metabolism or ATP generation. The K+-induced cytosolic [Ca2+] rise and Ca2+-evoked exocytosis (membrane capacitance) were not abrogated. CONCLUSIONS/INTERPRETATION: The severely impaired proinsulin processing combined with decreased GLP-1R expression and cellular cAMP content, rather than metabolic defects or altered exocytosis, may contribute to the beta cell dysfunction induced by Pdx-1 deficiency.

Adenosine Triphosphate↗
PubMed2006

Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity.

AIMS/HYPOTHESIS: Glucokinase (GCK) acts as a glucose sensor in the pancreatic beta cell and regulates insulin secretion. In the gene encoding GCK the heterozygous mutations that result in enzyme inactivation cause MODY2. Functional studies of naturally occurring GCK mutations associated with hyperglycaemia provide further insight into the biochemical basis of glucose sensor regulation. MATERIALS AND METHODS: Identification of GCK mutations in selected MODY patients was performed by single-strand conformation polymorphism and direct sequencing. The kinetic parameters and thermal stability of recombinant mutant human GCK were determined, and in pull-down assays the effect of these mutations on the association of GCK with glucokinase (hexokinase 4) regulator (GCKR, also known as glucokinase regulatory protein [GKRP]) and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB1, also known as PFK2) was tested. RESULTS: We identified three novel GCK mutations: the insertion of an asparagine residue at position 161 (inserN161) and two missense mutations (M235V and R308W). We also identified a fourth mutation (R397L) reported in a previous work. Functional characterisation of these mutations revealed that insertion of asparagine residue N161 fully inactivates GCK, whereas the M235V and R308W mutations only partially impair enzymatic activity. In contrast, GCK kinetics was almost unaffected by the R397L mutation. Although none of these mutations affected the interaction of GCK with PFKFB1, we found that the R308W mutation caused protein instability and increased the strength of interaction with GCKR. CONCLUSIONS/INTERPRETATION: Our results show that different MODY2 mutations impair GCK function through different mechanisms such as enzymatic activity, protein stability and increased interaction with GCKR, helping further elucidate the regulation of GCK activity.

Adaptor Proteins, Signal Transducing↗
PubMed2000

A high prevalence of glucokinase mutations in gestational diabetic subjects selected by clinical criteria.

AIMS/HYPOTHESIS: Patients with glucokinase mutations are characterised by mild, persistent fasting hyperglycaemia, a small increment in glucose in response to an oral load and a dominant family history. These patients frequently present with gestational diabetes and often require insulin treatment during pregnancy. We assessed whether the selection of gestational diabetic subjects by clinical criteria would result in a high detection rate of glucokinase mutations. METHODS: Caucasian gestational diabetic subjects from the United Kingdom who had fasting hyperglycaemia in pregnancy but did not meet the diagnostic criteria for maturity-onset diabetes of the young (MODY) were selected for direct sequencing of the glucokinase gene if they fulfilled the following four criteria; (1) persisting fasting hyperglycaemia outside pregnancy (5.5-8 mmol/l) (2) a small increment (< 4.6 mmol/l) during a 2-h oral glucose tolerance test (3) insulin treatment during at least one pregnancy but subsequently controlled on diet and (4) a history of Type II (non-insulin-dependent) diabetes mellitus, gestational diabetes or fasting hyperglycaemia (> 5.5 mmol/l) in a first-degree relative. RESULTS: Of the 15 subjects 12 (80%) with all these clinical criteria had glucokinase gene mutations. These included four previously unreported mutations (N180K, R191W, Y215X and L288-1G --> A). CONCLUSION/INTERPRETATION: Phenotypic selection of subjects with gestational diabetes greatly increases the likelihood of detecting a mutation in the glucokinase gene as previous studies have suggested a prevalence of 2.5% (range 0-6%). Our study in gestational diabetes to successfully used clinical criteria to assist in the definition of a genetic subgroup.

Amino Acid Substitution↗
PubMed2000

Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in type II diabetes.

Insulin is stored in secretory granules in the beta-cell and is secreted by exocytosis. This process is precisely controlled to achieve blood glucose homeostasis. Many forms of diabetes mellitus display impaired glucose-induced insulin secretion. This has been shown to be the primary cause of the disease in the various forms of maturity-onset diabetes of the young (MODY) and has also been implicated in adult-onset Type II (non-insulin-dependent) diabetes mellitus. Glucose generates ATP and other metabolic coupling factors in the beta-cell mitochondria. By plasma membrane depolarisation ATP promotes Ca2+ influx, which raises cytosolic Ca2+ and triggers insulin exocytosis. Through hyperpolarisation of the mitochondrial membrane glucose also increases the Ca2+ concentration in the mitochondrial matrix activating Ca(2+)-sensitive dehydrogenases in the tricarboxylic acid cycle. The resulting generation of glutamate participates in Ca(2+)-stimulated exocytosis. Mitochondrial DNA (mtDNA) encodes some of the polypeptides of the respiratory chain enzyme complexes. Mutations in mtDNA lead to maternally inherited diabetes mellitus characterised by impaired insulin secretion. The impact of altered mtDNA on insulin secretion has been shown in mtDNA-deficient beta-cell lines which have lost glucose-stimulated insulin secretion but retain a Ca(2+)-induced insulin secretion. A cellular model of MODY3 expressing dominant-negative hepatocyte nuclear factor-1 alpha (HNF-1 alpha) also displayed deletion of glucose-induced but not Ca(2+)-induced insulin secretion. Reduced mitochondrial metabolism explains this secretory pattern. Thus, genetically manipulated beta-cell lines are essential tools in the investigation of the molecular basis of beta-cell dysfunction in diabetes and should explain the role of other transcription factors in the disease.

Calcium↗
PubMed1994

Mitochondrial diabetes mellitus: prevalence and clinical characterization of diabetes due to mitochondrial tRNA(Leu(UUR)) gene mutation in Japanese patients.

Mutations in the mitochondrial gene were recently identified in a large pedigree of diabetes mellitus and deafness. As the mitochondrial gene is materially inherited, Japanese diabetic patients whose mothers were also diabetic were screened, using peripheral leucocytes, for an A to G transition at nucleotide pair 3243 of the mitochondrial gene, a tRNA(Leu(UUR)) mutation. This mutation was identified in four pedigrees from among 300 unrelated patients who were screened. Diabetes co-segregated with the mutation, except in one young subject, and was maternally inherited. The apparent onset of disease occurred between 11 and 68 years of age. Some of the affected members developed hearing impairment and congestive heart failure due to cardiomyopathy, though generally long after the onset of diabetes, and these patients had therefore not been diagnosed as having a specific form of diabetes. The duration of sulphonyl-urea treatment was not more than 8 years in these pedigrees and affected members were prone to progression to insulin-requiring diabetes. Thus, these patients were secondary sulphonylurea failures. Long-term follow-up revealed that the underlying disorder in affected members is a progressive impairment of insulin secretion. Some were initially diagnosed as having IDDM based on an apparent acute onset in youth and the clinical severity of their diabetes. Others were regarded as having MODY with an aggressive course. The mitochondrial gene mutation or diabetes is not transmitted to all offspring of the affected mothers.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1996

High prevalence of a missense mutation of the glucokinase gene in gestational diabetic patients due to a founder-effect in a local population.

A high proportion of the female patients who are members of maturity onset diabetes of the young (MODY) pedigrees, and whose diabetes mellitus is due to a glucokinase mutation, originally presented with gestational diabetes. To establish whether glucokinase mutations could be a common cause of gestational diabetes, we studied 50 subjects who presented with gestational diabetes and on follow-up had hyperglycaemia (5.5-10.0 mmol/l). Screening for glucokinase mutations using single-stranded conformational polymorphism (SSCP) analysis detected a missense mutation at position 299 (Gly299-->Arg) in three subjects. As two pedigrees in the Oxford area had the same glucokinase mutation, we suspected the role of a founder-effect, and carried out pedigree extension, haplotype construction (using microsatellite markers GCK1 and GCK2) and mutation screening of at-risk subjects from the same geographical area. One of the gestational diabetic subjects was found to be related to one of the previous pedigrees via her paternal grandmother. Subjects with the mutation were found to have the Z + 4/2 (GCK1/ GCK2) haplotype, suggesting that the observed high prevalence of the Gly299-->Arg glucokinase mutation in the Oxford region was due to a founder-effect. Since glucokinase mutations predominantly induce subclinical hyperglycaemia, it is likely that in the locality of other pedigrees there will be undiagnosed subjects with the same glucokinase mutation, which remains undetected unless pregnancy occurs.

Adult↗
PubMed1998

Chronic diabetic complications in patients with MODY3 diabetes.

MODY3 diabetes, which is caused by a mutation in the hepatocyte nuclear factor-1alpha gene (HNF-1alpha) on chromosome 12, represents a relatively common monogenic form of diabetes in Finland. Age at onset of the disease can vary from 10 to 60 years, but little is known about the natural course of the disease, particularly the development of diabetes-related chronic complications. The availability of genetic markers now allows description of the clinical course of the disease. In order to examine the prevalence of chronic diabetic complications in MODY3, we examined 57 carriers with HNF-1alpha mutations for the presence of micro- and macrovascular complications. Thirty-four percent of the MODY patients had mild and 13% had severe non-proliferative or proliferative retinopathy; this figure did not differ from the figures in insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) patients matched for duration and glycaemic control but not for age. Neither did the prevalence of microalbuminuria differ between MODY3 and IDDM or NIDDM patients (19 vs 24 and 23%). Neuropathy was observed with the same frequency as previously reported in IDDM. Hypertension was less frequent in MODY3 and IDDM than in NIDDM (24.5 and 19 vs 53.7%; p < 0.001). Coronary heart disease was more common in MODY3 than in IDDM (16 vs 4.5%; p < 0.02) but less common than in the older NIDDM patients (33.3%; p < 0.02). In a multiple logistic regression analysis, poor glycaemic control was an independent risk factor for retinopathy (p = 0.03), microalbuminuria (p < 0.04) and neuropathy (p = 0.03). In conclusion, microangiopathic complications are observed with the same frequency in patients with MODY3 diabetes as in IDDM and NIDDM and are strongly related to poor glycaemic control.

Adult↗
PubMed1998

Mutations in the hepatocyte nuclear factor-1alpha gene in Caucasian families originally classified as having Type I diabetes.

Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene are the cause of maturity-onset diabetes of the young type 3 (MODY3), which is characterised by a severe impairment of insulin secretion and an early onset of the disease. Also at onset of diabetes some MODY patients show similar clinical symptoms and signs as patients with Type I (insulin-dependent) diabetes mellitus. The objective of this study was to estimate the prevalence of MODY3 patients misclassified as Type I diabetic patients. From a large population-based sample of unrelated Danish Caucasian Type I diabetic patients with an affected first degree relative, 39 patients (6.7%) who did not carry any high-risk HLA-haplotypes, i.e. DR3 or DR4 or both were examined by single-strand conformational polymorphism scanning and direct sequencing of the coding region and the minimal promoter of the HNF-1alpha gene. Four of the 39 Type I diabetic patients (10%) were identified as carrying mutations in the HNF-1alpha gene. One patient carried a missense mutation (Glu48Lys) in exon 1, two patients carried a missense mutation (Cys241Gly) in exon 4 and one patient carried a frameshift mutation (Pro291fsdelA) in exon 4. The mutations were all identified in heterozygous form, segregated with diabetes, and were not identified in 84 unrelated, healthy subjects. Furthermore, family history in three of the four families showed diabetes in four consecutive generations, suggestive of an autosomal dominant inheritance. In conclusion, about 10% of Danish diabetic patients without a high-risk HLA-haplotype, originally classified as having Type I diabetes could have diabetes caused by mutations in the HNF-1alpha gene. Clinical awareness of family history of diabetes and mode of inheritance might help to identify and reclassify these diabetic subjects as MODY3 patients.

Adolescent↗
PubMed1999

Hepatocyte nuclear factor-6: associations between genetic variability and type II diabetes and between genetic variability and estimates of insulin secretion.

AIMS/HYPOTHESIS: The transcription factor hepatocyte nuclear factor (HNF)-6 is an upstream regulator of several genes involved in the pathogenesis of maturity-onset diabetes of the young. We therefore tested the hypothesis that variability in the HNF-6 gene is associated with subsets of Type II (non-insulin-dependent) diabetes mellitus and estimates of insulin secretion in glucose tolerant subjects. METHODS: We cloned the coding region as well as the intron-exon boundaries of the HNF-6 gene. We then examined them on genomic DNA in six MODY probands without mutations in the MODY1, MODY3 and MODY4 genes and in 54 patients with late-onset Type II diabetes by combined single strand conformational polymorphism-heteroduplex analysis followed by direct sequencing of identified variants. An identified missense variant was examined in association studies and genotype-phenotype studies. RESULTS: We identified two silent and one missense (Pro75 Ala) variant. In an association study the allelic frequency of the Pro75Ala polymorphism was 3.2% (95% confidence interval, 1.9-4.5) in 330 patients with Type II diabetes mellitus compared with 4.2% (2.4-6.0) in 238 age-matched glucose tolerant control subjects. Moreover, in studies of 238 middle-aged glucose tolerant subjects, of 226 glucose tolerant offspring of Type II diabetic patients and of 367 young healthy subjects, the carriers of the polymorphism did not differ from non-carriers in glucose induced serum insulin or C-peptide responses. CONCLUSION/INTERPRETATION: Mutations in the coding region of the HNF-6 gene are not associated with Type II diabetes or with changes in insulin responses to glucose among the Caucasians examined.

Adult↗
PubMed2000

R127W-HNF-4alpha is a loss of function mutation but not a rare polymorphism and causes Type II diabetes in a Japanese family with MODY1.

AIMS/HYPOTHESIS: Mutations in the hepatocyte nuclear factor (HNF)-4alpha gene cause the type 1 form of maturity-onset diabetes of the young (MODY1). The R127W mutation is a missense mutation located in the T-box region of HNF-4alpha that was first identified in a Japanese family with MODY. We have examined the functional properties of this mutation in order to clarify the molecular basis of MODY1. METHODS: The intracellular localisation, DNA binding ability, transactivation activity and functional synergism with the coactivator CREB-binding protein (CBP) of R127W-HNF-4alpha were investigated. RESULTS: The nuclear import and functional synergy with CBP of R127W-HNF-4alpha were normal. The DNA binding ability of the mutant was decreased as was its transcriptional activation of the HNF-1alpha and L-type pyruvate kinase (PKL) genes. CONCLUSION/INTERPRETATION: The R127W mutation seems to be a loss-of-function mutation.

Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗
PubMed2000

Identification of missense mutations in the hepatocyte nuclear factor-3beta gene in Japanese subjects with late-onset Type II diabetes mellitus.

AIMS/HYPOTHESIS: Hepatocyte nuclear factor (HNF)-3beta, a transcription factor expressed in pancreatic beta cells, is an upstream regulator of HNF-1alpha/MODY3, HNF-4alpha/MODY1 and IPF1/MODY5 genes. Our previous screening of MODY subjects showed that mutations in the HNF-3beta gene are not a common cause of this form of diabetes in the Japanese. We tested the hypothesis that mutations in the HNF-3beta gene cause late-onset Type II (non-insulin-dependent) diabetes mellitus in this population. METHODS: Genotyping of the polymorphic TCC repeat in the HNF-3beta gene was done in 112 Japanese subjects with Type II diabetes (age at diagnosis > 35 and family history of Type II diabetes among their second-degree relatives) and 96 Japanese control subjects. Furthermore, we screened 57 Type II diabetic patients for mutations of the HNF-3beta gene. Transactivation activity of variant HNF-3beta was investigated by transfection assay. RESULTS: The distribution of alleles of the TCC repeat was similar between diabetic and control groups. Mutation screening identified two missense mutations, A86T and G114E. Neither mutation was observed in 225 control subjects. The transactivation activity of G114E-HNF-3beta was similar to that of wild typeHNF-3beta. In contrast, the activity of A86T-HNF-3beta was statistically significantly reduced to 83-86 % of that of wild type. CONCLUSIONS/INTERPRETATION: The A86T mutation in the HNF-3beta gene might be involved in the development of late-onset Type II diabetes in a small group of Japanese people.

Adult↗
PubMed2001

Functional consequences of mutations in the MODY4 gene (IPF1) and coexistence with MODY3 mutations.

AIMS/HYPOTHESIS: The aim of this study was to examine the putative role of mutations in the insulin promoter 1 (IPF1) gene in early-onset diabetes. METHODS: We carried out mutation screening of the IPF1 gene in 115 Scandinavian families with at least two members with onset of diabetes younger than 40 years. The allele frequencies were also tested in 183 unrelated patients with late-onset Type II (non-insulin-dependent) diabetes mellitus and in 92 non-diabetic control subjects. RESULTS: Two novel IPF1 variants (G212R and P239Q) and one previously reported (D76N) IPF1 variant were identified in the 115 families (3.5%). The D76N variant was found in one MODY3 family (S315fsinsA of HNF1alpha) and also in two families with late-onset Type II diabetes. The P239Q variant was identified in two families with early-onset diabetes including one with MODY3 (R272C of HNF1alpha) and in three families with late-onset Type II diabetes. Despite the fact that the variants did not segregate completely with diabetes, the non-diabetic carriers of the IPF1 variants had increased blood glucose concentrations (p < 0.05) and reduced insulin:glucose ratios (p < 0.05) during an oral glucose tolerance test compared with non-diabetic family members without these variants. In addition, when the G212R and P239Q variants were expressed in cells without IPF1 i.e.. Nes2y cells, both variants showed about a 50% reduction in their ability to activate insulin gene transcription compared to wild-type IPF1, as measured by reporter gene assay. CONCLUSION/INTERPRETATION: Although mutations in the IPF-1 gene are rare in early- (3.5 %) and late-onset (2.7 % ) Type II diabetes, they are functionally important and occur also in families with other MODY mutations.

Aged↗
PubMed1996

Co-localization of the ketohexokinase and glucokinase regulator genes to a 500-kb region of chromosome 2p23.

The glucokinase regulator (GCKR) is a 65-kDa protein that inhibits glucokinase (hexokinase IV) in liver and pancreatic islet. The role of glucokinase (GCK) as pancreatic beta cell glucose sensor and the finding of GCK mutations in maturity onset diabetes of the young (MODY) suggest GCKR as a further candidate gene for type 2 diabetes. The inhibition of GCK by GCKR is relieved by the binding of fructose-1-phosphate (F-1-P) to GCKR. F-1-P is the end product of ketohexokinase (KHK, fructokinase), which, like GCK and GCKR, is present in both liver and pancreatic islet. KHK is the first enzyme of the specialized pathway that catabolizes dietary fructose. We have isolated genomic clones containing the human GCKR and KHK genes. By fluorescent in situ hybridization (FISH), KHK maps to Chromosome (Chr) 2p23.2-23.3, a new assignment corroborated by somatic cell hybrid analysis. The localization of GCKR, originally reported by others as 2p22.3, has been reassessed by high-resolution FISH, indicating that, like KHK, GCKR maps to 2p23.2-23.3. The proximity of GCKR and KHK was further demonstrated both by two-color interphase FISH, which suggests that the two genes lie within 500 kb of each other, and by analysis of overlapping YAC and P1 clones spanning the interval between GCKR and KHK. A new microsatellite polymorphism was used to place the GCKR-KHK locus between D2S305 and D2S165 on the genetic map. The colocalization of these two metabolically connected genes has implications for the interpretation of linkage or allele association studies in type 2 diabetes. It also raises the possibility of coordinate regulation of GCKR and KHK by common cis-acting regulatory elements.

Base Sequence↗
PubMed2006

Relative suppression of the sodium-dependent Vitamin C transport in mouse versus human lens epithelial cells.

Vitamin C is a major antioxidant and UV absorbent in the human lens. In the rodent lens, the levels are very low for unknown reasons. Searching for clues to explain this suppression, we investigated the comparative uptake of Vitamin C in cultured human and mouse lens epithelial cells. When compared to human HLE-B3 lens epithelial cells, (14)C-ASA uptake was 4- to 10-fold impaired in confluent mouse lens 17EM15 (p < 0.0001) and 21EM15 (p < 0.001) cells, respectively. High glucose concentrations reduced the uptake by 30-50% in all cells (p < 0.005). Incubation of cells with 6-deoxy-6-fluoro-ascorbic (F-ASA), i.e. a probe specific for the sodium-dependent Vitamin C uptake (SVCT2), revealed a 10-fold uptake suppression into mouse 17EM15 relative to human HLE-B3 and JAR choriocarcinoma cells (a control), that could be overcome by overexpressing hSVCT2 using two different promoter constructs. The relative Vitamin C uptake differences suggest either low expression of SVCT2, molecular differences between the transporters themselves or their biological regulation, since a recent study has shown that exogenous feeding of ascorbic acid to rats increased only modestly lenticular uptake (Mody et al., Acta Ophthalmol Scand 83: 228-223, 2005). Elucidation of the mechanism by which SCVT2 activity is suppressed in mouse lens may help unravel a major question of evolutionary significance for night vision in nocturnal animals.

Amino Acid Sequence↗
PubMed1993

Immunoglobulin A and M patterns to human cytomegalovirus during recurrent infection in patients with AIDS using a modified western blot.

Immunoglobulin A and M patterns to human cytomegalovirus (HCMV) were investigated in sera from actively HCMV infected AIDS patients (n = 61) and healthy HCMV seropositive controls (n = 28) by a Western blot method (modi-blotting) and ELISA. The Western blot showed a higher detection rate for both IgA (78.7% vs. 52.5%) and IgM (83.6% vs. 13.1%) than ELISA in the immunocompromised patients suffering from active HCMV infection. Of the healthy seropositive individuals, 35.7% and 21.4% had a weak positive IgA- and IgM-class antibody reactivity respectively with HCMV-specific bands in the immunoblot. Immunoglobulins M and A were not detected by ELISA in the healthy control group. Immunoreactions in this group were restricted to viral polypeptides with M(r) of 68 kDa and 123 kDa. Additional bands were found in the actively infected patients only and were observed more frequently with IgA than IgM (47.5% vs. 29.5%). Results from the present study indicate, that using a sensitive Western blot technique, a higher serologic detection rate of active recurrent infection is achieved in AIDS patients. Nevertheless, immunoglobulin A and M are detected in a certain percentage of HCMV-seropositive healthy individuals not suffering from active HCMV infection. Broader immune reactions of HCMV-IgA as determined by HCMV Western blot assay are associated with an active infection, but were not present in all the actively infected patients.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Glycosuria and diabetes mellitus in children and adolescents in south India.

In Madras city (India) 10,513 school students between 3 and 20 yr of age were investigated for glycosuria and its causes. While no previously known cases of diabetes mellitus of any type were encountered, four students (0.038%) in the survey population were found to have glycosuria. One (0.009%) had renal glycosuria, two (0.019%) were possibly NIDDY (MODY) and one (0.009%) had transient glycosuria while receiving anti-tuberculous chemotherapy. It is therefore concluded that neither diabetes mellitus nor glycosuria of non-diabetic causes is a crucial health problem in Indian children and adolescents. While the reasons for this are not known, further research in this field could be of global interest.

Adolescent↗
PubMed1994

NIDDM--genetic marker; glucose transporter, glucokinase, and mitochondria gene.

Candidate genes for NIDDM have been screened in Japanese. Mutations in the glucokinase gene were found in apparent late-onset NIDDM patients as well as in MODY patients. Clinical characteristics in the subjects with glucokinase gene mutations are similar to those in Caucasian subjects; diabetes mellitus is generally mild and some patients actually remain as having impaired glucose tolerance. Of great interest is that all affected subjects show blunted insulin secretion response to the glucose challenge, which is most commonly observed in Japanese NIDDM patients. Thus, it is possible that impairment in the regulation of glucokinase gene expression or its enzyme activity is associated with at least some Japanese NIDDM patients, though the prevalence of the mutations in the coding region is relatively low. In contrast, a mitochondrial tRNA(Leu(UUR)) gene mutation at np 3243 appears to be much more common, and diabetes due to this mutation has a progressive nature. Insulin secretory capacity progressively decreases, eventually reaching an insulin-dependent state in most patients. A surprising result is that this gene mutation is often observed in ICA-positive IDDM patients who were initially non-insulin-dependent, so called slowly progressive IDDM patients. These results suggest that the mitochondrial gene mutation may cause beta cell loss in addition to defects in glucose-induced signaling in pancreatic beta cells, which explains that the mitochondrial gene mutation manifests a wide range of diabetic phenotypes, from NIDDM to IDDM.

Asian People↗
PubMed1995

CA-repeated microsatellite polymorphism of the glucokinase gene and its association with non-insulin-dependent diabetes mellitus in Taiwanese.

Mutation of the glucokinase gene has recently been identified as a cause of maturity-onset diabetes of the young (MODY), a subset of non-insulin-dependent diabetes mellitus (NIDDM). However, its role in the wide variety of NIDDM remains controversial due to conflicting reports of association studies, negative results of linkage studies and low prevalence of glucokinase mutations in the common variety of NIDDM. In this study, two (CA)n-microsatellite polymorphisms flanking both ends of the glucokinase gene, termed GCK1 and GCK2, were used to evaluate the role of glucokinase on NIDDM susceptibility of Taiwanese. For GCK1, three alleles (Z,Z+2 and Z+4 with a polymorphic information content index (PIC) of 0.53) and six genotypes were evident in 119 Taiwanese. When compared with control subjects, the NIDDM group had a much less frequency of the Z+2 allele (14.0% vs. 23.9%). In addition, the Z+2 allele was noted to have a marginal protective effect for NIDDM in Taiwanese with the odds ratio of 0.52 (95% confidence interval (C.I.) 0.26-1.03, P = 0.058). For GCK2, four alleles (0, 2, 4 and 6 with a PIC of 0.48) and seven genotypes were identified. There was no significant difference in allele frequency between NIDDM and control groups in the locus of GCK2. Our data were in agreement with reports from American Blacks, Mauritian Creoles, Asian Indians, Japanese and Finnish--that there is a positive association of GCK1 and a negative association of GCK2 with NIDDM. Furthermore, the Z+2 allele was a protective factor for NIDDM in Taiwanese.

Alleles↗