Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029713 (immaturity)
 4,335 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cause of the poor secretion of insulin in response to glucose by the beta-cell in the fetal rat pancreas is thought to be immaturity of the metabolism of glucose. Glucokinase (GK), a key enzyme in glycolysis, is the glucose sensor that maintains glucose homeostasis in the adult beta-cell; its role in the fetal beta-cell has not been determined. The aim of this study was to examine whether GK was functional in phosphorylation of glucose in the fetal islet, and if so, to determine what factors regulated this activity. Similar Km values were found in both fetal and adult islets: 7.4 vs. 7.7 mmol/l. The maximal GK velocity (Vmax) of the fetal islet and the contribution of GK to total glucose phosphorylation were also not significantly different from their adult counterparts. Western blot analysis of protein extracts from fetal and adult islets confirmed the presence of GK at 52 kDa. To determine if glucose had any effect on the Vmax of GK, islets were cultured for 7 days in medium containing low (1.4 or 2.8 mmol/l), normal (5.6 mmol/l), or high (11.2 or 16.8 mmol/l) concentrations of glucose. The maximal GK velocity increased linearly with increasing concentrations of glucose (r = 0.93; P < 0.01). To determine whether it was possible to up- and down-regulate Vmax of GK, islets were cultured in either a low (1.4 mmol/l) or high (30 mmol/l) concentration of glucose for 7 days and then switched to the opposite concentration for a further 3 days. The Vmax of GK in the fetal islet was upregulated 3.8-fold when the glucose concentration was raised. Conversely, the Vmax was downregulated 3.6-fold when the glucose concentration was lowered. The same phenomenon was also observed in the adult islet. These data indicate that GK is the glucose sensor for the fetal rat islet, just as it is for the adult islet. Since glucose did not cause insulin secretion from the fetal islet, it was important to examine whether this substrate had any effect on its own metabolism. Glucose utilization was estimated, and its Vmax was found to increase linearly with increasing concentrations of glucose (r = 0.96; P < 0.01). We conclude that the inability of the fetal rat beta-cell to secrete insulin in response to glucose cannot be explained by immaturity of GK or the glycolytic pathway.
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PMID:Glucose regulates the maximal velocities of glucokinase and glucose utilization in the immature fetal rat pancreatic islet. 869 Jan 54

Glucokinase (GK) is the glucose sensor in the adult beta-cell, resulting in fuel for insulin synthesis and secretion. Defects in this enzyme in the beta-cell are responsible for the genetic disorder maturity-onset diabetes of the young, with the beta-cell being unable to secrete insulin appropriately when challenged with glucose. The human fetal beta-cell is also unable to secrete insulin when exposed to glucose, but whether GK is present and functional in this developing cell is unknown. To determine the expression of GK in human fetal pancreatic tissue, cytosolic protein was extracted from human fetal islet-like cell clusters (ICCs) at 17-19 weeks gestation and examined for protein content and enzyme activity. On Western blots, a single band corresponding to GK was seen at 52 kDa, and this was similar to that obtained from human adult islets. The maximal velocity (Vmax) of GK was less in fetal ICCs than that in adult islets (8.7 vs. 20.7 nmol/mg protein x h); similar K(m) values were found in both ICCs and islets. No attempt was made to determine which cells in an ICC contained GK. Glucose utilization was determined radiometrically; the Vmax of the high K(m) component was less in ICCs than in islets (31.3 pmol/ICC x h vs. 101.4 pmol/islet.h). Culture of ICCs for 3-7 days in medium containing 11.2 mmol/L glucose resulted in a 3.7-fold increase in the Vmax of GK and a 1.8-fold increase in glucose utilization. These enhanced activities of glucose phosphorylation and glycolysis, however, did not lead to the beta-cell being able to secrete insulin when exposed to glucose. In conclusion, glucokinase is present and functional in human fetal ICCs, but the inability of the human fetal beta-cell to secrete insulin in response to an acute glucose challenge is not due to immaturity of this enzyme.
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PMID:Expression of glucokinase in glucose-unresponsive human fetal pancreatic islet-like cell clusters. 906 11

Insulin-dependent neonatal diabetes (ND) mellitus is uncommon with a frequency of 1/500,000 neonates in Europe. ND is characterised by hyperglycaemia, very low or undetectable insulin levels associated with intrauterine growth retardation and malformations. HLA haplotypes of juvenile diabetes or autoimmunity are not present in ND patients. Sporadic and familial forms are observed. ND could be persistent (PND) or transient (TND). Diabetes relapses occur in approximately 40% of TND patients. Hypothesis for ND aetiology such as pancreatic or beta pancreatic islets of Langerhans immaturity or abnormalities of pancreas organogenesis are postulated. Different genetic basis underlie transient or permanent forms though their clinical features do not allow to distinguish them. TND may in about 20-30% of the cases be associated with chromosome 6 paternal uniparental disomy. A candidate locus for an imprinted gene is mapped to 6q24. The permanent forms are less understood. Homozygous mutations of the IPF1/PDX1 (MODY4) and of the Glucokinase (GK, MODY2) genes have been reported. The association of a ND with a macroglossia should be a strong indicator for genetic testing. The genetic findings of a paternal disomy uniparental allows the prediction of a transient rather than a permanent form. Mutation in the Glucokinase gene should be sought in an infant with ND whose first degree relatives have glucose intolerance.
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PMID:[Insulin-dependent neonatal and infant diabetes: genetics and physiopathology]. 1208 68