Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.1.1 (hexokinase)
 5,274 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The importance of the glucose transporter isoform, GLUT2, in the construction of glucose-sensitive surrogate insulin-secreting cells was evaluated using murine pituitary AtT20 cells. The cells were double transfected with cDNAs for human preproinsulin (hppI-1) driven by the cytomegalovirus promoter, and human GLUT2 driven by the beta-actin promoter. The stably transfected clone, AtTinsGLUT2.36, which strongly expressed both the hppI-1 and GLUT2 genes, constitutively released 7.5 ng/10(6) cells/24 h of immunoreactive insulin-like material, 75% of which was fully processed mature human insulin. Increasing glucose concentrations in the subphysiological range up to 50 microM increased insulin release, but greater glucose concentrations did not further increase insulin release. Suppression of the low-K(m) glucose-phosphorylating enzyme, hexokinase, with 2-deoxy-D-glucose increased glucose-stimulated insulin release by two- to threefold in the presence of subphysiological and physiological glucose concentrations up to 10 mM. Physiological glucose concentrations increased the amount of GLUT2 mRNA, indicating that the beta-actin promoter responds in a glucose-dependent manner. Implantation of 2 x 10(7) AtTinsGLUT2.36 cells intraperitoneally into streptozotocin-diabetic nude mice slowed the progression of hyperglycaemia. The implanted cells formed vascularised tumour-like cell aggregates attached to the peritoneum. The results demonstrate that the beta-actin promoter is partially regulated by glucose. Expression of GLUT2 enables glucose to enter the cell at high K(m), but high-K(m) glucose phosphorylation is also required to signal glucose-stimulated genes affecting insulin release.
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PMID:Expression of GLUT2 in insulin-secreting AtT20 pituitary cells. 951 84

Obese individuals are more likely to suffer from diseases termed the "metabolic syndrome," which includes type 2 diabetes. It is now recognized that early life dietary experiences play an important role in the etiology of such diseases. In this context, the consequences of a high carbohydrate (HC) dietary intervention in neonatal rats is being studied in our laboratory. Artificial rearing of 4-day-old rat pups on a HC milk formula up to Day 24 results in the immediate onset of hyperinsulinemia, which persists throughout the period of dietary intervention. Several adaptations at the biochemical, cellular, and molecular levels in the islets of these HC rats support the onset and persistence of the hyperinsulinemic condition during this period. Some of these adaptations include a distinct leftward shift in the insulin secretory capacity, increased hexokinase activity, increased gene expression of preproinsulin and related transcription factors and specific kinases in 12-day-old HC islets, and alterations in the number and size of islets. These adaptations are programmed and expressed in adulthood thereby sustain the hyperinsulinemic condition in the postweaning period and form the basis for adult-onset obesity. HC females spontaneously transmit the HC phenotype (chronic hyperinsulinemia and adult-onset obesity) to their progeny. Collectively, our results indicate that even a mere switch in the nature of the source of calories (from fat rich in rat milk to carbohydrate rich in the HC milk formula) during critical phases of early development in the rat results in metabolic programming of islet functions leading to chronic hyperinsulinemia (throughout life) and adult-onset obesity. This metabolic programming, once established, forms a vicious cycle because HC female rats spontaneously transmit the HC phenotype to their progeny. The results from our laboratory in the context of metabolic programming due to neonatal nutritional experiences are discussed in this review.
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PMID:Neonatal nutrition: metabolic programming of pancreatic islets and obesity. 1252 68

Neonatal female rat pups that were raised artificially on a high-carbohydrate (HC) milk formula during their suckling period developed hyperinsulinemia immediately, maintained chronic hyperinsulinemia in the postweaning period on laboratory diet, and developed obesity in adulthood. Pups (second-generation HC [2-HC]) born to such female rats (first-generation HC [1-HC]) spontaneously developed chronic hyperinsulinemia and adult-onset obesity (HC phenotype) without the requirement for any dietary intervention in their suckling period. Leftward shift in the insulin secretory response to a glucose stimulus, increase in hexokinase activity, and increased preproinsulin gene transcription were observed in islets from 28-day-old 2-HC rats, and these adaptations are similar to those reported for islets from 12-day-old and 100-day-old 1-HC rats. Unlike 1-HC islets, the ability to secrete moderate amounts of insulin in the absence of glucose and calcium and the incretin input for augmentation of insulin secretion were not observed in 2-HC islets. These results show that a dietary modification in the early postnatal life of the 1-HC female rat sets up a vicious cycle of spontaneous transfer of the HC phenotype to its progeny, implicating a new component to the growing list of factors that contribute to the fetal origins of adult-onset diseases.
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PMID:Programming of islet functions in the progeny of hyperinsulinemic/obese rats. 1266 70