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At least 1,171 records · Page 65Linked to original sources
PubMed1999

Relative hyperproinsulinemia as a sign of islet dysfunction in women with impaired glucose tolerance.

Proinsulin release is increased relative to insulin secretion in subjects with type 2 diabetes, indicative of islet dysfunction. However, it has not been conclusively shown whether there is an increased relative proinsulin release in subjects with impaired glucose tolerance (IGT), i.e. whether it precedes the development of diabetes. We therefore determined the proinsulin to insulin ratios in the fasting state and after acute stimulation of insulin secretion in 23 postmenopausal women, aged 61-62 yr (mean +/- SD, 61.7 +/- 0.5 yr). Ten women had normal glucose tolerance (NGT), and 13 had IGT. The groups were matched for insulin sensitivity and did not differ in body mass index. Proinsulin and insulin secretion were measured after arginine stimulation (5 g, i.v.) at three glucose levels (fasting, 14 mmol/L, and >25 mmol/L), and the acute insulin (AIR(arg)) and proinsulin responses (APIR(arg)) were calculated as the mean 2-5 min postload increase. At fasting glucose, levels of insulin, proinsulin, or the proinsulin/insulin ratio (13.6 +/- 5.0% vs. 11.1 +/- 2.7%; P = NS) did not differ between NGT and IGT. Although the AIR(arg) values were decreased in the IGT group at all glucose levels (P < 0.05), the absolute proinsulin levels and the APIRs(arg) were similar between IGT and NGT women. Therefore, the IGT women had higher proinsulin/insulin ratios at 14 mmol/L (10.7 +/- 4.4% vs. 6.4 +/- 1.8%; P = 0.006) and more than 25 mmol/L glucose (11.4 +/- 5.2% vs. 6.7 +/- 2.1%; P = 0.007). The IGT group had increased APIR(arg)/AIR(arg) at fasting (2.2 +/- 1.4% vs. 1.3 +/- 0.6%; P = 0.047) and more than 25 mmol/L glucose (3.5 +/- 1.6% vs. 2.3 +/- 0.7%; P = 0.037). We conclude that women with IGT exhibit increased relative proinsulin secretion, suggesting a defect in the intracellular proinsulin processing before diabetes develops.

Arginine↗
PubMed2001

Early-onset type 2 diabetes: metabolic and genetic characterization in the mexican population.

The objective of this study was to investigate possible defects in the insulin sensitivity and/or the acute insulin response in a group of Mexican patients displaying early-onset type 2 diabetes and to evaluate the contribution of mutations in three of the genes linked to maturity-onset diabetes of the young. We studied 40 Mexican patients with an age of diagnosis between 20 and 40 yr in which the insulin sensitivity as well as the insulin secretory response were measured using the minimal model approach. A partial screening for possible mutations in 3 of the 5 genes linked to maturity-onset diabetes of the young was carried out by PCR-single strand conformation polymorphism analysis. A low insulin secretory capacity (AIRg = 68.5 +/- 5 muU/mL.min) and a near-normal insulin sensitivity (3.43 +/- 0.2 min/muU.mL x 10(4)) were found in these patients. Among this group we found two individuals carrying missense mutations in exon 4 of the hepatocyte nuclear factor-1alpha (HNF-4alpha) gene (Asp(126)-->His/Tyr and Arg(154)-->Gln, respectively) and one carrying a nonsense mutation in exon 7 of the HNF-1alpha gene (Gln(486)-->stop codon); 7.5% had positive titers for glutamic acid decarboxylase antibodies. Thirty-five percent of cases had insulin resistance; these subjects had the lipid abnormalities seen in the metabolic syndrome. A defect in insulin secretion is the hallmark in Mexican diabetic patients diagnosed between 20 and 40 yr of age. Mutations in either the HNF-1alpha or the HNF-4alpha genes are present among the individuals who develop early-onset diabetes in our population. These particular sequence changes have not been previously reported and therefore represent putative new mutations. Even in the absence of endogenous hyperinsulinemia, insulin resistance is associated with an adverse lipid profile.

Adult↗
PubMed2002

Poor reproducibility of IGF-I and IGF binding protein-3 generation test in children with short stature and normal coding region of the GH receptor gene.

The IGF-I generation test has been proposed to select patients with GH insensitivity. Studies have shown that children with idiopathic short stature and GH deficiency, who were expected to be sensitive to GH, presented absent IGF-I and IGF binding protein (IGFBP)-3 responses and/or discordant results at IGF-I and IGFBP-3 generation test for unknown reasons. To assess the reproducibility of the generation test, we studied a group of 12 prepubertal children with short stature and normal GH secretion in whom defects in coding region of GH receptor gene were ruled out. All patients underwent the test twice. Discordant responses between the first and second test were found in five and six patients for IGF-I and IGFBP-3, respectively. When the results of the generation tests were compared, one notices that IGF-I generation has more concordant positive results than IGFBP-3. In eight generation tests that showed discordant results between IGF-I and IGFBP-3, seven presented a positive IGF-I with a negative IGFBP-3 response. Taking both tests into account, all children presented a normal IGF-I generation. Our findings showed that IGF-I and IGFBP-3 generation test was not reproducible in children that should have responded to GH stimulation. We suggest that, when IGF-I and IGFBP-3 levels fail to respond in the generation test, another test should be performed to confirm GH insensitivity.

Adolescent↗
PubMed2001

Sustained hyperglycemia and insulin resistance induced by dietary restriction.

This investigation considered whether defects in insulin secretion and insulin action may result in the development of sustained hyperglycemia induced by refeeding standard chow pellets. Hyperglycemia, sustained for 36 h was induced, in mice that ate standard chow pellets ad libitum after 48 h fasting, but not 24 h fasting. In 48 h-fasted mice, serum insulin levels were remarkably low and the ability of insulin secretion to respond to glucose was decreased, although insulin-stimulated glucose disposal was not impaired. However, hyperinsulinemia was observed after refeeding for 12 h. The 12 h-refed mice had impaired glucose tolerance and were remarkably insulin resistant. These results suggest that hyperglycemia induced by the fasting-refeeding was caused by hyperphagia and the failure of insulin secretion, and maintained the resulting induced insulin resistance.

Animals↗
PubMed2001

Signal integration and the specificity of insulin action.

Insulin is a potent metabolic hormone essential for the maintenance of normal circulating blood glucose level in mammals. The physiologic control of glucose homeostasis results from a balance between hepatic glucose release (glycogenolysis and gluconeogenesis) and dietary glucose absorption versus skeletal muscle and adipose tissue glucose uptake and disposal. Disruption of this delicate balance either through defects in insulin secretion, liver glucose output, or peripheral tissue glucose uptake results in pathophysiological states of insulin resistance and diabetes. In particular, glucose transport into skeletal muscle and adipose tissue is the rate-limiting step in glucose metabolism and reduction in the efficiency of this process (insulin resistance) is one of the earliest predictors for the development of Type II diabetes. Importantly, recent studies have directly implicated an impairment in insulin receptor signal transduction as the prime mechanism for peripheral tissue insulin resistance. In this review, we have focused on recent developments in our understanding of the molecular mechanisms and signal transduction pathways that insulin utilizes to specifically regulate glucose uptake. The detailed understanding of these events will provide a conceptual framework for the development of new therapeutic targets to treat this chronic and debilitating disease process.

Adipose Tissue↗
PubMed2000

Fecal pancreatic elastase 1 in the work up of patients with chronic diarrhea.

BACKGROUND: Quantitative determination of pancreatic elastase-1 (E1) in stools has been proposed as a novel, noninvasive test of pancreatic function. The aim of the study was to verify its role in the differential diagnosis of chronic diarrhea. METHODS: E1 was measured in spot stool samples of 50 patients with pancreatic disease (PD), 62 with inflammatory bowel disease (IBD), 45 with chronic diarrhea (CD), 34 with other gastroduodenal and liver disease (gastrointestinal; GI), and in 18 normal controls, by a commercial kit (Schebo-Tech., Wettemburg, Germany). RESULTS: In PD, patients with severe damage and diarrhea displayed E1 levels below 100 microg/g; normal values were found in mild-moderate disease. Abnormal values were detected in 4 CD and in 14 IBD patients, either in the presence of severe protein malnutrition or in patients with previous ileo-anal pouch anastomosis and pouchitis. In nine cases, values reverted to normal after adequate treatment. Diagnostic accuracy of E1 in discriminating diarrhea of pancreatic and nonpancreatic origin was: SS, 97%; SP, 84%; VP+, 66%; VP-, 100%. CONCLUSION: 1) The finding of a normal E1 value rules out a malabsorption of pancreatic origin. 2) in CD and IBD, decreased E1 might be owing to bacterial elastase degradation (pouchitis) or transient defective pancreatic enzyme secretion.

Adolescent↗
PubMed1978

Development of the insulin secretory defect in genetically diabetic (db/db) mouse.

Genetically diabetic mice (C57BL/KsJ-db/db) were used as a model to study the development of defects of insulin secretion in relation to common metabolic indicators (body weight, serum glucose and insulin, and islet insluin contant). Consistent with the idea of a protective effect of oestrogen on the pancreatic beta-cell, the female diabetic mice survived longer than the males. In males, while serum insulin decreased in the later stages of the disease, serum glucose increased progressively with age. Perfusion of the diabetic pancreases revealed a rise and subsequent fall with age of the basal insulin released at 3 mM glucose. Despite previous reports of beta-cell hyperplasia, progressive impairment of the insulin response to 20 mM glucose, or to 20 mM glucose and 1 mM 3-isobutyl-1-methylxanthine, was seen with increasing age in experiments with perfused pancreas or microdissected islets. Islet content of insulin also decreased progressively with age in the diabetic animals.

Age Factors↗
PubMed1985

Comparison of histology and immunohistochemistry with thyroglobulin serum levels and radioiodine uptake in recurrences and metastases of differentiated thyroid carcinomas.

The importance of lightmicroscopical and immunohistochemical features of 38 recurrent differentiated thyroid carcinomas (27 papillary carcinomas (PC), 11 follicular carcinomas (FC] for post-operative serum thyroglobulin (TG) concentrations was analysed in regard to pre-operative serum TG levels with tumour type, histological and cytological differentiation, volume fraction of TG synthesizing tumour cells (TG immunohistomorphometry), tumour volume and radioiodine uptake (RIU). Serum TG concentrations increased with tumour size and the number of TG synthesizing tumour cells (r = 0.5). PC and FC did not differ in their volume proportions of TG synthesizing tumour cells, while TG serum levels in FC significantly exceeded those of PC of similar size. The low TG serum levels found in PC might be explained by a specific defect in thyroglobulin secretion. Carcinomas with partial or total cytologic metaplasia (e.g. oxyphilic carcinomas) had low volume proportions of TG synthesizing cells and low serum TG levels. Thirteen of the 38 differentiated carcinomas (34.2%) showed both high TG serum levels and positive RIU, 17 (44.7%) disclosed only elevated TG serum levels and 6 (15.8%) a positive RIU. In two cases (5.3%) TG serum levels were not elevated and RIU's were negative. TG immunostaining was positive in all 38 cases. In summary, TG serum levels depend on the following morphologic factors in differentiated thyroid carcinomas: 1) Number of TG synthesizing tumour cells, 2) Mode of TG secretion and 3) Cytological differentiation of the tumour cells. Serum TG levels did not predict total body iodine scan.

Adolescent↗
PubMed2000

The cystic fibrosis transmembrane regulator (CFTR) in the kidney.

The cystic fibrosis transmembrane regulator (CFTR) is a Cl - channel. Mutations of this transporter lead to a defect of chloride secretion by epithelial cells causing the Cystic Fibrosis disease (CF). In spite of the high expression of CFTR in the kidney, patients with CF do not show major renal dysfunction, but it is known that both the urinary excretion of drugs and the renal capacity to concentrate and dilute urine is deficient. CFTR mRNA is expressed in all nephron segments and its protein is involved with chloride secretion in the distal tubule, and the principal cells of the cortical (CCD) and medullary (IMCD) collecting ducts. Several studies have demonstrated that CFTR does not only transport Cl - but also secretes ATP and, thus, controls other conductances such as Na+ (ENaC) and K+ (ROMK2) channels, especially in CCD. In the polycystic kidney the secretion of chloride through CFTR contributes to the cyst enlargement. This review is focused on the role of CFTR in the kidney and the implications of extracellular volume regulators, such as hormones, on its function and expression.

Chlorides↗
PubMed1999

The use of sulphonylureas in the elderly.

Type 2 diabetes mellitus is a heterogeneous disorder characterised by defects in insulin secretion as well as reduced insulin action. During aging, glucose intolerance will gradually develop, and this is manifested primarily by an increase in the postprandial blood glucose response while fasting blood glucose levels are often less elevated. Abnormal beta-cell secretion of insulin is a main feature of this. Treatment of elderly patients with type 2 diabetes mellitus focuses on reduction of (hyperglycaemic) complaints and prevention of the development or progression of secondary complications. Although regular physical activity and dietary measures, aiming at bodyweight normalisation, are the cornerstones of therapy, pharmacological treatment with oral blood glucose lowering-agents often proves necessary to control the hyperglycaemia. In the United Kingdom Prospective Diabetes Study (UKPDS) it was clearly shown that patients with type 2 diabetes mellitus who were intensively treated with oral blood glucose-lowering agents or insulin developed less microvascular complications. The question whether achievement of strict metabolic control is also of benefit in elderly patients, is still unanswered. Sulphonylureas are drugs which stimulate insulin secretion by enhancing the release of insulin from the pancreatic beta-cells without an effect on insulin synthesis. They are frequently used in the treatment of type 2 diabetes mellitus, and several preparations are available. In general, there are no major differences in effectiveness between the various sulphonylureas. Long term treatment with sulphonylureas will decrease fasting and postprandial plasma glucose levels by 3 to 5 mmol/L, and glycosylated haemoglobin by 20%. However, after its initial decline, plasma glucose level will often go up slightly during the following months to years. Sulphonylureas are usually well tolerated. Hypoglycaemia is the most frequently occurring adverse effect, which may be very serious and damaging in the elderly. It has been associated primarily with long-acting sulphonylureas, like chlorpropamide and glibenclamide (glyburide). Hypoglycaemic episodes may trigger serious events like myocardial infarction or stroke. Therefore, shorter-acting compounds like tolbutamide and gliclazide have been relatively well tolerated and appear to be the best choice to treat elderly patients. It is advisable to start with a low dose and increase the dose, when needed, in small steps. The efficacy of sulphonylureas is much greater when they are taken before a meal. Because of the fact that type 2 diabetes mellitus is a progressive disease, and residual beta-cell function decreases with time, insulin therapy may ultimately be warranted in a significant number of patients.

Aged↗
PubMed2007

Pharmacokinetic interactions with thiazolidinediones.

Type 2 diabetes mellitus is a complex disease combining defects in insulin secretion and insulin action. New compounds called thiazolidinediones or glitazones have been developed for reducing insulin resistance. After the withdrawal of troglitazone because of liver toxicity, two compounds are currently used in clinical practice, rosiglitazone and pioglitazone. These compounds are generally used in combination with other pharmacological agents. Because they are metabolised via cytochrome P450 (CYP), glitazones are exposed to numerous pharmacokinetic interactions. CYP2C8 and CYP3A4 are the main isoenzymes catalysing biotransformation of pioglitazone (as with troglitazone), whereas rosiglitazone is metabolised by CYP2C9 and CYP2C8. For both rosiglitazone and pioglitazone, the most relevant interactions have been described in healthy volunteers with rifampicin (rifampin), which results in a significant decrease of area under the plasma concentration-time curve [AUC] (54-65% for rosiglitazone, p<0.001; 54% for pioglitazone, p<0.001), and with gemfibrozil, which results in a significant increase of AUC (130% for rosiglitazone, p<0.001; 220-240% for pioglitazone, p<0.001). The relevance of such drug-drug interactions in patients with type 2 diabetes remains to be evaluated. However, in the absence of clinical data, it is prudent to reduce the dosage of each glitazone by half in patients treated with gemfibrozil. Conversely, rosiglitazone and pioglitazone do not seem to significantly affect the pharmacokinetics of other compounds. Although some food components have also been shown to potentially interfere with drugs metabolised with the CYP system, no published study deals specifically with these possible CYP-mediated food-drug interactions with glitazones.

Diabetes Mellitus↗
PubMed1997

Drug treatment of non-insulin-dependent diabetes mellitus in the 1990s. Achievements and future developments.

Non-insulin-dependent diabetes mellitus (NIDDM, type 2 diabetes) is a heterogeneous disease resulting from a dynamic interaction between defects in insulin secretion and insulin action. There are various pharmacological approaches to improving glucose homeostasis, but those currently used in clinical practice either do not succeed in restoring normoglycaemia in most patients or fail after a variable period of time. For glycaemic regulation, 4 classes of drugs are currently available: sulphonylureas, biguanides (metformin), alpha-glucosidase inhibitors (acarbose) and insulin, each of which has a different mode and site of action. These standard pharmacological treatments may be used individually for certain types of patients, or may be combined in a stepwise fashion to provide more ideal glycaemic control for most patients. Adjunct treatments comprise a few pharmacological approaches which may help to improve glycaemic control by correcting some abnormalities frequently associated with NIDDM, such as obesity (serotoninergic anorectic agents) and hyperlipidaemia (benfluorex). There is intensive pharmaceutical research to find new drugs able to stimulate insulin secretion (new sulphonylurea or nonsulphonylurea derivatives, glucagon-like peptide-1), improve insulin action (thiazolidinediones, lipid interfering agents, glucagon antagonists, vanadium compounds) or reduce carbohydrate absorption (miglitol, amylin analogues, glucagon-like peptide-1). Further studies should demonstrate the superiority of these new compounds over the standard antidiabetic agents as well as their optimal mode of administration, alone or in combination with currently available drugs.

Acarbose↗
PubMed1998

Oral antidiabetic agents. A guide to selection.

Type 2 diabetes mellitus (formerly named non-insulin-dependent diabetes mellitus or NIDDM) is a heterogeneous disease resulting from a dynamic interaction between defects in insulin secretion and insulin action. Various pharmacological approaches can be used to improve glucose homeostasis via different modes of action: sulphonylureas essentially stimulate insulin secretion, biguanides (metformin) act by promoting glucose utilisation and reducing hepatic-glucose production, alpha-glucosidase inhibitors (acarbose) slow down carbohydrate absorption from the gut and thiazolidinediones (troglitazone) enhance cellular insulin action on glucose and lipid metabolism. These pharmacological treatments may be used individually for certain types of patients, or may be combined in a stepwise fashion to provide more ideal glycaemic control for most patients. Selection of oral antihyperglycaemic agents as first-line drug or combined therapy should be based on both the pharmacological properties of the compounds (efficacy and safety, profile) and the clinical characteristics of the patient (stage of disease, bodyweight, etc.). Mildly hyperglycaemic patients should preferably be treated with metformin, acarbose or thiazolidinediones (which are not associated with any hypoglycaemic risk), while more severely hyperglycaemic individuals should receive a sulphonylurea. In moderately hyperglycaemic patients, sulphonylureas should be preferred in nonobese patients while metformin, and probably also thiazolidinediones, should have priority in obese insulin-resistant type 2 diabetic patients. Acarbose is mainly indicated to reduce post-prandial glucose fluctuations and improve glycaemic stability. Each antihyperglycaemic agent may also be combined with insulin therapy to improve glycaemic control and/or reduce the insulin requirement of diabetic patients after secondary failure to oral treatment. Finally, safety should be taken into account in elderly patients and/or those with renal impairment, especially as far as the use of sulphonylureas (higher risk of hypoglycaemia) and metformin (higher risk of lactic acidosis) is concerned.

Administration, Oral↗
PubMed2004

Genetic basis of type 2 diabetes mellitus: implications for therapy.

Type 2 diabetes mellitus represents a multifactorial, heterogeneous group of disorders, which result from defects in insulin secretion, insulin action, or both. The prevalence of type 2 diabetes has increased dramatically worldwide over the past several decades, a trend that has been heavily influenced by the relatively recent changes in diet and physical activity levels. There is also strong evidence supporting a genetic component to type 2 diabetes susceptibility and several genes underlying monogenic forms of diabetes have already been identified. However, common type 2 diabetes is likely to result from the contribution of many genes interacting with different environmental factors to produce wide variation in the clinical course of the disease. Not surprisingly, the etiologic complexity underlying type 2 diabetes has made identification of the contributing genes difficult. Current therapies in the management of type 2 diabetes include lifestyle intervention through diet modification and exercise, and oral or injected hypoglycemic agents; however, not all individuals with type 2 diabetes respond in the same way to these treatments. Because of variability in the clinical course of the disease and in the responsiveness to pharmacologic therapies, identification and characterization of the genetic variants underlying type 2 diabetes susceptibility will be important in the development of individualized treatment. Findings from linkage analyses, candidate gene studies, and animal models will be valuable in the identification of novel pathways involved in the regulation of glucose homeostasis, and will augment our understanding of the gene-gene and gene-environment interactions, which impact on type 2 diabetes etiology and pathogenesis. In addition, identification of genetic variants that determine differences in antidiabetic drug responsiveness will be useful in assessing a first-line pharmacologic therapy for diabetic patients.

Calpain↗
PubMed1977

Deranged insulin-secretory dynamics in offspring of two diabetic parents after double stimulation with intravenous glucose.

Nine offspring of two diabetic parents and 18 normals were studied with two intravenous glucose loads (o.5 gm./kg. body weight), 60 minutes apart. By thus stressing the beta cell, subtle defects could be identified in the prediabetics: (1) An inverse relationship between insulin peak response and insulin concentration 60 minutes postglucose was seen, a phenomenon exactly the opposite to that seen in normals. (2) Insulin peak response was delayed slightly after the first pulse and significantly after the second. (3) A less effective handling of the glucose load when compared with normals was brought out by the second stimulation. (4) There was a significant reduction in the insulin response per unit change in glucose after the first glucose pulse that was accentuated after the second pulse. This double-stimulation technique amplifies previously detected slight but significant defects in insulin secretion that might help to identify a diabetes-prone population.

Adolescent↗
PubMed1995

Localization of MODY3 to a 5-cM region of human chromosome 12.

Maturity-onset diabetes of the young (MODY) is a heterogeneous disorder that appears to be characterized by a primary defect in insulin secretion. Mutations in an unknown locus (MODY1) on chromosome 20 and the glucokinase gene (MODY2) on chromosome 7 can cause this form of non-insulin-dependent diabetes. Recent genetic studies have identified a third locus on chromosome 12 (MODY3) that is linked to MODY in a group of French families. We have identified three families from Denmark, Germany, and the U.S. (Michigan) showing evidence of linkage with MODY3 and a family from Japan showing suggestive evidence. Analysis of key recombinants in these families localized MODY3 to a 5-cM interval between the markers D12S86 and D12S807/D12S820.

Adult↗
PubMed2001

Hepatocyte nuclear factor-4alpha involved in type 1 maturity-onset diabetes of the young is a novel target of AMP-activated protein kinase.

Mutations in the HNF4alpha gene are responsible for type 1 maturity-onset diabetes of the young (MODY1), which is characterized by a defect in insulin secretion. Hepatocyte nuclear factor (HNF)-4alpha is a transcription factor that plays a critical role in the transcriptional regulation of genes involved in glucose metabolism in both hepatocytes and pancreatic beta-cells. Recent evidence has implicated AMP-activated protein kinase (AMPK) in the modulation of both insulin secretion by pancreatic beta-cells and the control of glucose-dependent gene expression in both hepatocytes and beta-cells. Therefore, the question could be raised as to whether AMPK plays a role in these processes by modulating HNF-4alpha function. In this study, we show that activation of AMPK by 5-amino-4-imidazolecarboxamide riboside (AICAR) in hepatocytes greatly diminished HNF-4alpha protein levels and consequently downregulates the expression of HNF-4alpha target genes. Quantitative evaluation of HNF-4alpha target gene expression revealed diminished mRNA levels for HNF-1alpha, GLUT2, L-type pyruvate kinase, aldolase B, apolipoprotein (apo)-B, and apoCIII. Our data clearly demonstrate that the MODY1/HNF-4alpha transcription factor is a novel target of AMPK in hepatocytes. Accordingly, it can be suggested that in pancreatic beta-cells, AMPK also acts by decreasing HNF-4alpha protein level, and therefore insulin secretion. Hence, the possible role of AMPK in the physiopathology of type 2 diabetes should be considered.

AMP-Activated Protein Kinases↗
PubMed2002

Hepatocyte nuclear factor-1alpha recruits the transcriptional co-activator p300 on the GLUT2 gene promoter.

Mutations in the hepatocyte nuclear factor (HNF)-1alpha gene have been linked to subtype 3 of maturity-onset diabetes of the young (MODY), a disease characterized by a primary defect in insulin secretion. Here we show that the human GLUT2 gene is closely regulated by HNF-1alpha via sequences downstream of the transcriptional start site by interaction with transcriptional co-activator p300. The promoter region of the human GLUT2 gene was subcloned into luciferase expression plasmids that were transfected together with HNF-1alpha expression plasmid into a pancreatic beta-cell line, HIT-T15, to evaluate transcriptional activities. HNF-1alpha enhanced human GLUT2 promoter activity sixfold. Site-direct mutagenesis and footprint analyses showed that the HNF-1alpha binding site (+200 to +218) is critical in human GLUT2 gene expression. Furthermore, mammalian two-hybrid and immunoprecipitation studies revealed the transactivation domain of HNF-1alpha (amino acids 391-540) to interact with both the NH(2)-terminal region (amino acids 180-662) and the COOH-terminal region (amino acids 1,818-2,079) of p300. These findings demonstrated that HNF-1alpha binds to the 5'-untranslated region of GLUT2 and that p300 acts as a transcriptional co-activator for HNF-1alpha. In addition, these results provided new insight into the regulatory function of HNF-1alpha by suggesting a molecular basis for human GLUT2 gene expression.

5' Untranslated Regions↗