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

Why is it important to understand the mechanisms controlling intestinal adaptation? There are two major answers to this question. Firstly, in establishing the cellular and molecular events associated with intestinal adaptation, we will formulate a general framework that may be applied to the understanding of adaptation of other cell membranes. For example, alterations in the synthesis of glucose carriers and their subsequent insertion into membranes may alter sugar entry across the intestinal brush border membrane (BBM) using the sodium-dependent D-glucose transporter, SGLT1, or the BBM sodium-independent facultative fructose transporter, GLUT5, and may alter facilitated sugar exit across the basolateral membrane (BLM) using GLUT2. The precise role of transcriptional and translational processes in the up- or down-regulation of sugar transport requires further definition. Alterations in enterocyte microsomal lipid metabolic enzyme expression occurring during the course of intestinal adaptation will direct the synthesis of lipids destined for trafficking to the BBM and BLM domains of the enterocyte. This will subsequently alter the passive permeability properties of these membranes and ultimately influence lipid absorption. Therefore, establishing the physiological, cellular and molecular mechanisms of adaptation in the intestine will define principles that may be applied to other epithelia. Secondly, enterocyte membrane adaptation is subject to dietary modification, and these may be exploited as a means to enhance a beneficial or to reduce a detrimental aspect of the intestinal adaptive process in disease states. Alterations in membrane function occur in association with changes in dietary lipids, and these are observed in a variety of cells and tissues including lymphocytes, testes, liver, adipocytes, nerve tissue, nuclear envelope and mitochondria. Therefore, the elucidation of the mechanisms of intestinal adaptation and the manner whereby dietary manipulation modulates these processes affords the future possibility of dietary engineering aimed at using food as a therapeutic agent. It is hoped this approach will form the centerpiece for future investigation that would focus on disease prevention, as well as on the development of better therapeutic strategies to prevent the development or to treat the complications of conditions such as diabetes mellitus, obesity, hyperlipidemia and inflammatory bowel diseases. This review deals with the physiology of glucose transport with specific emphasis on transporters of the brush border membrane (BBM) and the basolateral membrane (BLM). On the BBM the sodium (Na)/glucose transporters (SGLT1 and SGLT2), the Na-independent transporter (GLUT5), and on the BLM the hexose transporter (GLUT2) are discussed. The molecular biology of these transporters is also reviewed.
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PMID:Adaptation of intestinal nutrient transport in health and disease. Part I. 907 26

The first part of this review dealt with the physiology of glucose transport with specific emphasis on transporters of the brush border membrane (BBM) and the basolateral membrane (BLM). On the BBM, the sodium (Na)/glucose transporters (SGLT1 and SGLT2), the Na-independent transporter (GLUT5) and on the BLM the hexose transporter (GLUT2) are discussed. The molecular biology of these transporters is also reviewed. In the second part of the review, we discuss the manner in which intestinal adaptation may be modified by alterations in the diet, especially the lipid constituents, and two important examples of intestinal adaptation will be given: diabetes mellitus and inflammatory bowel disease.
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PMID:Adaptation of intestinal nutrient transport in health and disease. Part II. 907 27

Impaired glucose-stimulated insulin secretion and impaired insulin-mediated glucose uptake are both prominent phenotypic features of non-insulin-dependent diabetes mellitus (NIDDM). Membrane proteins GLUT1 (HepG2), GLUT2 (liver/islet), and GLUT4 (muscle/adipose tissue) facilitate glucose uptake into cells, and their genes are candidates for NIDDM. To assess their role in primary defects of diabetes, we performed linkage analyses between NIDDM and 10 polymorphic markers near GLUT1, GLUT2 and GLUT4 genes in 79 multiplex French NIDDM families. Linkage analyses were performed using both parametric (lodscore) and non-parametric (allele sharing among affected sib pairs) methods. No evidence was found for linkage between NIDDM and GLUT1, GLUT2 and GLUT4 regions, regardless of the methods or models used for analyses. Thus, these familial linkage studies demonstrate that GLUT1, GLUT2 and GLUT4 loci did not contribute significantly to NIDDM in this cohort. The decreased expression of glucose transporters observed in some NIDDM patients may be secondary to other genetic or environmental defects.
Diabetes Metab 1997 Apr
PMID:Genetic analyses of glucose transporter genes in French non-insulin-dependent diabetic families. 913 2

Cellular engineering studies in our group are directed at creating insulin-secreting cell lines that simulate the performance of the normal islet beta-cell. The strategy described in this article involves the stepwise stable introduction of genes relevant to beta-cell performance into the RIN 1046-38 insulinoma cell line, a process that we term "iterative engineering." RIN cells stably engineered to contain multiple copies of the human insulin gene exhibit a large increase in insulin content, such that they approach the content of human islets assayed in parallel. Analysis by high-performance liquid chromatography demonstrates that these engineered cell lines process human proinsulin to mature insulin with high efficiency. Cell lines that are further engineered to express the GLUT2 and glucokinase genes demonstrate stable expression of the three transgenes for the full lifetime of the lines produced to date (6 months to 1 year in continuous culture). Transplantation of the engineered cell lines into nude rats reveals that stably integrated genes are expressed at constant levels in the in vivo environment over the full duration of experiments performed (48 days). Several endogenous genes expressed in normal beta-cells, including rat insulin, amylin, sulfonylurea receptor, and glucokinase, are stably expressed in the insulinoma lines during these in vivo studies. Endogenous GLUT2 expression, in contrast, is rapidly extinguished during in vivo passage. The loss of GLUT2 is overcome in engineered cell ines in which transporter expression is provided by a stably transfected transgene. These results suggest that a potential advantage of the iterative engineering approach may be to preserve stability of function and phenotype, particularly in the in vivo setting.
Diabetes 1997 Jun
PMID:Novel insulinoma cell lines produced by iterative engineering of GLUT2, glucokinase, and human insulin expression. 916 66

In the accompanying article, we describe the creation of novel cell lines derived from RIN 1046-38 rat insulinoma cells by stable transfection with combinations of genes encoding human insulin, GLUT2, and glucokinase. Herein we describe the regulation of insulin secretion and glucose metabolism in these new cell lines. A cell line (betaG I/17) expressing only the human proinsulin transgene exhibits a clear increase in basal insulin production (measured in the absence of secretagogues) relative to parental RIN 1046-38 cells. betaG I/17 cells engineered for high levels of GLUT2 expression and a twofold increase in glucokinase activity (betaG 49/206) or engineered for a 10-fold increase in glucokinase activity alone (betaG 40/110) exhibit a 66% and 80% suppression in basal insulin secretion relative to betaG I/17 cells, respectively. As a result, betaG 49/206 and betaG 40/110 cells exhibit potent insulin-secretory responses to glucose alone (6.1- and 7.6-fold, respectively) or to glucose plus isobutylmethylxanthine (10.8- and 15.1-fold, respectively) that are clearly larger than the corresponding responses of betaG I/17 or parental RIN 1046-38 cells. betaG 49/206 and betaG 40/110 cells also exhibit a rapid and sustained response to glucose plus isobutyl-methylxanthine in perifusion studies that is clearly larger in magnitude than that of the two control lines. Glucose dose-response studies show that both engineered and non-engineered lines respond maximally to submillimolar concentrations of glucose and that betaG 49/206 cells are the most sensitive to low concentrations of the hexose, consistent with their clearly elevated rate of [5-3H]glucose usage. Finally, 5-thioglucose, a potent inhibitor of low-K(m) hexokinases, most effectively normalizes glucose concentration dependence for insulin secretion in the cell line with highest glucokinase expression (betaG 40/110). We conclude that GLUT2 and/or glucokinase expression imposes tight regulation of basal insulin secretion in cell lines that overexpress human proinsulin, allowing a marked improvement in the range of secretagogue responsiveness in such cells.
Diabetes 1997 Jun
PMID:Regulation of insulin secretion from novel engineered insulinoma cell lines. 916 67

Renal tubular reabsorption of glucose is substantially increased in humans and rats with diabetes mellitus. The influx of luminal glucose is mediated by Na+/glucose cotransporter system and glucose efflux from tubules to interstitium by facilitative glucose transporters (GLUT). In Zucker diabetic rats, GLUT2 protein levels of renal proximal tubules were higher than in control litter mates: 9.67 +/- 1.95 versus 4.72 +/- 1.55 (P = 0.0073). In the same proximal tubules, diabetes was associated with minor decreases in GLUT1 protein levels: 1.96 +/- 0.37 for diabetics and 2.37 +/- 0.34 for controls (P = 0.12). Na+/glucose cotransporter system protein levels were similar in both groups, whereas Na+/K+ ATPase levels were slightly decreased in diabetic rats, but the difference was not statistically significant. In this report, it is suggested that in long-term uncontrolled diabetes, GLUT2 transporters are overexpressed in renal tubules. This adaptation promotes low-affinity, high-capacity glucose efflux. The higher number of high K(m) GLUT2 ensures that glucose reabsorption is increased by promoting glucose efflux, which could be rate-limiting in the face of hyperglycemia.
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PMID:Overexpression of GLUT2 gene in renal proximal tubules of diabetic Zucker rats. 918 62

GLUT2 may play an important role in pancreatic beta-cell glucose metabolism. A decrease in glucose uptake due to underexpression of GLUT2 has been considered as the cause of beta-cell dysfunction in diabetes with different pathogenesis. However, this view has been challenged by recent studies, in which the underexpression of GLUT2 was not accompanied by a decrease in glucose uptake. Our present aim is to evaluate the presumed importance of GLUT2 in maintaining the efficiency of beta-cell glucose uptake. We studied the kinetic characteristics of 3-O-methylglucose uptake in two beta-cell lines. One of these is the beta TC3 cell line which expresses GLUT1 and the other is the beta HC9 cell line which expresses both GLUT1 and GLUT2. Under equilibrium exchange conditions, 3-O-methylglucose transport in these two cell lines showed similar values of K(m) and V(max). The apparent IC50 of cytochalasin B for inhibiting 3-O-methylglucose transport in beta HC9 cells was nine times as high as in beta TC3 cells, indicating that GLUT1 is the critically important glucose transporter in the beta TC3 cell line and GLUT2 in the beta HC9 cell line. In both cell lines, the rates of glucose uptake were at least three times as fast as that of glucose phosphorylation. Our results suggest that GLUT1 is able to compensate for GLUT2 loss as it occurs in beta TC3 and maintains a commensurately high capacity of glucose uptake to sustain glucose metabolism in pancreatic beta-cells.
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PMID:GLUT1 is adequate for glucose uptake in GLUT2-deficient insulin-releasing beta-cells. 923 Mar 44

The effects of 1 day of streptozotocin-induced diabetes in rats on glucose transport across the brush border membrane (BBM) and basolateral membrane (BLM) prepared from jejunal enterocytes has been studied. The effects on glucose transport of treatment of diabetic animals with insulin to reduce to normal the elevated blood glucose levels has also been assessed. The maximum capacity (Vmax) for SGLT1-mediated glucose uptake by BBM vesicles was unaffected by diabetes or insulin treatment of diabetic rats. In contrast, Vmax for BLM glucose uptake was increased by 206% in diabetes, a response that could not be reversed by treatment with insulin. Western blotting of BBM for SGLT1 protein revealed a single band with a molecular weight of 73 kDa and the intensity of this band was unaffected by diabetes. However, an increased level of GLUT2 was noted in diabetic BLM and this was not a consequence of changes in glycaemic or insulin status. Diabetes hyperpolarised the BBM, implying an increased driving force for Na(+)-sugar co-transport but insulin treatment only partially reversed this enhanced potential difference. Benzamil (2 microns), an epithelial Na+ channel blocker, hyperpolarised the BBM of control but not diabetic enterocytes, implying that a reduced Na+ permeability was responsible for the diabetic hyperpolarisation. It was concluded that in early diabetes, before the onset of hyperphagia, a greater driving force for Na(+)-dependent BBM sugar transport together with increased GLUT2 activity at the BLM promotes sugar movement across the enterocyte. Possible triggers for the transport responses are discussed.
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PMID:Early diabetes-induced changes in rat jejunal glucose transport and the response to insulin. 924 34

Weaning onto chow diets causes the highest incidence of diabetes in the BB rat. Changes in gut development and absorption of nutrients in the diabetes prone rat and the subsequent effect on pancreatic function may play a role in the ultimate development of the disease. BB diabetes prone (dp) and BB normal (n) dams were fed chow diets. Pups were killed at various ages ranging from 7 to 30 days. BBdp rats had higher small intestine and colon weights expressed per body weight at all ages (p < 0.0001). RNA content (mg/g) in the jejunum, ileum and colon was higher in the BBdp rats beginning at the critical period at 21 days and maintained at 24 days and 30 days (p < 0.0001). Proglucagon message decreased with age in both BBdp and BBn animals (p < 0.0001). Levels of proglucagon mRNA were higher in BBdp compared to BBn animals only in the ileum at 10 days (p < 0.01). Adjusting for total ileal and colonic RNA content resulted in BBdp animals having higher total colonic proglucagon mRNA at 21, 24 and 30 days (p < 0.0001). Plasma GLP-1(7-36) amide was more than doubled in BBdp compared to BBn animals (p < 0.0005) at 30 days. Expressing sodium-dependent D-glucose co-transporter (SGLT-1), GLUT2 and GLUT5 mRNA per total jejunal RNA shows increased transporter mRNA in BBdp compared to BBn rats at weaning (21 days) (p < 0.05). Radical differences exist between BBdp and BBn animals at 'critical periods' in both proglucagon and glucose transporter gene expression. These differences may help explain altered growth and diseases incidence between these two strains.
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PMID:Ontogenic changes in proglucagon mRNA in BB diabetes prone and normal rats weaned onto a chow diet. 926 80

The molecular mechanisms underlying increased hepatic phosphoenolpyruvate carboxykinase (PEPCK) gene transcription and gluconeogenesis in type II diabetes are largely unknown. To examine the involvement of glucocorticoids and the cis-acting insulin response sequence (IRS, -416/-407) in the genetically obese db/db mouse model, we generated crosses between C57BL/KsJ-db/+ mice and transgenic mice that express -460 or -2000 base pairs of the rat PEPCK gene promoter containing an intact or mutated IRS, linked to a reporter gene. Transgenic mice expressing the intact PEPCK(460)-CRP (C-reactive protein) transgene bred to near homozygosity at the db locus were obese, hyperinsulinemic, and developed fasting hyperglycemia (389 +/- 26 mg/100 ml) between 4 and 10 weeks of age. Levels of CRP reporter gene expression were increased 2-fold despite severe hyperinsulinemia compared with non-diabetic non-obese transgenic mice. Reporter gene expression was also increased 2-fold in transgenic obese diabetic db/db mice bearing a mutation in the IRS, -2000(IRS)-hGx, compared with non-obese non-diabetic transgenic 2000(IRS)-hGx mice. Treatment of obese diabetic db/db transgenic mice with the glucocorticoid receptor blocker RU 486 decreased plasma glucose by 50% and reduced PEPCK, GLUT2, glucose-6-phosphatase, tyrosine aminotransferase, CRP, and hGx reporter gene expression to levels similar to those of non-obese normoglycemic transgenic mice. Taken together, these results establish that -460 bp of 5'-flanking sequence is sufficient to mediate the induction of PEPCK gene transcription in genetically obese db/db mice during the development of hyperglycemia. The results further demonstrate that the mechanism underlying increased expression of gluconeogenic enzymes in the db/db mouse requires the action of glucocorticoids and occurs independently of factors acting through the PEPCK IRS (-416/-407) promoter binding site.
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PMID:Phosphoenolpyruvate carboxykinase (GTP) gene transcription and hyperglycemia are regulated by glucocorticoids in genetically obese db/db transgenic mice. 939 82


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