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1.
Underexpression of beta cell high Km glucose transporters in noninsulin-dependent diabetes 总被引：15，自引：0，他引：15
J H Johnson A Ogawa L Chen L Orci C B Newgard T Alam R H Unger 《Science (New York, N.Y.)》1990,250(4980):546-549
The role of defective glucose transport in the pathogenesis of noninsulin-dependent diabetes (NIDDM) was examined in Zucker diabetic fatty rats, a model of NIDDM. As in human NIDDM, insulin secretion was unresponsive to 20 mM glucose. Uptake of 3-O-methylglucose by islet cells was less than 19% of controls. The beta cell glucose transporter (GLUT-2) immunoreactivity and amount of GLUT-2 messenger RNA were profoundly reduced. Whenever fewer than 60% of beta cells were GLUT-2-positive, the response to glucose was absent and hyperglycemia exceeded 11 mM plasma glucose. We conclude that in NIDDM underexpression of GLUT-2 messenger RNA lowers high Km glucose transport in beta cells, and thereby impairs glucose-stimulated insulin secretion and prevents correction of hyperglycemia. 相似文献
2.
Virus persists in beta cells of islets of Langerhans and is associated with chemical manifestations of diabetes 总被引：7，自引：0，他引：7
Molecular hybridization, monoclonal antibody, and electron microscopic analyses showed lymphocytic choriomeningitis virus (strains Armstrong and WE) persistently infecting cells of the islets of Langerhans in BALB/WEHI mice. When monoclonal or monospecific antibody conjugated with two different fluorochrome dyes was used to mark insulin-containing beta cells or viral antigens, viral nucleoprotein was identified predominantly in beta cells. Electron microscopy confirmed these findings by showing virions budding from the beta cells. Persistent infection was associated with chemical evidence of diabetes (hyperglycemia, abnormal glucose tolerance, and normal or low-normal concentrations of insulin). Concentrations of cortisol and insulin-like growth factor in blood were normal, as was the level of growth hormone in the pituitary gland. The virus-infected islet cells showed normal anatomy and cytomorphology. Neither cell lysis nor inflammatory infiltrates were routinely seen. Thus a virus may persistently infect islet cells and provide a biochemical and morphological picture comparable to that of early adult-onset diabetes mellitus in humans. 相似文献
3.
Mitochondrial dysfunction and type 2 diabetes 总被引：1，自引：0，他引：1
Maintenance of normal blood glucose levels depends on a complex interplay between the insulin responsiveness of skeletal muscle and liver and glucose-stimulated insulin secretion by pancreatic beta cells. Defects in the former are responsible for insulin resistance, and defects in the latter are responsible for progression to hyperglycemia. Emerging evidence supports the potentially unifying hypothesis that both of these prominent features of type 2 diabetes are caused by mitochondrial dysfunction. 相似文献
4.
Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes 总被引：46，自引：0，他引：46
An accelerated rate of glucose transport is among the most characteristic biochemical markers of cellular transformation. To study the molecular mechanism by which transporter activity is altered, cultured rodent fibroblasts transfected with activated myc, ras, or src oncogenes were used. In myc-transfected cells, the rate of 2-deoxy-D-glucose uptake was unchanged. However, in cells transfected with activated ras and src oncogenes, the rate of glucose uptake was markedly increased. The increased transport rate in ras- and src-transfected cells was paralleled by a marked increase in the amount of glucose transporter protein, as assessed by immunoblots, as well as by a markedly increased abundance of glucose transporter messenger RNA. Exposure of control cells to the tumor-promoting phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) for 18 hours had a similar effect of increasing the rate of glucose transport and the abundance of transporter messenger RNA. For ras, src, and TPA, the predominant mechanism responsible for activation of the transport system is increased expression of the structural gene encoding the glucose transport protein. 相似文献
5.
Localization of the pancreatic beta cell glucose transporter to specific plasma membrane domains 总被引：25，自引：0，他引：25
Immunocytochemical techniques revealed that the "liver-type" glucose transporter is present in the insulin-producing beta cells of rat pancreatic islets but not in other islet endocrine cells. Ultrastructural analysis of the transporter by the protein A-gold technique showed that it is restricted to certain domains of the plasma membrane, its density being sixfold higher in microvilli facing adjacent endocrine cells than in the flat regions of the plasma membrane. These results support a possible role for this glucose transporter in glucose sensing by beta cells and provide evidence that these cells are polarized. 相似文献
6.
M B Oldstone 《Science (New York, N.Y.)》1988,239(4839):500-502
The nonobese diabetic (NOD) mouse is an animal model of type I diabetes and develops a characteristic autoimmune lesion in the islets of Langerhans with lymphocytic infiltration and destruction of pancreatic beta cells. The result is hypoinsulinemia, hyperglycemia, ketoacidosis, and death. Diabetes usually begins by the sixth month of age but can occur earlier when young NOD mice are infused with lymphocytes from older NOD donors. When newborn or adult NOD mice were infected with a lymphotropic virus they did not become diabetic. The interaction between viruses and lymphocytes is pivotal in aborting diabetes, as established by experiments in which lymphocytes from virus-infected donors failed to transfer diabetes. In contrast, lymphocytes from age- and sex-matched uninfected donors caused disease. Therefore, viruses and, presumably, their products can be developed to be beneficial and may have potential as a component for treatment of human diseases. Further, these results point to the utility of viruses as probes for dissecting the pathogenesis of a nonviral disease. 相似文献
7.
8.
Suri A Calderon B Esparza TJ Frederick K Bittner P Unanue ER 《Science (New York, N.Y.)》2006,311(5768):1778-1780
Type 1 diabetes mellitus results from the autoimmune destruction of the beta cells of the pancreatic islets of Langerhans and is recapitulated in the nonobese diabetic strain of mice. In an attempt to rescue islet loss, diabetic mice were made normoglycemic by islet transplantation and immunization with Freund's complete adjuvant along with multiple injections of allogeneic male splenocytes. This treatment allowed for survival of transplanted islets and recovery of endogenous beta cell function in a proportion of mice, but with no evidence for allogeneic splenocyte-derived differentiation of new islet beta cells. Control of the autoimmune disease at a crucial time in diabetogenesis can result in recovery of beta cell function. 相似文献
9.
Grimsby J Sarabu R Corbett WL Haynes NE Bizzarro FT Coffey JW Guertin KR Hilliard DW Kester RF Mahaney PE Marcus L Qi L Spence CL Tengi J Magnuson MA Chu CA Dvorozniak MT Matschinsky FM Grippo JF 《Science (New York, N.Y.)》2003,301(5631):370-373
Glucokinase (GK) plays a key role in whole-body glucose homeostasis by catalyzing the phosphorylation of glucose in cells that express this enzyme, such as pancreatic beta cells and hepatocytes. We describe a class of antidiabetic agents that act as nonessential, mixed-type GK activators (GKAs) that increase the glucose affinity and maximum velocity (Vmax) of GK. GKAs augment both hepatic glucose metabolism and glucose-induced insulin secretion from isolated rodent pancreatic islets, consistent with the expression and function of GK in both cell types. In several rodent models of type 2 diabetes mellitus, GKAs lowered blood glucose levels, improved the results of glucose tolerance tests, and increased hepatic glucose uptake. These findings may lead to the development of new drug therapies for diabetes. 相似文献
10.
Hydropic degeneration of the islands of Langerhans and permanent severe diabetes mellitus have followed the prolonged injection of intraperitoneal glucose-saline solution in normal as well as in partially depancreatized cats. Positive results were associated with prolonged hyperglycemia. These findings add further evidence in support of the hypothesis that a sustained elevation of blood glucose may, under certain conditions, lead to the production of damage to the islands of Langerhans in this species. Besides hyperglycemia, other disturbances which might be responsible wholly or in part for the island lesions are under study. 相似文献
11.
Diabetes mellitus: induction in mice by encephalomyocarditis virus 总被引：22，自引：0，他引：22
Hyperglycemia and lesions of the pancreatic islets of Langerhans developed in some, but not all, adult mice infected with a variant of the encephalomyocarditis virus. Large amounts of virus were recovered from the pancreas during acute stages of infection. At this time blood glucose concentrations were markedly elevated and the islets of Langerhans exhibited focal necrosis and degranulation of beta cells. Evidence of abnormal glucose metabolism persisted for varying periods after recovery from the infection. The islets of Langerhans of chronically hyperglycemic mice were distorted and decreased in size, and the beta cells were degranulated. Encephalomyocarditis virus appears to cause diabetes mellitus by reducing the mass of functional beta cells of the islets of Langerhans. 相似文献
12.
In Gram-negative bacteria, the import of essential micronutrients across the outer membrane requires a transporter, an electrochemical gradient of protons across the inner membrane, and an inner membrane protein complex (ExbB, ExbD, TonB) that couples the proton-motive force to the outer membrane transporter. The inner membrane protein TonB binds directly to a conserved region, called the Ton-box, of the transporter. We solved the structure of the cobalamin transporter BtuB in complex with the C-terminal domain of TonB. In contrast to its conformations in the absence of TonB, the Ton-box forms a beta strand that is recruited to the existing beta sheet of TonB, which is consistent with a mechanical pulling model of transport. 相似文献
13.
Sequence and structure of a human glucose transporter 总被引：134，自引：0，他引：134
M Mueckler C Caruso S A Baldwin M Panico I Blench H R Morris W J Allard G E Lienhard H F Lodish 《Science (New York, N.Y.)》1985,229(4717):941-945
The amino acid sequence of the glucose transport protein from human HepG2 hepatoma cells was deduced from analysis of a complementary DNA clone. Structural analysis of the purified human erythrocyte glucose transporter by fast atom bombardment mapping and gas phase Edman degradation confirmed the identity of the clone and demonstrated that the HepG2 and erythrocyte transporters are highly homologous and may be identical. The protein lacks a cleavable amino-terminal signal sequence. Analysis of the primary structure suggests the presence of 12 membrane-spanning domains. Several of these may form amphipathic alpha helices and contain abundant hydroxyl and amide side chains that could participate in glucose binding or line a transmembrane pore through which the sugar moves. The amino terminus, carboxyl terminus, and a highly hydrophilic domain in the center of the protein are all predicted to lie on the cytoplasmic face. Messenger RNA species homologous to HepG2 glucose transporter messenger RNA were detected in K562 leukemic cells, HT29 colon adenocarcinoma cells, and human kidney tissue. 相似文献
14.
The mechanisms by which hydrophobic molecules, such as long-chain fatty acids, enter cells are poorly understood. In Gram-negative bacteria, the lipopolysaccharide layer in the outer membrane is an efficient barrier for fatty acids and aromatic hydrocarbons destined for biodegradation. We report crystal structures of the long-chain fatty acid transporter FadL from Escherichia coli at 2.6 and 2.8 angstrom resolution. FadL forms a 14-stranded beta barrel that is occluded by a central hatch domain. The structures suggest that hydrophobic compounds bind to multiple sites in FadL and use a transport mechanism that involves spontaneous conformational changes in the hatch. 相似文献
15.
Transgenic mice with I-A on islet cells are normoglycemic but immunologically intolerant 总被引：13，自引：0，他引：13
J B?hme K Haskins P Stecha W van Ewijk M LeMeur P Gerlinger C Benoist D Mathis 《Science (New York, N.Y.)》1989,244(4909):1179-1183
Insulin-dependent diabetes mellitus (IDDM) is caused by a specific loss of the insulin-producing beta cells from pancreatic Langerhans islets. It has been proposed that aberrant expression of major histocompatibility complex (MHC) class II molecules on these cells could be a triggering factor for their autoimmune destruction. This proposal was tested in transgenic mice that express allogeneic or syngeneic class II molecules on the surface of islet cells at a level comparable with that normally found on resting B lymphocytes. These animals do not develop diabetes, nor is lymphocyte infiltration of the islets observed. This immunological inactivity does not result from tolerance to the "foreign" class II molecules. 相似文献
16.
A large deletion within the T-cell receptor beta-chain gene complex in New Zealand white mice 总被引：16，自引：0，他引：16
The T-cell receptor beta-chain gene complex contains a duplication of D beta, J beta, and C beta gene segments in mice and man. When DNA from many inbred strains of mice was screened an unusual allele of the beta locus was identified in New Zealand White (NZW) mice. This allele is distinguished by the deletion of an 8.8-kilobase segment of DNA containing C beta 1, D beta 2 and the J beta 2 cluster. Despite the fact that all NZW T-cell receptors must be derived from a single set of beta-chain gene segments, this strain has functional T cells and is phenotypically normal. This deletion of T-cell receptor beta-chain segments occurs in a strain known to contribute to lupus-like autoimmune disease. 相似文献
17.
Chong AS Shen J Tao J Yin D Kuznetsov A Hara M Philipson LH 《Science (New York, N.Y.)》2006,311(5768):1774-1775
Autoimmune destruction of beta cells is the predominant cause of type 1 diabetes mellitus (T1DM) in humans and is modeled in non-obese diabetic (NOD) mice. Many therapeutic interventions prevent the development of T1DM in NOD mice, but few can induce its reversal once established. Intervention with Freund's complete adjuvant, semi-allogeneic splenocytes, and temporary islet transplantation has been reported to cure NOD mice of established T1DM. Using the same approach, we report here that this treatment cured 32% of NOD mice of established diabetes (>340 milligrams per deciliter blood glucose), although beta cells in these mice were not derived from donor splenocytes. 相似文献
18.
Cloning and expression of a cocaine-sensitive rat dopamine transporter 总被引：33，自引：0，他引：33
The action of dopamine and other monoamine neurotransmitters at synapses is terminated predominantly by high-affinity reuptake into presynaptic terminals by specific sodium-dependent neurotransmitter transport proteins. A complementary DNA encoding a rat dopamine transporter has been isolated that exhibits high sequence similarity with the previously cloned norepinephrine and gamma-aminobutyric acid transporters. Transient expression of the complementary DNA in HeLa cells confirms the cocaine sensitivity of this transporter. 相似文献
19.
Effects of cyclosporine immunosuppression in insulin-dependent diabetes mellitus of recent onset 总被引：19，自引：0，他引：19
C R Stiller J Dupré M Gent M R Jenner P A Keown A Laupacis R Martell N W Rodger B von Graffenried B M Wolfe 《Science (New York, N.Y.)》1984,223(4643):1362-1367
Type I diabetes may be an autoimmune disorder, although the evidence is largely circumstantial. The natural history of the disease after diagnosis includes partial remission in most patients, but only about 3 percent achieve transient insulin independence. beta Cell function, as indicated by the plasma concentration of C-peptide, is lost over 6 to 30 months and islet cell antibodies disappeared over 1 to 2 years. This article describes a pilot study in which 41 patients were treated with the immunosuppressive agent cyclosporine for 2 to 12 months. Of 30 patients treated within 6 weeks of diagnosis, 16 became insulin independent with concentrations of plasma C-peptide in the normal range and decreasing titers of islet cell antibodies. Of 11 patients who entered the study 8 to 44 weeks after diagnosis, two achieved this state. These results indicate that a controlled trial of the effects of cyclosporine in type I diabetes should be conducted. 相似文献
20.
Neonatal thymectomy results in a repertoire enriched in T cells deleted in adult thymus 总被引：15，自引：0，他引：15
In B6AF1 mice, T lymphocytes that use the V beta 11-positive (and not V beta 6-positive or V beta 8-positive) segment in their receptor for antigen are greatly reduced in the thymus and peripheral lymphoid tissues, most likely as a result of clonal deletion. The relative number of V beta 11-positive cells in adult lymph nodes was ten times as high in B6AF1 mice thymectomized 1 to 4 days after birth as in normal mice. Moreover, for the first 10 days of life of B6AF1 mice, mature V beta 11-positive T cells were readily detected in the thymus and spleen. Thus neonatal thymectomy results in the maintenance of the receptor repertoire of early postnatal life, and this correlates with the subsequent development of organ-specific autoimmune diseases. 相似文献