Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-stimulated glucose transport activity and GLUT4 glucose transporter protein expression in rat soleus, red-enriched, and white-enriched skeletal muscle were examined in streptozotocin (STZ)-induced insulin-deficient diabetes. Six days of STZ-diabetes resulted in a nearly complete inhibition of insulin-stimulated glucose transport activity in perfused soleus, red, and white muscle which recovered following insulin therapy. A specific decrease in the GLUT4 glucose transporter protein was observed in soleus (3-fold) and red (2-fold) muscle which also recovered to control values with insulin therapy. Similarly, cardiac muscle displayed a marked STZ-induced decrease in GLUT4 protein that was normalized by insulin therapy. White muscle displayed a small but statistically significant decrease in GLUT4 protein (23%), but this could not account for the marked inhibition of insulin-stimulated glucose transport activity observed in this tissue. In addition, GLUT4 mRNA was found to decrease in red muscle (2-fold) with no significant alteration in white muscle. The effect of STZ-induced diabetes was time-dependent with maximal inhibition of insulin-stimulated glucose transport activity at 24 h in both red and white skeletal muscle and half-maximal inhibition at approximately 8 h. In contrast, GLUT4 protein in red and white muscle remained unchanged until 4 and 7 days following STZ treatment, respectively. These data demonstrate that red skeletal muscle displays a more rapid hormonal/metabolic-dependent regulation of GLUT4 glucose transporter protein and mRNA expression than white skeletal muscle. In addition, the inhibition of insulin-stimulated glucose transport activity in both red and white muscle precedes the decrease in GLUT4 protein and mRNA levels. Thus, STZ treatment initially results in a rapid uncoupling of the insulin-mediated signaling of glucose transport activity which is independent of GLUT4 protein and mRNA levels.
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PMID:Differential regulation of glucose transporter activity and expression in red and white skeletal muscle. 182 59

Effective fuel metabolism is dependent on balances among exogenous and endogenous fuel availability, the glucagon/insulin ratio, and tissue insulin sensitivity. Diabetes mellitus results when imbalances occur. The resultant metabolic derangement is accompanied by abnormalities in carbohydrate, protein, and fat metabolism. The two most common forms of diabetes are insulin dependent (IDDM) and noninsulin dependent (NIDDM). IDDM is an autoimmune disease, characterized by insulinopenia and ketosis. NIDDM is related to impaired insulin secretion, defective tissue sensitivity, and abnormalities in glucose transporter proteins. This article describes normal fuel metabolism and traces the abnormal metabolic processes that lead to both IDDM and NIDDM.
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PMID:Normal fuel metabolism and alterations in diabetes mellitus. 184 Sep 66

Genetic factors are essential to the occurrence of insulin-dependent diabetes (IDD) and non-insulin-dependent diabetes (NIDD), and all that environmental factors do is facilitate the development of diabetes in genetically predisposed subjects. Recent advances in molecular biology have improved our understanding of diabetic heredity. IDD is closely linked to the HLA region of chromosome 6. Ninety percent of IDD belong to the DR3 or DR4 group. The occurrence of IDD is facilitated by a peculiar conformation of the HLA DQ molecule which permits the presentation of antigens to the T-cells. Other genes still have to be discovered since IDD seems to be of polygenic origin. NIDD is even more "hereditary" than IDD, but owing to the lack of an unquestionable marker the responsible genes cannot be located with certainty. Several possible genes such as those of insulin, insulin receptor and glucose transporter, are suspected, at least in some forms of NIDD--a clinically and biologically highly heterogeneous disease. Widespread family studies should, in a not too distant future, locate the responsible gene thereby leading to early detection or even prevention of NIDD.
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PMID:[Diabetes and heredity]. 185 94

A mathematical model of insulin sensitive glucose transporter regulation is developed. Model structure is based on experimental evidence from adipocytes and myocytes. Model parameters correspond with known cellular processes. As an example, computer simulation results are compared with data from rat adipocytes. Cellular processes explicitly represented in the model include state-dependent glucose transporter synthesis and degradation rates, insulin sensitive glucose transporter translocation rates, and a glucose transporter endocytosis rate. Most of these processes are represented as first-order events. Using more complex representations of the model structure (e.g. higher order rate constants or saturable pathways) or alternative structures did not result in qualitatively better results. The model is able to accurately simulate the insulin sensitive, insulin concentration dependent, reversible translocation of glucose transporters observed in normal adipocytes. The model is also able to accurately simulate the changes in regulation of glucose transporter translocation observed with increases in cell surface area. Finally, the model can simulate pathogenic states which induce impairment of glucose transporter regulation (e.g. altered glucose transporter regulation in adipocytes from rats on high fat diets, rats with streptozotocin induced diabetes, and fasted rats). Since the structure of our model is sufficient to explain glucose transporter regulation in both normal and pathological states, it may aid in understanding the post-receptor components of insulin resistance (decreased sensitivity or responsiveness to insulin) seen in pathological states such as obesity and diabetes mellitus.
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PMID:A mathematical model and computer simulation study of insulin sensitive glucose transporter regulation. 189 Aug 50

Family studies suggest a strong genetic component in the aetiology of non-insulin dependent diabetes (NIDDM), with evidence for a major gene of co-dominant or dominant effect. A gene-dosage effect, whereby diabetes develops earlier in people with two susceptibility genes than in those with one susceptibility gene is likely. The search for the diabetes gene has led to the cloning and characterization of many genes involved in controlling glucose homeostasis. These include the insulin, insulin receptor, glucose transporter, amylin and glucokinase genes. Molecular techniques have permitted rapid screening of these genes in NIDDM patients and controls. There is now a rather contradictory genetic literature for NIDDM, with weak disease associations reported and refuted for most candidate genes. However, pedigree analyses and DNA sequencing of available candidate genes and their regulatory regions have failed to implicate any of these in the common form of diabetes, NIDDM. Methodical application of random clones in well-defined NIDDM families may be the strategy of choice in finding the NIDDM genes, given the wide range of genes potentially involved in the glucose and lipoprotein metabolic disturbances seen in NIDDM.
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PMID:Genetics of non-insulin dependent diabetes mellitus in 1990. 189 73

Insulin-stimulated glucose uptake into muscle and fat involves regulation of the subcellular distribution and the expression of a specific facilitative glucose transporter protein (GLUT4). Peripheral glucose uptake is lowered in diabetes, and the expression of GLUT4 is depressed in animals that have been made diabetic (i.e. insulin deficient) by destruction of the pancreatic beta-cells. In the present study we found that GLUT4 expression is also decreased in an animal model for type II diabetes mellitus (noninsulin-dependent diabetes mellitus), KKAY obese mice. These KKAY mice have elevated circulating insulin levels, but target cell resistance to the metabolic actions of insulin. Treatment of both types of diabetic animals with pioglitazone, a new antihyperglycemic compound, corrects deficits in glucose transport and GLUT4 mRNA and protein abundance. Such corrections are, however, more readily detected in fat than in muscle. Increases in GLUT4 mRNA and protein levels and glucose transport function by pioglitazone are dependent upon the presence of circulating insulin. Treatment with pioglitazone alone is sufficient for correction of glucose transport in hyperinsulinemic insulin-resistant animals, but hypoinsulinemic animals require insulin therapy along with pioglitazone treatment for similar corrections. In these insulin-deficient animals, neither treatment with the drug alone nor minimal insulin replacement therapy results in substantial correction. Since insulin and this antihyperglycemic agent seem to work synergistically, it is likely that pioglitazone acts to amplify cellular responses to insulin.
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PMID:Glucose transport deficiency in diabetic animals is corrected by treatment with the oral antihyperglycemic agent pioglitazone. 191 75

In normal fed rats the low Km glucose transporter GLUT-1 is expressed only in one row of hepatocytes immediately surrounding a terminal hepatic venule, while the high Km GLUT-2 is expressed in every hepatocyte. Previously, we showed that additional perivenous hepatocytes express GLUT-1 in fasting animals. In diabetes, as in starvation, the liver functions to release glucose into the circulation, but unlike starvation, circulating extracellular glucose is high in diabetes. By immunofluorescence and Western blotting we studied whether glucose or insulin is the primary extracellular signal for inducing GLUT-1 expression in hepatocytes. We observed that streptozocin-induced diabetes causes induction of GLUT-1 expression in the plasma membrane of hepatocytes within four cell rows of a terminal hepatic venule; GLUT-2 expression is unaltered. Chronic insulin treatment of diabetic rats reduces the number of rows of hepatocytes expressing GLUT-1 from approximately four to approximately two. In contrast, chronic insulin infusion into nondiabetic rats does not affect the number of hepatocytes expressing GLUT-1. Thus, both fasting and diabetes induce GLUT-1 expression in specific hepatocytes that normally do not express this gene. This induction correlates with low insulin levels in the blood, and not with circulating glucose levels.
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PMID:Expression of the low Km GLUT-1 glucose transporter is turned on in perivenous hepatocytes of insulin-deficient diabetic rats. 191 77

Insulin resistance is a common feature of non-insulin-dependent diabetes mellitus (NIDDM) and "diabetes susceptibility genes" may be involved in this abnormality. Two potential candidate genes are the insulin receptor (IR) and the insulin-sensitive glucose transporter (GLUT-4). To elucidate whether structural defects in the IR and/or GLUT-4 could be a primary cause of insulin resistance in NIDDM, we have sequenced the entire coding region of the GLUT-4 gene from DNA of six NIDDM patients. Since binding properties of the IRs from NIDDM subjects are normal, we also analyzed the sequence of exons 16-22 (encoding the entire cytoplasmic domain of the IR) of the IR gene from the same six patients. When compared with the normal IR sequence, no difference was found in the predicted amino acid sequence of the IR cytoplasmic domain derived from the NIDDM patients. Sequence analysis of the GLUT-4 gene revealed that one patient was heterozygous for a mutation in which isoleucine (ATC) was substituted for valine (GTC) at position 383. Consequently, the GLUT-4 sequence at position 383 was determined in 24 additional NIDDM patients and 30 nondiabetic controls and all showed only the normal sequence. From these studies, we conclude that the insulin resistance seen in the great majority of subjects with the common form of NIDDM is not due to genetic variation in the coding sequence of the IR beta subunit, nor to any single mutation in the GLUT-4 gene. Possibly, a subpopulation of NIDDM patients exists displaying variation in the GLUT-4 gene.
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PMID:Analysis of the gene sequences of the insulin receptor and the insulin-sensitive glucose transporter (GLUT-4) in patients with common-type non-insulin-dependent diabetes mellitus. 191 82

DNA from non-diabetic Caucasians (n = 16), Blacks (n = 22), Hispanics (n = 13) and Japanese (n = 21), as well as DNA from 34 Caucasian, 19 Black, 19 Hispanic and 20 Japanese non-insulin-dependent diabetes mellitus (NIDDM) patients were examined for restriction fragment length polymorphism (RFLP) after digestion with enzymes BglII and XbaI, and hybridization with the glucose transporter probe, hGT2-2. There were significant differences in the incidence of the RFLPs between Caucasians and Blacks, both controls and patients with NIDDM. Digestion with XbaI revealed a higher incidence of the homozygotic state for allele I in NIDDM Caucasians (12 vs. 0%) than in controls. In NIDDM Blacks and Hispanics, we found a high incidence of a combination of two traits: 42% of the Black and 47% of the Hispanic NIDDM patients were homozygous for the BglII allele I and heterozygous for XbaI. Only 23% of non-NIDDM Blacks or Hispanics had this combination (P less than 0.05). There was no association between RFLP frequency and NIDDM among Japanese subjects. These data support the influence of race on both BglII and XbaI RFLPs. The homozygotes for XbaI in Caucasians and the presence of two specific traits in Blacks and Hispanics appear with higher frequency in NIDDM.
Diabetes Res Clin Pract
PMID:Hep-G2 glucose transporter gene polymorphism in Caucasian, black, Hispanic and Japanese patients with NIDDM. 197 13

Diabetes (db) is an autosomal recessive mutation located in the midportion of mouse chromosome 4 that results in profound obesity with hyperphagia, increased metabolic efficiency, and insulin resistance. To clone this gene and generate a molecular map of the region around this mutation, two genetic crosses were established: an intraspecific backcross between C57BL/6J db/db females and C57BL/6J db/db x DBA/2J +/+ F1 (B6D2 db/+ F1) male mice and an interspecific intercross between B6D2 db/+ F1 males and C57BL/6J db/db x Mus spretus F1 (B6spretus db/+ F1) females. The progeny of both crosses were characterized for genotype at the db locus to map a series of restriction fragment length polymorphisms relative to the db locus. Measurements of body weight, body length, and plasma concentrations of glucose and insulin in the animals allowed the assignment of genotype (db/db vs. db/+ or +/+). A total of 132 progeny of the intraspecific cross and 48 db/db progeny of the interspecific cross were typed for individual restriction fragment length polymorphisms to generate a gene order of: centromere-brown (Mt4)-P lambda Mm3(2)-Ifa (Inta)-Cjun-db-D4Rp1-Glut1-Mtv-13-Lck. Several of the genes that are linked to db [Cjun, glucose transporter (Glut1) and Lck] map to human chromosome 1p, suggesting that db may be part of a syntenic group between human 1p and the distal portion of mouse chromosome 4. In addition, phenotyping of the progeny of these crosses revealed a wide range in plasma concentrations of glucose and insulin among the obese progeny, with some animals developing overt diabetes and other remaining euglycemic. Distributions of age-controlled plasma [glucose] and [insulin] among the intraspecific-cross obese progeny were not bimodal, suggesting a role for polygenic differences between the progenitor strains (C57BL/6J and DBA/2J) in the development of overt diabetes.
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PMID:Molecular mapping of the mouse db mutation. 197 28


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