Because a central feature of non-insulin-dependent diabetes mellitus (NIDDM) is an imparied ability of insulin to enhance glucose disposal in skeletal muscle, we examined the hypothesis that reduced expression of GLUT4 is a characteristic finding in the skeletal muscle of subjects with NIDDM.
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.
All 11 exons of the GLUT4 gene from 30 British white subjects with NIDDM were amplified using the polymerase chain reaction and screened for nucleotide sequence variation using the single-stranded conformation polymorphism (SSCP) method.
The possibility that the insulin receptor and GLUT4 may be candidate genes for inherited insulin resistance in NIDDM has been addressed with the aid of genetic screening techniques such as SSCP.
However, in vastus lateralis, relative amounts of GLUT4 per milligram membrane protein were similar (NS) among lean (1.0 +/- 0.2) and obese (1.5 +/- 0.3) subjects and patients with IGT (1.4 +/- 0.2) and NIDDM (1.2 +/- 0.2).
To study whether insulin resistance in Type 2 (non-insulin-dependent) diabetes mellitus is due to a defect in the expression of the insulin-responsive glucose transporter gene (GLUT-4) in human skeletal muscle, we measured the level of GLUT-4 mRNA and (in some of the subjects) its protein in muscle biopsies taken from 14 insulin-resistant patients with Type 2 diabetes, 10 first-degree relatives of the diabetic patients and 12 insulin-sensitive control subjects.
The present study does not support the hypothesis that genetic variation within the GLUT1 or GLUT4 gene loci may be responsible for familial susceptibility to Type 2 diabetes.
Using pooled SNuPE, we also examined a large British Caucasian control population for the prevalence of GLUT4 Ile383, a variant which has previously been reported only in NIDDM.
The discovery of a very common silent polymorphism at codon 130 of GLUT 4 allowed examination of the association of this locus with Type 2 diabetes using allele-specific oligonucleotide hybridisation in a subset of the Welsh subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
The potential contributions of genetic mutation and disruption of short- or long-term regulation of glucose transporters, particularly GLUT4, in insulin-sensitive tissues to the etiology of NIDDM are examined.
The GLUT4 protein per DNA of muscle obtained in the basal state correlated positively with the in vivo insulin-stimulated glucose uptake rate in the control group (r = 0.82, P < 0.05), whereas there was no comparable correlation in the NIDDM group (r = 0.05, P = 0.88).
Skeletal muscle GLUT 4 expression is normal in obesity, impaired glucose tolerance (IGT), GDM, and NIDDM, indicating that functional activity or translocation of GLUT 4 may be impaired.4.
These results suggest that reduction of GLUT-4 levels in the adipose cell plays an important role in the pathogenesis of insulin resistance, an early feature of NIDDM.
Levels of GLUT-4 mRNA and protein were measured in muscle biopsies taken before and after a euglycaemic insulin clamp from 14 NIDDM patients, 13 of their first-degree relatives and 17 control subjects.
Failure to detect Glut4-Ile383 and IR-Gln1152 variants in NIDDM (non-insulin dependent diabetes mellitus) and control subjects in an Italian population.
In summary, the improvement in glycemic control and glucose disposal in NIDDM subjects receiving gliclazide therapy cannot be explained by increased expression of GLUT4 in muscle.
The effects of increased GLUT4 (insulin-regulatable muscle/fat glucose transporter) expression on glucose homeostasis in a genetic model of non-insulin-dependent diabetes mellitus were determined by expressing a human GLUT4 transgene (hGLUT4) in diabetic C57BL/KsJ-db/db mice.
Since the insulin receptor substrate-1 (IRS-1) is the major substrate of the insulin receptor tyrosine kinase and has been shown to activate phosphatidylinositol (PI) 3-kinase and promote GLUT4 translocation, the IRS-1 gene is a potential candidate for development of non-insulin-dependent diabetes mellitus (NIDDM).
Genetic contribution of polymorphism of the GLUT1 and GLUT4 genes to the susceptibility to type 2 (non-insulin-dependent) diabetes mellitus in different populations.