Stimulation of glucose uptake by the natural coenzyme alpha-lipoic acid/thioctic acid: participation of elements of the insulin signaling pathway.

Thioctic acid (alpha-lipoic acid), a natural cofactor in dehydrogenase complexes, is used in Germany in the treatment of symptoms of diabetic neuropathy. Thioctic acid improves insulin-responsive glucose utilization in rat muscle preparations and during insulin clamp studies performed in diabetic individuals. The aim of this study was to determine the direct effect of thioctic acid on glucose uptake and glucose transporters. In L6 muscle cells and 3T3-L1 adipocytes in culture, glucose uptake was rapidly increased by (R)-thioctic acid. The increment was higher than that elicited by the (S)-isomer or the racemic mixture and was comparable with that caused by insulin. In parallel to insulin action, the stimulation of glucose uptake by thioctic acid was abolished by wortmannin, an inhibitor of phosphatidylinositol 3-kinase, in both cell lines. Thioctic acid provoked an upward shift of the glucose-uptake insulin dose-response curve. The molar content of GLUT1 and GLUT4 transporters was measured in both cell lines. 3T3-L1 adipocytes were shown to have >10 times more glucose transporters but similar ratios of GLUT4:GLUT1 than L6 myotubes. The effect of (R)-thioctic acid on glucose transporters was studied in the L6 myotubes. Its stimulatory effect on glucose uptake was associated with an intracellular redistribution of GLUT1 and GLUT4 glucose transporters, similar to that caused by insulin, with minimal effects on GLUT3 transporters. In conclusion, thioctic acid stimulates basal glucose transport and has a positive effect on insulin-stimulated glucose uptake. The stimulatory effect is dependent on phosphatidylinositol 3-kinase activity and may be explained by a redistribution of glucose transporters. This is evidence that a physiologically relevant compound can stimulate glucose transport via the insulin signaling pathway.

Regulation of glucose transport and expression of GLUT3 transporters in human circulating mononuclear cells: studies in cells from insulin-dependent diabetic and nondiabetic individuals.

We have previously shown that human circulating mononuclear cells (CMCs) respond to physiological concentrations of insulin with a rapid increase in glucose transport rate. The responding cells were found to be the monocytes, and cells derived from individuals with insulin-dependent diabetes mellitus (IDDM) had lower basal and insulin-stimulated glucose transport rates. Of interest, both cell types were found to express the GLUT1 but not the typical insulin-responsive GLUT4 transporter isoform. To further study the mechanisms responsible for stimulation of transport in these cells, we investigated (1) the response to insulin-like growth factor-I (IGF-I) and insulin-mimetic agents, and (2) the expression of other glucose transporter isoforms in CMCs of nondiabetic and IDDM individuals. The time course of insulin-stimulated glucose uptake in CMCs was rapid, reaching a plateau within 30 minutes. CMCs showed a dose-dependent and highly sensitive increase in glucose uptake to IGF-I (maximal response reached at 0.1 to 0.5 nmol/L IGF-I). The IGF-I dose-response curve was similar for CMCs of control and IDDM individuals, but both the basal and maximal response to IGF-I were lower in the diabetic group (P < .01). CMCs did not respond to vanadate, lithium, hydrogen peroxide, or short incubation (1 hour) with metformin, but glucose uptake increased in response to peroxides of vanadate and longer-duration (14 hours) metformin incubations. The glucose transporter isoforms of separated monocytes and lymphocytes were further investigated by Northern blotting of total RNA with a GLUT3-specific cDNA probe and by Western blotting of total membranes using GLUT3-specific antiserum.(ABSTRACT TRUNCATED AT 250 WORDS)