Glucosamine and glucose induce insulin resistance by different mechanisms in rat skeletal muscle

Abstract

It has been hypothesized that glucose-induced insulin resistance is mediated by accumulation of UDP- N-acetylhexosamines (UDP-HexNAcs). In a previous study on rat epitrochlearis muscles incubated with high concentrations of glucose and insulin (Kawanaka K, D-H Han, J Gao, LA Nolte, and JO Holloszy. J Biol Chem 276: 20101–20107, 2001), we found that insulin resistance developed even when the increase in UDP-Hex-NAcs was prevented. Furthermore, actinomycin D completely prevented glucose-induced insulin resistance despite a greater accumulation of UDP-HexNAcs. In the present study, we used the same epitrochlearis muscle preparation, as well as the rat hemidiaphragm, to determine whether, like glucose, glucosamine causes insulin resistance by an actinomycin D-inhibitable process. Incubation of diaphragm muscles with 10 mM glucosamine for 3 h resulted in an approximately fivefold increase in UDP-HexNAcs, an ∼50% reduction in insulin responsiveness of glucose transport, and a 58% reduction in ATP concentration. These effects of glucosamine were not prevented by actinomycin D. Incubation of epitrochlearis muscles with 20 mM glucosamine for 3 h or with 10 mM glucosamine for 5 h also caused large decreases in insulin responsiveness of glucose transport but with no reduction in ATP concentration. Actinomycin D did not prevent the glucosamine-induced insulin resistance. The insulin-induced increases in tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and the binding of PI 3-kinase to IRS-1 were decreased ∼60% in epitrochlearis muscles exposed to glucosamine. This is in contrast to glucose-induced insulin resistance, which was not associated with impaired insulin signaling. These results provide evidence that glucosamine and glucose induce insulin resistance by different mechanisms.

Glucosamine-induced endoplasmic reticulum stress affects GLUT4 expression via activating transcription factor 6 in rat and human skeletal muscle cells

“…A widely accepted hypothesis regarding the mechanism responsible for glucose-induced insulin resistance is that glucose toxicity is mediated by increased flux of glucose into the HBP [17,26,27]. protein kinase B activation by insulin is associated with glucose-but not GlcN-mediated insulin resistance in adipocytes [31]. Nevertheless, studies in several model systems, including overexpression of GFAT and infusion/ treatment with GlcN have confirmed that increased flux through HBP can lead to impaired glucose metabolism [27,32].…”

“…None of these agents was able to prevent GlcN-induced insulin resistance [34], suggesting that GlcN does not impair insulin sensitivity by altering the upstream steps of insulin signalling. It has been shown that inhibition of insulin-stimulated glucose uptake by GlcN is due to intracellular ATP depletion in rat skeletal muscle [31], adipocytes [39] and chondrocytes [40]. However, in other cell types, ATP depletion by exposure to sodium azide or dinitrophenol did not mimic the effects of GlcN to induce insulin resistance [41].…”

Astragalus polysaccharide improves insulin sensitivity in KKAy mice: Regulation of PKB/GLUT4 signaling in skeletal muscle

“…Among factors that contribute to insulin resistance are: impaired skeletal muscle glucose use, disorders of fatty acid/lipid metabolism, increased hepatic gluconeogenesis, and decreased microvascular perfusion, etc. (Ruderman et al, 1990;Han et al, 2003;Clark, 2008;Turcotte and Fisher, 2008). In humans and other mammals, the skeletal muscle is the main tissue responsible for approximately 75% of whole-body insulin-stimulated glucose transport.…”

Protective Role of Glucagon-like Peptide-1 Against Glucosamine-induced Cytotoxicity in Pancreatic Beta Cells

“…In beta cells, glucosamine-induced N-glycosylation of F1-F0-ATP synthase resulted in less glucose-dependent ATP production and insulin secretion [5]. However, several reports have suggested that there may be another mechanism of glucosamine besides protein glycosylation [11][12][13]. In support of this hypothesis, rare beta-cell apoptosis was shown to occur along with peripheral insulin resistance in 8-wk-old transgenic mice with overexpression of glucosamine:fructose-6-phosphate amidotransferase (GFAT), which is the rate-limiting enzyme of HBP [14].…”