Sustained hyperglycemia induces insulin resistance, but the mechanism is still incompletely understood. Glucosamine (GlcN) has been extensively used to model the role of the hexosamine synthesis pathway (HSP) in glucose-induced insulin resistance. 3T3-L1 adipocytes were preincubated for 18 h in media ± 0.6 nmol/l insulin containing either low glucose (5 mmol/l), low glucose plus GlcN (0.1-2.5 mmol/l), or high glucose (25 mmol/l). Basal and acute insulin-stimulated (100 nmol/l) glucose transport was measured after re-equilibration in serum and insulin-free media. Preincubation with high glucose or GlcN (1-2.5 mmol/l) inhibited basal and acute insulinstimulated glucose transport only if insulin was present during preincubation. However, only preincubation with GlcN plus insulin inhibited insulin-stimulated GLUT4 translocation. GLUT4 and GLUT1 protein expression were not affected. GlcN
Sleep may be a modifiable factor to improve glycemic control and reduce parental distress.
3T3-L1 adipocytes develop insulin-resistant glucose transport upon preincubation with high glucose or glucosamine, provided insulin (0.6 nM) is present during preincubation. Insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol (PI) 3-kinase activity is unaffected (30). Total cellular IRS-1, PI 3-kinase, or Akt concentrations were unchanged. Akt activation in subcellular fractions was assessed by immunoblotting with two phospho-Akt-specific antibodies. Upon acute 100 nM insulin stimulation, plasma membrane (PM)-associated phospho-Akt was highest in cells preincubated in low glucose with no insulin, less in high glucose with no insulin, even less in low glucose+insulin, and lowest in high glucose+insulin. Only high glucose+insulin caused insulin-resistant glucose transport. Acute insulin stimulation increased total PM-Akt about twofold after preincubation without insulin in low or high glucose. Preincubation with 0.6 nM insulin decreased Akt PM translocation by ∼25% in low and ∼50% in high glucose. Preincubation with glucosamine did not affect Akt phosphorylation or translocation. Conclusions: chronic exposure to high glucose or insulin downregulates acute insulin-stimulated Akt activation, acting synergistically distal to PI 3-kinase. Maximal insulin activates more Akt than required for maximal glucose transport stimulation. Insulin resistance may ensue when PM-associated phospho-Akt decreases below a threshold. High glucose and glucosamine cause insulin resistance by different mechanisms in 3T3-L1 adipocytes.
Glutamine:fructose-6-phosphate amidotransferase (GFAT) is the rate-limiting enzyme of the hexosamine synthesis pathway. Products of this pathway have been implicated in insulin resistance and glucose toxicity. GFAT1 is ubiquitous, whereas GFAT2 is expressed mainly in the central nervous system. In the course of developing a competitive reverse transcriptase-polymerase chain reaction assay, we noted that GFAT1 cDNA from muscle but not from other tissues migrated as a doublet. Subsequent cloning and sequencing revealed two GFAT1 mRNAs in both mouse and human skeletal muscles. The novel GFAT1 mRNA (GFAT1Alt [muscle selective variant of GFAT1]) is likely a splice variant. It is identical to GFAT1 except for a 48 or 54 bp insert in the mouse and human, respectively, at nucleotide position 686 of the coding sequence, resulting in a 16 or 18 amino acid insert at position 229 of the protein. GFAT1Alt is the predominant GFAT1 mRNA in mouse hindlimb muscle, is weakly expressed in the heart, and is undetectable in the brain, liver, kidney, lung, intestine, spleen, and 3T3-L1 adipocytes. In humans, it is strongly expressed in skeletal muscle but not in the brain. GFAT1 and GFAT1Alt expressed by recombinant adenovirus infection in COS-7 cells displayed robust enzyme activity and kinetic differences. The apparent K m of GFAT1Alt for fructose-6-phosphate was approximately twofold higher than that of GFAT1, whereas K i for UDP-N-acetylglucosamine was approximately fivefold lower. Muscle insulin resistance is a hallmark and predictor of type 2 diabetes. Variations in the expression of GFAT isoforms in muscle may contribute to predisposition to insulin resistance. Diabetes 50: 2419 -2424, 2001
Aim To compare the characteristics of children and adolescents with type 1 vs. type 2 diabetes in the Pediatric Diabetes Consortium (PDC) registries.Methods Participants were 10 to < 21 years of age at diagnosis; there were 484 with type 1 diabetes and 1236 with type 2 diabetes.Results Children and adolescents with type 2 diabetes were more likely to be female, overweight/obese, and from lowincome, minority ethnic families. Children and adolescents with type 1 diabetes were more likely to present with diabetic ketoacidosis and have higher mean HbA 1c levels at diagnosis. More than 70% in both cohorts achieved target HbA 1c levels < 58 mmol/mol (< 7.5%) within 6 months, but fewer participants with type 1 than type 2 diabetes were able to maintain target HbA 1c levels after 6 months consistently throughout 3 years post diagnosis. Of the 401 participants with type 2 diabetes with ≥ 24 months diabetes duration on enrolment in the registry, 47% required no insulin treatment. Median C-peptide levels were 1.43 mmol/l in the subset of participants with type 2 diabetes in whom it was measured, but only 0.06 mmol/l in the subset with type 1 diabetes.Conclusions Although families of children and adolescents with type 2 diabetes face greater socio-economic obstacles and risk factors for poor diabetes outcomes, the greater retention of residual endogenous insulin secretion likely contributes to the increased ability of children and adolescents with type 2 diabetes to maintain target HbA 1c during the first 3 years of diabetes diagnosis.
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