Transcriptional Profiling of Diabetic Neuropathy in the BKS db/db Mouse

Abstract

OBJECTIVEA better understanding of the molecular mechanisms underlying the development and progression of diabetic neuropathy (DN) is essential for the design of mechanism-based therapies. We examined changes in global gene expression to define pathways regulated by diabetes in peripheral nerve.RESEARCH DESIGN AND METHODSMicroarray data for 24-week-old BKS db/db and db/+ mouse sciatic nerve were analyzed to define significantly differentially expressed genes (DEGs); DEGs were further analyzed to identify regulated biological processes and pathways. Expression profile clustering was performed to identify coexpressed DEGs. A set of coexpressed lipid metabolism genes was used for promoter sequence analysis.RESULTSGene expression changes are consistent with structural changes of axonal degeneration. Pathways regulated in the db/db nerve include lipid metabolism, carbohydrate metabolism, energy metabolism, peroxisome proliferator–activated receptor signaling, apoptosis, and axon guidance. Promoter sequences of lipid metabolism–related genes exhibit evidence of coregulation of lipid metabolism and nervous system development genes.CONCLUSIONSOur data support existing hypotheses regarding hyperglycemia-mediated nerve damage in DN. Moreover, our analyses revealed a possible coregulation mechanism connecting hyperlipidemia and axonal degeneration.

Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications

“…Targeted pathway analysis of our previously published transcriptomic data (18) revealed significant enrichment of several pathways involved in fatty acid oxidation, glycolysis, catabolism of amino acids feeding into the TCA cycle and TCA cycle activity ( Figure 1B and Supplemental Figure 2, A-C). Similar to findings in the kidney, we detected significantly increased expression of mRNAs encoding glycolytic enzymes, including hexokinase 3 (Hk3), phosphofructokinase (Pfkl) and neuron-specific phosphopyruvate hydratase (Eno2) (18). Transcripts for several enzymes involved in fatty acid metabolism were also significantly upregulated, including the fatty acid transporter Slc27a1, long-chain acyl-CoA synthetase 1 (Acsl1), acyl-CoA oxidase 1 (Acox1), and hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (Hadha) (18).…”

“…Similar to findings in the kidney, we detected significantly increased expression of mRNAs encoding glycolytic enzymes, including hexokinase 3 (Hk3), phosphofructokinase (Pfkl) and neuron-specific phosphopyruvate hydratase (Eno2) (18). Transcripts for several enzymes involved in fatty acid metabolism were also significantly upregulated, including the fatty acid transporter Slc27a1, long-chain acyl-CoA synthetase 1 (Acsl1), acyl-CoA oxidase 1 (Acox1), and hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (Hadha) (18). The encoded enzymes are involved in insulin-stimulated fatty acid uptake, activation of long-chain fatty acids for metabolism, and the first and last three steps of β-oxidation, respectively.…”

“…The encoded enzymes are involved in insulin-stimulated fatty acid uptake, activation of long-chain fatty acids for metabolism, and the first and last three steps of β-oxidation, respectively. In contrast to the kidney, we observed significant changes in expression of mRNAs encoding TCA cycle enzymes, with increased expression of citrate synthase (Cs) and isocitrate dehydrogenase 3 (Idh3a), catalyzing the first and rate-limiting steps of the TCA cycle, respectively (18).…”

“…Total RNA were extracted from 24-week-old mouse SCN samples (control n = 9, diabetic n = 10) and analyzed as previously described (18). Total RNA were extracted from 24-week-old mouse kidney cortex samples (n = 5/group) using the RNeasy Mini Kit (QIAGEN).…”

LIM-homeodomain Transcription Factor Isl-1 Mediates the Effect of Leptin on Insulin Secretion in Mice

“…Isl-1 is also required for pancreatic development and cell functions (21-25, 42, 43). The mutation of OBRb (44,45) or Isl-1 (46) results in type 2 diabetes. But it has not been established about the functional relationship between leptin and Isl-1 in regulating insulin secretion.…”