The identification of gene expression profiles associated with progression of human diabetic neuropathy

Abstract

Diabetic neuropathy is a common complication of diabetes. While multiple pathways are implicated in the pathophysiology of diabetic neuropathy, there are no specific treatments and no means to predict diabetic neuropathy onset or progression. Here, we identify gene expression signatures related to diabetic neuropathy and develop computational classification models of diabetic neuropathy progression. Microarray experiments were performed on 50 samples of human sural nerves collected during a 52-week clinical trial. A series of bioinformatics analyses identified differentially expressed genes and their networks and biological pathways potentially responsible for the progression of diabetic neuropathy. We identified 532 differentially expressed genes between patient samples with progressing or non-progressing diabetic neuropathy, and found these were functionally enriched in pathways involving inflammatory responses and lipid metabolism. A literature-derived co-citation network of the differentially expressed genes revealed gene subnetworks centred on apolipoprotein E, jun, leptin, serpin peptidase inhibitor E type 1 and peroxisome proliferator-activated receptor gamma. The differentially expressed genes were used to classify a test set of patients with regard to diabetic neuropathy progression. Ridge regression models containing 14 differentially expressed genes correctly classified the progression status of 92% of patients (P < 0.001). To our knowledge, this is the first study to identify transcriptional changes associated with diabetic neuropathy progression in human sural nerve biopsies and describe their potential utility in classifying diabetic neuropathy. Our results identifying the unique gene signature of patients with progressive diabetic neuropathy will facilitate the development of new mechanism-based diagnostics and therapies.

Long-Chain Acyl Coenzyme A Synthetase 1 Overexpression in Primary Cultured Schwann Cells Prevents Long Chain Fatty Acid-Induced Oxidative Stress and Mitochondrial Dysfunction

“…Microarray studies have allowed us to explore the role of hyperlipidemia-driven gene changes in the diabetic peripheral nerve (13,21). Given that Schwann cells are the primary cellular components of peripheral nerves (28) and Schwann cell dysfunction contributes to DN (8), we sought to understand the implications of our identified gene changes on Schwann cell function and survival.…”

“…Our laboratory has completed a series of microarray studies on human and mouse diabetic peripheral nerves (13,21), primarily assessing gene expression changes within Schwann cells. We have found increased mitochondrial long-chain acyl-CoA synthetase 1 (Acsl1), carnitine palmitoyltransferase 1a (Cpt1a), carnitine palmitoyltransferase 1b (Cpt1b), and carnitine/acylcarnitine translocase (CACT) gene expression in sciatic nerves (SCN) from a murine model of type 2 diabetes with DN, the leptin receptor-deficient db/db mouse (21).…”

“…The proteins encoded by these genes are involved in long chain fatty acid (LCFA) transport across the mitochondrial membrane (14). In parallel, we discovered the Acsl1 gene is significantly regulated in sural nerves from patients with diabetes and DN (13). The encoded Acsl1 enzyme catalyzes the addition of a CoA group to LCFAs of 16-18 carbons in length, a step required for mitochondrial uptake and LCFA metabolism (17).…”

Diabetic Peripheral Neuropathy: Should a Chaperone Accompany Our Therapeutic Approach?

“…These results suggest that a high-fat diet may differentially affect metabolic functions in myelinated versus unmyelinated fibers. Given the complex interactions between glucose and lipid metabolism, as well as nerve function and psychosensory behaviors, systems biology approaches will undoubtedly prove useful in dissecting how the up-/down-regulation of gene networks by diabetes and dyslipidemia may differentially contribute to the progression and severity of DPN (Wiggin et al, 2008;Hur et al, 2011;Pande et al, 2011).…”

Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental Diabetic Neuropathy

“…This question can be approached by implementing extensive -omic technologies to measure many transcripts, proteins, or metabolites in parallel. Gene microarrays were among the first of these technologies to be used, and transcriptomic analyses have been performed on tissues such as the dorsal root ganglia (DRG) from streptozotocin (STZ)-diabetic rats compared with healthy controls (6), the sciatic nerve (SN) of db/db mice compared with those from db/+ mice (7), and sural nerve biopsy specimens from human patients whose neuropathy progressed over 1 year compared with those whose neuropathy did not (based on myelinated fiber density loss) (8). Common changes across these gene array studies highlight altered carbohydrate and lipid metabolism.…”