Metabolomic signature of type 1 diabetes-induced sensory loss and nerve damage in diabetic neuropathy

Abstract

Objective: Diabetic-induced peripheral neuropathy (DPN) is a highly complex and frequent diabetic late complication, which is manifested by prolonged hyperglycemia. However, the molecular mechanisms underlying the pathophysiology of nerve damage and sensory loss remain largely unclear. Recently, alteration in metabolic flux have gained attention a basis for organ damage in diabetes; however, peripheral sensory neurons have not been adequately analyzed with respect to metabolic dysfunction. In the present study, we attempted to delineate the sequence of event occurring in alteration of metabolic pathways in relation to nerve damage and sensory loss.Methods: C57Bl6/j wild type mice were analyzed longitudinally up to 22 weeks (wks) in the streptozotocin (STZ) model of type1 diabetes. The progression of DPN was investigated by behavioral measurements of sensitivity to thermal and mechanical stimuli and quantitative morphological assessment of intraepidermal nerve fiber density. We employed a mass spectrometry-based screen to address alterations in levels of metabolites in peripheral sciatic nerve and amino acids in serum over several months post-STZ administration to elucidate metabolic dysfunction longitudinally in relation to sensory dysfunction.Results: Although hyperglycemia and body weight changes occurred early, sensory loss and reduced intraepithelial branching of nociceptive nerves was only evident at 22 wks post-STZ. The longitudinal metabolites screen in peripheral nerves demonstrated that compared to buffer-injected age-matched control mice, mice at 12 wks and 22 wks post-STZ showed an early impairment the tricaoboxylic acid (TCA cycle), which is the main pathway of carbohydrate metabolism leading to energy generation. We found that levels of citric acid, ketoglutaric acid (2 KG), succinic acid, fumaric acid and malic acid were observed to be significantly reduced in sciatic nerve at 22 wks post-STZ. In addition, we also found the increase in levels of sorbitol and L-Lactate in peripheral nerve from 12 wks post-STZ injection. Amino acid screen in serum showed that the amino acids Valine (Val), Isoleucine (Ile) and Leucine (Leu), grouped together as BCAA, increased more than 2-fold from 12 wks post-STZ. Similarly, the levels of Tyrosine (Tyr), Asparagine (Asn), Serine (Ser), Histidine (His), Alanine (Ala), and Proline (Pro) showed progressive increase with progression of diabetes. Conclusion:Our results indicate that the impaired TCA cycle metabolites in peripheral nerve is the primary cause of shunting metabolic substrate to compensatory pathways which leads to mitochondrial dysfunction and nerve damage.

The fecal metabolome is associated with gestational diabetes mellitus

“…43 The abundance of L-malic acid was signicantly reduced in liver of the diabetic rats 44 and in peripheral nerves of type I diabetes. 45 The fecal abundance of L-malic acid was signicantly reduced in GDM women in this study, suggesting an opposite effect of fecal metabolites on hyperglycemia.…”

A Metabolic Insight Into the Neuroprotective Effect of Jin-Mai-Tong (JMT) Decoction on Diabetic Rats With Peripheral Neuropathy Using Untargeted Metabolomics Strategy

“…In our study, pathway analysis highlighted the TCA cycle in diabetic rats (Supplementary Figure S4). The abnormality of TCA cycle was also described in urine and sciatic nerve of STZ-induced diabetic mice (You et al, 2016;Rojas et al, 2019). From another integrated proteomics and metabolomics study (Freeman et al, 2016), six enzymes in TCA cycle were significantly increased in the sciatic nerves of diabetic rats.…”

“…These results indicated that the mechanism of JMT decoction relieving DPN was closely associated with the regulation of abnormal lipid metabolism. Tricarboxylic acid (TCA) cycle, the main pathway of carbohydrate metabolism in mitochondria, was reported to be impaired in diabetes and its complications (Filla and Edwards, 2016;Wu et al, 2017;Mathew et al, 2019;Rojas et al, 2019). TCA cycle that is also related to mitochondrial function plays a central role in maintaining peripheral nervous function and structure.…”

“…In addition, JMT decoction treatment at high dosage also restored the serum levels of two amino acid residues [Tyr-Pro-Phe and N-(1-Deoxy-1-fructosyl) leucine] and one secondary bile acid (lithocholic acid glycine conjugate). The relationship between alteration in amino acid metabolism and peripheral nerve damage in diabetes also attracted attentions recently (Rojas et al, 2019). For example, some ranched-chain amino acids were reported to elevate in sciatic nerves of type 1 diabetic mice as early as 5 weeks post-STZ injection, suggesting that peripheral nervous system occurs disorders of amino acids metabolism under diabetes (Rojas et al, 2019).…”

“…The relationship between alteration in amino acid metabolism and peripheral nerve damage in diabetes also attracted attentions recently (Rojas et al, 2019). For example, some ranched-chain amino acids were reported to elevate in sciatic nerves of type 1 diabetic mice as early as 5 weeks post-STZ injection, suggesting that peripheral nervous system occurs disorders of amino acids metabolism under diabetes (Rojas et al, 2019). Bile acid are metabolized by enzymes derived from intestinal bacteria and linked to gut microbiota, lipid and carbohydrate metabolism (Jia et al, 2018).…”