Collateral Glucose-Utlizing Pathwaya in Diabetic Polyneuropathy

Abstract

Diabetic polyneuropathy (DPN) is the most common neuropathy manifested in diabetes. Symptoms include allodynia, pain, paralysis, and ulcer formation. There is currently no established radical treatment, although new mechanisms of DPN are being vigorously explored. A pathophysiological feature of DPN is abnormal glucose metabolism induced by chronic hyperglycemia in the peripheral nerves. Particularly, activation of collateral glucose-utilizing pathways such as the polyol pathway, protein kinase C, advanced glycation end-product formation, hexosamine biosynthetic pathway, pentose phosphate pathway, and anaerobic glycolytic pathway are reported to contribute to the onset and progression of DPN. Inhibitors of aldose reductase, a rate-limiting enzyme involved in the polyol pathway, are the only compounds clinically permitted for DPN treatment in Japan, although their efficacies are limited. This may indicate that multiple pathways can contribute to the pathophysiology of DPN. Comprehensive metabolic analysis may help to elucidate global changes in the collateral glucose-utilizing pathways during the development of DPN, and highlight therapeutic targets in these pathways.

Essential Oil of Croton zehntneri Prevents Conduction Alterations Produced by Diabetes Mellitus on Vagus Nerve

“…Several studies indicate that inflammatory mechanisms and oxidative stress are important factors in the pathogenesis of DN [14][15][16][17]. Since the neuroprotective effect of EOCz does not depend on glycemic control, its mechanism of action is very likely related to its antioxidant and putative anti-inflammatory effects [20,21].…”

“…The need for new drugs for DN treatment has been investigated in several studies [11][12][13]. In the search for new treatments for DN, three major components of the physiopathology of the disease are to be stressed: pain, inflammation, and the deterioration of redox balance [14][15][16][17]. Our research team studied the plant Croton zehntneri (Euphorbiaceae), abundant in the Brazilian Caatinga, which has widespread use in folk medicine [18,19].…”

Painful Diabetic Neuropathy: The Need for New Approaches

“…This cascade causes neuronal mitochondrial damage and cell death. 29,40 Treatments to lower glucose and lipid levels can help reverse this process. 41…”

“…Excessive intraneuronal glucose in people with diabetes can be shunted away from physiological glycolysis to produce the intermediate metabolite pyruvate and into one of four pathological pathways associated with neuropathy and pain. This alternate series of biochemical reactions includes (1) activation of the polyol pathway, (2) increased flux through the hexosamine pathway, (3) increased activation of protein kinase C (PKC), and (4) increased production of advanced glycation end products (AGEs) 9,28-30 (Figure 2). Alternatively, excessive glucose shunted into the pentose phosphate pathway can act as a protective mechanism.…”

Therapeutic Approach of Flavonoid in Ameliorating Diabetic Cardiomyopathy by Targeting Mitochondrial-Induced Oxidative Stress

“…Oxidative stress is a contributing factor for DCM progression [ 31 ]. Uncontrolled and persistent hyperglycemia encourage excessive generation of reactive oxygen species (ROS) via several metabolic pathways; elevated glucose uptake through the polyol pathway, enhanced advanced glycation end products (AGEs) production, activation of protein kinase C (PKC) pathway, overactivation of hexosamine pathway and incapacitated antioxidant defense [ 32 ].…”