A review of the molecular mechanisms leading to diabetic and statin induced neuropathies: exploring the similarities between the two and the role of coenzyme Q in its treatment

Introduction: Neuropathy is an agonizing debility seen commonly in diabetic patients. Statins can also lead to similar neuropathic symptoms independent of diabetic status. When statins are prescribed in patients of diabetes, it is not possible to distinguish whether neuropathic pain is secondary to diabetes or to statin therapy. This review analyzes the molecular mechanisms involved in etio pathogenesis of neuropathy caused either by diabetes or by statin therapy. ATP deficiency and ion channel abnormalities may be responsible for the symptoms of neuropathy in diabetes, and a similar mechanism is at play in statin induced neuropathy. This is seen to occur independent of blood sugar levels. Areas covered: Literature published between 1980 and 2019 on the etio pathogenesis of neuropathy, insulin receptor defects, cholesterol biosynthesis, action of statins and of Coenzyme Q, KATP and calcium channels was reviewed. A comprehensive search on PubMed, Embase and Cochrane databases was carried out. Expert opinion: Statins activate KATP channels and directly affect neurons. Activation of KATP channels inhibits calcium channels which should theoretically be beneficial in neuropathic symptoms. However, statins lead to a simultaneous deficiency in levels of ubiquinone because of their inhibitory action on cholesterol biosynthesis pathway, This leads to neuropathy. Insulin receptor defects in diabetes may be leading to a similar pathogenesis in the causation of diabetic neuropathy. *Correspondence to: Devindra Sehra MD, DTCD, Sehra Medical Center ,Punjabi Bagh, New Delhi -110026 , India, E-mail: sehradev@yahoo.com Received: August 01, 2019; Accepted: August 26, 2019; Published: August 28, 2019 Introduction Statins are prescribed widely for both primary and secondary prevention of coronary artery disease. They act by their lipid lowering action, as well as by their pleiotropic effects. The number of patients who are on statin therapy is gradually and steadily increasing [1,2] Statins have been found to be generally safe; but they may be responsible for the side effects which so far have been attributed to the disease process per se for which they are being prescribed; and long term trials specifically exploring this aspect would unravel their real safety [3,4] That statins lead to increasing incidence of new onset diabetes has recently been reported in literature [5]. Since a large number of patients who have been prescribed statins are already suffering from diabetes, it is practically not possible to evaluate whether the worsening of diabetes in these patients is because of diabetes per se or because of statin therapy. Statin therapy per se may be causing polyneuropathy, which itself is a common complication of diabetes. It is difficult to interpret whether the reported polyneuropathy is because of statin therapy in a diabetic patient, or because of disease process of diabetes per se. This becomes significant because statins are prescribed very commonly in diabetic patients. In a nested case control study [6] in country of Funen comprising 465,000 inhabitants, ‘first time ever’ cases of polyneuropathy registered in between 1994 and 1998 were identified. Using relevant statistical analysis and a prescription register to assess drug exposure; the researchers estimated the odds ratio of statin use in case of polyneuropathy as compared to control subjects, and concluded that chronic use of statins increased the risk of polyneuropathy significantly. There was a 4-14 fold increased risk of developing polyneuropathy as compared to general population. Statin use and peripheral neuropathy has been found to be interlinked in many studies [7-11]. A 36 months prospective clinical and neurophysiological follow up in 42 patients with dyslipidaemia was conducted where patients were initiated on statin therapy ie Simvastatin 20mg daily and followed up. This study confirmed that statins cause a silent but definite damage to peripheral nerves if the treatment is given for more than 2 years [12]. A recent study suggests that statin consumption can lead to axonal involvement preferentially while causing damage to the peripheral nerves [13]. Though statins are used in all diabetic patients irrespective of lipid levels due to their pleiotropic effects, there use is almost universal in patients of diabetes with dyslipidemia. Whether neuropathy which manifests in these diabetic patients is because of statin therapy or because of diabetes has not been discussed in literature so far. Sehra D (2019) A review of the molecular mechanisms leading to diabetic and statin induced neuropathies: Exploring the similarities between the two and the role of coenzyme Q in its treatment Diabetes Updates, 2019 doi: 10.15761/DU.1000131 Volume 5: 2-5 Present hypothesis is that disprortionately high lipid levels are responsible for neuropathy in dyslipidemic patients, and hyperlipidemia is one of the contributing factors in the etiology of neuropathy. However, axonal sensory motor large nerve fiber involvement is the one seen in patients suffering from neuropathy on statin therapy; in contrast to the one seen in patients with hyperlipidemia induced neuropathy, where pain symptoms consistent with small nerve fibre neuropathy are seen [14-19]. Statins inhibit the synthesis of ubiquinone. We propose in this review that the ubiquinone deficiency caused due to statin therapy may be one of the factors leading to neuropathy in patients who are being administered these medications, How decreased production of ubiquinone in patients on statin therapy is responsible for neuropathy has been discussed in this review. This review will focus on the actions of statins on body tissues at the cellular level; and the molecular mechanisms involved in HMG CoA reductase inhibition The pleiotropic actions of statins shall also be discussed in brief. Material and methods A comprehensive search has been carried out on PubMed, Cochrane and Medline Embase and the molecular mechanisms, available in literature between 1980 to 2019, involved in neuropathy and statin induced neuropathy have been analyzed and discussed. Role of calcium channels and that of ubiquinone has been discussed in relation to polyneuropathy. The review concludes by strengthening the premise built thereon that statins lead to polyneuropathy primarily by decreasing the production of ubiquinone. Sensory neuropathy Histology of the neural tissue exhibiting Neuropathy In diabetic neuropathy, histological examination of the neural tissue reveals microangiopathy; involvement of schwan cells, degeneration of axons and axonal demylenation [8-10]. Maximal neuronal degeneration is observed in the longest axons of sensory neurons [18]. Oxidative stress, involvement of polyol pathway, elevated reactive oxygen species, and advanced glycated end products have all been implicated in the pathophysiology of diabetic neuropathy [18,19]. Pathogenesis of sensory neuropathy and the role of ion channels Pain sensation is initiated or sustained by neural afferent overactivity. This occurs when peripheral neuronal activity is increased, or when there is a mismatch between DRG cell bodies and adjacent neuron cross excitation. Axonal firing is determined by voltage gated sodium channels. Local anesthetics are exploited to alleviate pain because they block these voltage gated sodium channels [20]. Changes in intracellular calcium levels also determine sensory neuron excitability [21-23] Cav 3.2 subtype calcium channels (low voltage activated T-type calcium channels) located on primary afferent terminals and cell bodies are exploited for modulating neuronal excitability. A decrease in expression of these channels results in alleviation of neuropathic pain. Elevated calcium concentration in cytoplasm secondary to chronic dysregulation of calcium homeostasis leads to increased aberrant pain sensation [24]. Diabetes tends to involve sensory pathways in a symmetrical manner and the nerve conduction studies in the affected patients suggest a diminishing nerve conduction velocity. Pathogenesis of sensory neuropathy Diabetic neuropathy: and the role of ATP and ion channels [25] One of the proposed mechanisms in the etiopathogenesis of diabetic neuropathy is that the mitochondrial function and cellular calcium levels are altered; and this is caused not by hyperglycemia per se in a diabetic patient, but by impaired signals directed by changes in insulin receptors. A decreased stimulation of insulin receptors leads to dysfunction of mitochondria, and this dysfunction leads to decreased ATP production. A decreased level of ATP alters the functioning of plasmalemmal and ER calcium pumps. ER calcium uptake is lowered and this results in decreased calcium concentration in intra ER compartment. This leads to decreased supply of voltage gated channels. Nerve conduction velocity is thereby diminished. When this is coupled later on with other pathways associated with hyperglycemia viz. polyol pathway, oxidative stress, protein glycosylation, the result is manifestation neuropathic symptoms. Diabetes can lead to polyneuropathy by at least three mechanisms. They are 1) calcium ion channel dysregulation 2) decreased ATP production. 3) activation of KATP channels It is interesting to note that administration of statins in patients leads to both disturbances in calcium ion channel regulation, and also decreased synthesis of ATP, irrespective of their diabetic status. Statin induced neuropathy: statins lead to calcium ion deregulation, and decrease in ATP production Statins are inhibitors of an enzyme called 3 hydroxy methylglutoryl coenzyme A (HMG CoA) reductase. HMG CoA · Polyneuropathy is a known complication of diabetes. Statins prescribed commonly in diabetes may also cause similar symptomatology. · In diabetes, mitochondrial function and cellular calcium levels are altered by impaired signals directed by defects in insulin receptors, independent of hyperglycemia. ·