A Role for Insulin in Diabetic Neuropathy

Abstract

The peripheral nervous system is one of several organ systems that are profoundly affected in diabetes. The longstanding view is that insulin does not have a major role in modulating neuronal function in both central and peripheral nervous systems is now being challenged. In the setting of insulin deficiency or excess insulin, it is logical to propose that insulin dysregulation can contribute to neuropathic changes in sensory neurons. This is particularly important as sensory nerve damage associated with prediabetes, type 1 and type 2 diabetes is so prevalent. Here, we discuss the current experimental literature related to insulin's role as a potential neurotrophic factor in peripheral nerve function, as well as the possibility that insulin deficiency plays a role in diabetic neuropathy. In addition, we discuss how sensory neurons in the peripheral nervous system respond to insulin similar to other insulin-sensitive tissues. Moreover, studies now suggest that sensory neurons can also become insulin resistant like other tissues. Collectively, emerging studies are revealing that insulin signaling pathways are active contributors to sensory nerve modulation, and this review highlights this novel activity and should provide new insight into insulin's role in both peripheral and central nervous system diseases.

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“…Diabetic neurological complication is one of the most common chronic complications of diabetes . In recent years, the incidence of diabetic central nervous system complications (CNS) with mild‐to‐moderate cognitive impairment has increased . Hippocampus is the main structure of short‐term memory loop, which plays an important role in the transition from short‐term memory to long‐term memory .…”

New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain

“…Supplementation with insulin restores glucose homeostasis and activates IR-insulin mediated pathways, with return of near normal PNS function in rodent models of T1D and DN (Brussee et al, 2004). Whether the beneficial therapeutic effects of insulin are due to normoglycemia or return of insulin-mediated neuronal signaling, or a combination of both, is unknown and a source of controversy in the field of experimental DN (Grote and Wright, 2016). In parallel, the exact mechanism(s) underlying the treatment effects of insulin therapy in patients with T1D and DN is unknown, with the same controversy concerning potential mechanisms (Martin et al, 2014).…”

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“…Secondly, insulin resistance within the peripheral nervous system has been reported in animal models of type 2 diabetes . Insulin is a potent neurotrophic factor that supports axonal growth as well as Schwann cell physiology and receptors for insulin are abundantly expressed on peripheral nerves, at the node of Ranvier, and on Schwann cell membranes . Schwann cell dysfunction has recently been recognized as an integral factor in the development of diabetic neuropathy as these cells envelope the internode and export metabolites necessary for energy production within the axon .…”

“…35 Insulin is a potent neurotrophic factor that supports axonal growth as well as Schwann cell physiology and receptors for insulin are abundantly expressed on peripheral nerves, at the node of Ranvier, and on Schwann cell membranes. [36][37][38] Schwann cell dysfunction has recently been recognized as an integral factor in the development of diabetic neuropathy as these cells envelope the internode and export metabolites necessary for energy production within the axon. 39 Interestingly, the degree of insulin resistance in people with LADA has been found to be similar to that of individuals with type 2 diabetes and long-term type 1 diabetes.…”