Insulin prevents aberrant mitochondrial phenotype in sensory neurons of type 1 diabetic rats

Abstract

Diabetic neuropathy affects approximately 50% of diabetic patients. Down-regulation of mitochondrial gene expression and function has been reported in both human tissues and in dorsal root ganglia (DRG) from animal models of type 1 and type 2 diabetes. We hypothesized that loss of direct insulin signaling in diabetes contributes to loss of mitochondrial function in DRG neurons and to development of neuropathy. Sensory neurons obtained from age-matched adult control or streptozotocin (STZ)-induced type 1 diabetic rats were cultured with or without insulin before determining mitochondrial respiration and expression of mitochondrial respiratory chain and insulin signaling-linked proteins. For in vivo studies age-matched control rats and diabetic rats with or without trace insulin supplementation were maintained for 5 months before DRG were analyzed for respiratory chain gene expression and cytochrome c oxidase activity. Insulin (10nM) significantly (P<0.5) increased phosphorylation of Akt and P70S6K by 4-fold and neurite outgrowth by 2-fold in DRG cultures derived from adult control rats. Insulin also augmented the levels of selective mitochondrial respiratory chain proteins and mitochondrial bioenergetics parameters in DRG cultures from control and diabetic rats, with spare respiratory capacity increased by up to 3-fold (P<0.05). Insulin-treated diabetic animals exhibited improved thermal sensitivity in the hind paw and had increased dermal nerve density compared to untreated diabetic rats, despite no effect on blood glucose levels. In DRG of diabetic rats there was suppressed expression of mitochondrial respiratory chain proteins and cytochrome c oxidase activity that was corrected by insulin therapy. Insulin elevates mitochondrial respiratory chain protein expression and function in sensory neurons and this is associated with enhanced neurite outgrowth and protection against indices of neuropathy.

Modulation of Sensory Nerve Function by Insulin: Possible Relevance to Pain, Inflammation and Axon Growth

“…It has also been proposed that loss of insulin signaling is involved in the development of mitochondrial changes of DRGs [126,133,134]. Interestingly, a recent study has revealed that insulin promotes mitochondrial gene expression of cultured DRG neurons derived from control and STZ-diabetic rats [135]. Additionally, it has also been demonstrated that insulin treatment enhanced thermal sensitivity and increased dermal nerve density in diabetic animals [135].…”

“…Interestingly, a recent study has revealed that insulin promotes mitochondrial gene expression of cultured DRG neurons derived from control and STZ-diabetic rats [135]. Additionally, it has also been demonstrated that insulin treatment enhanced thermal sensitivity and increased dermal nerve density in diabetic animals [135]. It has also been shown that chronic administration of fructose, which induces insulin resistance, and neuropathic pain, reduced InsR protein expression in DRGs and sciatic nerve [123].…”

Diabetic neuropathy and the sensory neuron: New aspects of pathogenesis and their treatment implications

“…Given these growth supportive roles of insulin in peripheral neurons, we have hypothesized that deficiency of insulin–PI3K–Akt trophic support during insulinopenic diabetes mellitus influences the development of DPN. For example, direct neuronal or axonal insulin administration, even if insufficient to alter blood glucose levels, reverses diabetic neuropathic changes in type 1 diabetes mellitus models that are characterized by the absence of the insulin ligand.…”

FGF21 Attenuates Neurodegeneration though Modulating Neuroinflammation and Oxidant-stress

“…Male C57BL/ksj-db/db mice (7-8 weeks, blood glucose concentration 20mmol/L, Shanghai Silaike Experimental Animals LTD) and the C57BL/6 mice (7-8weeks) fed and maintained under constant SPF conditions and temperature 23±2℃, humidity 50±5%, with 12h light and 12h dark cycles. In the mouse experiment, diabetic mice were divided into 5 groups : (1) wild type group for db/db mice (normal control, n=10), (2) diabetic mice treated with PBS (model control, n=10), (3) diabetic mice treated with FGF21 (0.5mg/kg, n=10), (4) diabetic mice treated with FGF21 (1.0mg/kg, n=10), (5) diabetic mice treated with FGF21 (2.0mg/kg, n=10). PBS or FGF21 injected into the mice once daily for four months.…”

“…Diabetes and AD shared corporate abnormalities, including impaired glucose metabolism, increased oxidant stress, chronic inflammation, insulin resistance, aggregation of Amyloid and Tau protein [4]. The diabetes and aging mice have provided a relevant animal model for nerve damage, and developed many AD-like neuropathological features, including inhibited AKT, aggregation of Tau protein and glycogen synthase kinase-3β (GSK-3β) overactivation [5,6]. The db/db mice were used usually [7].…”