BackgroundA reduction in peripheral nervous system (PNS) insulin signaling is a proposed mechanism that may contribute to sensory neuron dysfunction and diabetic neuropathy. Neuronal insulin resistance is associated with several neurological disorders and recent evidence has indicated that dorsal root ganglion (DRG) neurons in primary culture display altered insulin signaling, yet in vivo results are lacking. Here, experiments were performed to test the hypothesis that the PNS of insulin-resistant mice displays altered insulin signal transduction in vivo. For these studies, nondiabetic control and type 2 diabetic ob/ob mice were challenged with an intrathecal injection of insulin or insulin-like growth factor 1 (IGF-1) and downstream signaling was evaluated in the DRG and sciatic nerve using Western blot analysis.ResultsThe results indicate that insulin signaling abnormalities documented in other “insulin sensitive” tissues (i.e. muscle, fat, liver) of ob/ob mice are also present in the PNS. A robust increase in Akt activation was observed with insulin and IGF-1 stimulation in nondiabetic mice in both the sciatic nerve and DRG; however this response was blunted in both tissues from ob/ob mice. The results also suggest that upregulated JNK activation and reduced insulin receptor expression could be contributory mechanisms of PNS insulin resistance within sensory neurons.ConclusionsThese findings contribute to the growing body of evidence that alterations in insulin signaling occur in the PNS and may be a key factor in the pathogenesis of diabetic neuropathy.

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.

Insulin signaling depends on tyrosine phosphorylation of insulin receptor substrates (IRSs) to mediate downstream effects; however, elevated serine phosphorylation of IRS impairs insulin signaling. Here, we investigated IRS protein expression patterns in dorsal root ganglia (DRG) of mice and whether their signaling was affected by diabetes. Both IRS1 and IRS2 are expressed in DRG; however, IRS2 appears to be the prevalent isoform and is expressed by many DRG neuronal subtypes. Phosphorylation of Ser(731)IRS2 was significantly elevated in DRG neurons from type 1 and type 2 diabetic mice. Additionally, Akt activation and neurite outgrowth in response to insulin were significantly decreased in DRG cultures from diabetic ob/ob mice. These results suggest that DRG neurons express IRS proteins that are altered by diabetes similar to other peripheral tissues, and insulin signaling downstream of the insulin receptor may be impaired in sensory neurons and contribute to the pathogenesis of diabetic neuropathy.

Evaluation of periarticular traumatic wounds for joint penetration is a common clinical concern for orthopaedic surgeons. Wounds that violate the joint capsule can result in deep infection and sepsis. Understanding the anatomic landmarks and capsular extensions of the major joints is key to proper evaluation. Initial evaluation of periarticular wounds includes thorough examination of the wound and plain radiographs. Historically, the saline load test has been the diagnostic test of choice for assessing traumatic arthrotomy; however, CT has recently been shown to have excellent sensitivity and specificity for detecting open knee joint injuries. Current treatment of traumatic arthrotomy includes intravenous antibiotics and surgical irrigation and débridement. Future areas of research must focus on further validation of CT evaluation and its use in other major joints, standardizing antibiotic treatment, and further delineating the role of nonsurgical management in minor injuries.

FNDC5/irisin, has recently been identified as a novel protein that stimulates the “browning” of white adipose by inducing thermogenesis via increased uncoupling protein 1 (UCP1). We tested the hypothesis that high fat diet‐induced prediabetic mice would exhibit increased FNDC5 and this effect would be attenuated by chronic exercise. C57BL/6 mice were randomized into three groups for the 4 week intervention: Standard diet (Std, n = 12), High fat diet (HF, n = 14), or High fat diet and free access to a running wheel (HFEX, n = 14). Body weight, glucose, insulin, and the homeostatic model assessment of insulin resistance (HOMA‐IR) were greater in HF compared to Std and HFEX after the 4 week intervention. In support of our hypothesis, FNDC5 was higher in HF in both skeletal muscle and adipose compared to Std and was lower in adipose only in HFEX compared to HF mice. Following the same pattern, PGC‐1α was significantly higher in HF compared to Std in skeletal muscle and significantly lower in HFEX compared to HF in adipose. UCP1 was significantly lower in HFEX versus Std (in skeletal muscle) and versus HF (in adipose). HOMA‐IR was significantly correlated with FNDC5 protein levels in adipose. Increased FNDC5 in adipose and skeletal muscle may be a compensatory mechanism to offset high fat diet‐induced weight gain and insulin resistance by increasing energy expenditure.

Alterations in peripheral nervous system (PNS) insulin support may contribute to diabetic neuropathy (DN); yet, PNS insulin signaling is not fully defined. Here, we investigated in vivo insulin signaling in the PNS and compared the insulin-responsiveness to that of muscle, liver, and adipose. Nondiabetic mice were administered increasing doses of insulin to define a dose response relationship between insulin and Akt activation in the DRG and sciatic nerve. Resulting EC50 doses were used to characterize the PNS insulin signaling time course and make comparisons between insulin signaling in the PNS and other peripheral tissues (i.e., muscle, liver, adipose). The results demonstrate that the PNS is responsive to insulin and that differences in insulin signaling pathway activation exist between PNS compartments. At a therapeutically relevant dose, Akt was activated in the muscle, liver, and adipose at 30 minutes, correlating with the changes in blood glucose levels. Interestingly, the sciatic nerve showed a similar signaling profile as insulin-sensitive tissues, however there was not a comparable activation in the DRG or spinal cord. These results present new evidence regarding PNS insulin signaling pathways in vivo and provide a baseline for studies investigating the contribution of disrupted PNS insulin signaling to DN pathogenesis.

Insulin is known to have neurotrophic properties and loss of insulin support to sensory neurons may contribute to peripheral diabetic neuropathy (PDN). Here, genetically-modified mice were generated in which peripheral sensory neurons lacked the insulin receptor (SNIRKO mice) to determine whether disrupted sensory neuron insulin signaling plays a crucial role in the development of PDN and whether SNIRKO mice develop symptoms of PDN due to reduced insulin neurotrophic support. Our results revealed that SNIRKO mice were euglycemic and never displayed significant changes in a wide range of sensorimotor behaviors, nerve conduction velocity or intraepidermal nerve fiber density. However, SNIRKO mice displayed elevated serum insulin levels, glucose intolerance, and increased insulin content in the islets of Langerhans of the pancreas. These results contribute to the growing idea that sensory innervation of pancreatic islets is key to regulating islet function and that a negative feedback loop of sensory neuron insulin signaling keeps this regulation in balance. Our results suggest that a loss of insulin receptors in sensory neurons does not lead to peripheral nerve dysfunction. The SNIRKO mice will be a powerful tool to investigate sensory neuron insulin signaling and may give a unique insight into the role that sensory neurons play in modifying islet physiology.

Metal-on-metal (MoM) total hip arthroplasty (THA) can be associated with adverse metal reactions, including pseudotumors. This case report describes a 58-year-old female with an MoM THA-related pseudotumor that caused unilateral leg edema from compression of her external iliac vein. After thorough preoperative workup to rule out infection and deep vein thrombosis and consultation with a vascular surgeon, the patient underwent revision THA and excision of her pseudotumor. She had complete resolution of her swelling at 4 years after surgery. Review of all available case reports for this rare complication revealed that almost all patients were female. All patients underwent revision THA, with resolution of their symptoms. Literature review demonstrates that women are disproportionally affected by complications associated with MoM THA. We recommend close monitoring of patients with MoM THA, particularly women, for development of adverse metal reactions.