Exercise is commonly prescribed as a lifestyle treatment for chronic metabolic diseases as it functions as an insulin sensitizer, cardio-protectant, and essential lifestyle tool for effective weight maintenance. Exercise boosts the production of reactive oxygen species (ROS) and subsequent transient oxidative damage, which also upregulates counterbalancing endogenous antioxidants to protect from ROS-induced damage and inflammation. Exercise elevates heme oxygenase-1 (HO-1) and biliverdin reductase A (BVRA) expression as built-in protective mechanisms, which produce the most potent antioxidant, bilirubin. Together, these mitigate inflammation and adiposity. Moderately raising plasma bilirubin protects in two ways: (1) via its antioxidant capacity to reduce ROS and inflammation, and (2) its newly defined function as a hormone that activates the nuclear receptor transcription factor PPARα. It is now understood that increasing plasma bilirubin can also drive metabolic adaptions, which improve deleterious outcomes of weight gain and obesity, such as inflammation, type II diabetes, and cardiovascular diseases. The main objective of this review is to describe the function of bilirubin as an antioxidant and metabolic hormone and how the HO-1–BVRA–bilirubin–PPARα axis influences inflammation, metabolic function and interacts with exercise to improve outcomes of weight management.
Isaac syndrome (IS) is a peripheral nerve hyperexcitability state associated with voltage-gated potassium channel (VGKC) complex antibodies. Major manifestations are muscle twitching, stiffness, hypertrophy, and dysautonomic features such as hyperhidrosis [Ahmed and Simmons. <i>Muscle Nerve</i>. 2015;52(1):5–12]. Neuropathic pain is a rare manifestation. We describe a case of IS characterized by muscle twitching and intractable neuropathic pain. Diagnostic workup included elevated VGKC complex antibodies and EMG/NC that showed neuromyotonic discharges. Neuropathic pain was initially difficult to relieve even after using multiple medications, including opiates, benzodiazepines, anticonvulsants, and intravenous immunoglobulin (IVIg). Moderate pain control was eventually achieved with long-term use of carbamazepine and subcutaneous immunoglobulin (SCIg). Common manifestations of IS are muscle twitching, stiffness hypertrophy, and dysautonomia [Ahmed and Simmons. <i>Muscle Nerve</i>. 2015;52(1):5–12]. Sensory manifestations such as neuropathic pain are rare, but, as illustrated by our patient, can be the most distressing symptom. In our patient, not only was neuropathic pain disabling but it also showed the least response to IVIg. The use of 200 mg of long-acting carbamazepine twice daily with weekly SCIg demonstrated the best response. This case highlights an uncommon but potentially resistant symptom of IS.
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