RESUMEN
Introduction: Subcutaneous insulin resistance syndrome (SIRS) is a rare condition in which patients poorly respond to subcutaneous (SC) insulin but maintain a normal response to intravenous (IV) insulin. The underlying pathophysiology remains elusive. Several treatment regimens have been tested for the management of SIRS, none of which included a sodium-glucose cotransporter-2 inhibitor (SGLT-2). Case Presentation: Two cases of type 1 diabetes initially achieved adequate glycemic control with subcutaneous insulin. Both cases later progressed into recurrent diabetic ketoacidosis that would resolve following IV insulin administration. Further investigation revealed unresponsiveness to SC, but not IV, insulin and the clinical diagnosis of SIRS was established accordingly. HbA1c values for cases 1 and 2 were 11% on 400 units/day of SC insulin, and 12% on 350 - 400 units/day of SC insulin, respectively. The patients required very high doses of intramuscular (IM) insulin. Subsequently, dapagliflozin as adjunct therapy significantly reduced the patients' IM insulin requirements beyond the anticipated dose reduction. Ultimately, case 1 achieved an HbA1c of 7 - 8% on 90 units/day of IM insulin and 10 mg/day of dapagliflozin, and case 2 achieved an HbA1c of 7 - 8% on 120 units/day of IM insulin and 10 mg/day of dapagliflozin. Conclusions: These are the first reported cases of SIRS in which dapagliflozin, an SGLT-2 inhibitor, was used. The substantial reduction in the IM insulin dose following the addition of dapagliflozin in our reported cases of SIRS suggests a possible novel mechanism for dapagliflozin beyond its glucosuric effects. In this report, we present a hypothetical basis for this possible novel mechanism.
RESUMEN
Neuropathic pain is a challenging complaint for patients and clinicians since there are no effective agents available to get satisfactory outcomes even though the pharmacological agents target reasonable pathophysiological mechanisms. This may indicate that other aspects in these mechanisms should be unveiled to comprehend the pathogenesis of neuropathic pain and thus find more effective treatments. Therefore, in the present study, several mechanisms are chosen to be reconsidered in the pathophysiology of neuropathic pain from a quantum mechanical perspective. The mathematical model of the ions quantum tunneling model is used to provide quantum aspects in the pathophysiology of neuropathic pain. Three major pathophysiological mechanisms are revisited in the context of the quantum tunneling model. These include: (1) the depolarized membrane potential of neurons; (2) the cross-talk or the ephaptic coupling between the neurons; and (3) the spontaneous neuronal activity and the emergence of ectopic action potentials. We will show mathematically that the quantum tunneling model can predict the occurrence of neuronal membrane depolarization attributed to the quantum tunneling current of sodium ions. Moreover, the probability of inducing an ectopic action potential in the axons of neurons will be calculated and will be shown to be significant and influential. These ectopic action potentials are generated due to the formation of quantum synapses which are assumed to be the mechanism behind the ephaptic transmission. Furthermore, the spontaneous neuronal activity and the emergence of ectopic action potentials independently from any adjacent stimulated neurons are predicted to occur according to the quantum tunneling model. All these quantum mechanical aspects contribute to the overall hyperexcitability of the neurons and to the pathogenesis of neuropathic pain. Additionally, providing a new perspective in the pathophysiology of neuropathic pain may improve our understanding of how the neuropathic pain is generated and maintained and may offer new effective agents that can improve the overall clinical outcomes of the patients.
RESUMEN
Lithium imposes several cellular effects allegedly through multiple physiological mechanisms. Membrane depolarization is a potential unifying concept of these mechanisms. Multiple inherent imperfections of classical electrophysiology limit its ability to fully explain the depolarizing effect of lithium ions; these include incapacity to explain the high resting permeability of lithium ions, the degree of depolarization with extracellular lithium concentration, depolarization at low therapeutic concentration, or the differences between the two lithium isotopes Li-6 and Li-7 in terms of depolarization. In this study, we implemented a mathematical model that explains the quantum tunneling of lithium ions through the closed gates of voltage-gated sodium channels as a conclusive approach that decodes the depolarizing action of lithium. Additionally, we compared our model to the classical model available and reported the differences. Our results showed that lithium can achieve high quantum membrane conductance at the resting state, which leads to significant depolarization. The quantum model infers that quantum membrane conductance of lithium ions emerges from quantum tunneling of lithium through the closed gates of sodium channels. It also differentiates between the two lithium isotopes (Li-6 and Li-7) in terms of depolarization compared with the previous classical model. Moreover, our study listed many examples of the cellular effects of lithium and membrane depolarization to show similarity and consistency with model predictions. In conclusion, the study suggests that lithium mediates its multiple cellular effects through membrane depolarization, and this can be comprehensively explained by the quantum tunneling model of lithium ions.
