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Efavirenz, tenofovir, rifampicin, simvastatin, lamotrigine and clarithromycin are known potential mitochondrial toxicants. Mitochondrial toxicity has been reported to disrupt the chain of events in the insulin signalling pathway. Considering the upward trajectory of diabetes mellitus prevalence, studies which seek to uncover probable risk factors for developing diabetes should be encouraged. This study aimed to evaluate the intracellular mechanisms leading to the development of insulin resistance in the presence of various conventional pharmacological agents reported as potential mitochondrial toxicants in skeletal muscle cell line. Differentiated C2C12 preparations were exposed to multiple concentrations of efavirenz, tenofovir, rifampicin, simvastatin, lamotrigine, and clarithromycin, separately. Glucose handling was evaluated by observing the changes in insulin-stimulated glucose uptake and assessing the changes in GLUT4 translocation, GLUT4 expression and Akt expression. The changes in mitochondrial function were evaluated by assessing mitochondrial membrane integrity, cellular ATP production, generation of intracellular reactive oxygen species, expression of tafazzin and quantification of medium malonaldehyde. Insulin stimulated glucose uptake was perturbed in C2C12 pre-treated with potential mitotoxicants. Additionally, ATP synthesis, alterations in mitochondrial membrane potential, excessive accumulation of ROS and malonaldehyde were observed in the presence of potential mitotoxicants. Particularly, we observed suppression of proteins involved in the insulin signalling pathway and maintenance of mitochondrial function namely GLUT4, Akt and tafazzin. Mitochondrial toxicants can potentially induce insulin resistance emanating from mitochondrial dysfunction. These new findings will contribute to the understanding of underlying mechanisms involved in the development of insulin resistance linked to mitochondrial dysfunction., Competing Interests: The authors have declared that no competing interests exist, (Copyright: © 2024 Kuretu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Since the discovery of insulin, continuous developments of this peptide have led to better management of diabetes mellitus, thus leading to a decrease in diabetes-related mortality. Despite these developments, we have seen an increase in diabetes cases, which has further necessitated more innovative methods for diabetes management. The subcutaneous administration of insulin remains the mainstay therapy for type 1 diabetes mellitus. However, despite the availability of insulin analogues with improved pharmacokinetics, challenges with conventional administration exist. The challenges associated with insulin injections include hypoglycaemic episodes, needle phobia, and injection-site inflammation, which all have been reported to reduce patient compliance. Ongoing research on diabetes management strives to develop therapies that provide improved glycaemic control with minimal side effects. In part, for these reasons, we have seen an increase in the search and development of alternative insulin delivery systems that are envisaged to circumvent the shortfalls associated with the conventional administration route. Several alternative drug delivery systems, such as oral, pulmonary, buccal, nasal, and transdermal, have been explored in the last century. These efforts have not been without victory, as we have seen the emergence of pulmonary (Exubera and Afrezza) and buccal insulin delivery systems licenced for therapeutic use. Despite the success seen in these two systems, their marketability and popularity have been severely compromised due to reported safety concerns. Although oral insulin delivery has always shown promise in the past decades; however, it was only limited to preclinical trials. The main challenge associated with this delivery route is poor bioavailability, which necessitates high insulin concentration to be administered. Due to recent developments, oral insulin has reached phase 3 clinical trials. It is believed that patients would prefer oral insulin as their preference is often observed for oral antidiabetics over injected ones. In the last decade, transdermal insulin has also gained interest, where delivery of insulin with a concomitant reduction in blood glucose concentration has been demonstrated in vivo. However, at present, there are no clinical studies that have reported the efficacy of transdermal insulin administration. With technological advancement, there is a potential to develop yet another insulin delivery system that would likely enter the markets. As these novel delivery systems have been found to be effective, emerging competing products should be welcome and appreciated., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Peripheral neuropathic condition is amongst the classical symptoms of progressed diabetes. An intensive glycemic control with insulin injections has been shown to delay the onset and the progression of this condition in diabetes. In this study, we investigated the effect of pectin-insulin patch application on peripheral neuropathic symptoms in streptozotocin-induced diabetic rats. Pectin-insulin patches (20.0, 40.8, and 82.9 μg/kg) were daily applied thrice in streptozotocin-induced diabetic rats for 45 days. The diabetic animals sham treated with insulin-free patch served as negative control, while diabetic animals receiving subcutaneous insulin served as positive controls. The locomotor activity, gripping strength, and thermal perception were assessed at day 36, day 40, and day 44, respectively. On the 45th day, the animals were sacrificed, after which the plasma insulin, nitric oxide, C-reactive protein, tumor necrosis factor alpha, and malondialdehyde were measured. The patch application attenuated hyperglycemia with an improvement in the locomotor activity, thermal perception, and gripping strength in diabetic animals. Furthermore, the application of the patch augmented plasma nitric oxide while attenuating plasma malondialdehyde and tumor necrosis factor alpha. The application of pectin-insulin patch delays the onset of peripheral neuropathic-like symptoms in diabetic animals.

Background: Cardiovascular complications are among the leading causes of morbidity and mortality in diabetes mellitus. Despite the beneficial effects of subcutaneous insulin, reports suggest that the therapy itself precipitates cardiovascular risks due to the high insulin concentration administered. It is therefore necessary to seek alternative routes of insulin administration that may bypass the undesirable effects associated with high plasma insulin concentrations. Accordingly, the present study investigated the effects of a novel transdermal pectin-insulin patch on selected markers of cardiovascular function in diabetes., Methods: Pectin-insulin matrix patches (20.0, 40.8, and 82.9 μg/kg) were prepared as described previously. The three formulations were applied to streptozotocin-induced diabetic rats thrice daily. Blood glucose concentrations and mean arterial pressure (MAP) were monitored weekly for 5 weeks. Rats were then killed and blood collected for analysis of the lipid profile, cardiotropin-1, tumor necrosis factor (TNF)-α, and high-sensitivity C-reactive protein (hsCRP)., Results: The patches decreased blood glucose concentrations and diabetes-induced disturbances in lipid profile were attenuated by patch application (82.9 μg/kg). The diabetes-induced increase in MAP was also attenuated in patch (82.9 μg/kg)-treated rats. Patch treatment resulted in a decreased heart weight: body weight ratio, as well as reductions in cardiotropin-1, TNF-α, and hsCRP concentrations., Conclusions: Application of the pectin-insulin patch protects against the debilitating cardiovascular effects associated with conventional diabetes treatment. This suggests that the pectin-insulin patch may provide an effective alternative therapeutic approach to the commonly used subcutaneous insulin injections in the management of diabetes., (© 2017 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background/aims: Renal damage and dysfunction is attributed to sustained hyperglycaemia in overt diabetes. Subcutaneous insulin injections are beneficial in delaying the progression of renal dysfunction and damage in diabetics. However, the current mode of administration is associated with severe undesirable effects. In this study, we evaluated the ameliorative effects of pectin-insulin dermal patches on renal dysfunction in diabetes., Methods: Pectin-insulin patches (20.0, 40.8 and 82.9 µg/kg) were applied on the skin of streptozotocin-induced diabetic rats, thrice daily for 5 weeks. Blood glucose concentration, blood pressure and urine output volume were recorded on week 5 after which the animals were sacrificed after which the kidneys and plasma were collected. Kidney nephrin expression and urinary nephrin concentration, albumin excretion rate (AER), creatinine clearance (CC) and albumin creatinine ratio (ACR) were assessed., Results: Patch application resulted in reduced blood glucose concentration and blood pressure. Furthermore, pectin-insulin patch treatment resulted in increased kidney nephrin expression and reduced urinary nephrin concentration. AER, CC ACR were also reduced post patch application., Conclusions: The application of pectin-insulin patch limited diabetes associated kidney damaged and improved kidney function. These observations suggest that pectin-insulin patches may ameliorate kidney dysfunction that is associated with chronic subcutaneous insulin administration., (© 2017 The Author(s). Published by S. Karger AG, Basel.)