Maternal prediabetes as a risk factor of preeclampsia and placental dysfunction in pregnant female Sprague-Dawley rats.

BACKGROUND: Prediabetes (PD) is associated with intermediate hyperglycaemia, dyslipidaemia, reduced nitric oxide (NO) bioavailability and moderate hypertension. All these factors are risk factor for preeclampsia (PE). However, the effects of the PD on placental function have not been shown. Accordingly, this study sought to investigate a possible link between maternal PD and the risk of developing PE. METHODS: Pregnant female Sprague-Dawley rats (N = 18) were divided into normal, preeclamptic and prediabetic groups (n = 6 in each group) to study the effects of maternal PD on placenta function over the period of 19 days. Blood glucose and blood pressure were measured on gestational day (GND) 0, 9 and 18. Placental vascular endothelial growth factor (VEGF), placenta growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) mRNA expression were measured terminally. Data were analysed using ANOVA followed by the Tukey-Kramer post hoc test. Values of p < .05 were used to indicate statistical significance. RESULTS: Maternal PD and PE significantly increased blood glucose, decrease NO concentration and increase in MAP by comparison to the normal pregnant control group. Maternal PD significantly decreased VEGF, PlGF mRNA expression with a slight increase in sFlt-1 mRNA expression comparison to the normal pregnant control group. CONCLUSIONS: Maternal PD is associated with placental dysfunction due to impaired glucose handling, endothelial dysfunction and an imbalance in angiogenic and antiangiogenic factors. Therefore, maternal PD is a risk factor of PE.

People with prediabetes (PD) are at risk of developing type 2 diabetes. Studies have shown that PD can cause blood vessel problems in both men and women. However, there have not been any studies on prediabetic pregnant women, so we do not know much about the pregnancy problems they might face. Looking into new factors related to blood vessel growth and health in PD could help us understand how to diagnose and manage PD during pregnancy. This could reduce the risk of problems similar to pre-eclampsia. Research in this area will help mothers and their doctors be more aware of the complications PD can cause during pregnancy. This could lead to fewer health problems and deaths for both mothers and babies linked to type 2 diabetes.

The Relationship between Renin-Angiotensin-Aldosterone System (RAAS) Activity, Osteoporosis and Estrogen Deficiency in Type 2 Diabetes.

Type 2 diabetes (T2D) is associated with a plethora of comorbidities, including osteoporosis, which occurs due to an imbalance between bone resorption and formation. Numerous mechanisms have been explored to understand this association, including the renin-angiotensin-aldosterone system (RAAS). An upregulated RAAS has been positively correlated with T2D and estrogen deficiency in comorbidities such as osteoporosis in humans and experimental studies. Therefore, research has focused on these associations in order to find ways to improve glucose handling, osteoporosis and the downstream effects of estrogen deficiency. Upregulation of RAAS may alter the bone microenvironment by altering the bone marrow inflammatory status by shifting the osteoprotegerin (OPG)/nuclear factor kappa-Β ligand (RANKL) ratio. The angiotensin-converting-enzyme/angiotensin II/Angiotensin II type 1 receptor (ACE/Ang II/AT1R) has been evidenced to promote osteoclastogenesis and decrease osteoblast formation and differentiation. ACE/Ang II/AT1R inhibits the wingless-related integration site (Wnt)/ß-catenin pathway, which is integral in bone formation. While a lot of literature exists on the effects of RAAS and osteoporosis on T2D, the work is yet to be consolidated. Therefore, this review looks at RAAS activity in relation to osteoporosis and T2D. This review also highlights the relationship between RAAS activity, osteoporosis and estrogen deficiency in T2D.

Discovery of Novel Thiazolidinedione-Derivatives with Multi-Modal Antidiabetic Activities In Vitro and In Silico.

Diabetes mellitus (DM) and related complications continue to exert a significant burden on health care systems globally. Although conventional pharmacological therapies are beneficial in the management of this metabolic condition, it is still necessary to seek novel potential molecules for its management. On this basis, we have synthesised and evaluated the anti-diabetic properties of four novel thiazolidinedione (TZD)-derivatives. The TZD derivatives were synthesised through the pharmacophore hybridisation strategy based on N-arylpyrrole and TZD. The resultant derivatives at different concentrations were screened against key enzymes of glucose metabolism and glucose utilisation in the liver (HEP-G2) cell line. Additionally, peroxisome proliferator-activated receptor-γ activation was performed through docking studies. Docking of these molecules against PPAR-γ predicted strong binding, similar to that of rosiglitazone. Hence, TZDD2 was able to increase glucose uptake in the liver cells as compared to the control. The enzymatic inhibition assays showed a relative inhibition activity; with all four derivatives exhibiting ≥ 50% inhibition activity in the α-amylase inhibition assay and a concentration dependent activity in the α-glucosidase inhibition assay. All four derivatives exhibited ≥30% inhibition in the aldose reductase inhibition assay, except TZDD1 at 10 µg/mL. Interestingly, TZDD3 showed a decreasing inhibition activity. In the dipeptidyl peptidase-4 inhibition assay, TZDD2 and TZDD4 exhibited ≥20% inhibition activity.

Ameliorative Effects of a Rhenium (V) Compound with Uracil-Derived Ligand Markers Associated with Hyperglycaemia-Induced Renal Dysfunction in Diet-Induced Prediabetic Rats.

Kidney disease is characterised by the improper functioning of the kidney as a result of kidney damage caused by hyperglycaemia-induced oxidative stress. The moderate hyperglycaemia seen in prediabetes can be treated using a combination of metformin and lifestyle interventions (low-calorie diets and exercising). However, patients have been reported to over-rely on pharmacological interventions, thus decreasing the efficacy of metformin, which leads to the development of type 2 diabetes mellitus (T2DM). In this study, we investigated the effects of a rhenium (V) compound in ameliorating renal dysfunction in both the presence and absence of dietary modification. Kidney function parameters, such as fluid intake and urine output, glomerular filtration rate (GFR), kidney injury molecule (KIM 1), creatinine, urea, albumin and electrolytes, were measured after 12 weeks of treatment. After treatment with the rhenium (V) compound, kidney function was restored, as evidenced by increased GRF and reduced KIM 1, podocin and aldosterone. The rhenium (V) compound ameliorated kidney function by preventing hyperglycaemia-induced oxidative stress in the kidney in both the presence and absence of dietary modification.

Cardio-protective effects of a dioxidovanadium(V) complex in male sprague-dawley rats with streptozotocin-induced diabetes.

Cardiovascular complications are among the leading causes of morbidity and mortality in diabetes mellitus (DM). Despite the anti-hyperglycemic effects of various anti-diabetic therapeutic agents like insulin, some of these drugs are implicated in precipitating cardiovascular dysfunction. There is therefore an imperative need to seek alternative drugs that may ameliorate these complications. Accordingly, the aim of the study was to investigate the effects of a dioxidovanadium (V) complex, cis-[VO2(obz)py]) on selected cardiovascular function markers in STZ-induced diabetic rats. The vanadium complex (40 mg kg) was administered orally twice every 3rd day 5 weeks, non-diabetic and diabetic control groups received distilled water whereas the insulin group received subcutaneous insulin injections twice daily for 5 weeks. Blood glucose concentrations, mean arterial pressure (MAP), heart rate, triglycerides (TG) and total cholesterol concentrations were monitored weekly for 5 weeks. Rats were then euthanised and blood and hearts were collected for biochemical analysis. There was a significant decrease in blood glucose, triglycerides, cholesterol concentrations as well as blood pressure of vanadium treated rats compared to the untreated diabetic animals. Vanadium treatment also attenuated cardiac oxidative stress and decreased the expression of transforming growth factor ß1 (TGFß1) and Smad7. Lastly, the administration of the vanadium complex significantly decreased C reactive protein (CRP) and cardiotropin 1(CT-1) concentrations in the plasma and heart tissues. The administration of the dioxidovanadium(V) complex to diabetic rats culminated into cardio-protective effects. Taken together, these observations suggest that this metal complex exhibit a significant potential as an alternative therapeutic drug for DM management.

Anti-hyperglycaemic effects of dioxidovanadium complex cis-[VO2(obz)py] avert kidney dysfunction in streptozotocin-induced diabetic male Sprague-Dawley rats.

Despite the success of antidiabetic drugs in alleviation of hyperglycaemia, diabetic complications, including renal dysfunction, continue to be a burden. This raises the need to seek alternative therapies that will alleviate these complications. Accordingly, the aim of this study was to investigate the effects of dioxidovanadium(V) complex cis-[VO2(obz)py] on renal function in diabetic rats. Streptozotocin-induced diabetic rats were treated with cis-[VO2(obz)py] (40 mg·kg-1) twice every third day for five weeks. Diabetic untreated and insulin-treated rats served as the diabetic control and positive control, respectively. Blood glucose concentrations, water intake, urinary output, and mean arterial pressure (MAP) were monitored weekly for five weeks. Rats were then euthanized, and blood and kidney tissues were collected for biochemical analysis. Significant decreases in blood glucose concentrations, MAP, glomerular filtration rate (GFR), and SGLT2 expression, as well as plasma angiotensin and aldosterone concentrations, were observed in the treated groups compared with the diabetic control. The complex also increased urinary glucose concentrations, antioxidant enzymes GPx and SOD concentrations, and decreased MDA concentrations and kidney injury molecule (KIM-1) concentrations. These findings suggest that the anti-hyperglycaemic effects of this vanadium complex may ameliorate kidney dysfunction in diabetes.

The effect of dioxidovanadium complex (V) on hepatic function in streptozotocin-induced diabetic rats.

Diabetics are susceptible to hepatic dysfunction risks due to hyperglycaemia and insulin therapy. Conventional diabetes treatments improve glycaemic control; however, hepatic hazards associated with these agents remains a challenge. Accordingly, this study sought to investigate the effect of a dioxidovanadium complex (V) on the hepatic function in streptozotocin-induced diabetic rats. Sprague-Dawley rats (240-250 g) were divided into 4 groups (n = 6): nondiabetic control, diabetic control, insulin-treated, and vanadium complex groups. The dioxidovanadium (10, 20, and 40 mg/kg) was administered twice every 2nd day for 5 weeks and blood glucose concentration was monitored weekly. At the end of the experimental period, all the experimental groups were sacrificed, and then the lipid profile, liver superoxide dismutase, glutathione peroxidase and malondialdehyde, plasma alanine aminotransferase and aspartate aminotransferase, and C-reactive protein (CRP) concentration were measured. The administration of dioxidovanadium significantly alleviated hyperglycaemia with concomitant attenuation in oxidative stress as evidenced by reduced malondialdehyde concentrations. Furthermore, vanadium complex abolished diabetes-induced dyslipidaemia. Lastly, vanadium complex administration attenuated the increase in alanine aminotransferase, aspartate aminotransferase, and plasma C-reactive protein. These findings suggest that this metallo-compound (dioxidovanadium) may ameliorate liver dysfunction often observed in diabetes.

The pectin-insulin patch application prevents the onset of peripheral neuropathy-like symptoms in streptozotocin-induced diabetic rats.

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.

The Ameliorative Effect of Pectin-Insulin Patch On Renal Injury in Streptozotocin-Induced Diabetic Rats.

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.

The role of high mobility group box-1 on the development of diabetes complications: A plausible pharmacological target.

BACKGROUND: Diabetes mellitus has emerged as a pressing global concern, with a notable increase in recent years. Despite advancements in treatment, existing medications struggle to halt the progression of diabetes and its associated complications. Increasing evidence underscores inflammation as a significant driver in the onset of diabetes mellitus. Therefore, perspectives on new therapies must consider shifting focus from metabolic stress to inflammation. High mobility group box (HMGB-1), a nuclear protein regulating gene expression, gained attention as an endogenous danger signal capable of sparking inflammatory responses upon release into the extracellular environment in the late 1990s. PURPOSE: Given the parallels between inflammatory responses and type 2 diabetes (T2D) development, this review paper explores HMGB-1's potential involvement in onset and progression of diabetes complications. Specifically, we will review and update the understanding of HMGB-1 and its inflammatory pathways in insulin resistance, diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy. CONCLUSIONS: HMGB-1 and its receptors i.e. receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs) present promising targets for antidiabetic interventions. Ongoing and future projects in this realm hold promise for innovative approaches targeting HMGB-1-mediated inflammation to ameliorate diabetes and its complications.

COVID-19-Induced Diabetes Mellitus: Comprehensive Cellular and Molecular Mechanistic Insights.

Despite evidence demonstrating the risks of developing diabetes mellitus because of SARS-CoV-2, there is, however, insufficient scientific data available to elucidate the relationship between diabetes mellitus and COVID-19. Research indicates that SARS-CoV-2 infection is associated with persistent damage to organ systems due to the systemic inflammatory response. Since COVID-19 is known to induce these conditions, further investigation is necessary to fully understand its long-term effects on human health. Consequently, it is essential to consider the effect of the COVID-19 pandemic when predicting the prevalence of diabetes mellitus in the future, especially since the incidence of diabetes mellitus was already on the rise before the pandemic. Additional research is required to fully comprehend the impact of SARS-CoV-2 infection on glucose tolerance and insulin sensitivity. Therefore, this article delves deeper into the current literature and links the perceived relationship between SARS-CoV-2 and diabetes. In addition, the article highlights the necessity for further research to fully grasp the mechanisms that SARS-CoV-2 utilises to induce new-onset diabetes. Where understanding and consensus are reached, therapeutic interventions to prevent the onset of diabetes could be proposed. Lastly, we propose advocating for the regular screening of diabetes and pre-diabetes, particularly for the high-risk population with a history of COVID-19 infection.

Elucidating the effect of drug-induced mitochondrial dysfunction on insulin signaling and glucose handling in skeletal muscle cell line (C2C12) in vitro.

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.

Glycaemic abnormalities induced by small molecule tryosine kinase inhibitors: a review.

In light of the expected increase in the prevalence of diabetes mellitus due to an aging population, sedentary lifestyles, an increase in obesity, and unhealthy diets, there is a need to identify potential pharmacological agents that can heighten the risk of developing diabetes. Similarly, it is equally important to also identify those agents that show blood glucose-lowering properties. Amongst these agents are tyrosine kinase inhibitors used to treat certain types of cancers. Over the last two decades, there has been an increase in the use of targeted chemotherapy for cancers such as renal cell carcinoma, chronic leukaemia, and gastrointestinal stromal tumours. Small molecule tyrosine kinase inhibitors have been at the forefront of targeted chemotherapy. Studies have shown that small molecule tyrosine kinase inhibitors can alter glycaemic control and glucose metabolism, with some demonstrating hypoglycaemic activities whilst others showing hyperglycaemic properties. The mechanism by which small molecule tyrosine kinase inhibitors cause glycaemic dysregulation is not well understood, therefore, the clinical significance of these chemotherapeutic agents on glucose handling is also poorly documented. In this review, the effort is directed at mapping mechanistic insights into the effect of various small molecule tyrosine kinase inhibitors on glycaemic dysregulation envisaged to provide a deeper understanding of these chemotherapeutic agents on glucose metabolism. Small molecule tyrosine kinase inhibitors may elicit these observed glycaemic effects through preservation of ß-cell function, improving insulin sensitivity and insulin secretion. These compounds bind to a spectrum of receptors and proteins implicated in glucose regulation for example, non-receptor tyrosine kinase SRC and ABL. Then receptor tyrosine kinase EGFR, PDGFR, and FGFR.

Exploring the Biological Effects of Anti-Diabetic Vanadium Compounds in the Liver, Heart and Brain.

The prevalence of diabetes mellitus and diabetes-related complications is rapidly increasing worldwide, placing a substantial financial burden on healthcare systems. Approximately 537 million adults are currently diagnosed with type 1 or type 2 diabetes globally. However, interestingly, the increasing morbidity rate is primarily influenced by the effects of long-term hyperglycemia on vital organs such as the brain, the liver and the heart rather than the ability of the body to use glucose effectively. This can be attributed to the summation of the detrimental effects of excessive glucose on major vascular systems and the harmful side effects attributed to the current treatment associated with managing the disease. These drugs have been implicated in the onset and progression of cardiovascular disease, hepatocyte injury and cognitive dysfunction, thereby warranting extensive research into alternative treatment strategies. Literature has shown significant progress in utilizing metal-based compounds, specifically those containing transition metals such as zinc, magnesium and vanadium, in managing hyperglycaemia. Amongst these metals, research carried out on vanadium reflected the most promising anti-diabetic efficacy in cell culture and animal studies. This was attributed to the ability to improve glucose management in the bloodstream by enhancing its uptake and metabolism in the kidney, brain, skeletal muscle, heart and liver. Despite this, organic vanadium was considered toxic due to its accumulative characteristics. To alleviate vanadium's toxic nature while subsequently manipulating its therapeutic properties, vanadium complexes were synthesized using either vanadate or vanadyl as a base compound. This review attempts to evaluate organic vanadium salts' therapeutic and toxic effects, highlight vanadium complexes' research and provide insight into the novel dioxidovanadium complex synthesized in our laboratory to alleviate hyperglycaemia-associated macrovascular complications in the brain, heart and liver.

Review of the direct and indirect effects of hyperglycemia on the HPA axis in T2DM and the co-occurrence of depression.

Type 2 diabetes mellitus (T2DM) is characterized by persistent hyperglycemia which is further associated with hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Several studies have shown that HPA axis hyperactivity is heightened in the chronic hyperglycemic state with severe hyperglycemic events more likely to result in a depressive disorder. The HPA axis is also regulated by the immune system. Upon stress, under homeostatic conditions, the immune system is activated via the sympatho-adrenal-medullary axis resulting in an immune response which secretes proinflammatory cytokines. These cytokines aid in the activation of the HPA axis during stress. However, in T2DM, where there is persistent hyperglycemia, the immune system is dysregulated resulting in the elevated concentrations of these cytokines. The HPA axis, already activated by the hyperglycemia, is further activated by the cytokines which all contribute to a diagnosis of depression in patients with T2DM. However, the onset of T2DM is often preceded by pre-diabetes, a reversible state of moderate hyperglycemia and insulin resistance. Complications often seen in T2DM have been reported to begin in the pre-diabetic state. While the current management strategies have been shown to ameliorate the moderate hyperglycemic state and decrease the risk of developing T2DM, research is necessary for clinical studies to profile these direct effects of moderate hyperglycemia in pre-diabetes on the HPA axis and the indirect effects moderate hyperglycemia may have on the HPA axis by investigating the components of the immune system that play a role in regulating this pathway.

DPP4 Inhibitors: Could they be One of the Solutions for COVID-19 Patients with Prediabetes?

Recent reports suggest that prediabetes is a risk factor for developing severe COVID-19 complications through underlying mechanisms involving undiagnosed sub-clinical inflammation. However, we remain without a clinical approach for managing COVID-19 in prediabetic cases. The subclinical inflammation in prediabetes is associated with elevated DPP4 levels and activity. DPP4 has pleiotropic actions, including glycaemia regulation and immuno-modulation. Recently, DPP4 has been recognised as a co-receptor for COVID-19 for entering host cells. In addition to improving glycaemia, DPP4 inhibition is associated with reduced inflammation. In this submission, we explore the potential use of DPP4 inhibitors as therapeutic agents for prediabetic patients in managing the deleterious effects of COVID-19. DPP4 inhibitors (gliptins), such as linagliptin and sitagliptin, have therapeutic effects, which have been shown to extend beyond glycaemic control with no risk of hypoglycaemia. By the nature of their mechanism of action, gliptins are not associated with hypoglycaemia, unlike their anti-glycaemic counterparts, as they mainly target postprandial glycaemia. Moreover, DPP4 inhibitors may represent a safer option for prediabetic individuals in managing prediabetes either as a prophylactic or curative treatment for COVID-19. We envisage that beyond improved glycaemic control, the use of DPP4 inhibitors would also alleviate the cytokine storm, resulting in a reduction in the severity of COVID-19 symptoms and consequently reducing the morbidity and mortality in prediabetic COVID- 19 patients.

Fluoroquinolone-induced Glycaemic Aberrations: Could Quinolones be Repurposed to Serve as New Antidiabetic Agents?

Nalidixic acid is a synthetic antibiotic discovered in the 1960s during the synthesis of chloroquine, an effective drug for treating malaria. Nalidixic acid became the backbone for developing quinolones that are now widely used clinically for the treatment of various bacterial infections. The mechanism of action of quinolone involves the inhibition of topoisomerase II and topoisomerase IV. In attempts to improve the potency of fluoroquinolones, modifications were made; these modifications resulted in the emergence of newer generations of fluoroquinolones. Also, due to these modifications, several side effects were noted, including blood glucose control aberrations. Among fluoroquinolones that disrupt glucose homeostasis is gatifloxacin, which is in the third-generation category. Fluoroquinolones have been demonstrated to induce glycaemic aberrations by enhancing pancreatic cells' insulin secretion and interaction with antidiabetic agents via inhibition of cytochrome P450 enzymes. Considering their ability to induce hypoglycaemia, few studies have reported repurposing of quinolones as antidiabetic agents. Hyperglycaemia has also been reported to often precede hypoglycaemia. Due to the ability to decrease blood glucose, it is not surprising that some authors have reported novel quinolone derivates with antidiabetic properties in experimental studies. However, there is still a paucity of data regarding the effect of quinolones derivatives on glycaemic control. Understanding how fluoroquinolones lower blood glucose concentration could serve as the basis for developing novel quinolone derivatives with the sole purpose of lowering blood glucose concentrations. Although there are various conventional anti-hyperglycaemic agents, due to their associated shortfalls as well as an increase in the prevalence of diabetes, the discovery and development of new antidiabetics are warranted.

Celebrating a Century of Insulin Discovery: A Critical Appraisal of the Emerging Alternative Insulin Delivery Systems.

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.

Drug-induced mitochondrial toxicity: Risks of developing glucose handling impairments.

Mitochondrial impairment has been associated with the development of insulin resistance, the hallmark of type 2 diabetes mellitus (T2DM). However, the relationship between mitochondrial impairment and insulin resistance is not fully elucidated due to insufficient evidence to support the hypothesis. Insulin resistance and insulin deficiency are both characterised by excessive production of reactive oxygen species and mitochondrial coupling. Compelling evidence states that improving the function of the mitochondria may provide a positive therapeutic tool for improving insulin sensitivity. There has been a rapid increase in reports of the toxic effects of drugs and pollutants on the mitochondria in recent decades, interestingly correlating with an increase in insulin resistance prevalence. A variety of drug classes have been reported to potentially induce toxicity in the mitochondria leading to skeletal muscle, liver, central nervous system, and kidney injury. With the increase in diabetes prevalence and mitochondrial toxicity, it is therefore imperative to understand how mitochondrial toxicological agents can potentially compromise insulin sensitivity. This review article aims to explore and summarise the correlation between potential mitochondrial dysfunction caused by selected pharmacological agents and its effect on insulin signalling and glucose handling. Additionally, this review highlights the necessity for further studies aimed to understand drug-induced mitochondrial toxicity and the development of insulin resistance.

The Insights on Why Diabetes Prevalence May Increase Amid or Post COVID-19 Pandemic.

BACKGROUND: Diabetes mellitus and prediabetes have been shown to be associated with high rates of developing severe COVID 19 complications resulting in morbidity and mortality. Emerging reports suggest that COVID 19 is associated with glycaemic control aberrations, although the extent is not clear at present. Accordingly, in this review, the efforts are directed to shed light on why we can anticipate an increase in diabetes cases amid or post-COVID 19 pandemic. METHODS: Articles reviewed were identified using the Google Scholar database, and the search was done using the English language. RESULTS: Previous studies have shown that viral inflammation triggers insulin resistance, which can progress to overt diabetes. SARS-CoV-2 has also been shown to cause acute pancreatitis, which can increase the risk of developing diabetes mellitus. The control of the COVID 19 pandemic partly relied on non-pharmaceutical measures, which included lockdowns. This resulted in a lack of physical activity and unhealthy eating behaviour, which could contribute to obesity and, ultimately, insulin resistance. CONCLUSION: While no concrete data has been established on the possibility of seeing an increase in diabetes prevalence due to COVID 19, studies are necessary to establish the link. Despite the unavailability of data at present, we suggest that frequent screening of diabetes and prediabetes should be encouraged, especially in those individuals with a history of COVID 19 infection.