Investigating the Effects of Diet-Induced Prediabetes on Skeletal Muscle Strength in Male Sprague Dawley Rats.

Type 2 diabetes mellitus, a condition preceded by prediabetes, is documented to compromise skeletal muscle health, consequently affecting skeletal muscle structure, strength, and glucose homeostasis. A disturbance in skeletal muscle functional capacity has been demonstrated to induce insulin resistance and hyperglycemia. However, the modifications in skeletal muscle function in the prediabetic state are not well elucidated. Hence, this study investigated the effects of diet-induced prediabetes on skeletal muscle strength in a prediabetic model. Male Sprague Dawley rats were randomly assigned to one of the two groups (n = 6 per group; six prediabetic (PD) and six non-pre-diabetic (NPD)). The PD group (n = 6) was induced with prediabetes for 20 weeks. The diet that was used to induce prediabetes consisted of fats (30% Kcal/g), proteins (15% Kcal/g), and carbohydrates (55% Kcal/g). In addition to the diet, the experimental animals (n = 6) were supplied with drinking water that was supplemented with 15% fructose. The control group (n = 6) was allowed access to normal rat chow, consisting of 35% carbohydrates, 30% protein, 15% fats, and 20% other components, as well as ordinary tap water. At the end of week 20, the experimental animals were diagnosed with prediabetes using the American Diabetes Association (ADA) prediabetes impaired fasting blood glucose criteria (5.6-6.9 mmol/L). Upon prediabetes diagnosis, the animals were subjected to a four-limb grip strength test to assess skeletal muscle strength at week 20. After the grip strength test was conducted, the animals were euthanized for blood and tissue collection to analyze glycated hemoglobin (HbA1c), plasma insulin, and insulin resistance using the homeostatic model of insulin resistance (HOMA-IR) index and malondialdehyde (MDA) concentration. Correlation analysis was performed to examine the associations of skeletal muscle strength with HOMA-IR, plasma glucose, HbA1c, and MDA concentration. The results demonstrated increased HbA1c, FBG, insulin, HOMA-IR, and MDA concentrations in the PD group compared to the NPD group. Grip strength was reduced in the PD group compared to the NPD group. Grip strength was negatively correlated with HbA1c, plasma glucose, HOMA-IR, and MDA concentration in the PD group. These observations suggest that diet-induced prediabetes compromises muscle function, which may contribute to increased levels of sedentary behavior during prediabetes progression, and this may contribute to the development of hyperglycemia in T2DM.

Bovine serum albumin uptake and polypeptide disaggregation studies of hypoglycemic ruthenium(II) uracil Schiff-base complexes.

Our prior studies have illustrated that the uracil ruthenium(II) diimino complex, [Ru(H3ucp)Cl(PPh3)] (1) (H4ucp = 2,6-bis-((6-amino-1,3-dimethyluracilimino)methylene)pyridine) displayed high hypoglycemic effects in diet-induced diabetic rats. To rationalize the anti-diabetic effects of 1, three new derivatives have been prepared, cis-[Ru(bpy)2(urdp)]Cl2 (2) (urdp = 2,6-bis-((uracilimino)methylene)pyridine), trans-[RuCl2(PPh3)(urdp)] (3), and cis-[Ru(bpy)2(H4ucp)](PF6)2 (4). Various physicochemical techniques were utilized to characterize the structures of the novel ruthenium compounds. Prior to biomolecular interactions or in vitro studies, the stabilities of 1-4 were monitored in anhydrous DMSO, aqueous phosphate buffer containing 2% DMSO, and dichloromethane (DCM) via UV-Vis spectrophotometry. Time-dependent stability studies showed ligand exchange between DMSO nucleophiles and chloride co-ligands of 1 and 3, which was suppressed in the presence of an excess amount of chloride ions. In addition, the metal complexes 1 and 3 are stable in both DCM and an aqueous phosphate buffer containing 2% DMSO. In the case of compounds 2 and 4 with no chloride co-ligands within their coordination spheres, high stability in aqueous phosphate buffer containing 2% DMSO was observed. Fluorescence emission titrations of the individual ruthenium compounds with bovine serum albumin (BSA) showed that the metal compounds interact non-discriminately within the protein's hydrophobic cavities as moderate to strong binders. The metal complexes were capable of disintegrating mature amylin amyloid fibrils. In vivo glucose metabolism studies in liver (Chang) cell lines confirmed enhanced glucose metabolism as evidenced by the increased glucose utilization and glycogen synthesis in liver cell lines in the presence of complexes 2-4.

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.

The Role of Pro-Opiomelanocortin Derivatives in the Development of Type 2 Diabetes-Associated Myocardial Infarction: Possible Links with Prediabetes.

Myocardial infarction is a major contributor to CVD-related mortality. T2DM is a risk factor for MI. Stress activates the HPA axis, SNS, and endogenous OPS. These POMC derivatives increase the blood glucose and cardiovascular response by inhibiting the PI3K/AkT insulin signaling pathway and increasing cardiac contraction. Opioids regulate the effect of the HPA axis and SNS and they are cardioprotective. The chronic activation of the stress response may lead to insulin resistance, cardiac dysfunction, and MI. Stress and T2DM, therefore, increase the risk of MI. T2DM is preceded by prediabetes. Studies have shown that prediabetes is associated with an increased risk of MI because of inflammation, hyperlipidemia, endothelial dysfunction, and hypertension. The HPA axis is reported to be dysregulated in prediabetes. However, the SNS and the OPS have not been explored during prediabetes. The effect of prediabetes on POMC derivatives has yet to be fully explored and understood. The impact of stress and prediabetes on the cardiovascular response needs to be investigated. This study sought to review the potential impact of prediabetes on the POMC derivatives and pathways that could lead to MI.

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.

Investigation into changes in inflammatory and immune cell markers in pre-diabetic patients from Durban, South Africa.

The prevalence of pre-diabetes is increasing in rapidly urbanizing cities, especially in individuals aged 25 - 45 years old. Studies also indicate that this condition is associated with aberrant immune responses that are also influenced by environmental factors. This study sought to investigate changes in the concentration of immune cells and select inflammatory markers in patients with pre-diabetes in Durban, South Africa. Blood samples collected from King Edward Hospital, after obtaining ethics approval, were divided into non-diabetic (ND), pre-diabetic (PD) and type 2 diabetic (T2D) using ADA criteria. In each sample, the concentration of immune cells and select inflammatory markers were determined. The results showed a significant increase in eosinophil and basophil levels in the PD group as compared to the ND group. Compared to ND, the PD and T2D groups had significant increases in serum TNFα, CD40L and fibrinogen concentrations. Additionally, there were decreases in serum CRP, IL-6, and P-selectin in the PD group while these markers increased in the T2D group. These findings were indicative of immune activation and highlight the impact of pre-diabetes in this population. More studies are recommended with a higher number of samples that are stratified by gender and represent the gender ratio in the city.

Momordica balsamina improves glucose handling in a diet-induced prediabetic rat model.

Prolonged exposure to high energy diets has been implicated in the development of pre-diabetes, a long-lasting condition that precedes type 2 diabetes mellitus (T2DM). A combination of pharmacological treatment and dietary interventions are recommended to prevent the progression of pre-diabetes to T2DM. However, poor patient compliance leads to negligence of the dietary intervention and thus reduced drug efficiency. Momordica balsamina (MB) has been reported to possess anti-diabetic effects in type 1 diabetic rats. However, the effects of this medicinal plant in conjunction with dietary intervention on pre-diabetes have not yet been established. Consequently, this study sought to evaluate the effects of MB on glucose homeostasis in a diet-induced pre-diabetes rat model in the presence and absence of dietary intervention. Pre-diabetes was induced on male Sprague Dawley rats by a high fat high carbohydrate (HFHC) diet for a period of 20 weeks. Pre-diabetic male Sprague Dawley rats were treated with MB (250 mg/kg p.o.) in both the presence and absence of dietary intervention once a day every third day for a period of 12 weeks. The administration of MB with and without dietary intervention resulted in significantly improved glucose homeostasis through reduced caloric intake, body weights, with reduced plasma ghrelin concentration and glycated hemoglobin by comparison to the pre-diabetic control. MB administration also improved insulin sensitivity as evidenced by the expression of glucose transporter 4 (GLUT 4) and glycogen synthase on the prediabetic treated animals. These results suggest that MB has the potential to be used to manage pre-diabetes and prevent the progression to overt type 2 diabetes as it demonstrated the ability to restore glucose homeostasis even in the absence of dietary and lifestyle intervention.

Phytochemical constituents from the roots and lignotubers of Rhoicissus tridentata and their in vitro uterotonic activity.

Rhoicissus tridentata is one of the most frequently used plants in preparing Isihlambezo, a herbal drink consumed by many South African women to induce labour and tone the uterus in pregnancy. This study aimed to identify the uteroactive compounds in this plant. Chromatographic purification of the methanol and water extracts from the roots yielded eight compounds, i.e. morin 3-O-α-L-rhamnopyranoside, trans-resveratrol 3-O-ß-glucopyranoside, a mixture of asiatic and arjunolic acids, quercetin 3-O-rhamnopyranoside, catechin, ß-sitosterol, and linoleic acid. All compounds were evaluated for their uterotonic effects using uterine smooth muscle isolated from stilboestrol-primed Sprague-Dawley rats. The mixture of asiatic and arjunolic acids showed the highest activity with EC50 of 0.02129 µg/mL for amplitude. These results validate the use of R. tridentata in ethnomedicine to facilitate labour in childbirth. Morin 3-O-α-L-rhamnopyranoside and trans-resveratrol 3-O-ß-glucopyranoside caused a relaxation of the uterine muscle, which suggests that some compounds in R. tridentata possess opposing activities.

The Potential Role of Gossypetin in the Treatment of Diabetes Mellitus and Its Associated Complications: A Review.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder caused by insulin resistance and dysfunctional beta (ß)-cells in the pancreas. Hyperglycaemia is a characteristic of uncontrolled diabetes which eventually leads to fatal organ system damage. In T2DM, free radicals are continuously produced, causing extensive tissue damage and subsequent macro-and microvascular complications. The standard approach to managing T2DM is pharmacological treatment with anti-diabetic medications. However, patients' adherence to treatment is frequently decreased by the side effects and expense of medications, which has a detrimental impact on their health outcomes. Quercetin, a flavonoid, is a one of the most potent anti-oxidants which ameliorates T2DM. Thus, there is an increased demand to investigate quercetin and its derivatives, as it is hypothesised that similar structured compounds may exhibit similar biological activity. Gossypetin is a hexahydroxylated flavonoid found in the calyx of Hibiscus sabdariffa. Gossypetin has a similar chemical structure to quercetin with an extra hydroxyl group. Furthermore, previous literature has elucidated that gossypetin exhibits neuroprotective, hepatoprotective, reproprotective and nephroprotective properties. The mechanisms underlying gossypetin's therapeutic potential have been linked to its anti-oxidant, anti-inflammatory and immunomodulatory properties. Hence, this review highlights the potential role of gossypetin in the treatment of diabetes and its associated complications.

The role of fibrinolysis in the development of prediabetes-associated coronary heart disease: a focus on the plasminogen activator inhibitor -1 and its potential use as a predictive marker in diet-induced prediabetes.

Introduction: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular diseases (CVD). However, the onset of T2DM is preceded by prediabetes, which is associated with sedentary lifestyles and consumption of high-calorie diets. Studies have shown that impaired glucose homeostasis creates an environment for developing T2DM-related complications. Using a high-fat-high-carbohydrate diet-induced prediabetes animal model, this study sought to assess the risk factors of coronary heart disease (CHD) in diet-induced prediabetes and identify biomarkers that can be used for early detection of prediabetes-associated CHD. Methods: Male Sprague Dawley rats were randomly grouped into two groups and were kept on different diets for 20 weeks (n = 6 in each group). One group was fed standard rat chow to serve as a non-prediabetes (NPD) control, while the other group consumed a high-fat-high-carbohydrate diet to induce prediabetes (PD). Post induction, the homeostasis model assessment- insulin resistance (HOMA-IR) and glycated haemoglobin (HbA1c) was used to test for insulin resistance. Body weight, mean arterial pressure (MAP), resting heart rate (HR), inflammatory cytokines (C-reactive protein (CRP), tumor necrosis factor (TNF-α), interleukin-6 (IL-6)), lipids (total cholesterol (TC), triglyceride (TG), lipoproteins (HDL, LDL, VLDL)), endothelial function (endothelial nitric oxide (eNOS), endothelin -1 (ET-1)), fibrinolysis (plasminogen activator inhibitor-1 (PAI-1)) were all measured to assess the risk of CHD. All data were expressed as means ± S.E.M. Statistical comparisons were performed with Graph Pad. Instat Software using Student's two-sided t-test. The Pearson correlation coefficient and linear regression were calculated to assess the association. The value of p < 0.05 was considered statistically significant. Results: There was significant insulin resistance accompanied by significantly increased HbA1c and body weight in PD compared to NPD. Simultaneously, there was a significant increase in inflammatory cytokines in PD compared to NPD. This was accompanied by significantly increased TG and VLDL and endothelial dysfunction in PD. The association between HOMA-IR and PAI-1 was insignificantly positive in NPD, whereas a significantly strong positive association was observed in PD. Conclusion: There is a positive correlation between insulin resistance and PAI-1 during prediabetes; therefore, suggesting that prediabetes increases the risk of developing vascular thrombosis. The current therefore study warrants further investigation on PAI-1 and other markers of fibrinolysis for the early detection of thrombosis and risk of CHD in prediabetes.

High-fat, high-carbohydrate diet-induced prediabetes preconception in Sprague-Dawley rats as a risk factor for the development of preeclampsia: assessing changes in placental metabolic insults.

Introduction: Hyperglycemia preconception deranges the establishment of a functional placenta; however, the risk of developing preeclampsia (PE) in prediabetic patients remains obscure. The aim was to assess abnormal placental changes as a risk factor for the development of PE in high-fat, high-carbohydrate (HFHC) diet-induced prediabetic (PD) rats. Methods: HFHC diet-induced female prediabetic Sprague-Dawley rats were mated, and blood glucose concentrations, mean arterial pressure (MAP), and body weights were monitored on gestational days (GNDs) 0, 9, and 18. On GND 18, animals were euthanized. Blood and placentas were collected for biochemical analysis. Results: Prediabetic rats showed significantly increased blood glucose concentration, proinflammatory cytokines, MAP, placental weight, and fetoplacental ratio compared with non-prediabetic (NPD) rats. Prediabetic rats showed significantly decreased placental vascular endothelial growth factor receptor 1 (VEGFR1) and placental growth factor (PLGF) and plasma nitric oxide (NO) compared with NPD. Discussion: Prediabetes may have promoted endothelial dysfunction in the placenta and hypoxia, thus reducing PLGF and VEGFR1, which may have promoted proinflammation, endothelial dysfunction associated with NO decline, and hypertension, which is also observed in preeclamptic patients. Prediabetes may have promoted lipogenesis in placentas and fetuses that may have induced macrosomia and IUGR, also observed in preeclamptic patients. The findings from this study highlight the need for screening and monitoring of prediabetes during pregnancy to reduce the risk of developing preeclampsia.

Prevalence of pre-diabetes in adults aged 25 - 45 years in a Durban-based clinical setting, South Africa: A retrospective study.

AIM: Due to pre-diabetes being underexplored, its prevalence was investigated in study participants aged 25-45 years in a Durban-based tertiary-level clinical setting in South Africa. METHODS: The study was done using a retrospective study design. Fasting blood samples from consented patients with no previous diagnosis of diabetes and within the specified age range were collected from King Edward Hospital in Durban. The pre-diabetes diagnosis was confirmed in participants with fasting glucose concentrations between 5.6 and 6.9 mmol/L and glycated haemoglobin (HbA1c) levels between 5.7 % and 6.4 % using the American Diabetes Association (ADA) and World Health Organisation (WHO) diagnosis criteria. The study participants' characterisation was stratified according to the diagnosis criterion, age, gender and ethnicity. RESULTS: An alarming 68 % average pre-diabetes prevalence across ADA and WHO criteria in the Durban, eThekwini district sample population. The highest prevalence was recorded using the IFG criterion (83%) and the lowest when using the HbA1c criterion (54 %). Between the White, Black and Indian ethnic groups, the Indian group were more predisposed to pre-diabetes onset, with a prevalence of 62.7 %. CONCLUSION: If pre-diabetes management is unattended, an unprecedented increase in metabolic disorders such as Type 2 Diabetes Mellitus (T2DM) and all-cause mortality incidence can be expected. Therefore, the study reveals a window of opportunity to intensify preventative measures and mitigate the incidence of T2DM.

Investigating the Association Between Diet-Induced "Leaky Gut" and the Development of Prediabetes.

INTRODUCTION: Chronic consumption of a high-calorie diet compromises the gut microbiota and the integrity of the intestinal wall, which causes translocation of bacterial lipopolysaccharides (LPS) into the blood. This elicits the secretion of pro-inflammatory cytokines, resulting in inflammation. However, how a high-fat high carbohydrate diet affects intestinal permeability and its possible role in the development of prediabetes have not been investigated. This study investigated the effects of HFHC diet-induced prediabetes on gut microbiota and intestinal permeability in male Sprague Dawley rats. METHODS: The animals were randomly assigned into the non-prediabetic (NPD) and diet-induced prediabetic (PD) groups (n=6) for 20 weeks. Then, the fecal samples were analyzed to measure the gut microbiota level of Firmicutes, Bacteroidetes, and Proteobacteria in both animal groups. Blood glucose, plasma insulin, serum zonulin, plasma LPS, soluble CD14, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), and intestinal fatty-acid binding protein (IFABP) concentrations were measured. RESULTS: The PD group had a reduction in the Firmicutes and an increase in Bacteroidetes and Proteobacteria levels compared to those in the NPD group. Blood glucose, insulin concentration, serum zonulin, and plasma sCD14 concentrations in the PD group increased significantly, while plasma LPS concentrations were similar to the NPD group. Concentrations of plasma TNF-α, IL-6, CRP, and IFABP, an intracellular protein expressed in the intestine, increased in PD compared to the NPD group. CONCLUSIONS: the study results cumulatively suggest that chronic consumption of the HFHC diet may be associated with the dysregulation of gut microbiota, leading to increased intestinal permeability.

The relationship between adipose tissue RAAS activity and the risk factors of prediabetes: a systematic review and meta-analysis.

METHODS: This systematic review was developed in compliance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-2020) standards. This was accomplished by searching clinical MeSH categories in MEDLINE with full texts, EMBASE, Web of Science, PubMed, Cochrane Library, Academic Search Complete, ICTRP and ClinicalTrial.gov. Reviewers examined all the findings and selected the studies that satisfied the inclusion criteria. The Downs and Black Checklist was used to assess for bias, followed by a Review Manager v5. A Forrest plot was used for the meta-analysis and sensitivity analysis. The protocol for this review was registered with PROSPERO CRD42022320252. RESULTS: The clinical studies (n = 2) comprised 1065 patients with prediabetes and 1103 normal controls. The RAAS measurements were completed in the adipose tissue. The RAAS components, renin and aldosterone were higher in the prediabetic (PD) compared to the control [mean difference (MD) = 0.16, 95% CI 0.16 (-0.13, 0.45), p = 0.25]. Furthermore, the PD group demonstrated higher triglycerides mean difference [MD = 7.84, 95% CI 7.84 (-9.84, 25.51), p = 0.38] and increased BMI [MD = 0.13, 95% CI 0.13 (-0.74, 0.99), p = 0.77] compared to the control. The overall quality of the studies was fair with a median score and range of 17 (16-18). CONCLUSION: The current study highlights the relationship between increased BMI, RAAS and insulin resistance which is a predictor of prediabetes. The renin is slightly higher in the prediabetes group without any statistical significance, aldosterone is rather negatively associated with prediabetes which may be attributed to the use of anti-hypertensive treatment.

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.

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.

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.

The Changes in Red Blood Cell Indices That Occur in Pre-Diabetic Patients of all Ethnicities from the 25-45 Years of Age: A Protocol for a Systematic Review and Meta-Analysis.

Introduction: Pre-diabetes is an intermediate, asymptomatic state between normoglycaemia and the onset of type 2 diabetes mellitus (T2D). Recent reports indicate that there are sub-clinical changes observed in red blood cells during pre-diabetes. This systematic review protocol will provide an outline of all procedures in the synthesis of the available data on the changes in red blood cell indices. Methods and Analysis: This protocol was prepared by adhering to the PRISMA 2015 guidelines for reporting protocols. Published clinical studies that involve observation, whether it is cross-sectional, comparative cross-sectional, case-control or cohort study designs that involve normal/non-diabetic and pre-diabetes reports were used. Additionally, this was accomplished by using clinical MeSH headings to search on MEDLINE, COCHRANE library and African Journal Online. Three reviewers (NCM, AMS & AK) screened all the results for eligibility criteria. Then, Downs and Black checklist was used to check the risk of bias. Review Manager v5.4 Forrest plot was used for meta-analysis and sensitivity analysis. Strength of evidence was then assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach (GRADE). Results and Conclusion: This protocol will give direction on the exploration of articles that report on changes in red blood cell indices in the pre-diabetic state. The results obtained from this protocol will further give direction on the research to be done at in the eThekwini district of South Africa. Ethics and Dissemination: The data that will be analyzed will be data that has already been published thus there will be no data collection from subjects. Therefore, no ethical clearance is required. Registration Details: This protocol has been registered with the International Prospective Registry of Systematic Reviews (PROSPERO) registration number "CRD42020189080" dated 05-07-2020.

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.