Current Pharmaceutical Design - Volume 25, Issue 23, 2019

The incidence of diabetes has increased globally in recent years and figures of diabetic patients were estimated to rise up to 642 million by 2040. The disorder is accompanied with various complications if not managed at the early stages, and interlinked high mortality rate and morbidity with time. Different classes of drugs are available for the management of type 2 diabetes but were having certain limitations of their safety. Alphaglucosidase is a family of enzyme originated from the pancreas which plays a role in the anabolism of 80-90% of carbohydrate consumed into glucose. This glucose is absorbed into the blood and results in frank postprandial hyperglycemia and worsens the conditions of diabetic patients which precipitate complications. Inhibition of these enzymes helps to prevent postprandial hyperglycemia and the formation of glycated end products. Alphaglucosidase inhibitors are reported to be more important in adequate control of type 2, but marketed drugs have various side effects, such as poor patient compliance and also expensive. This proves the needs for other class of drugs with better efficacy, safety, patient compliance and economic. In this review, we have emphasized the recent advances in the field of new alpha-glucosidase inhibitors with improved safety and pharmacological profile.

Diabetes is one of the most common endocrine non-communicable metabolic disorders which is mainly caused either due to insufficient insulin or inefficient insulin or both together and is characterized by hyperglycemia. Diabetes emerged as a serious health issue in the industrialized and developing country especially in the Asian pacific region. Out of the two major categories of diabetes mellitus, type 2 diabetes is more prevalent, almost 90 to 95% cases, and the main cause of this is insulin resistance. The main cause of the progression of type 2 diabetes mellitus has been found to be insulin resistance. The type 2 diabetes mellitus may be managed by the change in lifestyle, physical activities, dietary modifications and medications. The major currently available management strategies are sulfonylureas, biguanides, thiazolidinediones, α-glucosidase inhibitors, dipeptidyl peptidase-IV inhibitors, and glucagon-like peptide-1 (GLP-1) agonist. Binding of insulin on the extracellular unit of insulin receptor sparks tyrosine kinase of the insulin receptor which induces autophosphorylation. The phosphorylation of the tyrosine is regulated by insulin and leptin molecules. Protein tyrosine phosphatase-1B (PTP1B) works as a negative governor for the insulin signalling pathways, as it dephosphorylates the tyrosine of the insulin receptor and suppresses the insulin signalling cascade. The compounds or molecules which inhibit the negative regulation of PTP1B can have an inductive effect on the insulin pathway and finally help in the management of diabetes mellitus. PTP1B could be an emerging therapeutic strategy for diabetes management. There are a number of clinical and basic research results which suggest that induced expression of PTP1B reduces insulin resistance. In this review, we briefly elaborate and explain the place of PTP1B and its significance in diabetes as well as a recent development in the PTP1B inhibitors as an antidiabetic therapy.

Peroxisome Proliferator-Activated Receptors (PPARs) also known as glitazone receptors are a family of receptors that regulate the expression of genes and have an essential role in carbohydrate, lipid and protein metabolism apart from other functions. PPARs come in 3 sub-types: PPAR-α, PPAR-β/δ and PPAR-γ - with PPAR-γ having 2 isoforms - γ1 and γ2. Upon activation, the PPARs regulate the transcription of various genes involved in lipid and glucose metabolism, adipocyte differentiation, increasing insulin sensitivity, prevention of oxidative stress and to a certain extent, modulation of immune responses via macrophages that have been implicated in the pathogenesis of insulin resistance. Hence, PPARs are an attractive molecular target for designing new anti-diabetic drugs. This has led to a boost in the research efforts directed towards designing of PPAR ligands - particularly ones that can selectively and specifically activate one or more of the PPAR subtypes. Though, PPAR- γ full agonists such as Thiazolidinediones (TZDs) are well established agents for dyslipidemia and type 2 diabetes mellitus (T2D), the side effect profile associated with TZDs has potentiated an imminent need to come up with newer agents that act through this pathway. Several newer derivatives having TZD scaffold have been designed using structure based drug designing technique and computational tools and tested for their PPAR binding affinity and efficacy in combating T2D and some have shown promising activities. This review would focus on the role of PPARs in the management of T2D; recently reported TZD derivatives which acted as agonists of PPAR- γ and its subtypes and are potentially useful in the new drug discovery for the disease.

Neurodegenerative disorders are the most devastating disorder of the nervous system. The pathological basis of neurodegeneration is linked with dysfunctional protein trafficking, mitochondrial stress, environmental factors and aging. With the identification of insulin and insulin receptors in some parts of the brain, it has become evident that certain metabolic conditions associated with insulin dysfunction like Type 2 diabetes mellitus (T2DM), dyslipidemia, obesity etc., are also known to contribute to neurodegeneration mainly Alzheimer’s Disease (AD). Recently, a member of the fibroblast growth factor (FGF) superfamily, FGF21 has proved tremendous efficacy in diseases like diabetes mellitus, obesity and insulin resistance (IR). Increased levels of FGF21 have been reported to exert multiple beneficial effects in metabolic syndrome. FGF21 receptors are present in certain areas of the brain involved in learning and memory. However, despite extensive research, its function as a neuroprotectant in AD remains elusive. FGF21 is a circulating endocrine hormone which is mainly secreted by the liver primarily in fasting conditions. FGF21 exerts its effects after binding to FGFR1 and co-receptor, β-klotho (KLB). It is involved in regulating energy via glucose and lipid metabolism. It is believed that aberrant FGF21 signalling might account for various anomalies like neurodegeneration, cancer, metabolic dysfunction etc. Hence, this review will majorly focus on FGF21 role as a neuroprotectant and potential metabolic regulator. Moreover, we will also review its potential as an emerging candidate for combating metabolic stress induced neurodegenerative abnormalities.

Diabetes has turned out to be one of the biggest worldwide health and economic burdens, with its expanded predominance and high complexity proportion. The quantity of diabetic patients is expanding enormously around the world. Several reports have demonstrated the sharp increment in the sufferers. Stable and acceptable blood glucose control is fundamental to diminish diabetes-related complications. Consequently, ceaseless endeavors have been made in antidiabetic drugs, treatment strategies, and nanotechnology based products to accomplish better diabetes control. The nanocarriers pertaining hypoglycaemics provide improved diabetes management with minimum risk of associated side effects. Dendrimers have caught an incredible attention in the field of drug delivery and personalized medicines. Dendrimers are three-dimensional well-defined homogenous nanosized structures consisting tree-like branches. The present review highlights the different aspects of dendrimers including fabrication, surface engineering, toxicological profile as well as delivery of antidiabetic drugs for the effective cure of diabetes.

Mitochondria are the central power stations of the cell involved with a myriad of cell signalling pathways that contribute for whole health status of the cell. It is a well known fact that not only mitochondrial genome encodes for mitochondrial proteins but there are several other mitochondrial specific proteins encoded by nuclear genome which regulate plethora of cell catabolic and anabolic process. Anterograde pathways include nuclear gene encoded proteins and their specific transport into the mitochondria and regulation of mitochondrial homeostasis. The retrograde pathways include crosstalk between the mitochondria and cytoplasmic proteins. Indeed, ATP dependent and independent proteases are identified to be very critical in balancing anterograde to retrograde signalling and vice versa to maintain the cell viability or cell death. Different experimental studies conducted on silencing the genes of these proteases have shown embryonic lethality, cancer cells death, increased hepatic glucose output, insulin tolerance, increased protein exclusion bodies, mitochondrial dysfunction, and defect in mitochondrial biogenesis, increased inflammation, Apoptosis etc. These experimental studies included from eubacteria to eukaryotes. Hence, many lines of theories proposed these proteases are conservative from eubacteria to eukaryotes. However, the regulation of these proteases at gene level is not clearly understood and still research is warranted. In this review, we articulated the origin and regulation of these proteases and the cross talk between the nucleus and mitochondria vice versa, and highlighted the role of these proteases in diabetes and diabetic complications in human diseases.

Background: A number of observational studies examined the association between metformin therapy and ovarian cancer survival outcomes, but the results are inconsistent. Objective: The study aimed to investigate the effect of metformin on survival for ovarian cancer patients. Method: PubMed, Embase and Web of Science databases were searched for relevant studies from the inception to June 11, 2019. The strength of the relationship was assessed using summary of hazard ratios (HRs) with corresponding 95% confidence intervals (CI). Statistical analyses were carried out using the random-effects model. Results: Totally, 6 retrospective cohort studies involving 2,638 ovarian cancer patients were included. Metformin was not associated with improved overall survival (HR=0.78, 95% CI 0.54-1.12, P=0.175, I2= 61.6%) and disease- free survival (HR=0.49, 95% CI 0.20-1.17, P=0.106, I2=82.1%) in ovarian cancer patients compared to nonmetformin users. Conclusion: The current study provides preliminary evidence that metformin may not be associated with a survival benefit for ovarian cancer patients. More studies with rigorous designs are needed.

Insulin resistance and type 2 Diabetes mellitus resulting in chronic hyperglycemia is a major health problem in the modern world. Many drugs have been tested to control hyperglycemia which is believed to be the main factor behind many of the diabetes-related late-term complications. Wogonin is a famous herbal medicine which has been shown to be effective in controlling diabetes and its complications. In our previous work, we showed that wogonin is beneficial in many ways in controlling diabetic cardiomyopathy. In this review, we mainly explained wogonin anti-hyperglycemic property through AKT/GLUT4 pathway. Here we briefly discussed that wogonin increases Glut4 trafficking to plasma membrane which allows increased entry of glucose and thus alleviates hyperglycemia. Conclusion: Wogonin can be used as an anti-diabetic and anti-hyperglycemic drug and works via AKT/GLUT4 pathway.