Pharmacological and Molecular Perspectives on Diabetes

Type 2 diabetes mellitus (T2DM) is one of the most challenging public health issues of the 21st century. T2DM, a complex polygenic metabolic disorder, is characterized by hyperglycemia and hyperinsulinemia resulting from the interplay of genetic/epigenetic and environmental factors. Epigenetic alterations present in T2DM patients and not in normal healthy individuals may give an insight into how environmental factors contribute to T2DM. Epigenetic mechanisms involve DNA methylation, histone modification, and gene expression alterations via micro RNAs (miRNA). These changes lead to glucose intolerance, insulin resistance, β-cell dysfunction, and ultimately T2DM. Extensive studies based on alterations in gene expression associated with DNA methylation/histone modifications are required to elucidate the relationship between vital environmental factors and T2DM progression. Candidate genes responsible for inter-individual differences in antidiabetic responses may also undergo epigenetic alterations. Identification and characterization of such epigenetic biomarkers may help in the prediction of T2DM risk as well as response to antidiabetic treatment and form an essential part of personalized medicine

Based on research, several scientific publications proposed dietary trivalent chromium as an attractive alternative for the prevention of hyperglycemia in people at high risk of type 2 diabetes mellitus (T2DM). The objective of the study is to determine the influence of chromium on the reaction of glucose and insulin in individuals with type 2 diabetes and healthy subjects. The study was based on several clinical reports of randomized clinical trials (RCTs). Available RCTs that were issued before December 2020 were routinely looked for in PubMed/Medline, Scopus, Web of Sciences, Google Scholar, and Cochrane Library. Keywords, such as “chromium” OR “chromium supplements” OR “chromium picolinate” in combination with “type 2 diabetes” were also checked in English. The results of these clinical studies support the view that chromium can improve both insulin and glucose metabolism in patients with T2DM, especially in the form of dietary supplements (chromium picolinate). However, insufficient data are available to create a conclusive hypothesis that nutritional supplements of chromium could be useful for the treatment of T2DM, and thus there is no need to endorse a general prescription for the management of diabetes using these supplements. Chromium supplements have minimal usefulness based on the lower impact of established evidence, and there is no reason for promoting their use for glycemic control in patients with existing T2DM. Well-designed, high-quality, broad, and long-term trials are required to improve the current data and ensure the protection and efficacy of drugs.

 Osteocalcin, a well-known bone formation marker, is secreted from osteoblasts and exists in fully carboxylated, partially carboxylated, and completely uncarboxylated forms. The endocrine involvement of uncarboxylated osteocalcin in glucose homeostasis has recently been confirmed. It has been demonstrated that double recessive osteocalcin mutant mice are hyperglycemic, hypoinsulinemic, and have reduced β cell numbers and insulin resistance. In contrast, leptin (an adipocyte-derived hormone) indirectly regulates the secretion of insulin in part through inhibition of osteocalcin conversion to uncarboxylated form via β2 adrenergic receptor signaling in osteoblasts. Because uncarboxylated osteocalcin is a secretagogue of insulin, which in turn positively regulates the bone formation, osteocalcin lies at the centre of the complex mechanism of glucose homeostasis and bone remodeling network.

Diabetes is a condition that occurs due to a chronic increase in the blood sugar level either by no insulin production by beta cells of Langerhans of the pancreas or no response from body cells against insulin hormone. Although diabetes has serious complications on health among different kinds of diabetes. Type 2 diabetes mellitus has a more prominent role in the loss of memory and cognitive impairment. Diabetes exerts widely known noxious effects on the kidney and blood vessels. Besides these effects, it also causes damage to the nerve cells and glial cells in the brain that result in impaired memory. The altered memory formation in patients with diabetes might be due to Alzheimer’s, stroke, and high blood sugar levels. Among all of the above parameters, damage to blood vessels is the most common. Although both diabetes and Alzheimer’s patients share common symptoms, it can be concluded that diabetes might cause an increased risk in the development of Alzheimer’s Disease. Indeed, our brain has receptors for insulin that recognize the insulin hormone and thus can regulate the glucose metabolism and insulin signaling. Any imbalance in the blood sugar level, either by low or no secretion of insulin hormone or no response to insulin by body cells, results in the chance of development of memory and cognitive impairment. By managing the normal blood sugar level, memory loss can be prevented. 

 Type II diabetes mellitus (T2DM) and osteoarthritis (OA) are chronic diseases that exhibit a strong relationship with age and obesity, and their co-existence tends to be accompanied by more altered disease conditions. With the increase in precision medicine, understanding the effect of common co-morbidities, such as diabetes, should result in improved management of OA. A higher prevalence of OA has been reported among patients with metabolic syndrome and diabetes mellitus (DM) and is considered an independent predictor for OA. The review of the literature suggests that DM may accelerate the symptoms, severity, and risk associated with joint replacement. Also, clinical and laboratory studies have suggested that there is an involvement of biochemical and biomechanical changes in articular cartilage in DM. Thus, the molecular mechanism that is activated in a diabetes-like environment that may contribute to OA could be characterized. Diabetes-influenced mechanism may provide knowledge on disease etiopathology and an improved understanding of the biological underpinning of disease for more specific therapeutic OA outcomes.

According to the preliminary research, coronavirus disease 2019 (COVID19) has been found to be more severe in patients with diabetes mellitus. Furthermore, COVID-19 might also lead to hyperglycaemia. Along with other risk factors, high blood glucose may also affect immune and inflammatory responses, thus inclining patients to severe COVID-19 witha much higher mortality rate. Angiotensin-converting enzyme 2 (ACE2) receptors are the common entry point for SARS-CoV-2. Recent findings suggest that dipeptidyl peptidase 4 (DPP4) can also act as a binding and entry target. Glucose-lowering agents and anti-viral treatments can alter the risk, but there exist limitations to their use, and its possible interactions with COVID-19 treatments should be carefully assessed. TMPRSS2 and Neuropilin-1, the key components that facilitate SARS-CoV-2 infection, are also the potential targets forthe treatment of COVID-19. Finally, severe acute respiratory syndrome coronavirus 2 infections might represent a worsening factor for people with diabetes, as it can precipitate acute metabolic complications through direct negative effects on cell function. Thus, this chapter deals with the treatment options of diabetes and COVID-19. Most of these conclusions are preliminary, and further investigation of the optimal management in patients with diabetes mellitus is warranted.

 Metabolic syndrome is a group of diseases, which include high elevated blood pressure, increased glucose level, abdominal obesity, and low high-density lipoprotein cholesterol levels. Clinical implications of metabolic syndrome indicate the risk of insulin resistance. Convincing data in the literature demonstrate alterations in the expression of cytokine inflammatory gene (IL-1, IL-6, TNF-a) expression highly increased and reduced the expression of the anti-inflammatory gene (IL-1Ra, IL-4, IL10, and IL-13) in Type 2 diabetes (T2D). Various physical activities, like weight loss and exercise, are beneficial for patients with T2D. Many anti-diabetic drugs are effective against T2D in which liraglutide, sulfonylureas, and salsalate drugs exert an anti-inflammatory action in obese patients with T2D. They all have a potent antiinflammatory effect due to inhibition of the NF-kB pathway, upregulation of SIRT1 expression, and down-regulation of pro-inflammatory factors, including cytokines (TNF-α, IL-1β, and IL-6). They mediate a long-lasting effect by epigenetic regulation of the NF -kB pathway by SIRT1. These 3 drugs, namely liraglutide, sulfonylureas, and salsalate, are used for glycemic control by T2D patients. Moreover, with the help of different mechanisms, these three regulate the level of glucose by the inhibition of the NF-κB pathway.

Type 2 Diabetes Mellitus (T2DM) is the most challenging health issue of the 21st century; it results from a complex interaction between multiple gene and environmental factors. TCF7L2 encodes a transcription factor that is involved in the Wnt signaling pathway that regulates gene expression of pro-glucagon. Effective treatment is needed to properly manage T2DM patients. Currently, 5 major classes of oral pharmacological agents are available for the treatment of T2DM, like metformin, sulfonylureas, meglitinides, thiazolidinedione, and alpha-glucosidase inhibitors

Polycystic ovarian disease (PCOD), Alzheimer's disease (AD), and type 2 diabetes mellitus (T2DM) have strong co-relation with each other, according to the accumulated evidence. However, many pieces of evidence have suggested that diabetes is the major risk cause behind PCOD and AD. We have focused on shedding light on the close association between PCOD, AD, and anti-diabetic drugs. When the family history of diabetes is studied extensively, it is illustrated that there are known associations between insulin resistance and development of the PCOD.Studies have been performed on different individuals with PCOD, both oligomenorrheic and eumenorrheic women. Irrespective of the criteria of obese and non-obese women, there is a high prevalence of type 2 diabetes history in their family, hence proving the family inheritance of the ovarian disorder. While studying the pathophysiology of diabetes, it is observed that many characteristics of AD are similar to that of T2DM such as elevated oxidative stress, amyloid-beta (Aβ) production at a high level, cerebrovascular complication, and dysfunctional insulin signaling. Among the anti-diabetic drugs, metformin is most commonly used, and it has many useful functions, such as controlling serum lipid profiles, having positive control over the hemostasis process, and serving an anti-inflammatory role

A handful of pharmaceutical companies manufacture different types of insulin which treat type I diabetes mellitus. Insulin brands are grouped by the onset of their action and how long their blood glucose-lowering effects last. Insulin analogs were introduced way back in 1996; since then, there has been a lot of advancement in their production as well as the mechanism of action. Current insulin therapies more closely mimic the normal physiologic insulin secretion by the pancreas, which gives a better-glycosylated haemoglobin level in patients suffering from diabetes. This chapter focuses on the types of available insulins and their regimens, classification of types of insulin that are best for different age groups, diet to be followed, principles of dose adjustment, and a glimpse of insulin pump therapy

We live in a rhythmic world where both internal (in the body) and external (natural) processes are harmoniously synced to each other to function in a rhythmic pattern. Whenever this synchronization between the two is disturbed, it creates misalignment leading to rhythm disruption. In today’s 24x7 society, the majority of health issues are due to lifestyle disorders that have their genesis in circadian rhythm disruption. One such lifestyle disorder that has reached the heights equivalent to the epidemic is Type 2 diabetes mellitus (T2DM). In the current chapter, the role of the endogenous biological clock (of organ and tissue) in regulating glucose metabolism is discussed by citing the basal and advanced research done in the related field. Our effort is to build up a connection between circadian misalignment and its probable effect with special reference to T2DM. We started with the description of circadian rhythm, overviewing the daily glucose metabolism. We then discussed the pathophysiology of type 2 diabetes mellitus in light of circadian rhythm disruption. Every organ in the human body has its clock and rhythm, thus it is a complex mechanism involving dysfunction of pancreatic b-cells, deposition of fat near visceral organs and insulin resistance, etc. Workstress and schedules have increased the risks of obesity and diabetes. Thus, it seems the need of the hour to focus on chronopathology and chronomedicine as alternative treatment strategies to manage and prevent T2DM, which can further, contribute to the reduction of the risks of metabolic co-morbidities in the human population.

The field of pharmacogenetic is focused on find out the ways in which genetic variance in an individual affects the efficacy and potent action of drugs, moreover, in how many ways genetic variance affects the drugs toxicity has also been a major topic of discussion. Nowadays, pharmacogenomics is clearly focused on the establishing personalized medication and finding and developing new drugs. Many approaches have been identified that can play a major role in promoting the concept of personalized medicine and helping in identifying major genetic variance that can further work as a biomarker and provide major clinical insights. As it has been known, the patients of diabetes have been treated with more than one type of drugs that can be defined as oral antidiabetic drugs (OAD) that also plays major role in curing out the diabetes associated complications such as hypertension and dyslipidemia. If major steps should be taken to treat diabetes than only major changes can be made to control it’s associated complications and if any kind of genetic testing will be created than it can work as an predictor tool for the disease. Role of, microRNA (miRNA), which is a class of non-coding RNA, is also known to play a major role incausing chronic inflammation if it gets dysregulated along with that also causing β-cell degeneration, followed by insulin resistance.