Frontiers in Clinical Drug Research-Diabetes and Obesity

Metabolic syndrome is a complex pathology characterized by imbalances in lipid and glucose metabolism and weight gain, and consequently by an increase in the incidence of type II diabetes and cardiovascular disease. Metabolic syndrome is rapidly becoming one of the most important side effects of treatment with modern “atypical” antipsychotic agents, probably due to their specific mechanisms of action. Although the most recent members of this class (aripiprazole, asenapine, ziprasidone) seem to produce a reduce incidence of metabolic syndrome, the problem is far from being resolved. In this chapter, the three most important classical neuroleptics (chlorpromazine, haloperidol and loxapine) and the most important atypical antipsychotics will be individually analyzed in relation to their propensity to cause metabolic syndrome. The most reliable, current data will be presented, also in the perspective of possible interventions to mitigate metabolic imbalances, comparative studies, switching studies and augmentation strategies. An important strategy for metabolic syndrome prevention could also be the performing of an accurate therapeutic drug monitoring (TDM). Thus, an up-to-date overview will also be presented of recent and significant analytical methods for the determination of the drugs of interest and their main metabolites in human biological fluids.

Gestational diabetes mellitus (GDM) is a condition characterised by glucose intolerance first diagnosed in pregnancy. The first line of treatment for women diagnosed with GDM is diet control (GDMd). However, some of these women even after diet persist continue showing hyperglycaemia. The second line of treatment is insulin therapy (GDMi). The latter protocol is reported to be effective in restoring glycaemia of the mother and the baby at birth. However, it is difficult to reach a consensus between the variety of protocols for insulin therapy since it depends on several factors including the population studied, ethnicity, among others. GDMd associates with deleterious effects on the foetoplacental vascular function, mainly due to endothelial dysfunction. These alterations regard with alterations in the Larginine/ nitric oxide signalling pathway, as well as in the expression of insulin receptors A and B, and insulin response. More recent studies suggest that c-Jun Nterminal kinase 1–mediated insulin resistance may result from increased endoplasmic reticulum stress in this type of cells from the human placenta. Interestingly, the insulin therapy is a protocol that does not restore the dysfunctional endothelium as seen in GDMd. Indeed, insulin therapy may associate with additional deleterious effects on the mother, the placenta and foetus, and the newborn in GDM. In this chapter, we summarised some examples of the wide variety of protocols for insulin therapy and the potential consequences of this protocol on the foetoplacental unit and the neonate from women with GDM.

Diabetes mellitus (DM) is a serious health concern that affects millions of people worldwide. Despite numerous studies on the topic, the exact mechanisms underlying diabetes progression and its complications is still unclear. Growing evidence suggests that hyperglycemia results in increased reactive oxygen species (ROS) production, leading to oxidative stress which affects and damages various tissues and organs. Oxidative stress results from an imbalance between ROS and antioxidants. During cellular metabolism free radicals such as ROS and reactive nitrogen species (RNS) are produced, and these free radicals have dual effects (both positive and negative) on nearby tissues and activate several oxidative stress-related signaling pathways. Oxidative stress has been identified as a major player in the pathogenesis of diabetes and its associated complications such as stroke, neuropathy, retinopathy, peripheral vascular disease, nephropathy and lower limb ulceration. Oxidative stress damages the surrounding tissue, and the effects continue for extended periods even after blood glucose concentrations return to normal. Prolonged oxidative stress results in insulin resistance, β-cell dysfunction, glucose intolerance and mitochondrial damage. Antioxidants are a group of enzymatic or non-enzymatic molecules that encounter and neutralize free radicals, thereby protecting the body from oxidative stress. Many exogenous molecules such as antioxidant supplements, vitamins (vitamin C and E) and metal ion chelators detoxify free radicals and maintain physiological levels. A better understanding of the involvement of oxidative stress in the pathogenesis of diabetes could have major therapeutic implications for treatment. An effective approach to treat oxidative stress is by using exogenous drugs that mimic antioxidants. Overall, this chapter highlights the understanding of oxidative stressrelated mechanisms underlying the development of diabetes. It also elaborates on antioxidant therapy strategies to diminish oxidative stress and to treat diabetic associated complications.

Diabetes mellitus (DM) is a metabolic disorder which is the most alarming disease of the modern era, which occurs as a result of lack of insulin secretion or reduced insulin secretion or peripheral insulin resistance. Owing to the lifestyle changes, food habitus and stress, it has now become a pandemic. The incidence of diabetes is rapidly increasing worldwide at a dangerous rate. Over the past 30 years, the status of diabetes has changed from being considered as a mild disorder of the elderly to one of the major causes of morbidity and mortality, affecting the youth and middleaged people. As per the WHO, 171 million cases were reported in 2000 and are expected to increase to 366 million by 2030. DM incidences continuous to rise and pose a serious threat to human health. DM prevalence is increasing due to lifestyle, ethnicity, and age. Insulin has remained the main treatment for Type 1 diabetes and many Type 2 diabetic patients since its discovery, through parenteral insulin administration. Nanoparticles (NPs), which are minute structures ranging from size 1 to 100nm, are being studied for the treatment of various diseases. Considering the versatility of NPs, it also gives hope for better treatment options in diabetes. Different strategies have been used to manipulate insulin by using NPs, such as encapsulated delivery, etc. The objective of this chapter is to resolve the issues concerned with the oral delivery of insulin and also to discuss possible routes for the administration and the use of NPs for the best delivery of insulin. Nanotechnology, as a promising field, has opened new ways for the treatment of DM.

Diabetes mellitus (DM) is one of the most prevalent diseases of modern society. There are several therapeutic options available, but they also have many shortcomings. With the limitations and pitfalls of the existing therapies of diabetes, there is always a need for better drugs. This review is an attempt to give comprehensive details about the merits and demerits of a class of drugs called SGLT-2 inhibitors. SGLT-2 inhibitors act by increasing glucose excretion through urine and do not have any effect on insulin secretion, therefore, the risk of hypoglycemia is less. SGLT-2 inhibitors that are in clinical use are: dapagliflozin, empagliflozin, canagliflozin, and ertugliflozin. Considering the benefits offered by SGLT-2 inhibitors over existing antidiabetics, they deserve an important place in the therapy of T2DM and are found to be useful in T1DM, as studies have suggested previously. Beneficial effects of these drugs extend beyond controlling hyperglycemia, e.g., reduction in body weight, reduction in blood pressure and a proven and appreciable reduction in cardiovascular adverse events, maintenance of arterial elasticity and decrease in visceral adipose tissue deposition. The demonstration of such beneficial effects in various clinical studies has established them as one of the important components of antidiabetic therapy. However, in the light of recent safety concerns raised on such molecules would help prescribers to take an informed decision about risks versus benefits while prescribing these agents to their patients.