Frontiers in Clinical Drug Research-Diabetes and Obesity

After a thirteen-year hiatus, the FDA approved two new anti-obesity drugs in 2012, lorcaserin (brand-name Belviq®) and a fixed-combination of topiramide and phentermine (brand-name Qsymia®); one new anti-obesity drug was approved in 2014, a fixed-combination of naltrexone and bupropion (brand-name Contrave®), and in 2015 the “high dose” liraglutide (brand-name Saxenda®) was approved for weight loss. During this time, the marketed anti-obesity drug sibutramine was withdrawn due to increase in non-fatal myocardial infarction and stroke incidence [1], two drugs targeting cannabinoid receptors were not approvable in the United States and the European Union due to concerns regarding suicidality and leptin at pharmacologic doses was not marketed due to disappointing efficacy. All approved drugs, in conjunction with diet and exercise, achieve more weight gain as compared to placebo. Efficacy between different drugs cannot be directly compared since no head-to-head studies have been performed; however, some drugs/drug combinations appear to provide substantially bigger reductions in weight than others or the respective monotherapies. Cardiovascular parameters, especially systolic blood pressure, triglycerides and HDL-cholesterol respond positively to even small amounts of weight loss; the same holds true for insulin and insulin resistance. Uric acid, an emerging risk factor for type 2 diabetes and cardiovascular disease, also tends to improve in response to weight loss although there is an increased short-term risk of gout. All drugs have specific side effects and several drugs do have black-box warnings; for example, for female patients, pregnancy needs to be ruled-out before starting topiramate and a negative pregnancy test is required every 4 weeks while on treatment with Qsymia, and buproprion needs to be tapered off slowly and not discontinued abruptly to decrease the risk of seizures. Treating overweight/obese subjects presents an opportunity and a challenge to physicians and patients. To achieve optimal weight loss with least complications, patients need to work on hypocaloric diets and exercise and physicians need to know the prescribing information of the prescribed weight-loss drugs.

For more than a century the physiological role of bile acids was considered limited to their actions in cholesterol metabolism and lipid absorption from the gastrointestinal tract. Evidence emerging over the past 20 years has greatly changed this perspective. It is now apparent that these complex molecules play an integral signaling function within the gut and have extra-intestinal hormonal actions. Bile acid interaction with plasma membrane G protein-coupled receptors (e.g. TGR5, M3R) and nuclear receptors (e.g. FXR) expressed on intestinal epithelial cells modulates postreceptor signaling and gene transcription. Herein, we review the fundamentals of how bile acid structure governs the interaction of these molecules with cell receptors and transport proteins (e.g. ASBT), and how these interactions are important for nutritional balance. We focus on bile acid interaction with TGR5, a receptor whose activation stimulates release of glucagon-like peptide-1 (GLP-1) from enteroendocrine L cells; GLP-1, an intestinal incretin, is important for glucose homeostasis. Drugs that mimic the actions of GLP-1 or retard its degradation are effective treatments for diabetes, obesity, and their metabolic complications (e.g. non-alcoholic fatty liver disease). Altered gut and plasma levels of bile acids and GLP-1 are important for the clinical benefits of bariatric surgery. Hence, there is great interest in developing novel pharmaceutical approaches to imitate these changes and, in particular, the beneficial actions of bile acids. We offer a critical analysis of these approaches and propose novel opportunities for drug design to combat the current obesity epidemic and its metabolic complications.

Type 2 diabetes mellitus (T2DM) is a global crisis. Asia has a young, economically productive population at high risk of the disease. Poor blood glucose control and its associated risk factors resulting in disabling complications will have a catastrophic impact on patients with T2DM, their families, society, the healthcare system and the economy. Inhibiting sodium–glucose co-transporters (SGLT1/SGLT2) in the gastrointestinal tract and kidneys is the latest novel therapeutic pathway in managing the disease. In addition to controlling blood glucose, SGLT inhibitors may also reduce weight and lower blood pressure. However, these drugs are so new that long-term safety data is unavailable. Currently, six SGLT2 inhibitors are available for clinical use; they are continuously monitored for long-term adverse effects by drug regulatory authorities. Although there is some data suggesting benefits favouring Asians, most of the existing evidence from randomised controlled trials (RCTs) level are not applicable to patients in Asia with T2DM. High-quality RCTs reflecting realworld practice in this region are required for evidence-based medicine (EBM) to improve clinical care and justify the significant investments their development have required. Along with the production of high-quality EBM, emerging economies in Asia have the potential to play important roles in developing and facilitating evidence from RCTs for successful clinical practice utilisation. ‘First, do not harm’ is the fundamental tenet of clinical practice. Educating consumers of EBM about the importance of critical thinking, primary data accuracy, consistency and high-quality EBM for safe clinical practice are essential.

Current research has revealed that inflammation as the cardinal pathophysiological mechanism in the development and progression of diabetic nephropathy (DN). Diverse inflammatory cytokines interact with each other and together with other mechanisms; result in the progression of DN. It is now widely accepted that many inflammatory cytokines, such as transforming growth factor (TGF)-β1, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, interleukin (IL)-1, IL-18, etc. are involved in the pathogenesis and development of DN. Published articles reported that a large number of single Traditional Chinese Medicine (TCM) and their extracts could confer benefits to DN by regulating inflammatory cytokines; such as Astragalus, Danshen Root, Szechuan Lovage Rhizome, Kudzuvine Root, Common Threewingnut Root, etc. TCM formulae also could regulate inflammatory cytokines in DN; such as Buyang Huanwu Decoction, Fufang Danshen Diwan, Bushen Tongluo Formular, etc. This is usually associated with improved kidney histomorphology, proteinuria and renal function parameters in DN. Although some researches concerning TCM for inflammatory cytokines in DN are in-depth, most researches, if not all, are still very superficial. The signaling pathways and underlying mechanisms of TCM affecting inflammatory cytokines remain unclear. Although there are many shortcomings in this field, it is still fortunate that the experimental renobenefits of TCM can be translated for human into clinical treatment. This indicates new, effective and promising therapeutic drugs.

Since the 1990s The World Health Organisation (WHO) has stated that “… obesity should now be regarded as one of the greatest neglected public health problems of our time…” and defined the global epidemic of being overweight and obese as “globesity”. A positive energy balance, which consists of an imbalance between energy intake and calorie expenditure is the main cause of obesity, however, genetic, environmental, socioeconomical, behavioral and psychological factors may also be the inducing factors when it comes to obesity. The excess of adiposity has an enhancing effect on the development of hypertension, cardiovascular diseases and type 2 diabetes mellitus (T2DM) as a result of the resistance to insulin-mediated glucose disposal. T2DM which represents a common disease associated with obesity and often aging is characterized by high blood glucose levels, impaired insulin production and peripheral insulin resistance. Homeostatic degradation of glucose affects the cerebral functions directly or indirectly because glucose is a significant metabolic substrate for all cells and also for the cells of the brain. Insulin has a key effect on the regulation of energy metabolism of neurons and neuronal recovery, which acts as a growth factor on all cells including neurons in the central nervous system. Therefore, simply put, impairment in neuronal homeostasis which occurs as a result of insulin deficiency. These are considered to be a risk factor for Alzheimer’s disease (AD) development. Indeed, many studies have shown that glucose intolerance and impairment of insulin secretion are associated with a higher risk to develop dementia or AD. It is worth remembering that AD is associated with brain insulin resistance and deficiency, whereas T2DM is associated with peripheral insulin resistance. In short, it can be said that T2DM causes AD-type neurodegeneration in the brain. T2DM and AD share several molecular processes that underlie the degenerative developments. Dysregulated glucose metabolism, abnormalities in insulin signaling, the formation of advanced glycation end products, oxidative stress, the activation of inflammatory pathways and abnormal protein processing are the common characteristics of T2DM and AD. The misfolding of proteins plays an important role in both diseases, so as the aggregation of amyloid peptides. AD is characterized by the deposition of amyloid within neurons and amyloid plaques. Also in AD, the formation of amyloid fibers could be the product of ubiquitin-mediated protein degradation defects induced by a dysfunction of the proteasome. According to one study which was conducted on T2DM rats, T2DM-dependent decreases in p62 (a known cargo molecule that transports polyubiquitinated tau to proteosomal and autophagic degradation systems) transcription which is a primary mechanism underlying increased AD-like pathology. In some studies, brain amyloid deposition occurs as a result of increased blood-brain barrier permeability in case of diabetes conditions. In the recent years, according to some members of the diabetes community, AD is seen as a neuroendocrine disorder and the term “Type 3 Diabetes” defines the insulin deficiency and resistance in the brain of those with AD. In the context of these information, in this chapter, we propose a study about “Type 3 Diabetes” with the underlying mechanisms through the perspective of histology.

The worldwide prevalence of obesity has increased at alarming rates over the last four decades. Overweight and obesity featuring the excess of white adipose tissue are cardiovascular risk conditions consistently associated with the development of complex metabolic disorders, including insulin resistance, type 2 diabetes mellitus ( T2DM) and coronary heart diseases. Many natural and synthetic agonists of peroxisome proliferator-activated receptors (PPARs; nuclear receptors) are used in the treatment of glucose and lipid disorders. PPARs perform different activities, mainly via endogenous ligands produced in the metabolic pathways of fatty acids; and therefore, they are called lipid sensors. PPAR agonists have different properties and specificities for individual PPAR receptor, different absorption/distribution profiles, and distinct gene expression profiles, which ultimately lead to different clinical outcomes. The isoform PPARγ is expressed in white and brown adipose tissue, large intestine and spleen. However, its expression is highest in adipocytes and it plays a key role in the adipogenesis regulation, energy balance and lipid biosynthesis. PPARγ has been the focus of intense research once its ligands have been described to treat T2DM. Some of them are currently prescribed as anti-diabetic drugs, such as thiazolidinedione. PPARγ activation modulates not only insulin sensitization, but also lipid metabolism, vascular tone and inflammation, all processes involved in atherogenesis. Considering the impact of this subject in the public health and the necessity of new approaches for the development of new drugs to treat metabolic diseases and to improve the quality of life, this chapter has the aim of revising important points concerning the involvement of the nuclear receptors in obesity, diabetes and discuss the real possibility of this target to become an effective and safe pharmacological therapy.

Hydrogen sulfide (H₂S) is an important gasotransmitter with diverse biological actions in the body and has been receiving much attention over the last two decades. It has been characterized as a key regulator of cardiovascular homoeostasis, cell growth and differentiation, mitochondrial biogenesis, adipose tissue metabolism, inflammation and liver function. H₂S-donor molecules have hence been considered as being potential therapeutic options for a variety of human diseases including hypertension, atherosclerosis, obesity, oxidative stress and chronic inflammation. It has been shown that huge amount of endogenous H₂S originates in the liver, and may be involved in the development of insulin resistance and diabetes. H₂S is considered as an important mediator of carbohydrate homeostasis. H₂S production and bioavailability are impaired during development of obesity, diabetes and its complications, highlights the potential therapeutic effects of H₂S in metabolic syndrome. This issue is however controversial due to some findings that show increased H₂S disturbs pancreatic β-cell function and may be responsible for reduced insulin secretion. H₂S also contributes to increased blood glucose levels by accelerating glycogenolysis and gluconeogenesis, effects which could intensify hyperglycemia in diabetes. Furthermore, reduced basal and insulin-stimulated glucose uptake was observed following treatment of adipocytes with H₂S; in contrast, the protective effect of H₂S on β-cell function against a high-fat diet, as well as its insulin-sensitizing properties has been reported in both in vitro and in vivo models of insulin resistance. Regarding the increasing interest in therapeutic applications of H₂S-donors in cardiometabolic disorders, its potential unexpected effects on glucose/insulin metabolism, especially in the case of diabetes, should be considered. In this review, we focus on the current knowledge available on exogenous and endogenous H₂S and carbohydrate metabolism, including both regulation of hepatic glucose production and hepatic and peripheral glucose uptake and β-cell function.