Frontiers in Clinical Drug Research-Diabetes and Obesity

Exendin-4, a 39-amino-acid peptide found in lizard saliva, is a glucagon-like peptide-1 (GLP-1) receptor agonist that has been approved for the treatment of type 2 diabetes by the United States Food and Drug Administration (FDA) since 2005. More recently, exendin-4–loaded extended-release microspheres, the first once-weekly treatment for type 2 diabetes, were also approved by the FDA in 2012. Exendin-4 exerts many beneficial anti-diabetes bioactivities, including induction of glucosedependent insulin secretion, suppression of high glucagon secretion, slowing of gastric emptying to modulate nutrient absorption, reduction of food intake and body weight, improvement in pancreatic endocrine function, and an increase in β-cell mass. In this chapter, the historical perspective, present status and related mechanisms of exendin-4 for the treatment of type 2 diabetes are discussed. Moreover, strategies that have been applied for the design of exendin-4 derivatives and their potential applications are summarized and discussed. This chapter will benefit future prospects of the use of exendin-4 and its derivatives in the treatment of type 2 diabetes and obesity.

It is well recognised that the growth hormone (GH)/insulin-like growth factor (IGF) system is well recognised to have a role in diabetes and obesity. The IGFs (IGF-I and IGF-II) have structural similarity to proinsulin and the type 1 IGF receptors and insulin receptors are able to form heterodimers that participate in metabolic and mitogenic signalling. Obesity, diabetes and the metabolic syndrome are associated with alterations in the GH/IGF system. Perturbations in this system are also associated with predisposition to diabetes, obesity and the metabolic syndrome and also the risk of vascular and other complications.

Targeting this system holds therapeutic promise. Therefore, having introduced the relevant physiology and pathophysiology, the evidence base in to using GH and IGFs in the management of GH and IGFs therapy will be presented and the advantages and limitations of such approaches will be discussed.

Patients with long-term diabetes develop angiopathy and neuropathy. Macroangiopathy refers to myocardial infarction, strokes and ischemic gangrene. Retinopathy and nephropathy are due to microangiopathy. The development of late diabetic complications is often assumed to be due to hyperglycemia and production of reactive oxygen species (ROS) in mitochondria. Despite regulation of blood glucose and blood pressure many patients still die of diabetic angiopathy. Intensive blood glucose control did reduce the risk for retinopathy and neuropathy, but had no significant effect on clinical renal outcomes. Blood pressure lowering in type 2 diabetic patients leads to a significant reduction in albuminuria, whereas improvement in renal failure was not significant. Newer therapies are therefore of vital importance. Diabetes is caused by insulin deficiency. Insulin treatment may induce insulin resistance and increase body weight. The appearance in plasma after injection is delayed, and patients may have relative high insulin values during the day. Insulin has a number of specific effects on the cardiovascular system and the kidney. This review focuses on insulin’s effects on capillary permeability in muscle endothelial cells and in podocytes in the kidney. Insulin deficiency and resistance rather than hyperglycemia may be directly responsible for lack of capillary recruitment in muscles and abnormal function of podocytes in the glomerulus in the kidney. It is concluded, that it is unlikely that longterm complications can be eliminated without development of a more physiologic insulin delivery system or alternatively with development of drugs that temporarily can activate specific insulin signaling pathways in the cells.

Metabolic diseases are major public health problems both in developed and developing countries. Factors associated with lifestyle including physical inactivity and excessive consumption of high-energy diets are the primary causes for the increasing incidence of these pathologies. In parallel, an unprecedented decrease of fertility rates is also being witnessed. Male reproductive health is very sensitive to the insults induced by alterations in the metabolic status and the number of men suffering from metabolic diseases (such as diabetes mellitus and obesity) is dramatically high, being expected to increase even further in the next decades.

Diabetes mellitus is associated with a decrease in male reproductive potential and known to promote several sexual disorders, such as erectile dysfunction or retrograde ejaculation. Still, the “hidden effects” of this pathology on testicular physiology may lead to even more serious consequences for male fertility. Diabetes mellitus induces shifts in testicular metabolism, particularly in glucose metabolism, which is vital for the normal occurrence of spermatogenesis. So the maintenance of testicular glucose metabolism homeodynamics is of particular relevance; otherwise spermatogenesis may be arrested. For many years this issue was overlooked, but compelling evidence shows that spermatogenesis only occurs under a tight metabolic control. Thus, this subject is becoming a hot topic and will be on the spotlight in the next years. On the other hand, metabolic alterations induce pressure in biological systems whose responses are mediated by epigenetic modifications, particularly in sperm. These modifications are stable and can be passed to the subsequent generations, enhancing the transmission of phenotypes. Hence, the metabolic mechanisms responsible for the alterations in male reproductive health and subfertility/infertility in diabetic individuals deserve special attention.

The obesity epidemic has become one of the major challenges for the modern society, first of all because of its clinical and social consequences. In 1998 the World Health Organization (WHO) proclaimed obesity a worldwide epidemic encompassing both adults and children and acknowledged it one of the biggest threats to the human health. The cause of overweight and obesity is body mass increase as a result of fat tissue increment. It has been proven that obesity increases the risk of hypertension, type 2 diabetes (T2DM), as well as leads to cardiovascular complications such as stroke or heart attack. The fat tissue that is superfluous in obesity is the source of many hormonally active compounds influencing bodily homeostasis. The recent research has pointed to the particular importance of abdominal obesity in the pathogenesis of metabolic disturbances linked with the endocrine activity of the visceral fat. This visceral fat tissue produces many adipokines, such as tumour necrosis factor alpha (TNF-alpha), interleukin 6 (IL6), leptin, adiponectin, resistin, omentin, visfatin, nesfatin, vaspin, chemerin, ghrelin or apelin. Adipocytokines, released into the bloodstream thanks to specific receptors on the surface of the target cells, act as classic hormones influencing organ and tissue metabolism. Moreover adipokines may decrease tissue sensitivity to insulin and induce inflammatory processes, endothelial dysfunction and atherosclerotic changes. At present much attention is given to determination of adipokines as contemporary markers of insulin resistance. Research authors suggest that changes in adipokine concentrations can be seen at least a few years earlier that first symptoms of improper glucose metabolism. Although there are still many controversies regarding what is the most important causative factor for T2DM, it cannot be denied that the endocrine activity of fat tissue as well as the immunological status both play important roles in the pathogenesis of T2DM. Promising research results point to the necessity of elaborating methods of measuring pro-inflammatory factors, especially adipokines, that would be both diagnostically sensitive and specific and that could be implemented in the laboratory diagnostics as well as primary prevention of diabetes.