Ronald A Hill

Halki Diabetes Remedy

Diabetes Cure Diet

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chapter overview

A large and growing number of medicinal substances act on endocrine systems. Many are steroid analogs (i.e., ligands for estrogen, progestin, and androgen receptors), and, as suggested by the title of this chapter, will not be considered herein, but instead in Chapter 25. Neither will all nons-teroidal endocrine modulators be considered in the present chapter, however. Medicinals acting to modulate calcium deposition and resorption, particularly within bone, are discussed in Chapter 21 (including ligands for vitamin D receptors, parathyroid hormone receptors, and calcitonin receptors). Coverage of thyroid hormones, and of agents for treating hyperthyroid states, has been retained in Chapter 19 for this edition of the text. Numerous other endocrine system interventions are, at present, solely accomplished by administering a naturally occurring human protein produced by artificial means. For now, agents of this nature receive primary consideration within a chapter dedicated to "biologics" (Chapter 27); examples include human growth hormone, somatostatin, and the follitropins.

For more than 6 decades, a collection of disorders of primary metabolism, chiefly type 1 and type 2 diabetes, have, for obvious reasons, received great attention from the drug discovery community. These efforts have intensified over the past several decades, evolving to include a significant fraction of the biotechnology enterprise. Insulin remains central to the treatment of type 1 diabetes, and various details of insulin chemistry, biochemistry, and pharmacology are provided in Chapter 27. Within the past decade or so, however, various modified insulins have reached the market, and the molecular bases of their diverse characteristics are considered in the present chapter, along with a brief introduction to insulin itself. Two general classes of drugs that act primarily—but not necessarily exclusively—as insulin secretagogues for treating type 2 diabetes, namely the sulfonylureas and the glinides, are then considered in detail. It has long been realized that defective responsiveness to insulin plays a major role in the etiology and progression of type 2 diabetes. On this basis, biguanides that act, at least in part, as "insulin sensitizers" have been in clinical use for many years, and more recently the thiazolidinediones appeared on the market.

Hormones other than insulin and glucagon also play important roles in regulating the body's glucose handling and associated aspects of food consumption and primary metabolism. The identification of two of these, and subsequent characterization of their physiological actions and biochemistry, led to the creation of amylin and glucagon-like peptide type 1 (GLP-1) receptor agonists, which to date are represented in the market by analogs of the endogenous proteins. Enzymes catalyzing the degradation of these hormones were also identified as potential molecular targets for therapeutic intervention; thus, the first inhibitor of dipeptidyl peptidase type 4 (DPP-4 or DPP-IV), sitagliptin, recently reached the U.S. market, with others expected in the near future.

Given the fact that endocrine signals of a suitable nature are requisite to the survival and proliferation of many cancerous cells, various therapeutics used in oncology (Chapter 10) fall within the potential scope of this chapter. Among these, the gonadotropin-releasing hormone receptor (GnRH-R) agonists and antagonists receive consideration herein. These drugs represent treatment options for various gonadal hormone-dependent cancers, but also see such clinical uses as fertility modulation, mitigation of various uterine disorders, and in treating precocious puberty. The GnRH-R agonists and antagonists currently on the market are modified peptides, and examining how the molecular features of each of these drugs endow them with their particular pharmacological and biopharmaceutical properties offers the medicinal chemistry student some excellent lessons within a realm that is often lightly emphasized. Entry points to the literature in this area have been selected and provided to facilitate further explorations by students who may be motivated to expand the breadth and depth of these lessons.

o DISORDERS OF GLUCOSE METABOLISM: DIABETES AND THE METABOLIC SYNDROME

Various forms of diabetes afflict a large and increasing proportion of the population of much of the developed world, and (somewhat surprisingly) rapidly increasing numbers of individuals in the developing world. Diabetes causes impairments, and eventually often kills, in large measure, because of the secondary effects of excessively elevated circulating and tissue glucose levels. Perhaps more insidiously, tolerance to hypoglycemic excursions as a result of progressively impaired counterregulatory responses to the administration of insulin and drugs that elicit insulin release can cause individuals to suffer severe hypoglycemic episodes, involving shock and, in more extreme cases, coma or death.

Diabetes can be broadly classified as "type 1" or "type 2." Type 1 diabetes is also often referred to as insulin-dependent diabetes mellitus (IDDM), or sometimes as juvenile-onset diabetes mellitus, although onset can in fact occur in adults. The hallmark of type 1 diabetes is absent or insufficient insulin secretion by the insulin-secreting cells of the pancreas, namely the beta cells ([ cells) of the islets of Langerhans. In some individuals, this arises because of a genetic defect, whereas in other individuals, the disease is "idiopathic" (i.e., the cause is indeterminate), but in most cases, the [-islet cells are partially or completely destroyed as a result of an erroneous autoimmune response. Regardless of cause, type 1 diabetes must, at present, be treated with one or more types of insulin. Type 2 diabetes is often referred to as non-insulin-dependent diabetes mellitus (NIDDM). In type 2 diabetes, the insulin secretory response is impaired—increasingly so as the disease progresses with time, but in most cases, a comorbid defect is the failure of many cells of the body to properly respond to circulating insulin, particularly certain cells in the liver and skeletal muscles having a primary glucose storage role, and certain cells in adipose tissue. Another way of stating this is that the "insulin sensitivity" of these cells becomes impaired. This impairment often occurs secondary to obesity, although this contributor is apparently not obligatory, and the "obesity" may be so mild as to hardly be recognizable as such. In recent years, states of health have been characterized that, without intervention, often lead to type 2 diabetes. Such prediabetic states are now often broadly referred to as "the metabolic syndrome,"1,2 and various medical organizations are establishing criteria and treatment guidelines intended to avert further development into full-blown type 2 diabetes— that is, preventive medicine tactics. Although historically type 2 diabetes has most often been treated with insulin sec-retagogues (such as one of the sulfonylurea drugs, vide infra) or, in some cases, insulin, the recognition that this disorder— which is really an array of related disorders—is most often one of defective cellular insulin responsiveness has, in recent years, guided basic and drug discovery research onto paths culminating with the testing and marketing of therapeutic agents, having completely new mechanisms of action. Clinical results in some cases provide the hope not only that the damaging out-of-safe-range excursions of blood and tissue glucose levels might be prevented, but also that individuals with type 2 diabetes might be cured, and individuals with prediabetic syndromes be saved from developing the fullblown disease. For type 1 diabetics or those type 2 patients requiring insulin supplementation, devices allowing for continuous monitoring of blood glucose and microprocessor-controlled on-demand insulin delivery seem likely to soon revolutionize treatment. Until very recently, though, alternatives to lifelong insulin therapy for such patients seemed no more than hopeful dreams. Yet, scientific advances now suggest that, before many more years pass, it should be possible to implant alternative glucose-responsive, insulin-secreting cells in the pancreas or liver. Even more excitingly, it appears that it will be possible to stimulate regeneration of [-cell populations within the pancreatic islets while simultaneously arresting the autoimmune attack that would otherwise destroy them; therefore, type 1 diabetes could, for all practical purposes, be cured.

Insulins and Modified Insulins

Type 1 diabetes must, for now, be treated with insulin replacement therapy. After the demonstration c. 1900 that this disorder, which was invariably fatal within a short time, was one of pancreatic [-cell failure, more than 20 years passed before insulin was isolated and purified from fetal calf pancreases, and its clinical relevance demonstrated. Commercially viable production was achieved by Eli Lilly and Co., with initial marketing in 1923 (Iletin). The primary structure of human insulin was not reported until 1958 (Nobel Prize in Chemistry to Frederick Sanger, 1964), and the tertiary structure was not available until reported by Dorothy Crowfoot Hodgkin in 1969, a triumph of x-ray crystallography. Prior to the 1980s, treatment of type 1 diabetes was achieved via injections of porcine or bovine insulin, or combinations thereof. Although preparations containing porcine or bovine insulin may remain in use around the globe, the availability of human insulin produced artificially via methods of "biotechnology" has widely supplanted insulin from animal sources, and, undoubtedly, will soon completely replace them as cost barriers are conquered. No animal-sourced preparations are now available in the United States. Moreover, several modified insulin preparations have come on the market in recent years, and the development of technology for alternative routes of administration besides injection is also rapidly changing the therapeutic landscape.

Human insulin is a heterodimer (Fig. 20.1), consisting of two different peptide subunits linked covalently by two disul-fide bridges. This heterodimer is produced from a single, continuous, and substantially larger (110-amino-acid) protein, namely preproinsulin. Among other reasons, production in this manner ensures proper three-dimensional (3D) folding and cross-linking of insulin. Preproinsulin is converted to proinsulin (86-amino-acid residues), from which insulin is produced by removal of a 35-amino-acid segment joining the two subunits. Chapter 27 includes a more detailed treatment of the biosynthesis and structural attributes of human insulin, as well as further information regarding its storage within, and release from, pancreatic [ cells.

A chain

B chain

Ser-Leu

Gly-Ser-His-Leu-Val-Glu-Ala-Leu-Tyr-Leu-Val-N

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