36: Insulin, Oral Hypoglycemics, and Glucagon

CHAPTER 36 Insulin, Oral Hypoglycemics, and Glucagon

INSULIN AND THE ENDOCRINE PANCREAS

The pancreas has exocrine and endocrine functions. The exocrine system comprises the acinar cells, which secrete digestive enzymes. The islets of Langerhans, which make up the endocrine system, contain four types of cells, each of which synthesizes and secretes different polypeptide hormones (Table 36-1). Insulin is produced by the β cells, which constitute most (60% to 80%) of the islet and form its central core. The β cell is the primary glucose sensor for the islet.

TABLE 36-1 Pancreatic Islet Secretions

CELL TYPE HORMONE SECRETED
α (A) cell Glucagon
β (B) cell Insulin, amylin (islet amyloid polypeptide)
δ (D) cell Somatostatin
F (PP) cell Pancreatic polypeptide
G cell Gastrin

Insulin is a polypeptide containing 51 amino acids. It has a molecular weight of approximately 5800 Da. It is composed of two chains (called the A and B chains) that are joined by two disulfide bridges. Insulin is formed by proteolysis of a large, single-chain precursor, proinsulin. In proinsulin, shown in Figure 36-1, the A and B chains are joined by a connecting (C) peptide. Proinsulin is converted to insulin when the C peptide is removed; this occurs within the secretory granules of the pancreatic β cell. Approximately equimolar amounts of insulin and C peptide are stored in the granules and released by exocytosis when the β cell is stimulated. C peptide has no known biologic function, but it can serve as an index of insulin secretion. Units of insulin, originally defined by activity, are now defined on the basis of weight. There are approximately 28 U/mg of insulin.

Insulin is a member of a family of related peptides known as insulin-like growth factors (IGFs). IGF-I and IGF-II have molecular weights of approximately 7500 Da and structures that are homologous to proinsulin. The receptors for insulin and IGF-I are closely related. Insulin can bind to the receptor for IGF-I with low affinity and vice versa. The growth-promoting actions of insulin seem to be mediated, at least in part, through the IGF-I receptor. In contrast to insulin, IGFs are produced in many tissues, where they are more important in regulating growth than in regulating metabolism. IGFs mediate the anabolic and growth-promoting effects of growth hormone. IGF-I and IGF-II were originally known as nonsuppressible insulin-like activity (NSILA) because of their ability to produce insulin-like effects in bioassays that were not suppressed by the addition of excess anti-insulin antibodies.

Actions of Insulin

The classic action of insulin is to decrease the blood glucose concentration. Insulin does this by affecting glucose use and glucose production. Liver, muscle, and fat are the important target tissues for regulation of glucose homeostasis by insulin, but insulin exerts potent regulatory effects on other cell types as well. Insulin stimulates glucose transport into muscle and fat by promoting translocation of the intracellular transporter, glucose transporter 4 (Glut 4), to the cell surface (Figure 36-2).14 Insulin does not stimulate glucose uptake into the liver, but it inhibits hepatic glucose production. Insulin inhibits catabolic processes, such as breakdown of glycogen, fat, and protein. Glycogenolysis and gluconeogenesis are inhibited. Insulin receptors are found on virtually all cells. Activation of the insulin receptor leads to a cascade of phosphorylation or dephosphorylation reactions, or both. As a result, insulin affects the activities of various enzymes involved in intracellular use and storage of glucose, amino acids, and fatty acids. Glycolysis (use) and glycogen synthesis (storage) are promoted. The effects of insulin are summarized in Table 36-2.

TABLE 36-2 Metabolic Actions of Insulin

TYPE OF METABOLISM ACTION OF INSULIN MAJOR TARGET TISSUE*
Carbohydrate Increases glucose transport Muscle, fat
Increases glycogen synthesis Liver, muscle
Decreases gluconeogenesis Liver
Increases glycolysis Liver, muscle
Increases glucose oxidation Fat
Fat Increases lipogenesis Liver, fat
Decreases lipolysis Liver, fat
Increases synthesis of triglycerides Fat
Protein Decreases protein breakdown Liver
Increases protein synthesis Muscle, various
Increases amino acid uptake Muscle, various

* Insulin exerts potent regulatory effects on other cell types in addition to liver, muscle, and fat, the classically important target tissues for glucose regulation.

In addition to the short-term metabolic effects, insulin has other, longer term actions. It affects synthesis of key enzymes and is believed to have important growth-regulating effects in vivo. Insulin regulates gene transcription,13 affecting protein synthesis; increases cell proliferation and differentiation; and decreases apoptosis.

Insulin Signaling

There is evidence that insulin acts by synthesis of second messengers that enter the cell to mediate some of the hormone’s actions on intracellular enzymes (e.g., phosphorylation, dephosphorylation). These mediators are of the inositolphosphoglycan (IPG) class.8 IPGs represent a family of second messengers or mediators that are increasingly being implicated as having an important role in signal transduction, not only for insulin, but also for other hormones and growth factors. They are discussed later in this chapter.

DIABETES MELLITUS

Diabetes mellitus is a group of syndromes characterized by hyperglycemia. Virtually all forms of diabetes mellitus are due to either a decrease in the circulating concentration of insulin (insulin deficiency) or a decrease in the response of peripheral tissues to insulin (insulin resistance). The disease has two major forms. Currently, the preferred nomenclature is type 1 and type 2 diabetes mellitus. Older names include juvenile-onset or insulin-dependent diabetes mellitus for type 1 and maturity-onset or non–insulin-dependent diabetes mellitus for type 2.

Evidence indicates that the incidence of type 1 and type 2 diabetes mellitus is increasing worldwide. In 1999, the prevalence was predicted to double by 2010.7 Type 2 diabetes is becoming increasingly common and is an emerging problem in children and adolescents, particularly minorities.3 In the United States, the annual number of newly diagnosed diabetes cases tripled during 1980-2005. Major risk factors for type 2 diabetes are obesity and physical inactivity. The incidence of type 1 diabetes is reported to be increasing by approximately 3% per year.16

Type 2 Diabetes Mellitus

Approximately 90% to 95% of diabetics have type 2 diabetes mellitus. In type 2 diabetes, target cells are relatively insensitive to insulin.6 This is known as peripheral resistance to insulin. Impaired glucose metabolism in muscle and liver are key features of type 2 diabetes. Genetic predisposition is important in type 2 diabetes; there is greater than 95% concordance in identical twins.17 In addition, most type 2 diabetics are obese. Type 2 diabetics have impaired glucose taste detection,11 which may reflect a generalized defect in glucose sensitivity, including the glucose-sensing pancreatic β cells.

Insulin Therapy

Insulin is the mainstay for treatment of virtually all type 1 and many type 2 diabetic patients. When necessary, insulin may be administered intravenously or intramuscularly. Long-term treatment generally relies on subcutaneous injection of the hormone, however.

Subcutaneous administration of insulin differs from physiologic secretion of insulin in two major ways. First, the kinetics of absorption are relatively slow and do not mimic the normal rapid increase and decrease of insulin secretion in response to ingestion of nutrients. Second, the injected insulin diffuses into the peripheral circulation instead of being released into the portal circulation. Any preferential effect of secreted insulin on hepatic metabolic processes is lost.

Insulin preparations

Insulin occurs in the pancreas complexed with zinc and is extracted in the form of zinc insulin, which is not water-soluble at neutral pH. This form can be converted to the Na+ salt, which is water-soluble at neutral pH. Available preparations include human insulins and insulin analogues. Human insulins, so called because they have the same structure as normal human insulin, are made by genetic engineering (recombinant DNA). In ultrashort-acting insulin analogues (insulin aspart, glulisine, and lispro), amino acids are substituted, or reversed. Long-acting insulin analogues (insulin detemir and glargine) have groups added. Insulin analogues have been developed to alter the kinetics.

Insulin preparations are classified according to their duration of action into rapid-acting (ultrashort-acting and short-acting), intermediate-acting, and long-acting preparations. Insulin products available in the United States are listed in Table 36-3.

Jan 5, 2015 | Posted by in General Dentistry | Comments Off on 36: Insulin, Oral Hypoglycemics, and Glucagon
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