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• Adverse effects


  Hot flashes, leg cramps, and increased risk of venous thromboembolism
• Calcitonin


  Salmon calcitonin is indicated for the treatment of osteoporosis in women who are at least 5 years postmenopausal. The drug reduces bone resorption, but it is less effective than other agents, and is no longer routinely recommended for the treatment of osteoporosis.
• Intranasal calcitonin


  Adverse effects include rhinitis and other nasal symptoms
• The pancreas produces the peptide hormones insulin, glucagon, and somatostatin

  
• The peptide hormones are secreted from cells in the islets of Langerhans (β-cells produce insulin, α-cells produce glucagon, and delta-cells produce somatostatin)

  
• These hormones play an important role in regulating metabolic activities of the body, particularly glucose homeostasis
• A relative or absolute lack of insulin, as seen in diabetes mellitus, can cause serious hyperglycemia

  
• Left untreated, retinopathy, nephropathy, neuropathy, and cardiovascular complications may result
• Administration of insulin preparations or other glucose-lowering agents can reduce morbidity and mortality associated with diabetes

  
• The incidence of diabetes is growing rapidly in the United States and worldwide
• An estimated 30.3 million people in the United States and 422 million people worldwide are afflicted with diabetes
• Diabetes mellitus


  A heterogeneous group of syndromes characterized by elevated blood glucose attributed to a relative or absolute deficiency of insulin

  
• Clinical classifications of diabetes

  • Type 1 diabetes
  • Type 2 diabetes
  • Gestational diabetes
  • Diabetes due to other causes such as genetic defects or medications

  
• Gestational diabetes


  Carbohydrate intolerance with onset or first recognition during pregnancy

  
• Type 1 diabetes


  • Absolute deficiency of insulin due to destruction of β cells
  • Without functional β cells, the pancreas fails to respond to glucose, and a person with type 1 diabetes shows classic symptoms of insulin deficiency (polydipsia, polyphagia, polyuria, and weight loss)

  
• Insulin secretion in normal subjects

  Constant β-cell secretion of insulin suppresses lipolysis, proteolysis, and glycogenolysis. A burst of insulin secretion occurs within 2 minutes after ingesting a meal, in response to transient increases in circulating glucose and amino acids. This lasts for up to 15 minutes, followed by the postprandial secretion of insulin.

  
• Without functional β cells, those with type 1 diabetes can neither maintain basal secretion of insulin nor respond to variations in circulating glucose

  
• Treatment for type 1 diabetes

  A person with type 1 diabetes must rely on exogenous insulin to control hyperglycemia, avoid ketoacidosis, and maintain acceptable levels of glycosylated hemoglobin (HbA1c)

  
• HbA1c


  A marker of overall glucose control and is used to monitor diabetes in clinical practice. The rate of formation of HbA1c is proportional to the average blood glucose concentration over the previous 3 months. A higher average glucose results in a higher HbA1c.

  
• Goal of insulin therapy in type 1 diabetes

  Maintain blood glucose as close to normal as possible and to avoid wide fluctuations in glucose

  
• Type 2 diabetes


  Accounts for greater than 90% of cases. Influenced by genetic factors, aging, obesity, and peripheral insulin resistance, rather than autoimmune processes. The metabolic alterations are generally milder than those observed with type 1 diabetes, but the long-term clinical consequences are similar.

  
• Treatment goal for type 2 diabetes

  Maintain blood glucose within normal limits and to prevent the development of long-term complications

  
• Treatment for type 2 diabetes

  Weight reduction, exercise, and dietary modification decrease insulin resistance and correct hyperglycemia in some patients. However, most patients require pharmacologic intervention with oral glucose-lowering agents. As the disease progresses, β-cell function declines, and insulin therapy is often needed to achieve satisfactory glucose levels.

  
• Insulin


  A polypeptide hormone consisting of two peptide chains that are connected by disulfide bonds. It is synthesized as a precursor (proinsulin) that undergoes proteolytic cleavage to form insulin and C-peptide, both of which are secreted by the β cells of the pancreas.

  
• Measurement of C-peptide


  Provides a better index of insulin levels than plasma insulin levels, as insulin undergoes significant hepatic and renal extraction

  
• Insulin secretion


  Regulated by blood glucose levels, certain amino acids, other hormones, and autonomic mediators. Secretion is most often triggered by increased blood glucose, which is taken up by the glucose transporter into the β cells of the pancreas. There, it is phosphorylated by glucokinase, which acts as a glucose sensor. The products of glucose metabolism enter the mitochondrial respiratory chain and generate adenosine triphosphate (ATP). The rise in ATP levels causes a blockade of K+ channels, leading to membrane depolarization and an influx of Ca2+. The increase in intracellular Ca2+ causes pulsatile insulin exocytosis.

  
• Mechanism of action of exogenous insulin

  Administered to replace absent insulin secretion in type 1 diabetes or to supplement insufficient insulin secretion in type 2 diabetes

  
• Production of human insulin

  Produced by recombinant DNA technology using strains of Escherichia coli or yeast that are genetically altered to contain the gene for human insulin. Modification of the amino acid sequence of human insulin produces insulins with different pharmacokinetic properties.

  
• Insulin administration


  Generally administered by subcutaneous injection, although an inhaled insulin formulation is also available. In a hyperglycemic emergency, regular insulin is administered intravenously (IV). Continuous subcutaneous insulin infusion (also called the insulin pump) is another method of insulin delivery.

  
• Adverse effects of insulin

  Hypoglycemia is the most serious and common adverse reaction. Other adverse effects include weight gain, local injection site reactions, and lipodystrophy. Diabetics with renal insufficiency may require a decrease in insulin dose. Due to the potential for bronchospasm with inhaled insulin, patients with asthma, chronic obstructive pulmonary disease, and smokers should not use this formulation.

  
• Insulin preparations


  • Rapid-acting
  • Short-acting
  • Intermediate-acting
  • Long-acting

  
• Rapid-acting and short-acting insulin preparations


  Include regular insulin, insulin lispro, insulin aspart, insulin glulisine, and inhaled insulin. Rapid-acting insulins have more rapid absorption, a quicker onset, and a shorter duration of action after subcutaneous injection compared to regular insulin. Rapid- or short-acting insulins are administered to mimic the prandial (mealtime) release of insulins and to control postprandial glucose. They may also be used in cases where swift correction of elevated glucose is needed.

  
• Intermediate-acting insulin


  Neutral protamine Hagedorn (NPH) insulin is an intermediate-acting insulin formed by the addition of zinc and protamine to regular insulin. The combination with protamine forms a complex that is less soluble, resulting in delayed absorption and prolonged duration of action.

  
• Rapid-acting insulins


  Used in cases where swift correction of elevated glucose is needed

  
• Administration of rapid-acting insulins

  Injected subcutaneously 15 minutes preceding a meal or within 15 to 20 minutes after starting a meal

  
• Rapid-acting insulin suspensions


  Commonly used in external insulin pumps, suitable for IV administration

  
• Regular insulin


  Most commonly used when the IV route is needed

  
• Neutral protamine Hagedorn (NPH) insulin


  An intermediate-acting insulin formed by the addition of zinc and protamine to regular insulin

  
• NPH insulin


  • Used for basal (fasting) control in type 1 or 2 diabetes, usually given along with rapid- or short-acting insulin for mealtime control
  • Should be given only subcutaneously (never IV), and it should not be used when rapid glucose lowering is needed

  
• Insulin glargine


  A long-acting insulin with a slower onset than NPH insulin and a flat, prolonged hypoglycemic effect with no peak