A. Diabetes is due to an inadequate effect of insulin that can lead to hyperglycemia, ketonemia, and ketoacidosis.
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1. Type 1 (insulin-dependent) diabetes mellitus results from the loss of endoge-nous insulin and is thought to be an autoimmune disorder.
2. Type 2 (non–insulin-dependent) diabetes mellitus is probably due to insulin resistance, which is often associated with obesity. The disease begins with hyper-insulinemia and results in hyperglycemia due to inability of the β cells to compen-sate for the increasing insulin resistance.
3. Several rare forms of diabetes, called maturity-onset diabetes of the young (MODY), occur due to specific gene mutations.
4. Gestational diabetes is due to increased insulin resistance during pregnancy.
B. TREATMENT of diabetes involves balancing of caloric intake, exercise, and hypo-glycemic medications.
1. The diet is a major factor in diabetic control, and the caloric intake should be con-stant and regular.
2. Patients with type 1 diabetes mellitus must use insulin.
3. Patients with type 2 diabetes mellitus can use either insulin or oral hypoglycemic drugs. Insulin is preferred for gestational diabetes patients and type 2 diabetes mellitus patients with
a. Reduced renal function b. Reduced hepatic function c. Persistent hyperglycemia
4. The efficacy of treatment should be followed by self-monitoring of blood glucose by the patient and physician monitoring of glycosylated hemoglobin.
5. Effective treatment should eliminate the acute symptoms of diabetes, includ-ing the hyperglycemia, polyphagia, polydipsia, polyuria, hypoglycemia, and ketoacidosis.
6. Based on clinical studies, rigid control of blood glucose reduces the chronic com-plications of diabetes, including:
a. Neuropathy b. Retinopathy c. Nephropathy
d. Possibly cardiovascular disease
C. INSULIN is a polypeptide that is ineffective when given orally and is usually admin-istered subcutaneously by injection or infusion pump. It can also be adminadmin-istered intravenously.
1. Insulin
a. Increases glucose transport into muscle and adipose tissue
b. Increases glycogen synthesis, decreases glycogenolysis and decreases gluconeo-genesis in liver tissue
c. Decreases lipolysis in adipose tissue and stimulates lipogenesis 2. Several sources are available.
a. Animal insulin (bovine or porcine) is no longer used because of its potential immunogenicity.
b. Human insulin (Humulin, Novolin) is produced by recombinant DNA technology.
3. A variety of insulin analogs are available with different durations of action. The less soluble insulin preparations have slower onsets and are longer acting.
a. Rapid-onset/ultrashort acting
i. Regular insulin (crystalline zinc insulin).
ii. Lispro (Humalog), aspart (Novolog), and glulisine (Apidra) insulins are even faster onset and shorter duration than crystalline zinc insulin.
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115 ENDOCRINE PHARMACOLOGY
b. Intermediate acting
i. Insulin can be conjugated with proteins or crystallized in various forms which slows the onset and increases the duration of action.
ii. NPH lasts up to 24 hours.
c. Prolonged acting
i. Detemir (Levemir) is bound to albumin, which prolongs its action.
ii. Insulin glargine precipitates at the injection site to form crystals that slowly dissolve.
4. The side effects of insulin can be very severe.
a. Hypoglycemia can occur from excessive doses, inadequate food intake after insulin injection, exercise, or alcohol.
i. Initial symptoms are due to sympathetic activation (e.g., tachycardia).
Propranolol will block this sympathetic activation, making it more difficult for diabetics to sense that they are hypoglycemic.
ii. Severe hypoglycemia can produce CNS effects, which can progress to con-vulsions, loss of conciousness, permanent CNS injury, and death.
iii. The hypoglycemia can be reversed by
(a) Ingestion of candy, orange juice, or other sugar source (b) Glucagon, intramuscularly or subcutaneously (c) Glucose, intravenously
b. Formation of insulin antibodies can lead to cutaneous allergic reactions or resistance to insulin. The risk of antibody formation for the insulin prepara-tions is: bovine ⬎ porcine ⬎ purified porcine ⬎ human.
c. Increases in body weight frequently occur.
D. ORAL ANTIDIABETIC DRUGS are effective in type 2 diabetics who cannot be managed by diet and exercise alone.
1. Insulin secretagogues trigger insulin release from the pancreas; thus, a func-tional pancreas is required.
a. The sulfonylureas increase insulin release by inhibiting adenosine triphos-phate (ATP)-sensitive potassium channels in the ββ cells; they also slightly decrease peripheral resistance to insulin.
i. Tolbutamide (Orinase) is short acting (6–12 hours) and is metabolized in the liver by oxidation.
ii. Chlorpropamide (Diabinese) is long acting and is partially excreted in the unchanged form by the kidney.
iii. Glyburide (DiaBeta, Micronase), and glipizide (Glucotrol) are second-generation sulfonylureas.
iv. Glimeperide (Amaryl) is a third-generation sulfonylurea; its action is somewhat dependent on ambient glucose.
b. Meglitinide analogs such as repaglinide (Prandin) and nateglinide (Starlix) have the same mechanism of action as sulfonylureas, but a shorter onset of action and shorter duration. The side effects are milder compared to the sulfonylureas.
c. The side effects of the insulin secretagogues include hypoglycemia and weight gain.
2. Insulin sensitizers decrease insulin resistance but do not increase insulin secretion.
a. Metformin (Glucophage) is a biguanide that enhances the hepatic response to insulin and decreases gluconeogenesis in the liver.
i. A rare, but serious, complication is lactic acidosis.
ii. Metformin can also be used to treat polycystic ovary disease.
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b. Thiazolidinediones (glitazones) activate peroxisome proliferator–activated receptor-gamma receptors, thereby reducing insulin resistance primarily in muscle and fat tissue.
i. Currently available glitazones include rosiglitazone (Avandia) and piogli-tazone (Actos).
ii. Liver function should be monitored in patients on these drugs due to the potential for hepatotoxicity. Weight gain can also occur.
3. Acarbose (Precose) and miglitol (Glyset) are αα-glucosidase inhibitors, which slow the breakdown of carbohydrates in the gut. Both have gastrointestinal side effects (flatulence, diarrhea).
4. Dipeptidyl peptidase (DPP)-IV inhibitors increase the action of incretins, which are hormones (glucagonlike peptide-1 [GLP-1] and glucose dependent insulinotropic peptide [GIP]) that cause the body to secrete more insulin and less glucagon in response to meals. Incretins also are thought to suppress appetite and increase gastric emptying time.
a. Type 2 diabetics are GLP-1 deficient, but they will respond more normally to glucose when given GLP-1. However, GLP-1 is too short lived to use as a drug.
Exenatide (Byetta) is an analog of GLP-1.
b. Sitagliptin (Januvia) is a dipeptidyl peptidase-IV (DPP-IV) inhibitor.
Inhibition of DPP-IV prevents breakdown of incretins, thereby increasing their concentration.
E. DIABETIC KETOACIDOSIS OR HYPEROSMOLAR (NONKETOTIC) COMA should be managed with
1. Fluid and electrolytes, especially potassium 2. Crystalline zinc insulin, intravenously
3. Correction of acidosis 4. Carbohydrates