Chapter 32- Drug Treatment for Diabetes

Insulin _____ the storage of glucose in skeletal muscle and other tissues, thereby _____ plasma glucose levels after a meal. A. increases; increasing B. increases; decreasing C. decreases; increasing D. decreases; decreasing E. none of the above are true

B. increases; decreasing

Drugs that stimulate insulin secretion (e.g., sulfonylureas) or increase tissue sensitivity to insulin (e.g. metformin) A. are used to treat patients with poor glucagon production B. are effective in some patients with Type I diabetes. C. are effective in some patients with Type II diabetes. D. all the above are true E. none of the above are true; these drugs have no clinical indications

C. are effective in some patients with Type II diabetes.

People who are on insulin therapy for diabetes mellitus are more at risk for hypoglycemia if A. they administer too much insulin B. they skip a meal C. they exercise too strenuously D. all the above are true E. none of the above are true

D. all the above are true

All of the following are characteristics of type I diabetes mellitus EXCEPT A. disease onset usually occurs in childhood B. body weight is usually at or below normal levels C. pancreatic insulin production is low or absent D. tissue sensitivity to insulin is low E. diet and exercise are used in conjunction with drug therapy to maintain optimal health

D. tissue sensitivity to insulin is low

Glucagon : primary effect? what does it do? what happens if glycogen stores are depleted? MOA?

Hormonal antagonist of Insulin o Primary effect = increase blood glucose to maintain normal blood glucose levels in cases of hypoglycemia. o Produces a rapid increase in glycogen breakdown(glycogenolysis ) in the liver so more glucose goes to the blood stream from hepatic glycogen stores. o Stimulates a more prolonged increase in hepatic gluconeogenesis to sustain blood glucose levels even if glycogen stores are depleted . o MOA: Uses c-AMP second messenger mechanism to activate specific enzymes to increase glycogen breakdown and stimulate gluconeogenesis.

Side Effects of Insulin Therapy (10)

Hypoglycemia • Headache • Fatigue • Hunger • Tachycardia • Sweating • Anxiety, confusion • Late stages : loss of consciousness, convulsions and death

Possible mechanism of insulin action on glucose metabolism in skeletal muscle cells.

Possible mechanism of insulin action on glucose metabolism in skeletal muscle cells. An insulin receptor located on the cell's surface consists of two alpha (!) and two beta (B) subunits. Binding of insulin to the alpha subunits causes addition of phosphate groups (PO4) to the B subunits. This receptor autophosphorylation causes the activation of one or more insulin receptor substrates (IRSs), which promote translocation of glucose carriers (GLUTs) to the cell membrane, where they increase facilitated diffusion of glucose (Glu) into the cell. Activated IRSs also increase the activity of enzymes that promote glucose storage.

Primary Agents for Type II Diabetes: Sulfonylureas ( glipizide or Glucotrol) & Meglitinides ( repaglinide or Prandin) MOA Adverse effects

o MOA: act on pancreatic beta cells and stimulate them to secrete insulin , decrease liver production of glucose , facilitate use of glucose by muscle. o Adverse effects: hypoglycemia, heart burn, GI distress , headache, vomiting, skin rashes, dizziness etc.

Type 1 Diabetes

• autoimmune disease in which the body produces antibodies that attack the beta cells of the pancreas. • Diabetes affect young children , adolescents, not linked to obesity. • Strong inherited predisposition and association with some specific histocompatibility antigens exist, but it is believed that exposure to a virus may be the precipitating event .

Insulin : produced by what cells? what is its primary effect? Allows the presence of what to have glucose go through the cell membrane? How does it affect the uptake and use of glucose in the liver? increase the activity of what enzyme? what affect does insulin have? promotes the storage of what? (2) how does it encourage protein synthesis in muscles? (3) in fat cells it stimulates what? (3) Insulin is involved with the metabolism of what?(3) DM will affect what?

o Produced by the *beta cells of the pancreatic islets* o Primary effect is lowering blood glucose levels by facilitating glucose entry into the *liver and other peripheral tissues. * o Allows the presence of a *transport carrier* to have glucose go through the cell membrane and *get into muscle cells and other cells.* o Affects the uptake and use of glucose in the liver by *stimulating the activity of the *glucokinase enzyme which phosphorylates glucose and traps it in the hepatic cell* . o Increases the activity of enzyme that promote glycogen synthesis and inhibit the enzymes responsible for glycogen breakdown . Thus it insulin *increases the storage of glucose in the form of hepatic glycogen. * o Promotes storage of *proteins and lipids* in muscle and adipose tissue. o Encourage protein synthesis in muscle cells by *stimulating amino acids uptake , increasing DNA/RNA involved in protein synthesis and inhibiting protein brake down. * o In fat cells, it stimulate the synthesis of fatty acids and triglycerides , increases the uptake of triglycerides from the blood into adipose tissue and muscle tissues. It will also prevent the breakdown of stored lipids o Thus, Insulin is involved in metabolism of carbohydrates, proteins and lipids. DM will affect the *storage and use of all primary energy* substrates because it alters the functions and use of insulin.

Insulin Delivery Device

subcutaneous injection port external insulin pump: can look at blood gluose level on there

Non-pharmacologic Intervention in Diabetes Mellitus (5)

• Diet and weight reduction • Exercise • Tissue Transplant and gene therapy

Other Drugs: Glucagon is used for what? Glucagon like peptide 1 used for what? what is taken for type 1 diabetes? aldose reductase inhibitors?

• Glucagon: used to reverse hypoglycemia • Glucagon -like Peptide 1 : administered by injection ( subcutaneous, IM, IV) help lower blood glucose in acute cases of hypoglycemia when the patient is unconscious. Decreases appetite , Increases the force of contraction of the heart. • Immunosuppressant • Aldose Reductase Inhibitors: possible to slow neuropathy. Not really effective.

Pathophysiology and Classification of Diabetes: how does glucose enter the blood? increased blood sugar leads to secretion of what? by what? how does insulin interact?

• Glucose enters the blood from breakdown of glycogen in the liver. • Increased blood sugar lead to secretion of insulin by the pancreas. • Insulin interacts with receptors on cell surfaces to allow glucose to enter the cell for energy.

Exercise and Insulin Therapy: high intensity exercise may produce what? how to avoid this? Type 1 diabetic should monitor when exercising?

• High intensity exercise may produce hypoglycemia. • To avoid exercise induced hypoglycemia insulin dose should be decreased proportionally depending on type, intensity and duration of the activity. • Type I diabetics should monitor blood glucose before and after exercise and insulin adjusted individually.

Insulin sensitizers MOA Adverse effects

• Metformin(Glucophage) : o MOA : 1)acts on the liver and inhibit glucose production.2) increases the sensitivity of peripheral tissues to insulin . o Adverse effects : GI problems ( nausea, diarrhea) Lactic acidosis ( confusion, stupor , shallow rapid breathing, tachycardia )especially during exercise .

Use of Exogenous Insulin : Needed for what? may also be administered?

• Needed for type I diabetes • May also be administered in some cases of type 2 diabetes to complement other drugs and to supplement endogenous insulin release.

Insulin Preparations:(duration) Rapid Acting Intermediate Acting Long acting Insulin Mixture

• Rapid Acting: 1-5 hours duration. o Aspart ( Novolog), Lispro( Humalog) o Short Acting : regular insulin, 5-7 hours (Humulin R) • Intermediate Acting: 18-28 hours duration o Isophane insulin ( Humulin N), glargine , extended insulin zinc. • Long acting: 18-24 hours o Glargine ( Lantus) • Insulin Mixtures o Glargine ( Lantus)

Insulin Administration Route:(3)

• Subcutaneous injections • Insulin Pump ( patient need to monitor glucose level several times a day) • New development : inhalant, nasal spray. This route was not successful and was removed from the U.S. market.

type 2 diabetes

• insulin is plentiful at least in the beginning of the illness , but resistance to insulin is present. • The liver and muscles become less sensitive to insulin, Pancreas tries to compensate by producing more insulin and eventually can no longer produce insulin. • Associated with obesity, • Familial disposition • Affect adults although lately more children are affected with this type of diabetes.