Medical Pharmacology Chapter 29:  Diabetes

• Four principal types

  • Ultra-short-acting-- (very rapid onset; short duration)

    • Clear solutions; neutral pH; zinc added to enhance stability

  • Short-acting --(rapid onset of action)

    • Clear solutions; neutral pH; zinc added to enhance stability

  • Intermediate-acting

  • Long acting -- (slow onset of action)

• Insulin modifications

  • Intermediate-acting and long acting insulins:

    • Turbid suspensions;neutral pH

    • Protamine and phosphate buffer added (NPH insulin)

    • Zinc in acetate buffer added (ultralente; lente insulins)

    • Note: protamine sink insulin-- discontinued; semilente insulin preparations -- discontinued

    • Note: excess zinc in ultralente and lente insulin can precipitate some soluble regular insulin--affecting absorption

  • Subcutaneously insulin therapy: split-dose injection

    1. Mixtures of short-acting and intermediate-acting insulins (NPH or lente)

    2. Multiple doses of ultra-short-acting or short-acting insulin before meals in association with prolonged duration insulin (NPH, lente or ultralente suspensions) for overnight maintenance.

• Ultra-short-acting insulin

  • Insulin lispro: new, monomeric insulin analog; recombinant technology

    • Interchange of two amino acids near the B chain terminal decreases tendency to form hexameric species-- lysine-proline switch

    • Insulin lispro binding to insulin receptor: unaffected by structural change

    • Insulin lispro half-life: unaffected by structural change

    • Insulin lispro immunogenicity: unaffected by structural change

    • Following subcutaneous administration, insulin lispro dissociates to monomers, rapidly absorbed -- peak serum values within one-hour (much more rapidly than hexameric human insulin)

    • Duration of action: no more than 3-4 hours for insulin lispro.

• Short-acting insulin

  • Regular insulin -- short-acting, soluble crystalline, zinc insulin

    • Onset of action: 30 minutes

    • Duration of action: 5-7 hours

    • Duration and intensity of action: increases with dosage

  • Clinical Use:

    1. IV treatment for  diabetic ketoacidosis

    2. Management for rapidly changing insulin requirements (e.g. post surgery, acute infection)

• Intermediate-acting and long acting insulins

  • Lente insulin (30% semilente {rapid onset and 70% ultralente forms (delayed onset, prolonged duration of action))

•  NPH (neutral protamine Hagedorn or isophane) insulin

  • Intermediate-acting; onset of action delayed by combining correct amounts of protamine insulin such that neither is uncomplexed.-Onset and duration of action: NPH insulin -- similar to lente insulin:

  • NPH insulin usually mixed with regular insulin: for twice daily administration

• Insulin Mixtures

  • Insulin lispro (popular, convenient pre-perennial insulin) may be mixed with a more sustained preparation for post-absorption control; acute insulin lispro mixing is acceptable:

• Insulin Species

  • Beef and pork insulins

    • Most commercial insulin contained: beef insulin -- primary component

    • Beef hormone: slightly more antigenic compared to pork insulin

    • Common ratio: 70% beef/30% pork insulin

    • Recombinant DNA techniques have allowed mass production of human insulin

  • Human insulins

    • Readily available: in regular, NPH, lente, or ultralente form.been

    • Premixed formulation of 70% NPH and 30% regular human insulin is available

    • Human insulin: Advantages

      1. As effective as animal insulins

      2. Much less immunogenic than beef-pork insulin; slightly less immunogenic import insulin

    • Human insulin: more rapidly absorbed; slightly shorter duration of action

• Human Proinsulin

  • Available through recombinant DNA synthesis

  • Proinsulin biological activity about 8-12% that of human insulin

  • Four-six times longer circulating half-life compared to human insulin.

  • Fatal cardiovascular reactions in a group of patients receiving human proinsulin have suspended clinical trials

• Delivery systems

  • Portable pen injectors: replaced syringes

  • Closed loop systems: blood glucose control a insulin infusion

  • Open-loop systems (insulin pumps)

  • Nasal insulin delivery: poor absorption

• Insulin Treatment Overview

  • Insulin-dependent diabetes: Type I diabetes;IDDM -- about 9% of the diabetic population

  • Non-insulin dependent diabetes: Type II diabetes; NIDDM -- about 20% of Type II diabetics use insulin

• Glycemic control in diabetes mellitus

  • Tight glycemic control is advantageous except for:

    •  Patients with advanced renal disease as detrimental risks are associated with hypoglycemia

    •  The elderly-- detrimental risks associated with hypoglycemia

    •  Children under the age of 7 years (hypoglycemia poses a significant risk in the developing brain)

•  Complications of insulin treatment

  • Hypoglycemia

    • Most common complication

    • Causes:

      • Delay in eating

      • Unusual physical exertion

      • Inappropriately high insulin dosage for the immediate need

    • Autonomic hyperactivity is a manifestation of hypoglycemia

      • Sympathetic -- tachycardia, palpitations, sweating, tremor

      • Parasympathetic-- nausea, hunger

      • Autonomic indications of hypoglycemia are less frequent perceived by elderly patients. These patients may exhibit impaired CNS function 22 hypoglycemic reactions including: mental confusion, bizarre behavior, coma

    • Treatment of hypoglycemia:

      • Glucose administration

      • For mild reactions: orange juice, glucose, sugar containing beverage, food (assumes patient is conscious)

      • For more severe hypoglycemia (unconsciousness patient):

        • Intravenous infusion -- 20-50 mL. All of 50% glucose solution over a 2-3 minute interval.

        • Alternatively, in the absence of intravenous infusion, 1 mg of glucagon (subcutaneous or intramuscular administration) should restore consciousness within about 15 minutes (then allowing food consumption)

• Insulin Therapy: immunopathology

  • Insulin allergy: immediate type hypersensitivity, rare

    • Urticaria follows history release from tissue mast cells (sensitized by anti-insulin IgE antibodies) the subcutaneous nodule appears that injection site {IgE-mediated complement-binding Arthus reaction}

    • Antihistamines, corticosteroids, or desensitization may be required

    • Less common with new, highly purified insulins

  • Immune insulin resistance:

    • Due to high titer circulating IgG anti-insulin antibodies

    • Very high IgG anti-insulin antibodies require high insulin levels to compensate

    • With highly purified insulin, now available, this reaction is very rare

  • Injection site lipodystrophy:

    • Atrophy of subcutaneous fat

    • Rare complication due to availability of more highly concentrated insulin preparations of neutral pH

    • Hypertrophy of subcutaneous fatty tissue is a problem if insulin is injected repeatedly at the same site -- liposuction can correct

Karam, J. H., Pancreatic Hormones and Antidiabetic Drugs, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 684-703

Foster, D. W., Diabetes Mellitus, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2060-2080