Insulin Pharmacology 1 & 2

Dr. Samir ATTOUB Department of Pharmacology & Therapeutics MSC2MSC2 Unit 7

2011-2012 2011 2012

Insulin Synthesis
Insulin is a peptide hormone composed of 51 amino acids secreted by the pancreatic -cells of Islets of Langerhans y p g Human insulin used in the treatment and control of diabetes mellitus is now produced by a special strain of Escherichia coli that has been genetically altered to contain the gene for human insulin

LANGERHANS, Paul (1847-1888)

Insulin Synthesis
Pro-hormone convertases/ Carboxypeptidase Pro-hormone convertases/ P h t / Carboxypeptidase

Pro-Insulin

Insulin

Insulin is synthesized as a pro-hormone, pro-insulin, that undergoes proteolytic cleavage to form insulin and peptide C Mature insulin is composed of two polypeptide chains (- and chain), chain) connected by disulfide bonds The entire human pancreas bonds. contains up to 8 mg of insulin Circulating C-peptide has no known biological function but serves as a better index of insulin secretion

Insulin Secretion
Insulin secretion is a tightly regulated process designed to provide stable concentrations of glucose in blood during both fasting and g g g feeding. This regulation is achieved by the coordinated interplay of various nutrients, gastrointestinal hormones, pancreatic hormones, and autonomic neurotransmitters Glucose is the principal stimulus to insulin secretion in human human. Glucose enters cell by facilitated transport via Glut 2 transporter gg The rise in intracellular Ca2+ triggers insulin secretion When evoked by glucose, insulin secretion is biphasic: The first phase reaches a peak after 1 to 2 minutes and is short-lived; the second phase has a delayed onset but a longer duration. These phases represents release of insulin stored in granules and newly synthesized insulin, respectively

Mechanism of Insulin Action

The insulin receptor is a transmembrane receptor tyrosine kinase located in the plasma membrane of insulin-sensitive cells (e. g. adipocytes, myocytes, hepatocytes). It mediates the effect of insulin on specific cellular responses (e. g. glucose transport, glycogen synthesis, synthesis lipid synthesis protein synthesis) synthesis, Insulin binds to an subunit of the insulin receptor activating the tyrosine kinase domain on its subunits. The major intracellular target molecules of the tyrosine kinase activity of the INSR -subunit are the insulin receptor substrates (IRS). Tyrosine phosphorylated IRS interacts with and activates phosphatidylinositol 3-kinase (PI 3kinase) subsequently phosphorylate and activate the serine/threonine kinase Akt (protein kinase B, PKB). The other major pathway is g p ( ) Grb2 activation of the mitogen activated protein (MAP) kinase cascade, which controls cell growth

Mechanism of Insulin Action

In adipose and muscle tissue, activation of PKB/Akt triggers the translocation of vesicles containing the glucose transporter GLUT4 from an intracellular pool to the plasma membrane stimulating glucose uptake by these tissues. This effect is reversible, the transporters return to the intracellular pool on removal of insulin

Release of insulin

Diabetes Mellitus
Diabetes mellitus is defined as hyperglycemia due to absolute or relative lack of insulin with various degrees of insulin resistance. By 2010, the number of diabetes persons is expected to approach 220 million The most common forms are type 1 diabetes, with absolute lack of insulin, and type 2 diabetes which is due to the combination of insulin resistance and insufficient insulin secretion A large number of individuals are asymptomatic and do not know they have the disease The chronic hyperglycemia of diabetes is associated with long-term g , y , g , p y damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart and blood vessels

Type 1 Diabetes
Insulin Dependent Diabetes Mellitus (IDDM) or Type 1 Diabetes, or juvenile diabetes: results from a destruction of insulin-secreting -cells by ll b an autoimmune mechanism d i a period of several i h i during i d f l years leading to absolute insulin deficiency Loss of -cells may be due to: - Antibodies against -cell proteins (glutamic acid decarboxylase, g p (g y , tyrosine phosphatase IA-2, insulin) - Viral infection -A i Actions of chemical toxins f h i l i ~ 10% of all patients yp y q Type 1 diabetes always requires treatment with insulin to maintain blood glucose concentrations close to normal

Type 2 Diabetes
Non-Insulin Dependent Diabetes Mellitus (NIDDM) or Type 2 Diabetes: is a frequent consequence of the metabolic syndrome (obesity, insulin resistance, dyslipidemia, hypertension) ~ 90% of all patients Type 2 DM with larger genetic component than type 1 is increasing DM, 1, in frequency. The genetic basis for type 2 DM cannot change in such a short time; thus, other contributing factors, including increasing age, obesity, sedentary lifestyle, and low birth weight, must account for this dramatic increase. In addition, type 2 DM is being diagnosed with remarkable frequency in preadolescents and adolescents Type 2 diabetes is characterized by tissue resistance to the action of insulin combined with a relative deficiency in insulin secretion

Causes of Insulin Resistance

Abnormal -cell secretory product Abnormal insulin molecule Incomplete conversion of proinsulin to insulin Target tissue defects T i d f Insulin receptor defects (mutations) Down-regulation in the number of insulin receptors (Obesity) Post receptor defects Circulating insulin antagonists Elevated levels of counter regulatory hormones e g growth hormones, e.g., hormone, cortisol, glucagon, or catecholamines p Anti-insulin and anti-insulin receptor antibodies

The birth of an idea

In 1889, Minkowski and Von Mering showed that pancreatectomized dogs exhibit a syndrome similar to diabetes mellitus in humans In October, 1920 Frederick Banting, a young surgeon in London, g y g g Ontario, Canada, first conceived the idea that led to the discovery of insulin Banting and Best thus obtained a pancreatic extract that decreased the concentration of bl d glucose i di b i d i f blood l in diabetic dogs

Beforeinsulinwasdiscovered, B f i li di d everyonewithtype1diabetesdied withinweekstoyearsofitsonset

First Human Patient

On Jan. 11, 1922, 14-year-old Leonard Thompson was the first human patient to receive insulin made by Banting and Best Leonard's blood glucose dropped to normal, and he began to gain weight The Nobel Prize in medicine and physiology was awarded to Banting and Macleod with remarkable rapidity in 1923, and a furor over credit followed immediately Banting announced that he would share immediately. his prize with Best; Macleod did the same with Collip

Treatment of Type 2 Diabetes

Weight normalization by hypocaloric, low fat diet and exercise may normalize glucose homeostasis for a period of several years More pharmacological control with hypoglycemic agents Individuals with type 2 diabetes may not require insulin to survive, but 30% or more will benefit from insulin therapy to control th bl d glucose t l the blood l

Treatment of Type 1 Diabetes

Type 1 diabetes always requires treatment with insulin. The goal of py p subcutaneous insulin therapy is to replace the normal basal (overnight, fasting, and between meal) as well as bolus or prandial (mealtime) insulin. Current regimens generally use long-acting insulins to provide basal or background coverage, and rapid-acting insulin to meet the mealtime requirements A variety of insulin p p y preparations are available; all have different times to onset of activity and durations of action

PRINCIPAL TYPES AND DURATION OF ACTION OF INSULIN PREPARATIONS

1. Rapid-acting, 1 Rapid acting with very fast onset and short duration (lispro and aspart insulin). All of the rapid-acting analogs have a quicker p g , onset of action when compared to regular insulin, reach maximal concentrations faster, and have a shorter duration of action; 2. Short-acting, with rapid onset of action (regular insulin); 3. Intermediate-acting 3 Intermediate acting (NPH insulin and zinc insulin); and 4. Long-acting, with slow onset of action (Ultralente and Insulin g g, ( glargine)

Rapid acting Insulins

Insulin li I li lispro (H (Humalog), a recombinant i li analogue, i l ) bi insulin l is identical to human insulin except for the transposition of proline and lysine at positions 28 and 29 in the C-terminus of the B chain This change reduced the ability to dimerize in solution and translates into more rapid absorption of insulin lispro than human regular insulin from subcutaneous sites When injected subcutaneously, the drug is rapidly absorbed with j y, g p y onset of action within 15-30 minutes and duration more than 3-5 hours, which is shorter than regular insulin. It is associated with g y p gy p g significantly improved glycemic control compared with regular insulin, with out increased incidence of hypoglycemia p g - Administer 0 - 15 min pre-meal vs. 30 - 45 min for regular insulin

Rapid acting Insulins

Insulin aspart (N I li t (Novolog) i h l ) is homologous with regular h l ih l human insulin with the exception of a single substitution of the amino acid proline by aspartic acid in position B28, and is produced by recombinant DNA technology and results i f bi A h l d l in faster absorption rates b i similar to Lispro after subcutaneous injection Following subcutaneous administration, insulin aspart has an onset of action of roughly 15 minutes which is quicker than the onset of g regular insulin With insulin aspart, patients may start eating within 10 minutes g g after dosing. Duration of action no longer than 3-5 hours

Short acting Insulins

Regular insulin is a short-acting soluble crystalline insulin made by recombinant DNA techniques to produce a molecule identical to human insulin. Its effect appears within 30 minutes and peaks between 2 and 3 hours after subcutaneous injection and generally lasts 6-8 hours. 1 mg = 27.5 units Regular insulin (soluble insulin) is used subcutaneously in ordinary maintenance regimens. Subcutaneously administered regular g y g insulin is best given 30-60 minutes before a meal Insulin is degraded in the GI tract if taken orally It may be given orally. intravenously in emergencies

Rapid-acting and short-acting insulins are often administered two to three times a day or more

Intermediate Acting Insulins

NPH insulin and zinc insulin have a more delayed onset of action, but they act longer. Both preparation are given by subcutaneous injection once a day before breakfast or twice a day 1. NPH insulin - Neutral Protamine Hagedorn / Isophane insulin suspension: insulin is conjugated with protamine @ neutral pH (7.2), the th complex slowly di l l l l dissolve i b d fl id Aft subcutaneous in body fluids. After b t injection, proteolytic tissue enzymes degrade the protamine to permit absorption of insulin. NPH insulin has an onset of approximately 1-2 hours and duration of 14-18 hours. It is usually mixed with regular, lispro or aspart insulin y g , p p and given for insulin replacement in patients with type 1 diabetes. In patients with type 2 DM, intermediate-acting insulin given at bedtime may h l normalize f i bl d glucose help li fasting blood l

Intermediate acting insulins

2. Lente insulin - insulin zinc suspension: Lente insulin is an intermediate-acting insulin that is produced by adding zinc ions to regular insulin, which causes a delay in absorption and a prolongation of the duration of action after subcutaneous administration Lente insulin has an onset of approximately 1-4 hours and duration of activity ranges from 12-18 12 18 Lente insulin is commonly administered twice daily in combination with a quick-acting insulin (regular insulin, insulin aspart, or insulin lispro)

Long acting Insulins

1. Ultralente insulin: is the first long-acting prep. 100% crystalline insulin zinc large particles which are slow to dissolve. They have slower absorption and a prolonged peak of action This insulin is used to provide a low basal level of insulin throughout the day. It is often given in the morning or in the morning and evening to provide maintenance of basal levels for 18 36 hours 18-36

Long acting Insulins

2. Insulin glargine (Lantus) insoluble insulin: is created by recombinant DNA modification of human insulin. Extension of the Cterminal of the B-chain with two arginine residues and the B chain substitution of glycine for asparagine at position A-21, resulting in precipitation of the insulin at the injection site and a slooowww release over 24 h with no pronounced peak. P id a b tt oncel ith d k Provides better daily 24-hour insulin coverage than ultralente or NPH insulin. To maintain solubility, the formulation is unusually acidic (pH 4.0) y, y (p ) and insulin glargine should not be mixed with currently available short-and rapid- acting insulin preparations (i.e., regular insulin, aspart, aspart or lispro) that are formulated at a neutral pH

Inhaled Insulin (Exubera)

In 2006 the U.S. FDA approved the use of Exubera, the first inhalable insulin. Inhaled insulin has similar efficacy to injected insulin Currently, inhaled insulin is short and rapid acting and is typically taken before meals; an injection of long-acting insulin at night is often still required f ill i d Used for type 1 and type 2 diabetes yp yp Contraindicated for: smokers and patients with unstable or poorly controlled lung disease (such as unstable or poorly controlled asthma asthma, chronic obstructive pulmonary disease, or emphysema) Side effects: reduced lung function cough dry mouth chest function, cough, mouth, discomfort, hypoglycemia In October 2007, Pfizer d id d to di I O t b 2007 Pfi decided discontinue E b i the US i Exubera in h secondary to limited use by patients and health care professionals

Adverse Reactions to Insulins Therapy

Hypoglycemic reactions are the most common complication of insulin therapy, which may result in confusion, anxiety, palpitation and tachycardia. It may result from a delay in taking a meal, inadequate carbohydrate consumed, unusual physical exercise, or a dose of insulin that is too large for immediate needs Hypoglycemia that occurs during sleep may be difficult to detect but should be suspected from a history of morning headaches, night p y g , g sweats, or symptoms of hypothermia All the manifestations of hypoglycemia are relieved by glucose administration. To treat mild hypoglycemia in a patient who is conscious and able to swallow, dextrose tablets, glucose gel, or any sugar-containing beverage or food may be given When hypoglycemia is severe, it should be treated with intravenous glucose or an injection of glucagon

Pharmakokinetic characteristics of the most commonly used insulin preparations and analogs

Insulin schedule: an example

As a rough guide, patients require a total daily insulin dose of an unit for each kilogram of their ideal weight (height 100) g ( g ) Daytime requirements are 2/3 and night time requirements 1/3 of the total i li i / f h l insulin e.g. height = 178 cm 100 = ideal weight 78 kg 78:2 = 39 units/d (26 u in the morning & 13 in the evening)