Use of Insulin in treatment of diabetes mellitus

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• Use of Insulin in treatment of diabetes mellitus

Prof. Hanan Hagar
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• Objectives
• by the end of this lecture, students should be
  able to
• Define diabetes and mention different types of
  diabetes
• Differentiate between difference in treating
  type I and type II
• diabetes.
• Understand mechanism of action, secretion, and
  actions of insulin.
• Describe different types of insulin analogues
• Be able to recognize the difference in
  pharmacokinetic of different insulin
• analogues.
• Know the uses of different insulin analogues

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Diabetes mellitus

• Is a chronic metabolic disorder characterized by
  high blood glucose level caused by insulin
  deficiency and sometimes accompanied with insulin
  resistance.

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Diabetes mellitus

• Fasting plasma glucose gt 7 mmol/L (126 mg/dl) is
  diagnostic of diabetes or
• Plasma glucose gt 11.1 mmol/L (200 mg/dl), 2h
  after a meal confirms a diagnosis of diabetes.

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Complications of diabetes

• Cardiovascular problems
• Micro-and macrovascular complications
• Renal failure (nephropathy).
• Blindness (retinopathy).
• Neuropathy
• Risk of foot amputation

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Types of diabetes

• Type I diabetes (IDDM)
• Type II diabetes (NIDDM)

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Type I Diabetes

• absolute deficiency of insulin.
• Pancreatic ß-cells are destroyed.
• due to autoimmune or viral diseases
• Treated by insulin.

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Type II Diabetes

• Partial deficiency of insulin.
• ß-cells produce inadequate quantity of insulin
• Insulin resistance in peripheral target tissues.
• Obesity and genetic factors are involved
• Treated by oral hypoglycemic drugs.

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Characteristic Type 1 Type 2
Onset (Age) Usually during childhood or puberty Usually over age 40
Type of onset Abrupt Gradual
Prevalence 10-20 80-90
Genetic predisposition Moderate Very strong
Defects ß-cells are destroyed ß-cells produce inadequate quantity of insulin
Endogenous insulin Absent Present (not enough)
Insulin resistance absent present
Nutritional status Usually thin Usually obese
Ketosis Frequent Usually absent
Clinical symptoms Polydipsia, polyphagia, polyuria, Wt loss Often asymptomatic
Related lipid abnormalities Hypercholesterolemia frequent Cholesterol triglycerides often elevated
Treatment Insulin Oral hypoglycemic drugs
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INSULIN
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Endogenous Insulin

• Basal level of insulin is 5-15 µU/ml.
• Half life of circulating insulin is 3-5 min.

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Insulin release during day time meals
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Insulin receptors

• Present on cell membranes of most tissues as
  liver, muscles and adipose tissues

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Effects of insulin
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I. Carbohydrate Metabolism

• Insulin decreases blood glucose level by
• ? glucose uptake utilization by
• peripheral tissues.
• ? Glycogen synthesis
• ? Conversion of carbohydrate to fats.
• ? Glycolysis (muscle).
• ? Glycogenolysis .
• ? Gluconeogenesis.

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II. Fat Metabolism

• Liver
• ? Lipogenesis ? lipolysis.
• Inhibits conversion of fatty acids to keto acids
• Adipose Tissue
• ? Lipolysis
• ? Triglycerides storage.
• ? Fatty acids synthesis.

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III. Protein Metabolism

• Liver
• ? protein catabolism.
• Muscle
• ? amino acids uptake.
• ? protein synthesis.
• ? glycogen synthesis (glycogenesis).

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IV. potassium

• ? potassium uptake into cells.

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Sources of Exogenous Insulin

• Beef Insulin
• Porcine Insulin
• Human Insulin
• Less immunogenic.
• Prepared by recombinant DNA techniques
• Modifications of amino acid sequence of human
  insulin can change its pharmacokinetics

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Routes of administrations of exogenous insulin

• Can not be given orally (why ?)
• Insulin is given subcutaneously (s.c)
• Insulin syringes (arms, abdomen, thighs).
• Portable pin injector (pre-filled).
• Insulin pump

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Pin injector
Insulin pump
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Routes of administrations of exogenous insulin

• Insulin pump
• more convenient
• no need for multiple daily injection
• programmed to deliver basal rate of insulin.
• Achieve better control of diabetes
• Intravenously (in a hyperglycemic emergency)
• http//www.youtube.com/watch?vBfG4-YMu0Vo

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Types of insulin preparations

• Differs in pharmacokinetic properties mainly
• Rate of absorption
• Onset duration of action
• Variation is due to
• Change of amino acid sequence.
• Size and composition of insulin crystals in
  preparations.

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Types of insulin preparations Insulin Analogues

• Ultra-short acting insulins
• e.g. Lispro, aspart
• very fast onset of action and short duration
• Short acting insulins
• e.g. regular insulin
• fast onset and short duration.

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Types of insulin preparations

• Intermediate acting insulins
• e.g. NPH, Lente
• slow onset, intermediate duration of action
• Long acting insulins
• e.g. glargine, detemir
• delayed onset and long duration of action

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Ultra-short acting insulins Insulin lispro,
insulin aspart

• monomeric analogue
• Clear solutions at neutral pH.
• Very fast onset of action (5-15 min)
• S.C. (5 min no more than 15 min before meal).
• mimic the prandial mealtime insulin release
• Short duration of action (3-5 h).
• 2-3 times/day.

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Ultra-short acting insulins Insulin lispro,
insulin aspart

• Uses
• Control postprandial hyperglycemia (s.c.)
• In emergency situations as in diabetic
  ketoacidosis (i.v).

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Insulin aspart
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Short acting insulins (Regular insulin) Humulin
R, Novolin R

• Soluble crystalline zinc insulin
• Clear solutions at neutral pH
• Forms hexamers.
• Fast onset of action 30-45 min (s.c.).
• Short duration of action (6-8 h).
• 2-3 times/day.
• Can mimic postprandial insulin release.

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Short acting insulins (regular insulin)

• Uses
• control postprandial hyperglycemia (s.c.)
• In emergency situations as in diabetic
  ketoacidosis (i.v).
• Can be used in pregnancy.

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Short-acting (regular) insulins e.g. Humulin R, Novolin R
Uses postprandial hyperglycemia emergency diabetic ketoacidosis
Physical characteristics Clear solution at neutral pH
chemistry Hexameric analogue
Route time of administration S.C. 30 45 min before meal I.V. in emergency (e.g. diabetic ketoacidosis)
Onset of action rapid 30 45 min ( S.C )
Peak level 2 4 hr
Duration 6 8 hr Short
Usual administration 2 3 times/day
Ultra-Short acting insulins e.g. Lispro, aspart, glulisine
postprandial hyperglycemia emergency diabetic ketoacidosis
Clear solution at neutral pH
Monomeric analogue
S.C. 5 min (no more than 15 min) before meal I.V. in emergency (e.g. diabetic ketoacidosis)
Fast 5 15 min ( S.C )
30 90 min
3 5 hr Shorter
2 3 times / day
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Advantages of Insulin Lispro vs Regular Insulin

• Rapid onset of action (due to rapid absorption)
• Reduced risk of postprandial hypoglycemia (due to
  short duration of action)
• Decreased risk of hyperinsulinemia
  (due to short duration of action)

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Intermediate acting insulins
Isophane (NPH) insulin Lente insulin
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Isophane (NPH) Insulin

• NPH, is a Neutral Protamine Hagedorn insulin in
  phosphate buffer.
• a combination of protamine crystalline zinc
  insulin.
• Turbid suspension at neutral pH.
• Given S.C. only NOT i.v.

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Isophane (NPH) Insulin

• Slow onset of action 1-2 h.
• Relatively long duration of action 13-18 h
• NPH is NOT used in emergencies (diabetic
  ketoacidosis).

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Isophane (NPH) Insulin

• Can be mixed with ultrashort or short insulin
• NPL NPH / lispro
• NPA NPH / aspart
• NPH/regular 75/25 - 70/30 - 50/50 .

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Prandial and basal insulin replacement
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Lente insulin (Humulin L, Novolin L)

• Mixture of 30 semilente insulin and 70
  ultralente insulin.
• Turbid suspension at neutral pH
• Given S.C., not intravenously
• Slow onset of action (1-3 h)
• Peak serum level 4-8 h.
• Relatively long duration of action 13-20 h.

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Lente insulin (Humulin L, Novolin L)

• Lente is not used in emergency or diabetic
  ketoacidosis.
• Lente and NPH insulins are equivalent in
  activity.

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Long acting insulinsInsulin glargine
(lantus) Insulin detemir (Levemir)

• Clear solution BUT forms precipitate at injection
  site.
• Slow onset of action 2 h.
• Given s.c., not intravenously
• absorbed less rapidly than NPH Lente insulin.
• Prolonged duration of action (24 h).
• Once daily
• Should not be mixed with other insulin

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Long acting insulins Insulin glargine -
Insulin detemir

• produce broad plasma concentration plateau (low
  continuous insulin level over 24 hr low).

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Advantages of long acting insulin over
intermediate-acting insulins

• Constant circulating insulin over 24 hr with no
  pronounced peak.
• safer than NPH Lente insulins
• ( reduced risk of nocturnal hypoglycemia).

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NPH vs Glargine
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Insulin preparations
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Complications of Insulin Therapy

• Hypoglycemia
• Lipodystrophy at injection site
• Weight gain (due to anabolic effects of insulin )
• Hypokalemia
• Insulin resistance (rare)
• Hypersensitivity reactions (rare).

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Summary

• Insulin analogues are used to treat type I
  diabetes.
• Fast acting insulins (lispro, aspart), given s.c.
  or i,.v., produce
• very fast action, used to mimic postprandial
  insulin emergency
• Short acting insulin (Regular insulin), given
  s.c. or i.v. produce
• fast action, used to mimic postprandial insulin,
  emergency
• pregnancy.
• Intermediate acting insulin (lente, Isophane)
  produce slower action, than regular insulin,
  given s.c. not i.v.
• Long acting insulins (glargine) produce constant
  circulating insulin over 24 hr with no peak
  (peakless profile), s.c. not i.v.