Insulin therapy for type 2 diabetes patients dr shahjadaselim1
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This document provides information about insulin therapy. It defines insulin as a polypeptide hormone secreted by the pancreas that has profound effects on carbohydrate, fat, and protein metabolism. Insulin deficiency results in hyperglycemia and other metabolic defects. The discovery of insulin in the 1920s by Banting and Best was a major medical milestone. Insulin is now manufactured recombinantly and comes in various rapid, short, intermediate, and long-acting forms to match physiological insulin secretion. Basal bolus regimens using basal and pre-meal bolus insulin are commonly used. New delivery methods like insulin pumps provide more flexibility but also challenges. Proper insulin storage and administration technique are important for effectiveness and safety.
Insulin therapy for type 2 diabetes patients dr shahjadaselim1
- 1. Insulin Therapy Dr Shahjada Selim Department of Endocrinology Bangabandhu Sheikh Mujib Medical University Email: [email protected]
- 2. What is Insulin? (1) • Polypeptide hormone • Beta-cells of islets of Langerhans in pancreas • Profound effects on • carbohydrate, fat & protein metabolism • To some extent on water & electrolyte balance • 2 chains • 2 bonds • Secreted as basal & meal related (2) • Meal related in 2 phases
- 3. What is Insulin? (2) • Insulin deficiency results in • Elevated plasma glucose -Hyperglycemia • Elevated plasma lipid - Hypertriglyceridemia • Altered protein metabolism - Metabolic & Immune defects • Insulin replacement in diabetes tends to restore normalcy
- 4. Insulin Secretion B L S HS Bolus Basal Bolus Bolus Basal Basal Normally secreted as basal (between meals & night time) & Meal-related peaks (1st & 2nd phase)
- 5. Actions of Insulin (1) • Integrated action on carbohydrate, protein and fat metabolism • Dominant effect on glucose homoeostasis predominantly exerted in 3 tissues Liver Skeletal muscle Fat
- 6. Actions of Insulin (2) In Liver • Inhibition of glycogenolysis & gluconeogenesis • Stimulation of glycogenesis & storage In skeletal muscle & adipocytes • Stimulation of glucose uptake, utilization & storage • Increases glucose transport • Activation/inactivation of enzymes responsible for storage & metabolism of glucose
- 7. Insulin: The Definitive Therapy for Diabetes • DM • Impaired insulin secretion (insulin deficiency) • Impaired insulin action (insulin resistance) • Insulin can overcome both the defects • Hence: Insulin-the definitive therapy for all types of diabetes Insulin- a valuable therapeutic tool for early intervention, to attain and maintain target levels of blood glucose control.
- 8. Discovery of insulin (1) “One of the greatest milestones in history of medicine”.
- 9. Discovery of insulin (2) Experiments in Toronto University F Banting, surgeon C Best, medical college student 30 July 1921 Banting & Best- extracted insulin from dog & proved that it controls symptoms of diabetes in dogs – 1921 Banting & Macleod-Nobel Prize for Medicine & Physiology in 1923
- 10. 1923 – Nobel prise to Banting and Macleod FG Banting JJR Macleod CH Best JB Collip
- 11. Discovery of Insulin (3) • 1st patient to receive pancreatic extract (insulin)-14-yr old Leonard Thompson. • 1st attempt (11th Jan 1922)- failed but the 2nd attempt (3rd May 1922) succeeded in reducing urine glucose excretion. First patient to benefit from insulin –saved from death Leonard Thompsom-1908-1935 •Grew cheerful, started eating more, gained weight, & cheeks started swelling out
- 12. Discovery of Insulin (4) Description of Structure • 1955- Frederick Sanger identified the amino acid sequence of insulin: • Insulin is a protein, consisting of • Alpha (21) and beta (30) chains • Half life time in blood is 4- 5 min. B-chain A-chain Connecting peptide s- s s-s s-s Another Nobel Prize in insulin history – 1958
- 13. Insulin Structure VAL 2 ASN 3 GLN 4 HIS 5 LEU 6 CYS 7 GLY 8 SER 9 HIS 10 LEU 11 LEU 15 ALA 14 GLU 13 VAL 12 THR 30 LYS 29 PRO 28 THR 27 TYR 26 PHE 25 PHE 24 GLY 23 ARG 22 GLU 21 GLY 20 TYR 16 LEU 17 VAL 18 CYS 19 GLY 1 ILE 2 VAL 3 GLU 4 GLN 5 CYS 6 CYS 7 THR 8 SER 9 ILE 10 CYS 11 GLN 15 TYR 14 LEU 13 SER 12 ASN 21 CYS 20 LEU 16 GLU 17 ASN 18 TYR 19 A - Chain B - Chain S S S S S S ALA PHE 1
- 14. Manufacture of Insulin (1) • 1923-Eli Lilly started manufacturing • 1923- Novo started manufacturing • ‘Most developments in insulin therapy have originated from the laboratories of Novo-Nordisk’ • NPH insulin • highly purified insulin • monocomponent insulin • semisynthetic insulin • biosynthetic human insulin • Insulin analogues: Insulin Aspart, Premixed analogue & Insulin Detemir Insulin
- 15. Manufacture of insulin (2) • Currently NN- human insulin from yeast (Saccharomyces cerevisiae) using rDNA technology. • Eli Lilly-human insulin using E. coli, a gram- negative bacterium. • Several Bangladeshi pharmaceutical companies have started marketing different types of insulin preparations.
- 16. Advancements Animal insulin preparations Recombinant human insulin Rapid-acting insulin analogues Basal insulin analogues Isolation of insulin (Banting & Best) Time1922 1977 Biphasic insulin 1990s 2000s Advancing insulin therapyAdvancing insulin therapy Towards a new stage in the evolving story of insulin therapyTowards a new stage in the evolving story of insulin therapy Insulin degludec Insulin degludec plus 2013 2015
- 17. Types of insulin Type of Insulin & Brand Names Onset Peak Duration Role in Blood Sugar Management Rapid-Acting Lispro 15-30 min. 30-90 min 3-5 hours Covers insulin needs for meals eaten at the same time as the injection.Aspart 10-20 min. 40-50 min. 3-5 hours Glulisine 20-30 min. 30-90 min. 1-2½ hours Short-Acting Regular 30 min- 60 min 2-5 hours 5-8 hours Covers insulin needs for meals eaten within 30-60 minutes Intermediate-Acting NPH (N) 1-2 hours 4-12 hours 18-24 hours Covers insulin needs for about half the day or overnight.
- 18. Types of insulin Name of Insulin Onset Duration Role in Blood Sugar Management Long-Acting Long-acting insulin covers insulin needs for about one full day. Degludec 30-90 min No peak: insulin is delivered at a steady level. Longer than 24 hours Glargine 30-90 min Up to 24 hours Detemir 1-120 min 20-24 hours
- 19. Types of insulin Type of Insulin Onset Peak Duration Role in Blood Sugar Management Pre-Mixed* Regular- Intermediate 30/70, 50/50, 25/75 30 min. 2-4 hours 14-24 hours These products are generally taken two or three times a day before mealtime. Short acting- Short acting biphasic 30/70, 50/50, 25/75 15-25 min. 40-50 min. 10-12 hours Co formulation Degludeg- Aspart 30/70 10-20 40-50 min. 4-42 hours These product is generally taken once or twice a day before major meal *Premixed insulins are a combination of specific proportions of intermediate- acting and short-acting insulin in one bottle or insulin pen (the numbers the brand name indicate the percentage of each type of insulin).
- 20. Types of insulin Type of Insulin Onset Peak Duration Role in Blood Sugar Management Inhaler Exubera Banned Afrezza With in min 12 to 15 min 2-3 hours Post prandial effects. *Premixed insulins are a combination of specific proportions of intermediate- acting and short-acting insulin in one bottle or insulin pen (the numbers the brand name indicate the percentage of each type of insulin).
- 21. Common Insulin Regimens (1) Split Mix Regimens Two injections (intermediate + soluble) per day * before breakfast & before bedtime Proportion/dosage of insulins titrated based on BG profile Drawback Mixing insulins is tedious and problematic Inaccuracy of dose Not preferred –more problems for patients
- 22. Common Insulin Regimens (2) Basal insulin Usually given at night Proportion/dosage of insulin titrated based on FBG Drawback Expensive Fasting blood glucose is primary targeted May be with sensitizer and or secretagogue
- 23. Common Insulin Regimens (3) Basal Plus Basal insulin at night Any rapid acting insulin premeal. May be useful during early years of T2DM and in uncomplicated well motivated patients. May be needed to shifted to Basal bolus regimen Not preferred –more problems for patients
- 24. Common Insulin Regimens (4) Basal Bolus Basal insulin at night and one rapid acting insulin immediately before each major meal (3 times). Basal insulin is titrated following FBG Rapid acting insulin is titrated by post meal BGs Drawback Expensive 4 times needle prick a day. Most preferred –most fexible
- 26. Common Insulin Regimens (5) Continuous subcutaneous insulin infusion (CSII): Recommended for adults and children 12 years and older with T2DM provided: To achieve target HbA1c levels with MDIs result in the person experiencing disabling hypoglycaemia or HbA1c levels have remained high (8.5% or above) on MDI therapy despite a high level of care.
- 27. CSII sets
- 28. Indications of insulin Continuous Use * Type 1 Diabetes * Type 2 Diabetes with OHA failure - Primary - Secondary Intermittent Use * Type 2 diabetes during - major surgery - pregnancy, labour and delivery - myocardial infarction - acute infections - Hypergycemic emergencies: DKA & HHS * GDM Life-saving in T1DM Essential in T2DM
- 29. Starting dose of insulin • T1DM: 1 -0.2-1 U/kg / day1 • T2DM: 0.2-0.3 U/kg / day In split mixed regimen- 2/3 as intermediate acting & 1/3 as short- acting 2 In basal bolus regimen: ½ basal at bed time and ½ bolus in 3 divided doses. Dosage is individualized and titrated soon 1 Goodman & Gillman’s The pharmacological basis of therapeutics ed. 9th .pg. 1501 2 Harrison’s Principles of Internal Medicine (15th Edition) pg. 2131
- 30. Current recommendations for the treatment of type 2 diabetes Diet/exercise Start metformin Start insulin Add incretin therapy Diabetes Disease Progression An alternative approach
- 31. Why Early insulin initiation? Clinical & Pharmacological Reasons(4) Insulin Improves beta-cell function (reduces glucotoxicity & lipotoxicity) Reverses insulin resistance Improves Quality of Life Beneficial effects on lipids Insulin provides 4 benefits beyond glycemic control
- 34. Insulin vials and syringes
- 35. Inhalation device or insulin
- 36. Insulin administration Sites • Abdomen (fastest absorption & most preferred) • Buttocks • Upper arm • Thigh-lateral & anterior aspects (slowest) • Rotate the site of injection around a selected area (Intermediate)
- 37. Side effects of Insulin 5 Side effects 1. Hypoglycemia 2. Allergic Reactions – • Local redness, itching – self limiting, disappears with continuation of therapy • Systemic allergy – angioedema, anaphylaxis; rare, requires desensitization 1. Insulin lipoatrophy 2. Insulin lipohypertrophy 3. Insulin Edema & weight gain
- 38. Barriers to Insulin therapy (1) Hypoglycemia Requires specialist Daily inj Compliance Dose titration difficult Patient Runs Away Serious illness Cost Insulin therapy in type 2 diabetes Insulin therapy in type 2 diabetes Insulin therapy in type 2 diabetes Insulin therapy in type 2 diabetes
- 39. Barriers to insulin therapy (2) • Fear of hypoglycemia • Inconvenient timing of injection • Complicated regimen • to be taken 30 minutes before meal • lifestyle to fit therapy • Hyperglycemia immediately after meal • Hypoglycemia before next meal • Fear of injection DIPPAP 2 - 53% Patient survey – ORG-MARG 2002 – 34% DIPPAP 2 – 35%
- 40. Storage of Insulin (1) • Vials, Penfills & Pens not in use stored between 2° & 8°C • Storage in or near freezing compartment is to be avoided (more important-suspensions) • Too high temp- gradual decrease in biological potency • In use stored at room temperature (25°C) up to 6wks (Vials) & up to 4 wks (Penfills & Devices) • Pens/ Penfills- in use- should not be kept in refrigerator
- 42. Storage of Insulin (2) Storage of patient supplies of insulin in warm climates is not an important practical issue, & should not interfere with supplies of vital insulin to pts. in developing countries.
Editor's Notes
- #2: In this session on Insulin therapy we will try address all issues related to insulin usage in diabetes with particular focus on usage of insulin in type 2 diabetes
- #3: We all know that insulin is a Polypeptide hormone produced by the Beta-cells of islets of Langerhans in pancreas It exerts profound effects on carbohydrate, fat & protein metabolism To some extent on water & electrolyte balance
- #4: Insulin deficiency that occurs in diabetes results in Elevated plasma glucose -Hyperglycemia Elevated plasma lipid - Hypertriglyceridemia Altered protein metabolism resulting in Metabolic & Immune defects HENCE Insulin replacement in diabetes tends to restore normalcy.
- #5: Here we look at the secretion of insulin which occurs as basal & meal-related secretion. We have discussed this in the previous session also hence no elaboration is required
- #8: Insulin is the definitive therapy for diabetes – we say this because type 2 Diabetes is associated with 2 defects –impaired insulin secretion & impaired insulin action & now there is enough data to show that Insulin can overcome both these defects Hence: Insulin is the definitive therapy for all types of diabetes. Moreover experts have said that insulin is a valuable therapeutic tool….
- #9: The discovery of insulin is an important event not only in the history of diabetes but also in the history of medicine. Discovery of insulin is therefore described as one of the greatest milestones in history of medicine “One of the greatest milestones in history of medicine”
- #10: In 1921 Banting and Best started working on the extraction of insulin from the pancreas of dogs. They were successful to prove that the extract could lower blood glucose in dogs. After improving the extraction procedure the team obtained more pure and potent extract with hypoglycemic action. In January 1922 the first injection of insulin was given to a 14-year old boy.
- #12: … this boy is the first patient to receive the pancreatic extract i.e. insulin in the year 1922 he was a type 1 diabetic by name Leonard Thompson. The first attempt to inject failed but the in the 2nd attempt on May 3rd 1922, this extract when injected succeeded in reducing the urine glucose excretion in the boy. As time passed this boy grew cheerfully and starting eating more, gained more weight & his cheeks started swelling out. This is the first patient to benefit from insulin and to be saved from death by insulin injections. This was just the beginning & since then millions of such patients have benefited from insulin ..
- #13: One another milestone in the history of insulin is the description of the structure of insulin by Fredrick Sanger in the year 1955. Fredrick Sanger of Cambridge identified the amino acid sequence in insulin & said that insulin is a protein consisting of two chains & it has a half life of 4-5 min in blood. Fredric sanger later got a nobel prize for his workinn the year 1958. So, yet another nobel prize in the history of insulin
- #15: The insulin extracted by Banting & Best was in small quantity, what was required is manufacturing insulin on a large scale so that many patients could reap the benefits of this wonder drug. It was in 1923 that Novo started manufacturing insulin in Denmark after obtaining permission From Banting & Best. At around the same time Eli LILLY started manufacturing insulin in the US. Since then Most developments in insulin therapy have originated from the laboratories of Novo-Nordisk’ and this includes NPH insulin highly purified insulin monocomponent insulin semisynthetic insulin biosynthetic human insulin Insulin analogues like Insulin aspart, Premixed analogue & Insulin detemir
- #16: Currently Novo Nordisk manufactures human insulin from yeast using rDNA technology. Eli Lilly on the other hand uses E.coli, a gram negative bacterium to produce human insulin by rDNA technology
- #18: Here we give the action profiles of NN brands including the newer introductions, NovoRapid & NovoMix 30 Note the difference in onset, peak & duration of action of NovoRapid & Actrapid & similarly NovoMix 30 & Mixtard 30
- #19: Here we give the action profiles of NN brands including the newer introductions, NovoRapid & NovoMix 30 Note the difference in onset, peak & duration of action of NovoRapid & Actrapid & similarly NovoMix 30 & Mixtard 30
- #20: Here we give the action profiles of NN brands including the newer introductions, NovoRapid & NovoMix 30 Note the difference in onset, peak & duration of action of NovoRapid & Actrapid & similarly NovoMix 30 & Mixtard 30
- #21: Here we give the action profiles of NN brands including the newer introductions, NovoRapid & NovoMix 30 Note the difference in onset, peak & duration of action of NovoRapid & Actrapid & similarly NovoMix 30 & Mixtard 30
- #22: In this regimen which is fairly commonly used two injections of a patient -mixed intermediate + soluble insulin are given per day These two injections are given before breakfast & before bedtime. The proportion/dosage of insulins can be titrated based on BG profiles. This regimen has its own drawbacks which include Mixing insulins is tedious and problematic for the patient Inaccuracy of dose is common Errors in dose could lead to problems. HENCE THIS REGIMEN IS NOT PREFERRED AS IT IS MORE PROBLEMATIC FOR THE PATIENT
- #23: In this regimen which is fairly commonly used two injections of a patient -mixed intermediate + soluble insulin are given per day These two injections are given before breakfast & before bedtime. The proportion/dosage of insulins can be titrated based on BG profiles. This regimen has its own drawbacks which include Mixing insulins is tedious and problematic for the patient Inaccuracy of dose is common Errors in dose could lead to problems. HENCE THIS REGIMEN IS NOT PREFERRED AS IT IS MORE PROBLEMATIC FOR THE PATIENT
- #24: In this regimen which is fairly commonly used two injections of a patient -mixed intermediate + soluble insulin are given per day These two injections are given before breakfast & before bedtime. The proportion/dosage of insulins can be titrated based on BG profiles. This regimen has its own drawbacks which include Mixing insulins is tedious and problematic for the patient Inaccuracy of dose is common Errors in dose could lead to problems. HENCE THIS REGIMEN IS NOT PREFERRED AS IT IS MORE PROBLEMATIC FOR THE PATIENT
- #25: In this regimen which is fairly commonly used two injections of a patient -mixed intermediate + soluble insulin are given per day These two injections are given before breakfast & before bedtime. The proportion/dosage of insulins can be titrated based on BG profiles. This regimen has its own drawbacks which include Mixing insulins is tedious and problematic for the patient Inaccuracy of dose is common Errors in dose could lead to problems. HENCE THIS REGIMEN IS NOT PREFERRED AS IT IS MORE PROBLEMATIC FOR THE PATIENT
- #29: Insulin being polypeptide hormone is destroyed in the stomach when given orally, and therefore needs to be given parenterally by subcutaneous injection (all insulins) or by intravenous infusion ( neurtral soluble regular rapid acting insulin). Insulin administration may be done on a regular basis or intermittent basis. Regular insulin administration is required in all patients with type 1 diabetes, and in those type 2 diabetes patients who have a primary or secondary failure of response to OHA therapy. Insulin is required intermittently in patients with type 2 diabetes whenever : 1. they are scheduled to undergo major surgery 2. during pregnancy, labor and delivery 3. during myocardial infarction 4. during the treatment of acute and chronic infections such as pneumonia and tuberculosis respectively 5. During acute metabolic crises like hyperosmolar coma, lactic acidosis or diabetic ketoacidosis 6. During gestational diabetes mellitus if diet and exercise do not provide adequate control In all intermittent use categories Human Insulin is the drug of first choice.
- #32: We now have evidence for action of insulin beyond glycemic control. These actions beyond glycemic control are shown in the right panels here.
- #37: As mentioned earlier insulin is inject able & has to be given subcutaneously. The common sites for administration of insulin are abdomen, buttocks, upper arm, Thigh- front & outer side. The patient is always advised to rotate the site of injection around a selected area. the absorption of insulin depends on several factors & one of them is the site of injection, as shown in the slide.. buttock slow absorption, abdomen faster absorption.
- #38: There are 5 side effects of insulin & they include hypo, allergic reactions, insulin lipoatrophy & lipohypertrophy, insulin edema & weight gain
- #39: There are many barriers to insulin therapy & these are more in the minds of doctors, which is why, we say that early insulin therapy in particular and insulin therapy in type 2 diabetes is caught in a jigsaw puzzle of perceptions. There is a gap between the perception of patients and their treating physicians If we bridge this gap in the perceptions, we can help insulin therapy in type 2 diabetes get out of this jigsaw and we could do this with a large study called ICEON done in 2002 in India.
- #40: Well, the reasons why doctors are not prescribing insulin are 3 – fear of hypoglycemia, compliance and fear of injection. DIPPAP 2 , a large physician survey conducted by NN in 1998 showed that 53% of doctors fear hypoglycemia. The survey showed that 35% of patients put on insulin are non-compliant for reasons shown. A ORG-MARG survey showed that 34% of diabetics are afraid of injection.
- #41: Here are the storage guidelines as per our package inserts ….
- #42: Another question is…. There is nothing dangerous about contamination Dont share FlexPens with other users
- #43: What do experts say … Dr. Gill G.V says that Storage of patient supplies of insulin in warm climates is not an important practical issue, & should not interfere with supplies of vital insulin to pts. in developing countries. Our preparations are robust & can be stored up to one month at room temperature