Insulin Medication: A Detailed Study

A detailed study of insulin medication from past to present & future.
Different types of insulin medications their storage & safety condition along with the sites for the administration of insulin dosage forms.

1. Mr. Shaktiprasad Pradhan M.P harm , P h .D* Research professional, UDPS [email protected] Utkal University, Bhubaneswar Odisha, India INSULIN MEDICATION: A DETAILED STUDY .

2. 1 INTRODUCTION

3. 2 Insulin Pancreas is primarily an exocrine gland & only 2% accounts for the endocrine portion, which is made by one to three millions of pancreatic islets. The pancreatic islets are made by 65–80% of the beta cells which synthesize the insulin hormone . Beta cells are sensitive to blood sugar levels, so they secrete insulin into the blood in response to high level of glucose & inhibit their secretion when glucose level is low. Insulin is produced from the pancreas in two different ways. Basal/ Background insulin is released 24 hours a day, whether or not a person eats & regulates glucose levels between meals. Bolus insulin   is released with direct response to the ingestion of food in order to manage the rise in blood glucose level that immediately follows. (Cont.)

4. 3 The molecular formula of human insulin is C 257 H 383 N 65 O 77 S 6 having a molecular mass of 5808 Da . Insulin is derived from Proinsulin a 74 amino acid prohormone molecule. Human insulin is composed of 51   amino acids, a combination of two peptide chains (hetero dimer) Chain-A and Chain-B composed of 21 & 30 amino acids respectively, linked together by two disulphide bonds. Insulin was the first peptide hormone discovered and also the first protein to be chemically synthesised & produced by DNA recombinant technology. It is included in the  Model List of Essential Medicines , the most important medications needed in a basic health system, by the World Health Organization (WHO).

5. 4 JOURNEY OF INSULIN

6. 5 Journey of Insulin The discovery and advancement of insulin as an antidiabetic medication can be traced back to the 19th century. Research into the development of insulin has motivated scientists to take historic steps towards understanding human biology, resulted a number of Nobel Prize awards for the investigation. In 1869 , Paul Langerhans, discovered a distinct collection of cells within the pancreas & later be called the Islets of Langerhans . In 1889 , Oskar Minkowski & Joseph von Mering during the study on pancreas effects on digestion found that after removing the pancreas gland from dogs, they died shortly. This led to the idea that the pancreas produces some “Pancreatic substances” (Insulin). (Cont.)

7. 6 In 1901 , Eugene Opie discovered that the Islets of Langerhans produce some pancreatic substance (Insulin) and diabetes resulted due to the damage of these cells. In 1910 , Edward Albert Sharpey Shafer suggested that only one chemical was missing from the pancreas in diabetic people. He decided to call this chemical Insulin , comes from the Latin word  insula ,  meaning “island.” In 1921 , Frederick Banting & Charles figured out how to remove insulin from a dog’s pancreas. In January 1922 , Leonard Thompson, a 14 years old boy with type 1 diabetes became the first human to be given the first medical administration of insulin by injection. (Cont.)

8. 7 In 1923 , Banting and Macleod were awarded the Nobel Prize in Physiology/ Medicine for these research. In 1923 ,  Eli Lilly produces commercial quantities of much purer bovine insulin than previously used. In 1936 , D.M. Scott & A.M. Fisher both Canadian, formulated a zinc insulin mixture and license it to  Novo . In 1936 , Danish physician Hans Christian Hagedorn discovered the action of insulin can be prolonged with the addition of protamine. In 1946 , Nordisk formulated Isophane porcine insulin aka Neutral Protamine Hagedorn or  NPH insulin. In 1950 , Nordisk marketed NPH insulin an intermediate acting insulin. (Cont.)

9. 8 In 1953 , Novo formulated Lente porcine and Bovine insulins by adding zinc for longer lasting insulin. In 1955 , Frederick Sanger sequenced the amino acid sequence of insulin & insulin became the first protein to be fully sequenced. In 1958 Sanger receives the Nobel Prize in Chemistry for his research. In 1965 , insulin became the first human protein to be chemically synthesised by Wang Yinglai, Chen Lu Tsou, et al. In 1978 , Genentech biotechnology firm produced biosynthetic human insulin in  Escherichia coli  bacteria using recombinant DNA techniques which made insulin, the first human protein to be manufactured through biotechnology. (Cont.)

10. 9 In 1983 , Eli Lilly company produced Humulin, the biosynthetic human insulin with recombinant DNA technology. In 1985 , Novo Nordisk introduced the Insulin Pen delivery system. In 1996 , Eli Lilly marketed the analogue insulin Lispro under the trade name Humalog. In 2000 , Sanofi Aventis marketed Lantus insulin glargine analogue. In 2013 , the University of Cambridge developed an artificial pancreas that pairs the technology of an insulin pump with a continuous glucose monitor. In 2015 , Dr Edward Damiano introduced the  iLet (a bridge to a cure) a bionic pancreas device that delivers both insulin & glucagon every five minutes as required.

11. 10 IMPORTANCE OF INSULIN

12. 11 Importance of Insulin Primarily insulin is regarded as the hormone that regulates blood sugar level. After a meal insulin helps to metabolize & use food for energy throughout the body so a problem with insulin can have a widespread effect on any or all of the tissues, organs and systems of the body. Insulin helps the body to use or store the glucose that's derived from carbohydrates in the diet. In liver insulin stimulates the creation and storage of glycogen from glucose. High insulin levels cause the liver to get saturated with glycogen. Insulin is important to overall health & survival, so problems with insulin production or utilization, insulin supplement is needed throughout the day. (Cont.)

13. 12 Insulin helps the amino acids in protein to enter cells, so without adequate insulin production, this process is slowed down, making it difficult to build muscle mass. Insulin also makes cells more receptive to electrolytes like potassium, magnesium and phosphate. These minerals help conduct electricity within the body, so they influence muscle function, blood pH, and the amount of water in the body. By causing excessive urination (Polyuria) with water and electrolyte loss, hyperglycaemia can worsen an electrolyte imbalance. Insulin helps to transport glucose from the bloodstream with the help of glucose transporters. Insulin may even influence the development or progression of Alzheimer disease.

14. 13 ADVERSE EFFECTS OF INSULIN MEDICATION

15. 14 Adverse Effects of Insulin Medication There may be chances of mild or serious side effects that occur during or after taking the insulin medication. The common side effects include Low blood sugar (Hypoglycaemia) Swelling of arms and legs Weight gain Short term salt & water retention (Peripheral edema) Injection site reactions : Redness, swelling, itching Skin changes at the site of injection (Lipodystrophy) : Can be managed by changing or rotating the injection site. (Cont.)

16. 15 Serious side effects can be life threatening if left untreated, which include Severe low blood sugar: Loss of consciousness, confusion including delirium, tingling or numbness in lips or tongue, blurred or impaired vision, seizures. Low blood potassium (Hypokalemia): Breathing problems, heart rhythm problems, muscle cramps, tiredness. Serious allergic reaction: Rash all over the body, trouble breathing, fast heart rate, sweating, feeling faint. Swelling of hands and feet. Heart failure: Shortness of breath, swelling of ankles or feet, sudden weight gain.

17. 16 INSULIN LINKED MAJOR ABNORMALITIES

18. 17 Insulin Linked Major Abnormalities Type 1 diabetes (T1D): It is an autoimmune disease & a chronic condition in which the pancreas produces little or no insulin. It typically appears in adolescence, supplemental insulin is vital but not always. Treatment aims at insulin therapy, diet & exercise. Type 2 diabetes (T2D): It is a chronic condition in which insulin production is lower than normal and/or the body isn't able to use it efficiently. There is no cure for T2D but can be managed by diabetic medication or insulin therapy, diet, exercise & weight loss. (Cont.)

19. 18 Insulin resistance: It can be due to a problem with the shape of the insulin (preventing receptor binding), not having enough insulin receptors, signalling problems, or glucose transporters not working properly & can occur as a result of excess body fat. Treatment includes insulin therapy, diet, physical exercise losing weight. The Dawn effect: It is an observed increase in blood sugar (glucose) levels takes place in very early morning, often between 2 am and 8 am, so an increase insulin demand occurs at dawn. It correlates the insulin, blood sugar (glucose) & night sleep. (Cont.)

20. 19 This is a natural occurring phenomenon happens to nearly everyone with diabetes, affecting their medical management. If you have diabetes, your body doesn’t release more insulin to match the Dawn effect/ phenomenon. There are a few ways to prevent the Dawn effect, including By adjusting the dose of insulin or other diabetic medication. Not eating carbohydrates closer to bedtime. Taking insulin closer to bedtime instead of closer to dinner time. Doing some light physical activity like walking, jogging, yoga after dinner. By using an insulin pump overnight.

21. 20 TYPES OF INSULIN MEDICATION

22. 21 Types of Insulin Medication The types of insulin medication are characterized by three different characteristics. Onset: Time taking for the insulin to start lowering blood glucose level. Peak time: After an injection the time when the insulin is most effective at lowering blood glucose level. Duration:  Total time continue to work for lowering blood glucose level by the insulin. Insulin is prescribed by matching the characteristics of particular insulin with the individual needs of the patient. Some patients need only one kind of insulin, while others take a combination of insulin medication to customize good glucose control. (Cont.)

23. 22 Currently seven different categories of insulin medications are available. Rapid acting: Onset of less than 15 minutes, peak at 30 to 90 minutes & duration of 2 to 4 hrs. Apidra, Humalog, Novolog. Short acting (Regular): Onset of 30 minutes, peak at 2 to 3 hrs & duration of 3 to 6 hrs. Humulin R, Novolin R. Intermediate acting: Onset of 2 to 4 hrs, peak at 4 to 12 hrs & duration of 12 to 18 hrs. Humulin N, Novolin N. Long acting: Onset of several hrs, minimal or no peak & duration of 24 hrs or more. Levemir, Lantus. (Cont.)

24. 23 Ultra long acting: Onset of 6 hrs, no peak & duration of 36 hrs. Toujeo. Combinations/ Pre mixed:   Onset of 15 minutes to 1 hr, peak time varies depending on the mix. & duration up to 24 hrs. Mixtures of Humulin or Novoline, Novolog Mix, Humalog Mix. Combination of intermediate acting insulins with regular insulin. Inhaled insulin: Onset of 12 to 15 minutes, peak at 30 minutes & duration of 3 hrs. Afrezza. Combination of long acting insulin. Approved by the USFDA in 2014 & became available in 2015. Different types of insulin medication, how long they will take to start lowering blood sugar, when the peak of action will occur and how long they will continue to work, all are summarized in Table-1 .

25. Table-1: Some Important Insulin Medication

26. Onset, Peak & Duration of Insulin Types

27. 26 STORAGE & SAFETY OF INSULIN MEDICATION

28. 27 Storage & Safety of Insulin Medication The efficacy of insulin medication may be affected by a wide range of change in temperature (extreme hot or cold), powerful sunlight and improper storage conditions (after & before opening). Unopened insulin should always be stored in a cool condition or at room temperature (15°C to 25°C & up to 30°C or 59°F to 77°F) or normal storage conditions as per the IP, as injecting cold insulin can sometimes be more painful. At room temperature, insulin vial can generally last about one month, once opened & insulin pens can only last about 28 days. A vial of insulin is considered open if its seal has been punctured & if the cap is removed but the seal isn't punctured, the bottle will be considered unopened. (Cont.)

29. 28 Expired insulin will no longer be potent or effective, so it should be discarded after the date of expiry. To use an insulin medication safety precautions should be adopted: By keeping the insulin medication out of direct heat or sunlight. By keeping the patient shaded, while administering insulin. By discarding or refusing any degraded quality insulin medication having an unusual appearance as cloudy or not clear, appearance of small crystals, clumps even after rolling it between the palms. By avoiding dosage related mistakes, so never guess the insulin dosage, never share the insulin vials with anyone, check insulin dosage each time before taking a dose.

30. 29 DOSES OF INSULIN MEDICATION

31. 30 Doses of Insulin Medication Insulin supplemental doses may be prescribed during illness, patients with type 2 diabetes receiving oral medications may be switched to insulin therapy temporarily. The daily doses of insulin medication may be higher during illness, stress, pregnancy, in obese patients, trauma, during concurrent use with medications having hyperglycaemic effects or after surgery. Daily doses of insulin medication may be lower with exercise, weight loss, calorie restricted diet, during concurrent use of hypoglycaemic medications. Individualize dose is based on the metabolic needs (in T1D & T2D), frequent monitoring of blood glucose level (in T1D & T2D) & HbA1c values (only in T2D). (Cont.)

32. 31 Regular human insulin is a short acting prandial insulin available in 2 concentrations as U-100 (100 units of insulin per mL ) & U-500 (500 units of insulin per mL ). To avoid any mix up with the availability of 2 different regular human insulin concentrations, insulin doses should always be ordered in units not in volume. Insulin resistant patients requiring daily insulin doses of more than 200 units may find U-500 insulin to be useful as large doses may be administered subcutaneously in a reasonable volume. For T1D total daily insulin requirements are generally between 0.5 to 1 unit/kg/day & for T2D the initial doses are often in the range of 0.2 to 0.4 units/kg/day. (Cont.)

33. 32 Most individuals with Type-1 or Type-2 diabetes should be treated with insulin medication, as multiple daily insulin (MDI) injections, continuous subcutaneous insulin infusion (CSII), intravenous administration, infusion fluids etc. Multiple daily insulin (MDI) injections Combination of bolus/ prandial (rapid or short acting) and basal (intermediate or long acting) insulin. Administered subcutaneously into the abdomen, buttocks, thigh or upper arm within 30 minutes before a meal, injection sites should be rotated within same region to reduce the risk of lipodystrophy. U-100 regular human insulin may be mixed with NPH insulin & U-500 regular human insulin should not be mixed with other insulins. (Cont.)

34. 33 Dose for T1D is U-100 insulin s.c 3 or more times, U-500 insulin s.c 2 to 3 times a day approximately 30 minutes prior to start of a meal. Dose for T2D is U-100 insulin s.c 3 or more times, U-500 insulin s.c 2 to 3 times a day approximately 30 minutes prior to start of a meal. May be used in combination with oral antihyperglycemic agents or longer acting basal insulin. Continuous subcutaneous insulin infusion (CSII) Insulin pump therapy. Intravenous administration U-100 insulin is administered by both i.v & s.c route, but U-500 regular human insulin should not be administered intravenously (i.v) only by s.c. Infusion fluids Humulin R & Novolin R. (Cont.)  

35. 34 The dose of insulin medication may be altered when the brand, type or species of insulin is changed, during stress, major illness or with changes in exercise, meal patterns or co administered drugs. The daily doses of insulin medications are quite different for the patients with kidney diseases, liver diseases, heart failure, low blood potassium level ( hypokalemia ), who are pregnant and breastfeeding women. Insulin may pass into breast milk and get broken down by the child’s stomach so the amount of insulin needed for breastfeed may change. However insulin doesn’t cause side effects in children who are breastfed by mothers with diabetes. (Cont.)  

36. 35 Daily insulin medication doses can be tough to manage, but developed new technology with sophisticated algorithms, can easily calculate how much insulin a patient needs per dose. Some are connected to specific prescription insulin pens and some are calculating applications that anyone can use.  Some common & popular apps for calculating the insulin doses are mySugr , PredictBGL , Diabetes:M , Insulia , InCalc , RapidCalc , BlueStar (approved by the FDA), Accu-Chek etc.

38. 37 However the daily doses of insulin medications are quite different for the Patients with kidney disease Patients with liver disease Patients with heart failure Patients with low blood potassium level (Hypokalemia) Women who are pregnant Women who are breastfeeding: Insulin may pass into breast milk and get broken down by the child’s stomach. Insulin doesn’t cause side effects in children who are breastfed by mothers with diabetes. However, if you breastfeed, the amount of insulin you need may change.

39. 38 DELIVERY DEVICES FOR INSULIN MEDICATION

40. 39 Delivery Devices for Insulin Medication There are a number of types & forms of devices to deliver or administer insulin medication. Insulin injection Insulin cannot be taken as a pill or tablet because digestive enzymes would break it down before it could get into the bloodstream, for that reason it must be injected. Insulin pen Two types of insulin pens are available as insulin filled cartridge pen containing an insulin filled cartridge & pre filled disposable insulin pen meant to be discarded after all the prefilled insulin has been used. For both types, the insulin dose is "dialed" on the pen & injected through a needle. (Cont.)

41. 40 Insulin jet injector Insulin jet injectors are designed for people who find insulin injections uncomfortable or unsettling in any way. Jet injectors are designed to send a fine spray of insulin through the skin using a high pressure air mechanism. However, this product remains relatively rare and also needs to be regularly boiled and sterilized. Insulin patch This is a credit card size device that adheres to the skin & the insulin patch holds a small reservoir and a pre filled needle. Insulin is triggered by pressing a button on the patch & it is designed to deliver both a continual flow of basal insulin and individual doses of bolus insulin. V-Go is an insulin patch marketed device.  (Cont.)

42. 41 Insulin pump Consisting of a reservoir to hold insulin & a pump, these devices connect to the body via tubing and use a cannula holding a needle for delivering insulin into body. These devices provide a slow, steady stream of fast or short acting basal insulin, with an option to deliver a larger dose of additional insulin (bolus) at meals.

43. 42 SITES OF APPLICATION FOR INSULIN MEDICATION

44. 43 Sites of Application for Insulin Medication Typically, insulin absorption is fastest in the abdomen, somewhat less quickly in the upper arms, slower in the thighs and slowest in the buttocks. Usually it is recommended to deliver mealtime insulin injections in abdomen, as they work fastest which helps to lower post prandial (after meal) blood sugars.  Long acting insulin, such as Lantus or Toujeo, can be injected into a slower absorption site, such as the buttocks or upper thigh, upper arm so that the absorption can happen gradually, covering the insulin needs throughout the night. However the best way to control blood sugar level is to aim, to use the same site at the same time of day and daily to rotate within that site. (Cont.)

45. 46 Fatty tissue: Insulin is meant to be injected subcutaneously (under the skin) into fatty tissue, such as the abdomen, outer parts of thighs, backs of arms and buttocks. Injecting insulin in fatty tissue helps the body to absorb insulin slowly and predictably, this layer of skin sits on top of the muscle and has fewer nerves, which can make injections more comfortable. Abdomen: Injecting insulin into the abdomen is very common amongst people with diabetes as the insulin absorption is fastest here and a greater surface area as well as less muscle, making it more comfortable & easier to rotate injections sites. (Cont.)

46. 47 Backs of arms: Injecting in the upper arm, using only the outer back area is also a good site (where the most fat is). Upper buttocks or love handles:   The love handles, area just above hip, is a good injection site for young children or very thin adults, as usually able to squeeze a small amount of fat. Outer side of thighs: The outer, fattier part of the thigh is also a good site for insulin injection and not the inner thighs.

47. 49 TIPS FOR INSULIN ADMINISTRATION

48. 50 Tips for Insulin Administration Injecting into the same exact spot on the same site repeatedly can cause the skin to develop hard lumps or extra fat deposits, so it should be avoided. If lumps and bumps are developed at injection sites, then the area of the bump should be avoided for several months as that area will absorb insulin differently affecting blood sugar level. Sites that are exercising, should be avoided for insulin injection, as this can increase the risk of hypoglycaemia due to increased absorption. Using impure insulin may result in fat atrophy. A painless injection seems positive, but this can damage the skin more, so this is not a good sign. Injecting into moles or scar tissue should be avoided, as these can also affect insulin absorption.  

49. 51 REFERENCES

50. 52 https://www.drugs.com/drug class/insulin.html. https://en.wikipedia.org/wiki/Insulin_(medication ). https:// medlineplus.gov/druginfo/meds/a682611.html. American Diabetes Association 2018 Annual Report (PDF ). Classification & Diagnosis of Diabetes:  Standards of Medical Care in Diabetes—2019. American Diabetes Association Diabetes Care 2019 Jan; 42(Supplement 1): S13-S28. https:// doi.org/10.2337/dc19-S002 . https:// www.endocrineweb.com/guides/insulin/insulin-delivery. https:// www.diabetes.co.uk/insulin/Diabetes-and-insulin-delivery-devices.html. https://www.diabetesselfmanagement.com/diabetes-resources/tools-tech/insulin-delivery-devices /. https://pubmed.ncbi.nlm.nih.gov/2226111 /. Short acting (Regular): Onset of 30 minutes, peak at 2 to 3 hrs & duration of 3 to 6 hrs. Humulin R, Novolin R .

51. . Thank You