Designer Insulin by Dr. Alisha Raj JR3 KGMU

About designer insulin

1. Designer Insulin Dr. Alisha Raj Junior Resident 3 Dept of Pharmacology & Therapeutics King George’s Medical University, Lucknow, UP, India-226003 Email id: [email protected]

2. Diabetes mellitus (DM) It is a metabolic disorder characterized by- Hyperglycaemia ( Fasting plasma glucose ≥ 126 mg/dl and/or ≥200 mg/dl 2 hours after 75 g oral glucose) G lycosuria H yperlipidaemia N egative nitrogen balance INSULIN and GLUCAGON regulates plasma glucose level

3. TRIAD Polyuria Polyphagia Polydipsia

4. TYPES Type-I Insulin-dependent diabetes mellitus (IDDM)/ juvenile onset diabetes mellitus Type-II NonInsulin -dependent diabetes mellitus (NIDDM) / maturity onset diabetes mellitus MODY maturity-onset diabetes of the young/ monogenic diabetes Gestational diabetes mellitus (GDM)

5. β cell destruction in pancreatic islets

6. Human proinsulin Insulin

7. Secretion of Insulin

8. Designer Insulin includes insulin analogues but extends beyond them Recombinant DNA technology by altering amino acid sequence include all engineered insulin formulation, including experimental and advanced delivery systems beyond amino acid modifications leading to- glucose responsiveness ultra-fast action prolonged stability

9. Insulin Analogues Designer Insulin subset of designer insulin that specifically involves modification of amino acid sequence to adjust its pharmacokinetics broader concept that includes all engineered insulin formulations , including experimental and advanced delivery systems analogues remain close to the structure and function of natural insulin Rapid-acting analogues (Insulin Lispro, Aspart) Long-acting analogues (Insulin Glargine, Detemir) involve more advanced or extensive changes Chemical Additions Smart Insulin Systems Delivery Innovations

10. Types of Designer Insulin Rapid-acting analogs : Lispro, Aspart – Ideal for mealtime glucose control. Long-acting analogs : Glargine, Detemir – Provide steady basal insulin levels. Ultra-long-acting analogs : Degludec – Lasts over 24 hours, reducing injection frequency. Emerging therapies: Bi-hormonal insulins incorporating glucagon for improved postprandial control.

11. Types Onset (hr) Peak (hr) Duration (hr) Comment SHORT ACTING Regular (soluble) insulin 0.5-1 2-3 6-8 Buffered neutral pH solution unmodified insulin stabilized by a small amount of zinc INTERMEDIATE ACTING Insulin zinc suspension or Lente 1-2 8-10 12-20 7:3 mixture of ultralente (crystalline, long-acting) and semilente (amorphous, short-acting) insulin zinc suspension. Neutral protamine hagedorn (NPH) or isophane insulin 1-2 8-10 12-20 Protamine is added Combined with regular insulin (70:30 or 50:50)

12. DESIGNER INSULIN Onset (hr) Peak (hr) Duration (hr) Comment RAPID ACTING - insulin response after meals Insulin lispro (Humalog) 0.2-0.3 1-1.5 3-5 Produced by reversing proline and lysine at B 28 and B 29 2–3 daily meal time insulin lispro injections Insulin aspart (Novolog) 0.2-0.3 1-1.5 3-5 proline at B 28 of human insulin is replaced by aspartic acid Insulin glulisine 0.2-0.4 1-2 3-5 used for continuous subcutaneous insulin infusion (CSII) by a pump LONG ACTING- maintain basal glucose control for an extended period Insulin glargine (Lantus) 2-4 24 depot is created from which monomeric insulin dissociates slowly to enter the circulation Peakless Injected at bed time Insulin detemir (Levemir) 1-4 20-24 Binds to albumin in the bloodstream for extended activity Twice daily

13. Types Onset (hr) Peak (hr) Duration (hr) Comment ULTRA LONG ACTING- designed for extended basal control, minimizing daily injections Insulin Degludec (Tresiba) 0.5-1 2-3 6-8 duration of action exceeding 42 hours, offering dosing flexibility Toujeo (Concentrated Insulin Glargine) A higher-concentration version of Insulin Glargine with a duration of up to 36 hours

14. ULTRA RAPID ACTING- for better control of postprandial glucose spikes FIAsp (Faster aspart) With two added excipients, L-arginine and niacinamide to speed up absorbtion URLi (Insulin lispro- aabc ) Lyumjev (Ultra-Rapid Lispro) Insulin Lispro combined with treprostinil and citrate for faster absorption Afrezza An inhalable insulin absorbed through the lungs, providing ultra-fast glucose control convenience for patients who avoid injections

15. Other Designer Insulins are as follows- Glucose-Responsive Designer Insulin (Experimental/Next-Generation) activated only when blood glucose levels are high, reducing the risk of hypoglycemia Eg : Smart Insulin- incorporates glucose-sensitive molecules that release insulin in response to elevated glucose levels (currently under development)

16. Designer Insulin for Advanced Delivery Systems used with advanced technologies like insulin pumps or artificial pancreas systems. Eg : Pump-Compatible Insulins : Many rapid-acting analogues, such as Insulin Aspart or Insulin Lispro, are used in continuous subcutaneous insulin infusion (CSII) systems. Closed-Loop Systems : used in automated insulin delivery systems that adjust dosing based on real-time glucose levels.

17. Mechanism of Action

18. Limitations of Conventional Insulin Injection Site Reactions- Pain, redness, and swelling at the injection site Higher Risk of Hypoglycemia- cause low blood sugar (hypoglycemia), leading to dizziness, confusion, and even unconsciousness. Frequent Monitoring- need frequent blood sugar monitoring to adjust dosing and avoid complications. Short Duration- has a shorter duration of action, requiring multiple injections throughout the day. Limited Flexibility- The fixed duration limits flexibility in dosing and timing for optimal blood sugar control.

19. Advantages of Designer Insulin Enhanced glycemic control, reducing fluctuations in blood sugar levels. Lower risk of hypoglycemia compared to traditional insulins. Convenience with flexible dosing schedules, improving patient adherence. Better quality of life: Reduced anxiety over blood sugar management.

20. Uses Of Insulin Diabetes mellitus type 1 - 0.4–0.8 U/kg/day type 2 patients dose varies 0.2–1.6 U/kg/day Diabetic ketoacidosis (Diabetic coma ) A bolus dose ( Regular insuline ) of 0.1–0.2 U/kg i.v. is followed by 0.1 U/kg/ hr infusion Hyperosmolar (nonketotic hyperglycaemic ) coma-BG >600 mg/dl Gestational Diabetes

21. Side effects of Insulin Hypoglycemia General weight gain Temporary visual disturbances Lipodystrophy Local allergic reactions Systemic allergic reactions

22. Summary Category Example Key feature Rapid-Acting Humalog, Fiasp Faster post meal control Long-Acting Lantus, Tresiba Stable basal control Ultra Rapid-Acting Lyumjev , Afrezza Ultra fast absorption Ultra Long-Acting Tresiba, Toujeo Extended basal coverage beyond 24hrs Glucose-Responsive Smart Insulins Activates only when glucose levels are high Inhalable Afrezza Needle free insulin delivery Pump-Compatible Rapid-Acting Optimised for insulin pump use

23. Reference Wilson LM, Castle JR. Recent Advances in Insulin Therapy. Vol. 22, Diabetes Technology and Therapeutics. Mary Ann Liebert Inc.; 2020. p. 929–36. Tripathi KD. Essentials of medical pharmacology. Eighth edition. New Delhi: Jaypee Brothers Medical Publishers; 2019. p280-305 Berenson DF, Weiss AR, Wan ZL, Weiss MA. Insulin analogs for the treatment of diabetes mellitus: therapeutic applications of protein engineering. Giorgino F, Battelino T, Bergenstal RM, Forst T, Green JB, Mathieu C, et al. The Role of Ultra-Rapid-Acting Insulin Analogs in Diabetes: An Expert Consensus. Journal of Diabetes Science and Technology. SAGE Publications Inc.; 2023. Danne T, Bolinder J, Forst T, Pfützner A, Flacke F, Krasner A, et al. Advanced Technologies and Treatments for Diabetes New insulins and insulin therapy LINJETA TM-A NEW RAPID ACTING INSULIN Postprandial vascular effects of VIAject compared with insulin lispro and regular human insulin in patients with type 2 diabetes.

24. THANK YOU

25. Questions What is the triad of Diabetes mellitus? What is Designer Insulin? Name some Rapid acting Insulin? Name some Long acting Insulin?