COMPLICATIONS, MANAGEMENT AND TREATMENT APPROACH OF DIABETES MELLITUS

Diabetes describes a group of metabolic diseases in which the person has high blood glucose (blood sugar), either because insulin production is inadequate, or because the body's cells do not respond properly to insulin, or both. Mellitus is Latin for “sweet as honey”.
Pancreas is an elongated, tapered gland that is located behind the stomach and secretes digestive enzymes and the hormones insulin and glucagon.
The Pancreas secretes insulin and Glucagon directly into the blood stream.
It also secretes digestive enzymes into the pancreatic duct, which joins the common bile duct from the liver and drains into the small intestine.
Insulin and Glucagon have opposite effects on liver and other tissues for controlling blood-glucose levels.

1. Presented by: ANAS HARUNA INDABAWA Submitted to: Associate Prof. Dr P.S.Gupta Final Year Project Presentation Department : Pharmacy School: Sam Higginbottom University of Agriculture, Tech. & Sciences (SHUATS) Year: March 2017

2. COMPLICATIONS, MANAGEMENT AND TREATMENT APPROACH OF DIABETES MELLITUS

3. Definition The Pancreas secretes insulin and Glucagon directly into the blood stream. It also secretes digestive enzymes into the pancreatic duct , which joins the common bile duct from the liver and drains into the small intestine. Insulin and Glucagon have opposite effects on liver and other tissues for controlling blood-glucose levels. Diabetes describes a group of metabolic diseases in which the person has high blood glucose (blood sugar), either because insulin production is inadequate, or because the body's cells do not respond properly to insulin, or both. Mellitus is Latin for “ sweet as honey ”. Pancreas is an elongated, tapered gland that is located behind the stomach and secretes digestive enzymes and the hormones insulin and glucagon.

4. Glucagon ( α alpha cells) Glucagon is produced in the α cells and is released when the glucose level in the blood is low. The liver then convert stored glycogen into glucose and release it into the bloodstream. Insulin ( β Beta cells) Beta Cells within the Islets of Langerhans produce insulin which is needed to metabolize glucose within the body. Insulin is secreted in response to increased glucose levels in the blood.

5. Epidemiology According to International Diabetic Federation (IDF) atlas (2015), Governments have acknowledged that diabetes is increasing at epidemic rates and is affecting all countries. Globally, an estimated 422 million adults were living with diabetes in 2014 , compared to 108 million in 1980 which is estimated to be 1 in 11 of the world’s adult population. About 46 % of people with diabetes are undiagnosed About 10% people with diabetes have Type 1 DM About 90% people with diabetes have Type 2 DM

6. Classification Type 1 diabetes Type 2 diabetes Other Genetic defects of beta cell function Genetic defects in insulin action Diseases of the exocrine pancreas Endocrinopathies Drug/ chemical - induced Infections Uncommon forms of immune-mediated diabetes Genetic syndromes sometimes associated with diabetes Gestational diabetes mellitus

7. Type 1 F ormerly known as Insulin – Dependent Diabetes Mellitus (IDDM) Type I diabetes occurs when the β-cell are destroyed by the body’s own immune system. M ay occur at any age, usually appears below age 15. Usually due to autoimmune destruction of the pancreatic beta cells or idiopathic. Patients with type 1 diabetes will need to take insulin injections for the rest of their life.

8. Type 2 Formerly known as Non Insulin – Dependent Diabetes Mellitus (NIDDM) Insulin is produced however there is less and there is a decrease in the number of receptors ( insulin resistance ). occurs over age 40 but can occur in children Gestational DM Gestational diabetes (GDM) occurs when pancreatic function is not sufficient to overcome the insulin resistance created by changes in diabetogenic hormones during pregnancy. Most have impaired glucose tolerance that begins in pregnancy Some have previous undiagnosed type 2 diabetes mellitus 10% have circulating islet cell antibodies

9. Etiology T here is no defined cause of diabetes because the causes of diabetes vary depending on the individual and the type. Some of the risk factors include: Obesity (BMI >25 kg/m 2 ) History of CVD Diet Physical inactivity Familial history Increase in age Smoking Race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander) Viral infection Gestational Diabetes

10. Clinical Manifestations ( Signs and Symptoms) Polyuria Polydipsia Polyphagia glycosuria weight loss weakness nausea / vomiting fatigue  blood sugar recurrent infection prolonged wound healing altered immune and inflammatory response, prone to infection. (glucose inhibits the phagocytic action of WBC   resistance )

11. Complications I. Acute complications : diabetic ketoacidosis hypoglycemia diabetic nonketotic hyperosmolar coma Lactic acidosis II. Chronic complications: a. Microvascular retinopathy nephropathy neuropathy diabetic foot dermopathy b. Macrovascular Cerbrovascular . Cardiovascular . peripheral vascular disease .

12. Diabetic complications cont … Diabetic ketoacidosis Diabetic Ketoacidosis (DKA) is a state of inadequate insulin levels resulting in high blood sugar and accumulation of organic acids and ketones in the blood. It is a potentially life-threatening complication in patients with diabetes mellitus. It happens predominantly in type 1 diabetes mellitus, but it can also occur in type 2 diabetes mellitus under certain circumstances. It may also be the first presentation in patients who had not previously been diagnosed as diabetics. There is often a particular underlying problem that has led to the DKA episode. This may be intercurrent illness (pneumonia, influenza, gastroenteritis, a urinary tract infection), pregnancy, inadequate insulin administration (e.g. defective insulin pen device), myocardial infarction (heart attack), stroke or the use of cocaine. This is more common in African, African-American and Hispanic people.

13. Diabetic complications cont … The ketone bodies, however, have a low pH and therefore turn the blood acidic (metabolic acidosis). The body initially buffers this with the bicarbonate buffering system, but this is quickly overwhelmed and other mechanisms to compensate for the acidosis, such as hyperventilation to lower the blood carbon dioxide levels. This hyperventilation, in its extreme form, may be observed as Kussmaul respiration .

14. Diabetic complications cont … D iabetic Hyperglycemic Hyperosmolar State (HHS) Relative insulin deficiency and inadequate fluid intake are the underlying causes of HHS. Insulin deficiency increases hepatic glucose production (through glycogenolysis and gluconeogenesis) and impairs glucose utilization in skeletal muscle . Hyperglycemia induces an osmotic diuresis that leads to intravascular volume depletion, which is exacerbated by inadequate fluid replacement. HHS is often precipitated by a serious, concurrent illness such as myocardial infarction or stroke.

15. Diabetic complications cont … Lactic Acidosis Lactic acidosis occurs in hypoxic individuals and is due to an excessive production of lactate by peripheral tissues. It is characterized by extreme metabolic acidosis. There is high anion gap with low or absent ketones and high lactate levels. Hypoglycemia Hypoglycaemia is caused by not eating enough sugary foods, taking too much insulin therapy or too much exercise. Low blood glucose can lead to coma.

16. Diabetic complications cont … Diabetic Retinopathy Diabetes causes an excessive amount of glucose to remain in the blood stream which may cause damage to the blood vessels. Within the eye, the damaged vessels may leak blood and fluid into the surrounding tissues and cause vision problems.

17. Diabetic complications cont … Other Eye Complications Cataracts. Glaucoma Macular edema. Ischaemic maculopathy. Proliferative retinopathy. Vitreous Bleeding. Rubeosis Iridis

18. Diabetic complications cont … Diabetic nephropathy Diabetic nephropathy ( nephropatia diabetica ), also known as Kimmelstiel -Wilson syndrome , and intercapillary glomerulonephritis, is a progressive kidney disease. The kidney becomes damaged and more protein than normal collects in the urine. Over time, the kidney's ability to function starts to decline, which may eventually lead to chronic kidney failure.

19. Diabetic complications cont … Diabetic Neuropathy Diabetes can damage the nerves. This generally begins as loss of sensation in the toes, and possibly fingers. It may manifest as polyneuropathy, mononeuropathy , and/or autonomic neuropathy. Both myelinated and unmyelinated nerve fibers are lost.

20. Diabetic complications cont … Diabetic Foot Diabetic foot ulceration is due to an interplay of neuropathy, tissue ischaemia ( microcirculatory and macrovascular disease) and secondary infection. The factors responsible for its development, in addition to peripheral vascular disease, are small vessel disease, peripheral neuropathy with loss of both pain sensation and neurogenic inflammatory responses, and secondary infection. The peripheral sensory neuropathy interferes with normal protective mechanisms and allows the patient to sustain major or repeated minor trauma to the foot, often without knowledge of the injury.

21. Diabetic complications cont … Macrovascular complications Accelerated atherosclerosis involving the aorta and large- and medium-sized arteries. Myocardial infarction , caused by atherosclerosis of the coronary arteries, is the most common cause of death in diabetics. Gangrene of the lower extremities. Hypertension due to Hyaline arteriolosclerosis .

22. Management of Diabetes Mellitus The goals of therapy for type 1 or type 2 DM are to: Eliminate symptoms related to hyperglycemia, Reduce or eliminate the long-term micro vascular and macro vascular complications of DM, and Allow the patient to achieve as normal a lifestyle as possible.

23. Current therapy of DM Non-Pharmacological TYPE 1 Management (Insulins) TYPE 2 Management (Oral Hypoglycemic Agents)

24. Non-Pharmacological Therapy of DM Weight Loss Regular Physical activity Medical Nutrition Therapy Lifestyle Changes Education

25. PHARMACOLOGICAL TREATMENT FOR DIABETES Agents used in diabetic therapy include the following: Biguanides Sulfonylureas Meglitinide derivatives Thiazolidinediones (TZDs ) Alpha-glucosidase inhibitors Glucagonlike peptide–1 (GLP-1) agonists Dipeptidyl peptidase IV (DPP-4) Inhibitors Amylinomimetics Selective sodium-glucose transporter-2 (SGLT-2) inhibitors Bile acid sequestrants Insulin

26. Biguanides Metformin (Glucophage , Fortamet , Glumetzam , Riomet ) Metformin inhibits hepatic and renal gluconeogenesis, and increases the sensitivity of insulin receptors. It does not cause hypoglycemia. It produces a significant ↓ TG and LDL, and ↑HDL. There is a serious concern about lactic acidosis especially in patients with kidney disease. Other preperations : penformin buformin Withdrawn due to high risk of lactic acidosis

27. Sulfonylureas First generation : Acetohexamide , Chlorpropamide , Tolbutamide , Tolazamide Second generation : Glipizide, Glyclazide , Glybenclamide – more potent, more efficacious and fewer adverse effects . Third generation : Glimiperide Mechanism of Action Sulfonylureas act by Binding to sulfonylurea receptors on pancreatic islet cells, closing KATP channels, stimulating insulin release; relatively long duration of action I ncreases the beta-cell insulin secretion and may also decrease rate of hepatic glucose production and increase insulin receptor sensitivity Adverse effects : Hypoglycemia Cholestatic jaundice Weight gain Cross placenta – fetal hypoglycemia. Chlorpropamide : It can cause water retention by ↑ release of ADH (SIADH)

28. Meglitinide Repaglinide , Nateglinide : More rapidly acting insulin enhancers and shorter duration than sulfonylurea. Mechanism of Action: Meglitinide Bind to sulfonylurea receptors on pancreatic islet cells, closing KATP channels, stimulating insulin release; relatively short duration of action Hypoglycemia is the common adverse effect. Less weight gain The drug has minimal renal excretion thus useful in patients with DM and impaired renal function. 

29. Thiazolidinediones Rosiglitazone, Pioglitazone Thiazolidinediones Activate the nuclear receptor PPAR-gamma, increasing peripheral insulin sensitivity ; also reduces hepatic glucose production Enhance sensitivity to insulin in muscle and fat by increasing the GLUT 4 glucose transporters . Beneficial effects on serum lipid; ↓TG and ↑HDL. Troglitazone is associated with hepatitis. Edema.

30. Alpha-Glucosidase Inhibitors Acarbose , Miglitol,Voglibose It inhibits α -glucosidase which converts dietary starch and complex carbohydrates into simple sugars It reduces absorption of glucose after meals.

31. Glucagon like Peptide: GLP-1 analog Exernatide , Albiglutide , Lixisenatide , liraglutide GLP is an incretin released from the small intestine which increase the glucose dependent insulin secretion. Exenatide suppress glucagon release and reduce appetite Glucagon like Peptide: GLP-1 analog Increase glucose-dependent insulin secretion, decrease glucagon secretion, and delay gastric emptying; inhibit degradation of endogenous GLP-1 (and GIP-1), thereby enhancing these effects of these incretins

32. Dipeptidyl peptidase 4 ( DPP-4) Inhibitors Sitagliptin , saxagliptin , Linagliptin , Vilda gliptin It inhibit the dipeptidyl peptidase 4 (DPP-4), an enzyme which inactivates the incretins GLP-1 and GIP, that are released in response to a meal. It potentiates the secretion of insulin and suppress the release of glucagon by the pancreas.

33. Amylinomimetics Pramlintide Amylin : a polypeptide produced by pancreatic beta cells which reduces glucagon secretion from alpha cells and delays gastric emptying It acts by stimulation of glucagon receptors and not through beta 1 receptors. It has positive inotropic action and chronotropic action on the heart.

34. SGLT2 Inhibitors Dapagliflozin , Empagliflozin SGLT2  Inhibitors Reduces glucose reabsorption in the proximal renal tubules and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion . Possible challenge: Increase in incidence of UTI Hypotension Bladder cancer, amputations, fractures

35. Bile acid sequestrants Bromocriptine ( Cycloset ) This quick- release formulation is the only bromocriptine product indicated for type 2 diabetes mellitus. It is indicated as an adjunct to diet and exercise to improve glycemic control.

36. Insulins Proinsulin is converted to insulin and C peptide. Insulin is referred as the storage hormone as it promotes anabolism and inhibits catabolism of carbohydrates, fatty acids and protein. In the absence of insulin, most tissues cannot use glucose and fats/proteins are broken down to provide energy. Mechanism of action : Insulin binds to insulin receptors on the plasma membrane and activates tyrosine kinase – primarily in adipose tissue, liver and skeletal muscle. The Nerves, RBC’s, Kidney, and Lens of the eye do not require insulin for glucose transport.

37. Insulins Methods of insulin administration 1) Insulin syringes and needles- Plastic disposable syringes are available in 1-mL, 0.5-mL, and 0.3-mL sizes. 2) Insulin pen injector devices- Insulin pens eliminate the need for carrying insulin vials and syringes. 3) Insulin pumps- Insulin infusion pumps are used for subcutaneous delivery of insulin. These pumps are small (about the size of a pager) and very easy to program. 4) Inhaled insulin- A novel method for delivering a pre-prandial powdered form of insulin by inhalation ( Exubera ) has been approved by the FDA.

38. Product (Manufacturer) Form Rapid Acting (Onset 15-30 min, duration hrs 3-4) Insulin Analog Aspart - Novolog (Novo Nordisk) Lispro - Humalog (Lilly) Glulisine – Apidra (Aventis) Analog** Analog** Short Acting (Onset 0.5-1 hr , duration hrs 5-7)* Human Insulin Novolin R ( Rugular ) (Novo Nordisk) Humulin R (Regular) (Lilly) Human** Human** Purified Insulin Regular Iletin II (Lilly) Pork Intermediate Acting (Onset 1-4 hrs , duration hrs 18-24)* Human Insulin Novolin N (NPH) (Lilly) Humulin N (NPH) (Lilly) Humulin L (Lente) (Lilly) Human** Human** Human** Purified Insulin NPH Iletin III (Lilly) Pork Long Acting (Onset 4-6 hrs , duration hrs 24-34)* Human Insulin Humulin Ultralente (Lilly) Human** Basal Peakless Insulin Glargine-Lantus (Aventis) Detemir – Levemir (Novo Nordisk) Analog** Analog** Product (Manufacturer) Form Mixed Insulins 70/30 Insulin Novolin 70/30 (Novo Nordisk) Humulin 70/30 (Lilly) Humulin 50/50 (Lilly) Humalog 50/50 Human** Human** Human** Analog** Insulin for Special Use Buffered Insulin (for pumps) Humulin BR Refills for Novolin Pen Novolin R PenFill Novolin N PenFill Novolin 70/30 PenFill Novolog Mix 70/30 PenFill Prefilled Pens Novolin R Novolin N Novolin 70/30 Novolog Novolog Mix 70/30 Humalog Humalog Mix 75/25 Humalog Mix 50/50 Humulin N Apidra Human** Human** Human** Analog** Human** Human** Human** Analog** Analog** Analog** Analog** Analog** Human** Analog** * Onset and duration are rough estimates. They can vary greatly within the range listed and from person to person ** Human insulin is made by recombinant DNA technology

39. Newer Approach New potential targets of Carbohydrate Metabolism Glucokinase (GK) Activators Fructose-1,6-Bisphosphatase (FBP) Inhibitors Glycogen Phosphorylase (GP) Inhibitors New potential targets of lipid Metabolism Beta3-Adrenergic Receptor ( β 3-AR) Agonists Hormone Sensitive Lipase (HSL) Inhibitors GPR40 /(Free Fatty Acid Receptor 1 (FFAR1)) Ligands

40. New Potential Targets of Carbohydrate Metabolism

41. Glucokinase (GK) Activators Enzymes of the glycolytic pathway that converts glucose to glucose-6-phosphate Glucose sensor Upregulating insulin (from pancreas) Promoting glucose storage as glycogen Piragliatin - Phase 2 Possible concern – Increased hepatic glycogen, lipid deposition in liver and muscle

42. Fructose-1,6-Bisphosphatase (FBP) Inhibitors (FBP) is the Gluconeogenesis enzyme that catalyzes the reverse conversion (F1,6P to F6P) FBPi - decrease Hepatic Glucose Production Efficacy has been an issue Phase 2 - MB07803

43. Glycogen Phosphorylase (GP) Inhibitors Glycogenolysis is a substantial contributor to hyperglycemia GP produces glucose-1-phosphate converted to glucose-6-phosphate which feeds into glycolysis GP(a) inhibition of the liver isoform in a selective fashion is important Ingliforib - phase 1

44. New potential targets of lipid Metabolism

45. Beta3-Adrenergic Receptor ( β 3-AR) Agonists Activate the uncoupling protein (UCP) which causes the expenditure of metabolic calories as heat Preclinical stages Lipolysis & β oxidation Low bioavailability Efficacy is less Is it suitable?? β 3AR stimulated thermogenesis to expend excess energy in human diabetic patients is still undefined

46. Hormone Sensitive Lipase (HSL) Inhibitors Rate-limiting step in adipose tissue lipolysis FFA’s - inhibits glucose uptake and utilization by muscle, increasing HGP HSLi improved lipid profiles and elevated insulin sensitivity (reduced plasma glucose levels) Preclinical stages

47. GPR40 /(Free Fatty Acid Receptor 1 (FFAR1)) Ligands FFAR1 facilitates glucose-stimulated insulin secretion from pancreatic β-cells GPR 40 regulates the secretion of glucagon-like peptide-1 in the intestine, as well as increases insulin sensitivity Potential therapeutic targets for type 2 DM Chronic exposure impairs β -cell function ( lipotoxicity ) Phase II : TAK-875

48. FUTURE PROSPECTS Islet cell transplantation is a minimally invasive procedure, wide application of this procedure for the treatment of type 1 diabetes is limited by the dependence on multiple donors and the requirement for potent long-term immunotherapy. Stem cell therapy- Stem cell therapy is one of the most promising treatments for the near future. It is expected that this kind of therapy can ameliorate or even reverse some diseases.

49. THANK YOU