DM type 1 (11111111111111111111111).pptx

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1. Physiology of insulin and type 1 diabetes mellitus Presenter: Mohamed Hufane , PGY1, IM Moderator: Zemir Abdi , MD (internist at Haramaya university)

2. Physiology of insulin

3. Islets of langerhans , wich are cluster of cells contain:- Beta cells(secrete insulin) Alpha cells (secrete glucagon) Delta cells (secrete somastostatin Remaining cells secrete pancreatic polypeptide The endocrine pancreas

4. Structure and synthesis of insulin Insulin is a peptide hormone consisting of two straight chains, an A chain (21 amino acids) and a B chain (30 amino acids). Two disulfide bridges link the A chain to the B chain, and a third disulfide bridge is located within the A chain. The synthesis of insulin is directed by a gene on chromosome 11. The secretion of connecting peptide (C peptide) is the basis of a test for β cell function in persons with type I diabetes mellitus who are receiving injections of exogenous insulin. Insulin is metabolized in the liver and kidney by enzymes that break disulfide bonds. The A chains and B chains are released, now inactive, and are excreted in the urine.

5. Factors affecting insulin secretion

6. Mechanism of insulin secretion Transport of glucose into the β cell. Metabolism of glucose inside the β cell. ATP closes ATP-sensitive K+ channels. Depolarization opens voltage-sensitive Ca2+ channels. Increased intracellular Ca2+ causes insulin secretion.

7. Actions of insulin

8. Diabetes Mellitus: Diagnosis, Classification, & Pathophysiology

9. ▶ Diabetes mellitus (DM) refers to a group of common metabolic disorders that share the phenotype of hyperglycemia . ▶ Several distinct types of DM are caused by a complex interaction of genetics and environmental factors. ▶ Depending on the etiology of the DM, factors contributing to hyperglycemia include reduced insulin secretion, decreased glucose utilization, and increased glucose production . ▶ The metabolic dysregulation associated with DM causes secondary pathophysiologic changes in multiple organ systems that impose a tremendous burden on the individual with diabetes and on the health care system.

10. ▶ In the United States, DM is the leading cause of end-stage renal disease (ESRD), non truamatic lower extremity amputations , and adult blindness . It also predisposes to CVD. ▶ With an increasing incidence worldwide, DM will be likely a leading cause of morbidity and mortality in the future.

11. CLASSIFICATION ▶ DM is classified on the basis of the pathogenic process that leads to hyperglycemia, as opposed to earlier criteria such as age of onset or type of therapy . ▶ There are two broad categories of DM, designated type 1 and type 2 . ▶ However, there is increasing recognition of other forms of diabetes in which the pathogenesis is better understood. ▶ These other forms of diabetes may share features of type 1 and/or type 2 DM. ▶ Both type 1 and type 2 DM are preceded by a phase of abnormal glucose homeostasis as the pathogenic processes progress. ▶ Type 1 DM is the result of complete or near-total insulin deficiency.

12. PATHOGENESIS

13. Type 1 diabetes mellitus (T1DM) results from the autoimmune destruction of the insulin-producing beta cells in the islets of Langerhans of the pancreas. This process is thought to be influenced by a combination of genetic and environmental factors.

14. Pathophysiological process in T1DM: T1DM is most commonly a type IV hypersensitivity autoimmune reaction , in which CD4+ T helper cells and CD8+ cytotoxic T cells attack pancreatic beta cells, eventually eliminating any insulin production. Destruction of the beta cells occurs over months to years and usually only results in hyperglycaemia once ~90% of the beta cells have been destroyed. Progressive beta cell destruction also leads to dysfunction of neighbouring alpha cells which produce the counter-regulatory hormone, glucagon. This dysfunction can cause overstimulation of glucagon, especially after meals, leading to gluconeogenesis, glycogenolysis and ketogenesis , thereby worsening hyperglycaemia and causing a metabolic acidosis (diabetic ketoacidosis).

15. Genetic factors The risk of T1DM can be influenced by many different gene polymorphisms, particularly those relating to human leukocyte antigen (HLA) alleles , specifically HLA-DR and HLA-DQ alleles. The HLA-DQ2 genotype sometimes seen in T1DM is also associated with coeliac disease , and therefore coeliac disease is more common in those with T1DM. People with T1DM are also more likely to have other co-existing autoimmune disorders such as Hashimoto's thyroiditis, Addison's disease, vitiligo , and systemic lupus erythematosus (SLE). The risk of developing T1DM is 3-5% if a parent has it, and 40-50% if an identical twin has it.

16. The presence of autoantibodies to islet cells, insulin, islet antigens (IA2 and IA2-beta), glutamic acid decarboxylase (GAD), or the zinc transporter ZnT8 indicate autoimmune beta-cell destruction and are suggestive of T1DM. However, it is unclear which of these are involved in initiating the insult or which develop secondary to the insult.

17. Environmental factors The wide geographic variation in prevalence of T1DM suggests an environmental contribution to its development, however specific causative factors have not been identified. In genetically susceptible patients, environmental associations which have been postulated include: Viral infections Cow's milk ingestion Vitamin D deficiency Early introduction of cereals Nitrate concentration in drinking water

18. Clinical features Type 1 diabetes mellitus (T1DM) predominantly presents in childhood, with the highest incidence of diagnosis between the ages of 10-14. Classical presentation:-The most common presentation of T1DM including the common triad of:- Polydipsia  - due to hyperglycaemia increasing plasma osmolarity , causing the blood to become more concentrated. Increased thirst is also an effect of fluid loss due to polyuria. Polyuria/ nocturia  - due to the body's attempts to excrete glucose renally , as well as secondary to increased fluid intake. Weight loss- due to loss of calories (in the form of glucose) in the urine.

19. Additional common symptoms include: Dry mouth - due to plasma hyperosmolarity and dehydration from polyuria. Lethargy   - lack of glucose uptake by cells results in reduced ability to meet the body's energy needs . Blurred vision - hyperglycemia can cause an acute, reversible swelling of the lens. This is a different mechanism to that seen in the chronic complication of diabetic retinopathy. Diabetic ketoacidosis (DKA) represents the second most common form of initial presentation of T1DM (30%, increasing to 50% of those under 3 years of age).

20. DIAGNOSIS ▶ Glucose tolerance is classified into three broad categories: normal glucose homeostasis DM impaired glucose homeostasis. ▶ Glucose tolerance can be assessed using the fasting plasma glucose (FPG), the response to oral glucose challenge , or the hemoglobin A1c (HbA1c). ▶ A FPG <5.6 mmol/L (100 mg/dL), a plasma glucose <140 mg/dL (11.1 mmol/L) following an oral glucose challenge, and an HbA1c <5.7% are considered to define normal glucose tolerance.

21. ▶ The International Expert Committee with members appointed by the ADA, the European Association for the Study of Diabetes, and the International Diabetes Federation have issued diagnostic criteria for DM based on the following premises: ▶ (1) the FPG , the response to an oral glucose challenge (oral glucose tolerance test [ OGTT ]), and HbA1c differ among individuals ▶ (2) DM is defined as the level of glycemia at which diabetes-specific complications occur rather than on deviations from a population-based ▶ A random plasma glucose concentration ≥ 11.1 mmol/L (200 mg/dL) accompanied by classic symptoms (polyuria, polyphagia, polydypsia , weight loss) of DM is also sufficient for the Dx of DM

22. Diagnosing T1DM as cause of diabetes mellitus: This is largely a clinical diagnosis based on the history and clinical presentation, therefore further investigations may not be required. Investigations which may be useful if the diagnosis is unclear include: Autoantibodies to islet cells, islet antigens (IA2, IA2-beta), insulin, glutamic acid decarboxylase (GAD), or zinc transporter ZnT8 indicate autoimmune beta cell destruction and suggest T1DM. C-peptide is a byproduct of insulin production, and therefore represents the presence of endogenous insulin.C -peptide will be low or undetectable in patients with T1DM.

23. Management of type 1 DM

24. Management of type 1 DM The goals of therapy for type 1 or type 2 diabetes mellitus (DM) are to: Eliminate symptoms related to hyperglycemia, Reduce or eliminate the long-term microvascular and macrovascular complications of DM ( 3) Allow the patient to achieve as normal a lifestyle as possible. To reach these goals, the physician should identify a target level of glycemic control for each patient , provide the patient with the educational and pharmacologic resources necessary to reach this level, and monitor/treat DM-related complications.

25. Ongoing aspects of comprehensive diabetic care.

26. Goals of treatment

27. These goals are achieved by: lifestyle management in diabetes care Diabetes self-management education and support Nutrition therapy Physical activity Monitoring the level of glycemic control Pharmacological treatment

28. Medical nutritional therapy

29. Monitoring the level of glycemic control: SMBG , a small drop of blood (3–10 μL ) and an enzymatic reaction allow rapid and accurate measurement of the capillary blood glucose by glucose monitors (calibrated to provide plasma glucose value even though blood glucose is measured) Assessment of Long-Term Glycemic Control Measurement of glycated hemoglobin (HbA1c) is the standard method for assessing long-term glycemic control.

30. Pharmacologic therapy (insulin therapy) Offer multiple daily injection basal–bolus insulin regimens, rather than twice-daily mixed insulin regimens, as the insulin injection regimen of choice for all adults with type 1 diabetes. The starting total daily insulin dose is typically weight based, ranging from 0.4 to 1.0 units per kilogram body weight, as recommended by various guidelines

31. Insulin regiments and dosing

32. Diabetic Ketoacidosis

33. ▶ Clinical Features: ▶ The symptoms and physical signs of DKA usually develop over 24 h.

34. Labs in DKA

35. Management of DKA

36. Thanks you for listening Any QUESTIONS?

37. References Harrisons Statmed pubmed