Diabetes mellitus an overview


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  • The classification of diabetes includes four clinical classesType 1 diabetes (results from β-cell destruction, usually leading to absolute insulin deficiency)Type 2 diabetes (results from a progressive insulin secretory defect on the background of insulin resistance)Other specific types of diabetes due to other causes; e.g., genetic defects in β-cell function, genetic defects in insulin action, diseases of the exocrine pancreas (such as cystic fibrosis), and drug- or chemical-induced diabetes (such as in the treatment of HIV/AIDS or after organ transplantation)Gestational diabetes mellitus (GDM; diabetes diagnosed during pregnancy that is not clearly overt diabetes)Some patients cannot be clearly classified as having type 1 or type 2 diabetesClinical presentation and disease progression vary considerably in both types of diabetesOccasionally, patients who otherwise have type 2 diabetes may present with ketoacidosisSimilarly, patients with type 1 diabetes may have a late onset and slow (but relentless) progression despite having features of autoimmune diseaseSuch difficulties in diagnosis may occur in children, adolescents, and adultsThe true diagnosis may become more obvious over time
  • Recommendations for testing for diabetes in asymptomatic patients are summarized on this slide; testing should be considered in adults of any age with BMI ≥25 kg/m2 and one or more of the known risk factors for diabetesFor many illnesses, there is major distinction between screening and diagnostic testing; however, for diabetes, the same tests would be used for “screening” as for diagnosisA1C, fasting plasma glucose (FPG), or 2-hour oral glucose tolerance test (2-h OGTT) are appropriate to test for diabetesThe same assays used for testing for diabetes will also detect individuals with prediabetesIn adults, prediabetes and diabetes meet established criteria for conditions in which early detection is appropriate; both conditions are common, increasing in prevalence, and impose significant health burdensThere is a long presymptomatic phase before the diagnosis of type 2 diabetes is usually made; relatively simple tests are available to detect preclinical diseaseAdditionally, the duration of glycemic burden is a strong predictor of adverse outcomes, and effective interventions exist to prevent progression of prediabetes to diabetes (see Section IV. Prevention/Delay of Type 2 Diabetes) and to reduce risk of complications of diabetes (see Section VI. Prevention and Management of Diabetes Complications)
  • In 1997 and 2003, The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus1,2 recognized an intermediate group of individuals whose glucose levels, although not meeting criteria for diabetes, are nevertheless too high to be considered normalThis group was defined as having impaired fasting glucose (IFG) or impaired glucose tolerance (IGT)IFG: fasting plasma glucose (FPG) of 100–125 mg/dL (5.6–5.9 mmol/L)*IGT: 2-hour plasma glucose (2-h PG) on the 75-g oral glucose tolerance test (OGTT) of 140–199 mg/dL (7.8–11.0 mmol/L)Individuals with IFG and/or IGT have been referred to as having prediabetes, indicating a relatively high risk for future development of diabetesIFG and IGT should not be viewed as clinical entities in their own right but rather risk factors for diabetes as well as cardiovascular disease (CVD)IFG and IGT are associated with obesity (especially abdominal or visceral obesity), dyslipidemia with high triglycerides and/or low HDL cholesterol, and hypertensionIndividuals with an A1C of 5.7–6.4% should be informed of their increased risk for diabetes as well as CVD and counseled about effective strategies to lower their risks (see Section IV. Prevention/Delay of Type 2 Diabetes)*The World Health Organization (WHO) and a number of other diabetes organizations define the cutoff for IFG at 110 mg/dL (6.1 mmol/L)A1CIn 2009, an International Expert Committee that included representatives of the American Diabetes Association (ADA), the International Diabetes Federation (IDF), and the European Association for the Study of Diabetes (EASD) recommended the use of the A1C test to diagnose diabetes, with a threshold of ≥6.5%1, and ADA adopted this criterion in 20102The diagnostic test should be performed using a method certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized or traceable to the Diabetes Control and Complications Trial (DCCT) reference assay3Point-of-care A1C assays, for which proficiency testing is not mandated, are not sufficiently accurate at this time to use for diagnostic purposes3The A1C has several advantages to the FPG and OGTT, including greater convenience (since fasting is not required), evidence to suggest greater preanalytical stability, and less day-to-day perturbations during periods of stress and illnessThese advantages must be balanced by greater cost, the limited availability of A1C testing in certain regions of the developing world, and the incomplete correlation between A1C and average glucose in certain individualsIn addition, HbA1C levels may vary with patients’ race/ethnicity4,5
  • Recommended glycemic goals for nonpregnant adults These recommendations are based on those for A1C values, with listed blood glucose levels that appear to correlate with achievement of an A1C of <7%The issue of preprandial versus postprandial self-monitoring of blood glucose (SMBG) is complex;2 in some epidemiological studies, elevated postchallenge two-hour oral glucose tolerance test (2-h OGTT) glucose values have been associated with increased cardiovascular risk independent of fasting plasma glucose (FPG)In diabetic subjects, some surrogate measures of vascular pathology, such as endothelial dysfunction, are negatively affected by postprandial hyperglycemia3Individualize based on duration of diabetes, age/life expectancy, comorbid conditions, known CVD or advanced macrovascular complications, hypoglycemia unawareness, individual patient concernsNOTE: A1c ≥6.5% are associated with an increased risk of blood vessel damage
  • 2nd generation is more potent than 1st generation1st generation (tolbutamide, chlorpropamide, tolazamide)Glimepiride is most potent,
  • Insulin secretion is glucose dependentUse with sulfonylureas is duplicate therapy
  • Due to risks of MI restrict use of rosiglitazone to those currently using or those whose blood sugar is not controlled with any other meds and prefer not to use actosAvandia is available only through a restricted distribution program – prescriber would call 1800avandia
  • DPP4 enzyme is known to suppress some cancer growth
  • Diabetes mellitus an overview

    2. 2. Objectives of the Lecture  Be able to define diabetes mellitus  Be able to classify diabetes mellitus  Be able to list predisposing factors  Be able to list clinical features of diabetes mellitus  Be able to list drugs used in treatment of diabetes mellitus Diabetes Mellitus: An Overview 229/03/2014
    3. 3. Outline  DM definition  DM epidemiology  Types of DM  Clinical features  Investigations  Treatment  Complications 29/03/2014 3Diabetes Mellitus: An Overview
    4. 4. What is Type 2 Diabetes Mellitus (T2DM)? – Current ADA definition1 • T2DM is a metabolic disease characterized by hyperglycemia, resulting from a combination of resistance to insulin action and an inadequate insulin secretory response – T2DM involves 2 primary pathogenic processes: • progressive decline in pancreatic islet function (↓ insulin secretion and inadequately suppressed glucagon secretion)2,3 • diminished tissue responses to insulin (insulin resistance)2,4 Diabetes Mellitus: An Overview 429/03/2014 ADA=American Diabetes Association 1American Diabetes Association. Diabetes Care. 2006; 29 (Suppl 1): S43–S48; 2Weyer C, et al. J Clin Invest. 1999; 104: 787–794; 3Müller WA, et al. N Engl J Med. 1970; 283: 109–115; 4Ahrén B, Pacini G. Diabetes Obes Metab. 2005; 7: 2–8.
    5. 5. Epidemiology  More than 285 million (2010) people affected worldwide  By 2030, some 566 million people are projected to have diabetes.  3.2% (12.1million) from Africa in 2010  By 2030, 3.7% (23.9 million) from Africa 2010 Diabetes Mellitus: An Overview 529/03/2014
    6. 6. CLASSIFICATION AND DIAGNOSIS Diabetes Mellitus: An Overview 629/03/2014
    7. 7. Classification of Diabetes  Type 1 diabetes  β-cell destruction  Type 2 diabetes  Progressive insulin secretory defect  Other specific types of diabetes  Genetic defects in β-cell function, insulin action  Diseases of the exocrine pancreas  Drug- or chemical-induced  Gestational diabetes mellitus Diabetes Mellitus: An Overview 729/03/2014
    8. 8. TYPE 1 DM  Due to B-cell destruction.  Require insulin for survival.  Presence of certain autoantibodies.  Type 1A – presence of autoantibodies (anti-GAD, IA2, ICAA, and anti-insulin antibodies).  Type 1B – absence of autoantibodies (idiopathic) Diabetes Mellitus: An Overview 829/03/2014
    9. 9. Type 2 DM  Most common form of DM  Characterized by disorder in insulin action and insulin secretion or both.  Specific etiology unknown  Insulin resistance  Progressive B-cell failure.  They are obese. Diabetes Mellitus: An Overview 929/03/2014
    10. 10. Predisposing Factors  Obesity  Hypertension  Strong family history  Sedentary lifestyle  Lack of exercise  Alcoholism  Smoking  Western diet  Advancing age  Diabetogenic drugs  Low birth weight  Artificial or cow milk formulae in neonates  Viruses  Migration Diabetes Mellitus: An Overview 1029/03/2014
    11. 11. Urbanisation/Westernisation Diabetes Mellitus: An Overview 1129/03/2014
    12. 12. Gestational diabetes  Carbohydrate intolerance associated with hyperglycemia of variable severity with the onset or first recognition during pregnancy.  In early pregnancy, fasting and post prandial glucose concentration are normally lower than in non pregnant women Diabetes Mellitus: An Overview 1229/03/2014
    13. 13. Risk of developing GDM  Old women  Previous history of glucose intolerance  History of babies large for gestational age Diabetes Mellitus: An Overview 1329/03/2014
    14. 14. Underlying causes of Type 2 Diabetes Diabetes Mellitus: An Overview 1429/03/2014 Obesity Insulin resistance -cell defect Impaired glucose tolerance Early diabetes Late diabetes Hyperinsulinaemia Decreased insulin secretion -cell failure Saltiel AR. J Clin Invest 2000;106:163–164. ACE/CDR/05/20746/1
    15. 15. Hyperinsulinaemia Hyperglycaemia Plasma insulin Blood glucose Insulin resistance Pancreatic failure Diagnosis of type 2 diabetes Insulin resistance Edelman SV. Type 2 diabetes mellitus. Adv Int Med 1998; 43:449–500. Underlying factors in type 2 diabetes are insulin resistance and -cell dysfunction Diabetes Mellitus: An Overview 1529/03/2014 ACE/CDR/05/20746/1
    16. 16. Diagnostic Criteria
    17. 17. Testing for Diabetes in Asymptomatic Patients  Consider testing overweight/obese adults (BMI ≥25 kg/m2) with one or more additional risk factors  In those without risk factors, begin testing at age 45 years  If tests are normal  Repeat testing at least at 3-year intervals  Use A1C, FPG, or 2-h 75-g OGTT  In those with increased risk for future diabetes  Identify and, if appropriate, treat other CVD risk factors Diabetes Mellitus: An Overview 1729/03/2014
    18. 18. Diagnostic Criteria Fasting Glucose mg/dL 2-h OGTT mg/dL Random Glucose mg/dL A1c Normal <100 <140 <200 <5.7% Prediabetes 100-125 (IFG) 140-199 (IGT) 5.7-6.4% Diabetes ≥ 126 ≥ 200 ≥ 200 ≥ 6.5% Diabetes Mellitus: An Overview 1829/03/2014 Note: In the absence of unequivocal hyperglycemia, result(s) should be confirmed by repeat testing.
    19. 19. DIAGNOSTIC CRITERIA FOR GDM ADA ADA WHO 75g oral glucose (Mg/dL) 100g oral glucose (Mg/dL) 75g oral glucose (Mg/dL) Fasting 95 95 >/= 126 1 hour 180 180 2 hour 155 155 3 hour NA 140 >/= 140 Diabetes Mellitus: An Overview 1929/03/2014
    20. 20. Clinical features  Classical symptoms:  Polyuria  Polydipsia  Polyphagia  Complications :  Acute  Chronic Diabetes Mellitus: An Overview 2029/03/2014
    21. 21. Acute complications  Diabetic ketoacidosis (DKA)  Hyperglyceamic hyperosmolar state(HHS) Diabetes Mellitus: An Overview 2129/03/2014
    22. 22. Eyes (retinopathy, glaucoma, cataracts) Brain and Cerebral Circulation (stroke, TIA) Heart and Coronary Circulation (angina, MI, CHF)Kidneys (nephropathy, ESRD) Peripheral Nervous System (peripheral neuropathy) Peripheral Vascular Tree (peripheral vascular disease, gangrene, amputation) Tissue Damage in Many Organ Systems Leads to Serious Long-term Complications in T2DM Diabetes Mellitus: An Overview 2229/03/2014 CHF=congestive heart failure; ESRD=end-stage renal disease; MI=myocardial infarction; TIA=transient ischemic attack; T2DM=type 2 diabetes mellitus Adapted from International Diabetes Federation. Complications. Available at: www.eatlas.idf.org/complications Accessed February 17, 2009.
    23. 23. Chronic Complications  Affects many organ systems.  Vascular :  Microvascular  Macrovascular  Non vascular:  Gastroparesis  Sexual dysfunction  Skin changes Diabetes Mellitus: An Overview 2329/03/2014
    24. 24. Mechanism of Complications  There are 3 major theories (not mutually exclusive);  Formation of Advanced Glycosylation End Products (AGEs) via the nonenzymatic glycosylation of cellular protein.  Increase glucose metabolism via the sorbitol pathway by enzyme aldose reductase.  Increase formation of diacyglycerol leading to activation of certain isoforms of protein kinase C (PKC). Diabetes Mellitus: An Overview 2429/03/2014
    25. 25. Complications  Ophthalmologic  Renal  Neuropathy  Cardiovascular  Lower extremities  Infections  Dermatologic Diabetes Mellitus: An Overview 2529/03/2014
    26. 26. Laboratory Diagnosis, Monitoring and Evaluation of Diabetes Mellitus
    27. 27. Outline  Purpose of laboratory testing  Confirmation of diagnosis of DM  Assessment of severity and level of DM control  Identification of co-morbidities and complications  Effect of treatment  Self urine and blood glucose monitoring  Laboratory monitoring 29/03/2014 27Diabetes Mellitus: An Overview
    28. 28. Confirmation of diagnosis  FPG and 2hrPP  Urinalysis  HBA1c  Serum lipids  Serum electrolytes  Imaging studies 29/03/2014 28Diabetes Mellitus: An Overview
    29. 29. Management
    30. 30. Aims of treatment  Reduce the symptoms of hyperglycaemia  Limit adverse effects of treatment  Maintain quality of life and psychological well- being  Prevent or delay vascular complications of diabetes Diabetes Mellitus: An Overview 3029/03/2014
    31. 31. Basis of Treatment  Reducing insulin resistance  Replacing or augmenting insulin secretion  Reducing gluconeogenesis  Treating effects of lipolysis and reducing lipolysis Diabetes Mellitus: An Overview 3129/03/2014
    32. 32. GOALS OF MANAGEMENT Diabetes Mellitus: An Overview 3229/03/2014
    33. 33. Glycemic Recommendations Diabetes Mellitus: An Overview 3329/03/2014 *Individualize goals based on these values. †Postprandial glucose measurements should be made 1–2 h after the beginning of the meal, generally peak levels in patients with diabetes Target Treatment Goal AACE/ACE 2011 ADA 2012 A1c ≤6.5% <7% Fasting Glucose FPG <110 mg/dl Preprandial PG 70- 130mg/dl Postprandial Glucose 2-hr postprandial <140mg/dl Peak <180mg/dl
    34. 34. Blood Pressure and Lipid Goals Blood pressure <130/80 mmHg† Lipids LDL cholesterol <100 mg/dL (<2.6 mmol/L)‡ Diabetes Mellitus: An Overview 3429/03/2014 †Based on patient characteristics and response to therapy, higher or lower systolic blood pressure targets may be appropriate. ‡In individuals with overt CVD, a lower LDL cholesterol goal of <70 mg/dL (1.8 mmol/L), using a high dose of statin, is an option.
    35. 35. Approach to Patient with DM History Physical examination Laboratory assessment. Diabetes Mellitus: An Overview 3529/03/2014
    36. 36. Management contd  Requires a multidisciplinary team:  Primary care provider  Endocrinologist/Diabetologist  Certified diabetic educator  Nutritionist Diabetes Mellitus: An Overview 3629/03/2014
    37. 37. Management contd  When complication arises, the team will include; Neurologist Nephrologists Cardiologist Vascular surgeon Ophthalmologist podiatrist Diabetes Mellitus: An Overview 3729/03/2014
    38. 38. Treatment Non pharmacologic Pharmacologic Surgical. Diabetes Mellitus: An Overview 3829/03/2014
    39. 39. Non pharmacologic treatment  Education of patients:  Individualized or group based  Done by various health professionals  Repetitive, interactive  Address causes, course, treatment  Define target for DM control 29/03/2014 Diabetes Mellitus: An Overview 39
    40. 40.  Lifestyle Modification: Quit smoking Quit drinking alcohol Regular exercise Healthy diet Weight reduction 29/03/2014 Diabetes Mellitus: An Overview 40 Non Pharmacologic Treatment
    41. 41. Dietary Management of DM  Individualized, simple instructions  Aim to achieve ideal body weight and encourage healthy eating habits and lifestyle modification  Calculate activity level and caloric requirements to achieve above  Diet should be able to reduce hyperglycaemia, glucotoxicity and lipotoxicity Diabetes Mellitus: An Overview 4129/03/2014
    42. 42. The Ideal or Paleolithic Diet  50 -65% carbohydrate, complex carbohydrates derived mainly from whole grains and legumes, low glycaemic index  0.6g/kg body weight proteins (15-20%) derived from game animals or fish, insects  15 -25% fat derived from vegetable and nut oils.  High fiber 25 – 30g daily Diabetes Mellitus: An Overview 4229/03/2014
    43. 43. EXERCISE IN DIABETES  Dynamic or isotonic  Graduated & individualised  Regular with adequate warm up  Appropriate footcare  Precautions in OHA or insulin dose  Contraindicated in some conditions 29/03/2014 43Diabetes Mellitus: An Overview
    44. 44. Exercise Therapy  Benefits  Increase insulin sensitivity  Improved long term glycaemic control – lower HbA1c  Improved circulating lipid profile  Improved BP control  May promote redistribution of body fat ( reduce CVD risk)  Health benefits – 3 days wkly 29/03/2014 44Diabetes Mellitus: An Overview
    45. 45.  Individualized regimen  State of control  Stretching & warm-up  Aerobic level sustainable for 30mins  Cool down  Full evaluation before prescribing exercise  Complications/risks  Precautions for patient 29/03/2014 45Diabetes Mellitus: An Overview
    46. 46. Pharmacotherapy  Oral glucose lowering agents.  Injectables: Insulin Insulin analogues Incretin mimetic agents.  Newer agents. Diabetes Mellitus: An Overview 4629/03/2014
    47. 47. Injectables Insulin Insulin analogues Exenatide Liraglutide Diabetes Mellitus: An Overview 4729/03/2014
    48. 48. Indications for Use of Insulin  All type 1DM patients  High risk type 2 DM patients  All pregnant diabetics not controlled with diet  All acutely or chronically ill persons with DM  All patients preparing for or just having surgery  All diabetics who have trauma, leg ulcers, gangrene, moderately severe nephropathy, myocardial infarction.  Any person who desires strict control Diabetes Mellitus: An Overview 4829/03/2014
    49. 49. INSULIN DOSAGE  0.6-1.0 units/kg body weight (ideal body weight)  Divide this dose into tds if soluble insulin OR into bd if 70/30 insulin (humulin) used  Additional 0.3 units/kg body weight added if infection, sepsis or DKA present  Insulin to be given 30 minutes premeals if 30:70 or soluble insulin and 30-45 min premeal if Isophane or Lente (Humulin N) insulin  Do not add insulin to N/Saline infusion  Do not give Humulin 30:70 or Isophane (Humulin N)insulin I.V  Adjust insulin dose with blood sugar Diabetes Mellitus: An Overview 4929/03/2014
    50. 50. Targets for Control  Absence of symptoms, well being  Ideal body weight, BMI 20-23, maximum waist 88cm in females and 94 in males  Blood pressure 130/80mmHg  FBS 70 -90mg/dL  2hpp 70 – 140mg/dL  HbA1c 6 – 7%  Total cholesterol <5mmol(200mg)  No proteinuria Diabetes Mellitus: An Overview 5029/03/2014
    51. 51. Non-Insulin Hypoglycemic Agents Oral Biguanides Sulfonylureas Meglitinides Thiazolidinediones Alpha Glucosidase inhibitors Incretin Enhancers (DPP-IV inhibitors) Resin binder Parenteral  Amylin analogs  Incretin mimetics Diabetes Mellitus: An Overview29/03/201451
    52. 52. Pharmacology - Biguanides Class Biguanides Compound Metformin Mechanism Activates AMP-kinase Action(s) • Hepatic glucose production • Intestinal glucose absorption • Insulin action Glucose Lowering Effect • Fasting • Post Prandial Advantages • No weight gain • No hypoglycemia • Reduction in cardiovascular events and mortality (UKPDS f/u) Disadvantages • Gastrointestinal side effects (diarrhea, abdominal cramping) • Lactic acidosis (rare) • Vitamin B12 deficiency • Contraindications: reduced kidney function Cost Low Diabetes Mellitus: An Overview29/03/201452
    53. 53. Pharmacology - SulfonylureasClass Sulfonylureas (2nd generation) Compound • Glibenclamide/Glyburide • Glipizide • Gliclazide • Glimepiride (3rd generation) Mechanism Closes KATP channels on β-cell plasma membranes Action(s) Insulin secretion Advantages • Generally well tolerated • Reduction in cardiovascular events and mortality (UKPDS f/u) Disadvantages • Relatively glucose-independent stimulation of insulin secretion: Hypoglycemia, including episodes necessitating hospital admission and causing death • Weight gain • Primary and secondary failure Cost Low Diabetes Mellitus: An Overview29/03/201453
    54. 54. Pharmacology – Meglitinides Class Meglitinides Compound • Repaglinide (Prandin®) • Nateglinide (Starlix®) Mechanism Closes KATP channels on β-cell plasma membranes Action(s) Insulin secretion Advantages Accentuated effects around meal ingestion Disadvantages • Hypoglycemia, weight gain • Dosing frequency Cost Medium Diabetes Mellitus: An Overview29/03/201454
    55. 55. Pharmacology – Thiazolidinediones (TZD) Class Thiazolidinediones (Glitazones) Compound Pioglitazone (Actos®) Mechanism Activates the nuclear transcription factor PPAR- Action(s) Peripheral insulin sensitivity Advantages • No hypoglycemia • HDL cholesterol • Triglycerides Disadvantages • Weight gain • Edema • Heart failure (CI with stage III and IV) • Bone fractures Cost High Diabetes Mellitus: An Overview29/03/201455
    56. 56. Pharmacology – Thiazolidinediones (TZD) Class Thiazolidinediones (Glitazones) Compound Rosiglitazone (Avandia®) Mechanism Activates the nuclear transcription factor PPAR- Action(s) Peripheral insulin sensitivity Advantages No hypoglycemia Disadvantages • LDL cholesterol • Weight gain • Edema • Heart failure (CI with stages III and IV) • Bone fractures • Increased cardiovascular events (mixed evidence) • FDA warnings on cardiovascular safety Cost High Diabetes Mellitus: An Overview29/03/201456
    57. 57. TZDs and the FDA  Rosiglitazone  Restricted by FDA – can only be used by patients currently benefiting from therapy or do not get adequate DM treatment from other agents and not willing to use pioglitazone  1-800-AVANDIA  Pioglitazone  FDA alert – ongoing analysis of risk of bladder cancer (with prolonged use >12 months) Diabetes Mellitus: An Overview29/03/201457
    58. 58. Pharmacology – Alpha-Glucosidase Inhibitors Class α-Glucosidase inhibitors Compound • Acarbose • Miglitol Mechanism Inhibits intestinal α-glucosidase Action(s) Intestinal carbohydrate digestion and absorption slowed Advantages • Nonsystemic medication • Postprandial glucose Disadvantages • Gastrointestinal side effects (gas, flatulence, diarrhea) • Dosing frequency Cost Medium Diabetes Mellitus: An Overview29/03/201458
    59. 59. Pharmacology – Incretin Enhancers Class DPP-4 inhibitors (incretin enhancers) Compound • Sitagliptin (Januvia®) • Vildagliptin (Galvus®) • Saxagliptin (Onglza®) • Linagliptin (Tradjenta®) Mechanism Inhibits DPP-4 activity, prolongs survival of endogenously released incretin hormones Action(s) • Active GLP-1 concentration • Insulin secretion • Glucagon secretion Advantages • No hypoglycemia • Weight “neutrality” Disadvantages • Occasional reports of urticaria/angioedema • Cases of pancreatitis observed • Long-term safety unknown (cancer ?) Cost High Diabetes Mellitus: An Overview29/03/201459
    60. 60. SGLT-2 Inhibitors  Sodium glucose cotransport 2 inhibitors  These are drugs which inhibit the reabsorption of glucose in the distal tubules of the kidney  Idea for using these drugs emanated from people with the rare familial glycosuria patients  Dapagliforzin, Canagliforzin are the first 2 in this group  Cause weight loss and reduce weight by glycosuria  Dapagliforzin failed FDA approval early last year  Canagliflorzin (Invokana) was approved by FDA in March 2013  Side effects are nasal stuffiness and mild increase in UTI 29/03/2014 Diabetes Mellitus: An Overview60
    61. 61. Pharmacology – Incretin Mimetics Class GLP-1 receptor agonists (incretin mimetics) Compound • Exenatide (Byetta®) • Liraglutide (Victoza®) Mechanism Activates GLP-1 receptors (β-cells/endocrine pancreas; brain/autonomous nervous system Action(s) • Insulin secretion (glucose-dependent) • Glucagon secretion (glucose-dependent) • Slows gastric emptying • Satiety Advantages • Weight reduction • Potential for improved β-cell mass/function Disadvantages • Gastrointestinal side effects (nausea, vomiting, diarrhea) • Cases of acute pancreatitis observed • C-cell hyperplasia/medullary thyroid tumors in animals (liraglutide) • Injectable • Long-term safety unknown Cost High Diabetes Mellitus: An Overview29/03/201462
    62. 62. Pharmacology – Amylin Analog Class Antihyperglycemic Synthetic Analog Compound • Pramlintide (Symilin®) Mechanism • Amylinomimetic Action(s) • Glucagon secretion (glucose-dependent) • Slows gastric emptying • Satiety Advantages • Potential weight loss Disadvantages • Meal time injections • Nausea • Hypoglycemia in combination with insulin Cost High Diabetes Mellitus: An Overview Lexi-Drugs Online [Internet]. Hudson (OH) : Lexi-Comp, Inc. 1978-2012[cited 2012 August 1]. 29/03/201463
    63. 63. Pharmacology – Bile Acid Sequestrants Class Bile acid sequestrants Compound Colesevelam (Welchol®) Mechanism Binds bile acids/cholesterol Action(s) Bile acids stimulate receptor on liver to produce glucose Results • Lowers fasting and post prandial glucose Advantages • No hypoglycemia • LDL cholesterol Disadvantages • Constipation • Triglycerides • May interfere with absorption of other medications Cost High Diabetes Mellitus: An Overview29/03/201464
    64. 64. Diabetic Complications
    65. 65. Outline  Acute complications of DM  - Hypoglycaemic emergencies  - Hyperglycaemic emergencies  Chronic complications of DM  - Vascular  - Neuropathic  - Mixed Diabetes Mellitus: An Overview 6629/03/2014
    66. 66. DIABETIC KETOACIDOSIS  Definition  Epidemiology  Aetiopathogenesis/Pathophysiology  Clinical features  Investigations  Treatment  Prognosis Diabetes Mellitus: An Overview 6729/03/2014
    67. 67. Definition  An acute metabolic complication of DM  Hyperglycaemia (>300mg/dL)  Acidosis , blood pH <7.3  Increased total blood ketones, > 5 mmol/L  In clinical practice it is suspected when there is ketonuria++ in the face of hyperglycaemia Diabetes Mellitus: An Overview 6829/03/2014
    68. 68. Epidemiology of DKA  Few published Nigerian data  Europeans and Americans quote 10 – 30 cases per 100, 000 population.  Commoner in females  Commoner in non-whites  Mortality higher in the elderly Diabetes Mellitus: An Overview 6929/03/2014
    69. 69. Aetiopathogenesis/Pathophysiology  Insulin deficiency and glucagon excess leads to excess acetyl-CoA  Acetyl CoA is converted to acetoacetate  Some acetoacetate is converted to other ketones  These ketones require to be buffered and thus bicarbonate is used up as pH drops  The respiratory centre is stimulated and Kussmaul’s breathing occurs Diabetes Mellitus: An Overview 7029/03/2014
    70. 70. Aetiopathogenesis/Pathophysiology  Urine becomes acidic, osmotic diuresis occurs  H and Na and K are lost in the urine together with ketones  FFAs are increased due to lipolysis from stimulation of lipoprotein lipase  A major role for initiating all the events is elevation of counter-regulatory hormones Diabetes Mellitus: An Overview 7129/03/2014
    71. 71. Diabetes Mellitus: An Overview 7229/03/2014
    72. 72. Clinical Features  Risk factors of infection, trauma, omission of medication  Malaise  Weight loss  Polyuria, polydipsia,  Nausea, vomiting, abdominal distension  Confusion, lethargy  Hypotension, arhythmias  Severe dehydration  Acetone breath  Glycosuria and ketonuria Diabetes Mellitus: An Overview 7329/03/2014
    73. 73. Clinical Features contd  Deep coma and or seizures may occur  Acute abdomen may be present and confused with surgical abdomen  Fluid loss is in range of 6 – 8 litres in adults Diabetes Mellitus: An Overview 7429/03/2014
    74. 74. Role of Insulin Diabetes Mellitus: An Overview 7529/03/2014
    75. 75. Investigations  Urinalysis  Ketostix  Electrolytes and urea  Haemogram incl WBC  Blood pH and ketones  ECG,  Urine and blood culture  Blood sugars Diabetes Mellitus: An Overview 7629/03/2014
    76. 76. Treatment  Admit to emergency or ICU, NPO, resuscitate  Intravenous saline 6 – 8 litres in 24 hours in adults  Saline given 1 litre fast, then 1 litre in an hour, then 1 litre in 2hrs, then 1 litre 4 hourly  Soluble insulin 10 units IM or IV stat, then give 6 units hourly till RBS <250mg/dL  Sugars should drop at 50-70mg/dL per hour  If not dropping double the dose of insulin Diabetes Mellitus: An Overview 7729/03/2014
    77. 77. Treatment (contd)  When RBS <250mg/dL change the IV fluids to 5% dextrose to run 1 pint 4 hourly and add KCl 20 – 40mmol per pint with soluble insulin 4-6 units per pint  When patient fully conscious and rehydrated then change insulin to s/c t.d.s pre-meals at dose of 0.2 – 0.3 units/kg body weight and allow patient eat Diabetes Mellitus: An Overview 7829/03/2014
    78. 78. Treatment 4  Antibiotics may be indicated if sepsis present but it should be remembered that leucocytosis is a regular feature of DKA  NG tube may be required if there is gastric dilatation  Dysequillibrium syndrome is a complication of excessive rapid lowering of blood sugar Diabetes Mellitus: An Overview 7929/03/2014
    79. 79. Prognosis  This is good if treatment commenced early and adequate monitoring of sugars, electrolytes and fluid balance is done. Diabetes Mellitus: An Overview 8029/03/2014
    80. 80. HYPEROSMOLAR HYPERGLYCAEMIC STATE (HHS)  Definition  Epidemiology  Aetiopathogenesis/Pathophysiology  Clinical Features  Investigations  Treatment  Prognosis Diabetes Mellitus: An Overview 8129/03/2014
    81. 81. Definition of HHS  Similar to DKA but:  Blood sugars in range of 600 – 2000mg/dL  No ketonuria or trace ketones  No anion gap or mild anion gap <10  Often have azotaemia, increased Na, K  Normal blood pH Diabetes Mellitus: An Overview 8229/03/2014
    82. 82. Epidemiology  HHS is not as common as DKA  Commoner in elderly patients who are often institutionalised or with cognitive impairment  Males slightly more commonly affected  Seen in type 2 DM  Rare in type 1 DM Diabetes Mellitus: An Overview 8329/03/2014
    83. 83. Aetiopathogenesis  Patient is fairly insulin sensitive  There is still some circulating insulin sufficient to suppress ketosis but insufficient to suppress gluconeogenesis  Renal impairment couple with dehydration from reduced fluid intake over a period  Often patient on diuretic  Hyperosmolarity ensues with thrombogenicity Diabetes Mellitus: An Overview 8429/03/2014
    84. 84. Clinical features  Polyuria, polydipsia and then oliguria  Confusion or coma  Severe dehydration  No Kussmaul’s respiration  DVT or PE is common Diabetes Mellitus: An Overview 8529/03/2014
    85. 85. Clinical Features  Severe dehydration, fluid deficit 8 – 10 litres  Altered sensorium, seizures, etc  Thromboembolic events eg DVT, PE, CVA, , MI, etc  Vomiting and gastroparesis  Gastric erosions and haematemesis common Diabetes Mellitus: An Overview 8629/03/2014
    86. 86. Investigations  E/U/C  Urinalysis  Blood sugars  Sepsis workup  Plasma osmolarity, plasma pH  ECG, CXR, D-dimer tests Diabetes Mellitus: An Overview 8729/03/2014
    87. 87. Treatment  Very similar to DKA treatment  Admit, NPO  Rehydrate with 6 – 10 litres of fluid preferably half normal saline  Hourly soluble insulin 4-6 units after a stat 10units IV  Use heparin or enoxaparin to anticoagulate  Watch out for fluid overload if CKD present Diabetes Mellitus: An Overview 8829/03/2014
    88. 88. Prognosis  Poorer than DKA, mortality being 50 – 90% in most centres  Mortality may follow cerebral oedema, embolic events or uraemia Diabetes Mellitus: An Overview 8929/03/2014
    89. 89. Hypoglycaemia  Defined as low blood sugar  Blood sugars below 2.2mmol/L taken as hypoglycaemia in general population  In DM patients the threshold for hypoglycaemia is lower so coma may occur in blood sugars 50 – 80mg/dL and in those with rapid decline in blood sugars Diabetes Mellitus: An Overview 9029/03/2014
    90. 90. Definition  Thus Whipple’s triad often used to identify and confirm hypoglycaemia in DM patient  Triad is made up of  - hypoglycaemic symptoms  - biochemically proven low blood sugar  - relief of symptoms after administration of sugar or carbohydrate containing drink/meal Diabetes Mellitus: An Overview 9129/03/2014
    91. 91. Aetiopathogenesis of Hypoglycaemia  Excess insulin whether from injections or secretagogue  Inadequate calorie intake  Inadequate counter-regulatory response  Continued insulin secretion or insulin action Diabetes Mellitus: An Overview 9229/03/2014
    92. 92. Risk factors for Hypoglycaemia  Skipping or postponing meals  Overdose of hypoglycaemic agents  Poor monitoring of blood sugars  Age – extremes of age, the very young and the elderly  Alcohol and other substances that potentiate hypoglycaemic drugs Diabetes Mellitus: An Overview 9329/03/2014
    93. 93. Clinical features  Adrenergic symptoms: eg palpitations, tremors, sweating  Neuroglycopenic symptoms: dizziness, headache, coma, seizures, confusion, etc  Glucagon related symptoms : nausea, vomiting, borboygmi Diabetes Mellitus: An Overview 9429/03/2014
    94. 94. Investigations  Blood sugars  Insulin assays  C-peptide  Liver, renal function tests Diabetes Mellitus: An Overview 9529/03/2014
    95. 95. Treatment  Resuscitate with glucose containing soft drink, sugar or glucose at home if conscious  Admit to hospital if unconscious or if first aid with sugar at home not working  Resuscitate and give IV 10% glucose or diluted 50% glucose via wide bore access  Give IM glucagon 1mg if available  Continue to monitor blood sugars, omit insulin or OHAs patient was taking Diabetes Mellitus: An Overview 9629/03/2014
    96. 96. Treatment contd  When conscious and alert encourage to eat  If delay in regaining consciousness KIV stroke, MI, uraemia or other co-morbidities  Thus CT scan, ECG, E/U/C may be required  Prevent recurrence by drug dose adjustment and patient education Diabetes Mellitus: An Overview 9729/03/2014
    97. 97. Conclusion  Early detection and recognition of metabolic complications is vital for full recovery  Self glucose monitoring will prevent these conditions Diabetes Mellitus: An Overview 9829/03/2014
    98. 98. QUESTIONS Diabetes Mellitus: An Overview29/03/201499