Diabetes handout 2024 .pdf

Classification, Pathogenesis and Diagnosis of Diabetes Mellitus Prof. Dr. Fathy El-Sewy Intended learning outcomes ILO’s: By the end of this lecture students will be able to: 1-Define hyperglycemia in clinical practice 2- Discuss clinical approach to a case of hype...

Classification, Pathogenesis and Diagnosis of Diabetes Mellitus Prof. Dr. Fathy El-Sewy Intended learning outcomes ILO’s: By the end of this lecture students will be able to: 1-Define hyperglycemia in clinical practice 2- Discuss clinical approach to a case of hyperglycemia 3-Classify DM and identify common categories;type 1,type 2, secondary diabetes, and GDM. 4- Discuss the state of IGT and its clinical importance. 5-Describe pathogenesis, diagnosis of different types of DM.. 6-Differentiate between type1, and type2 DM. What is Glucose? 1.The only source of energy for every organism in the body 2. Essential to fuel both aerobic and anaerobic cellular respiration. 3. Often enters the body as galactose and fructose (monosaccharides), lactose and sucrose (disaccharides), or starch (polysaccharide). 4. Once glucose is in the body, it is used by energy-requiring tissues. 5. Our body stores excess glucose as glycogen, which becomes liberated in times of fasting. 6. It is also derivable from products of fat and protein break-down through the process of gluconeogenesis. 7. Insulin and glucagon play pivotal role in its metabolism Diabetes mellitus It is a group of chronic metabolic disorders of carbohydrate metabolism in which glucose is both underutilized as an energy source and overproduced due to inappropriate gluconeogenesis and glycogenolysis, resulting in hyperglycemia. It results from defects of insulin secretion, insulin action or both. It is often accompanied by specific microvascular (retina, renal, peripheral nerves), and non-specific macrovascular (coronary, cerebral, peripheral blood vessels) complications. Epidemiology:  It is a major public health problem worldwide due to: - Increased number of persons affected (Epidemic). - The associated morbidity and mortality.  Prevalence rate in Egypt: 9.5% in the age group 20-79 years.  Incidence (new cases per year) of type 1 diabetes is very low, but for type 2 is very high.  The ratio between type 1 to type 2 diabetes is 1: 9.  Females affected more than males by type 2 diabetes. Classification of DM: Types of diabetes mellitus are: 1- Primary Diabetes Mellitus: Type 1 diabetes (due to autoimmune β-cell destruction, leading to absolute insulin deficiency, including LADA) Type 2 diabetes (due to a non-autoimmune progressive loss of adequate β-cell insulin secretion, frequently classified into: - Predominantly insulin resistance (80%,obese) - Predominantly insulin secretory defect (20%,non obese). Gestational Diabetes Mellitus (GDM). 2-Secondary Diabetes: - Pancreatic diseases: Pancreatitis, pancreatectomy, neoplasia, and hemochromatosis. - Endocrinopathies; acromegaly, Cushing's syndrome, pheochromocytoma and hyperthyroidism. - Drugs or chemicals induced: corticosteroid, thiazide diuretics, thyroid hormone, B-adrenergic agonists. Pathogenesis of diabetes mellitus:  Type 1 Diabetes  Type 1 diabetes is caused by destruction of the insulin producing cells.  A strong genetic component is involved but extragenetic factors also contribute.  Genetic Immunologic Environmental (e.g. Viral) Natural history of type 1 diabetes comprised 6 stages: Stage I: Genetic susceptibility: One diabetogenic gene within the HLA is necessary. 95% of patients are HLA-DR3 and or DR4 positive. Stage II: Triggering by environmental factors: Congenital rubella is the only proved environmental factor. Other suggested viruses include; mumps, coxsackie-B, reovirus and herpes. Chemicals and toxins. Stage III: Immune activation:  Autoimmune insulitis and destruction.  Autoantibodies: ICS , GAD and insulin antibodies. Stage IV: Progressive loss of glucose stimulated insulin secretion Stage V: Overt diabetes:  Progressive loss of beta cell function of islets of Langerhans.  When more than 90% of these cells have destroyed  frank diabetes. Stage VI: Endless beta cell failure:  Plasma insulin and c-peptide levels are absent or very low.  Type 2 Diabetes Type 2 diabetes is caused by a combination of decreased insulin action and inadequate insulin secretion. The two main risk factors are:  Genetic susceptibility: which is likely multigenic.   Environmental factors: - Obesity. - Sedentary life style. - Physical inactivity. - Hypertension. - Dyslipidemia. - Increased age - Smoking. - Stress. These factors lead to two pathogenic defects: 1- Pancreatic defect:  insulin secretion 2- Target tissues defect:  insulin action (insulin resistance). The contribution of these defects and which one precedes the other is still controversial * The  insulin action in the:  Liver:  hepatic glucose production (HGP): the major contributor of fasting hyperglycemia.  Adipose tissue:  lipolysis leads to  circulating free fatty acids (FFAs)  Muscle:  glucose uptake. Two deleterious changes occur: Glucotoxicity: high BG levels further impair  cell function. Lipotoxicity: high circulating FFAs impair  cell function and insulin action * If the insulin resistance is the primary defect, the pancreatic beta cells secrete more insulin to compensate for the peripheral defects of insulin action (hyperinsulinemia).  this occurs, till the  cells can no longer secrete more insulin   insulin secretion (stage of hyperglycemia)  Insulin deficiency Decreased anabolism Increased catabolism Glucose utilization Breakdown of: - glycogen - lipids - proteins Gluconeogenesis Hyperglycemia Glycosuria Osmotic diuresis Polyuria Polydipsia Clinical picture of Diabetes Mellitus Hyperglycemia 1- What is Hyperglycemia? 2- What are the clinical types of hyperglycemia 3- What are the causes of Hyperglycemia? 4- What are the symptoms of hyperglycemia? 5- Clinical approach of a case of hyperglycemia? Definition: Hyperglycemia is elevated blood glucose levels above the normal values Or, is a condition in which an excessive amount of glucose circulates in the blood plasma. Clinical types of hyperglycemia : Hyperglycemia may be: 1- Symptomatic Or 2- Asymptomatic. Symptomatic Hyperglycemia When the blood glucose level reaches above the renal threshold of the individual which is in average 180 mg/dl, it causes symptoms of (increased Urination (polyuria) and thirst(polydipsia). The commonest cause is DM especially Type1. Causes of Symptomatic Hyperglycemia 1- Primary Diabetes mellitus a- Acute, classic, and severe presentation: Type1 b- Aclassic,or subacute presentation: Type 2 2- Secondary diabetes mellitus: a- Endocrinopathies. b- Pancreatic diseases c- Drugs like corticosteroids, and thiazide diuretics. Clinical presentation of Symptomatic Hyperglycemia 1- Acute, Classic, and severe: - Polyuria: ↑ urine output > 2.5 liters/day due to osmotic diuresis. - Polydipsia: due to cellular dehydration. - Polyphagia: due to cellular starvation. - Weight loss: loss of fluids, and increase catabolism. 2- Subacute: older, several months - Thirst, weight loss and polyuria. - Lack of energy. - Blurring of vision. - Balanitis or pruritus vulvae. Signs of Symptomatic Hyperglycemia In Acute, Classic, and severe:Type 1 diabetes: - No clinical signs related. -In fulminant cases: signs of severe dehydration and acidosis (DKA). Asymptomatic Hyperglycemia A large number of individuals currently diagnosed as having DM (type 2), IGT, and GDM are asymptomatic. Causes of Asymptomatic Hyperglycemia 1- Primary Diabetes mellitus: mostly Type 2 a- Accidently discovered e.g. Glycosuria, Routine BG measurement. b- Presented by chronic complications(10-20% of cases): Macrosomic baby, PN. and premature atherosclerosis. 2- Prediabetes (IFG, and IGT) 3- GDM. Signs of Asymptomatic Hyperglycemia In type2 DM, this depend s on the mode of presentation: 1- Pruritus vulvae or balanitis is common. 2- Loss of ankle reflexes. 3- Loss of Peripheral sensation. 4- Hypertension and signs of atherosclerosis (weak pulsation of dorsalis pedis artery, bruit over the carotid). 5- Signs of insulin resistance e.g. Acanthosis Nigricans or Polycystic ovary syndrome.  Diagnosis of DM 1- Diabetes Mellitus is a very common disease 2- One third of cases are undiagnosed 3- 10-20% of cases of type 2 diabetes have serious vascular disease at presentation. Laboratory workup of Hyperglycemia Diabetes can be diagnosed by demonstrating increased concentrations of glucose in venous plasma or increased A1C in the blood. Urine testing: Glycosuria 1- It means +ve urine for glucose. 2- It requires urgent blood glucose measurements: 3- It is not used as a diagnostic tool of diabetes. Renal threshold for glucose is about 180 mg/dl and shows individual variations. Glucose testing in venous plasma Advantages: 1- these assays are inexpensive 2- widely available. Disadvantages include: 1- the high diurnal variation in glucose and fasting requirement. 2- Individuals may have difficulty fasting for the full 8-h period or may misreport their fasting status. 3- Its level is affected by recent physical activity, illness, or acute stress 4- Glycolysis is also an important and underrecognized concern with glucose testing. Glucose concentrations will be falsely low if samples are not processed promptly or stored properly prior to analysis Laboratory workup Blood glucose measurements: using venous plasma The following 3 blood tests are used for diagnosis: 1-Random plasma glucose: sample taken any time of day. 2-Fasting plasma glucose (FPG): a- No caloric intake for at least 8 hours up to 12 hours. b- Overnight fasting. 3-2 hours post oral glucose load (75gm oral glucose) plasma glucose (2h-PPPG): blood sample taken 2 hours after a person has consumed a 75 gms oral glucose powder dissolved in 250 ml water. Interpretation A- Diagnostic criteria of DM: a- Classical symptoms of hyperglycemia + any one of three positive tests: 1- Random plasma glucose:  200 mg/dl. Or 2- Fasting plasma glucose:  126 mg/dl. Or 3- 2h-PPPG:  200 mg/dl b- In the absence of unequivocal hyperglycemia, diagnosis requires two abnormal test results obtained at the same time or at two different time points.This may be either to repeat the initial test or a different test, which should be performed promptly B- Prediabetes: include individuals who have: 1- FPG: 100-125mg/dl (called impaired fasting glucose) And/or 2- 2h-PPPG: 140-199 mg/dl (called impaired glucose tolerance). C- Normoglycemia: include individuals who have: 1. FPG: < 100 mg/dl 2. 2h-PPPG: < 140 mg/dl Use of A1C for Diagnosis of Diabetes A1C reflects glucose bound to hemoglobin over the life span of the erythrocyte (∼120 days). Advantages: 1-Greater convenience (fasting not required) 2- Fewer day-to-day variations during stress, changes in nutrition, or illness Disadvantages include: 1- The A1C test should be performed using a well standarized method 2- Lower sensitivity of A1C compared with that of glucose tests 3- Greater cost and limited access 4- Limited to use for GDM diagnosis and sudden onset and early discovery of type1 diabetes 5- A1C may not be a suitable diagnostic test in people with anemia, people treated with erythropoietin, or people undergoing hemodialysis or HIV treatment 7- Some hemoglobin variants can interfere with A1C like sickle cell trait. Facts for using A1C in diabetes diagnosis A1C ≥ 6.5%:Diabetes diagnosis A1C ≥ 5.7%: prediabetes diagnosis. The use of A1C alone for diabetes diagnosis is not accurate because it has several limitations In cases of discripancies between A1C and glycemia plasma glucose criteria should be used to diagnose diabetes A1C commonly used to: 1- Determine the chronicity of hyperglycemia 2- Follow up for long term control of DM Categories of glucose intolerance I-Diabetes mellitus (Type 1, Type 2 & GDM). II-Prediabetes (IFG and IGT). I- Diabetes mellitus A) Type 1 diabetes: 1- Autoimmune: a- Rapidly progressive young. b- Slowly progressive LADA (Late onset Autoimmune Diabetes in the Adulthood). 2- Idiopathic non immune mediated. Features of rapidly progressive type I autoimmune diabetes a- Clinical markers: - Young < 30 years. - Classical, acute and severe presentation. - Never obese. - Ketosis prone(up to 30% of cases presented by DKA). - Insulin requiring for survival. b- Laboratory markers: - Plasma insulin and c-peptide levels are absent or very low. - GAD-Abs, ICA, insulin autoantibodies. - HLA- DR3, and or DR4 associated. Type 2 diabetes - Obese (80%): predominantly insulin resistant. - Non obese (20%): predominantly insulin secretory defect. - MODY: Maturity Onset Diabetes in the Young. Comparative clinical features of type 1 and type 2 diabetes Type 1 DM Type 2 DM 1. Age of onset < 30 years > 30 years. 2. Duration of S & S days-weeks months-years 3. Body wt never obese Obese 4. Ketonuria Yes No 5. Rapid progression Yes No 6. FH of DM No Yes 7. Insulin or c-peptide levels. absent, very low normal or high 8. HLA associated Yes No 9. Autoantibodies Yes No 10. Diabetic complication at diagnosis No 10-20% II- Prediabetes A metabolic stage intermediate between normal glucose homeostasis and diabetes. This stage includes individuals who have: 1- Impaired fasting glucose (IFG): when FPG: 100-125 mg/dl. 2- Impaired glucose tolerance (IGT): when 2h-PPPG: 140-199 mg/dl. 3- Also called, borderline, subclinical or early diabetes. IFG and IGT are not clinical entities but are risk factors for:  1- Cardiovascular /cerebrovascular diseases 2- A predictor for subsequent diabetes mellitus 3- Diabetic range glucose values unmasked with stress Glycosuria It means presence of glucose in urine I- Glycosuria with high blood glucose: Diabetes mellitus II- Glycosuria with normal or low blood glucose (Renal glycosuria): 1- Pregnancy: The commonest cause. It is due to lower renal threshold for glucose excretion. 2- Tubular dysfunction 3- Renal glycosuria (benign type): Rare inherited disorder, Asymptomatic, and normal kidney functions. 4- False positive test: Lactosuria, Fructosuria, and Ascorbic aciduria. Polyuria It means: ↑ urine output > 2.5 liters/day due to osmotic diuresis I- Pituitary: impaired production of ADH: Cranial diabetes insipidus. II- Renal: a- Inability to respond to ADH: - Nephrogenic diabetes insipidus. - Fanconi's syndrome. b- solute excretion (osmotic diuresis): DM. c- concentrating capacity: - CRF(early stage). - Hydronephrosis. - Hypercalcemia (nephrocalcinosis). - Hypokalemia. III- Drugs: Diuretics. VI- Others: Compulsive water drinking (Psychogenic).  III-Gestational Diabetes Mellitus (GDM) It is a type of Diabetes with onset or first recognition during second and third trimesters of pregnancy. It may or may not disappear after delivery and liable to recur with following pregnancies. It appears in about 2-5% of all pregnancies. Pathogenesis: Pregnancy is a diabetogenic state for the following reasons: 1- Human placental lactogen has anti-insulin and lipolytic effects. It increases the blood glucose levels and thus makes more glucose available to the fetus. 2- Steroid hormones (corticosteroids and progesterone) have anti-insulin effects. 3- Some insulin may be destroyed by the placenta. Risk factors for gestational diabetes include: Being overweight or obese Physically in active Having prediabetes Having had gestational diabetes during a previous pregnancy Having polycystic ovary syndrome Having an immediate family member with diabetes Having previously delivered a baby weighing more than 4 kilograms. Screening for GDM One-step strategy Performed at 24-28 weeks of gestation in individuals not previously diagnosed with diabetes: The two hours OGTT using 75 oral glucose load, with plasma glucose measurement at fasting ,1 and 2 h. The diagnosis of GDM is made when any of the following plasma glucose values are met or exceeded: Fasting: 92 mg/dL 1 h: 180 mg/dL 2 h: 153 mg/dL Low risks of GDM include : No screening is needed for any woman fulfilling all the following criteria: 1- Normal body weight. 2- -ve FH of DM in 1st degree relatives. 3- -ve history of abnormal glucose tolerance. 4- Age < 25 years. 5- -ve history of poor obstetric outcome. Screening of diabetes in High risk women In individuals who are planning pregnancy, screen those with risk factors for diagnosis of prediabetes or diabetes. Blood glucose testing should be performed as early as possible during the first trimester using venous plasma glucose: Before 15 weeks of gestation, screen for diabetes using the standard diagnostic criteria. Diagnostic criteria of DM in the first trimester: a- Classical symptoms of hyperglycemia + any one of three positive tests: 1- Random plasma glucose: 200 mg/dl. Or 2- Fasting plasma glucose: 126 mg/dl. Or 3- 2h-PPPG: 200 mg/dl b- In the absence of unequivocal hyperglycemia, diagnosis requires two abnormal test results obtained at the same time or at two different time points.  Acute diabetic complications (DKA and HHS) Diabetic ketoacidosis (DKA) Diabetic ketoacidosis (DKA) is a cardinal feature of type 1 diabetes. However, it is rare for DKA to occur in type 2 diabetes in the absence of some precipitating event. When DKA occurs in an individual with type 2 diabetes, the clinician should “look under the sheets” and initiate an intensive search for the precipitating factor DKA is a triad of : Uncontrolled hyperglycemia Increased total body ketone concentration Metabolic acidosis (High anion gap) Pathogenesis These metabolic derangements result from the combination of absolute or relative insulin deficiency and an increase in counter regulatory hormones: glucagon, catecholamines, cortisol and growth hormone. Absolute insulin deficiency→ Hyperglycemia and Intracellular starvation →Counter regulatory hormone response (stress response) 1-Gluconeogenesis: Breakdown of protein and conversion of amino acids into glucose. 2-Glycogenolysis: Breakdown of liver glycogen into glucose. 3-Lipolys, Ketogenesis (Hepatic fatty acid oxidation) and formation of Ketone bodies (betahydroxybutyrate and acetoacetate,acetone) that are acids (H+/anions) build up in the blood stream (increase in anion gap) → Ketonemia and metabolic acidosis. Precipitating factors of DKA: 1.Infections(the most common): Chest infections , UTI,… 2.Stress of illness such as: Trauma Surgery  Myocardial infarction Cerebrovascular stoke 3.Discontinuation of or inadequate insulin therapy. Clinical presentation: Symptoms:  Hyperglycemia Polyuria Polydipsia  Non-specific Weakness Lethargy Myalgia Headache  Gastrointestinal Anorexia Nausea Vomiting Abdominal pain  Respiratory: Dyspnea Signs: Hypotension & tachycardia Kussmaul respiration Acetone breath Dehydration Tender abdomen Stupor up to coma Focal neurological signs (hemiparesis, aphasia, seizeres..etc) especially in HHS Laboratory investigations of DKA: Hyperglycemia (Random Blood glucose >250 mg/dL) Ketonemia High anion gap metabolic acidosis PH < 7.30  HCO3- < 15 mEq/L ❖ Anion gap = [ Na+] – [ Cl- + HCO3- ] ❖ In typical case of DKA, the AG is > 10 mEq/L Mild to moderate DKA (can be managed in the ward) but severe DKA should be managed in ICU. Criteria of severe DKA: PH< 7 HCO3< 10mEq/L Ketone body positive Anion gap > 12 Stupor or coma Differential diagnosis of DKA: 1.Other Hyperglycemic States: Stress hyperglycemia and HHS 2. Other Ketotic States: Starvation ketosis Alcoholic ketosis 3. Other high anion gap metabolic Acidosis causes: Lactic acidosis and uremic acidosis 4. Drug-induced : Salicylate Methanol Paraldehyde Ethylene glycol Hyperglycemic Hyperosmolar State (HHS): HHS is characterized by severe hyperglycemia, hyperosmolality, and dehydration in the absence of significant ketosis due to relative insulin deficiency The relative insulin deficiency is inadequate to prevent hyperglycemia (Gluconeogenesis & Glycogenolysis) but adequate to prevent lipolysis and subsequent ketogenesis. Precipitating Factors for HHS: 1.Infection is the most common precipitant cause 2. Physical stress due to illness (eg. MI, stroke,…)  2.Restricted water intake that likely result in severe dehydration. This is due to: The patient being bedridden. The altered thirst response of the elderly. 3.Delayed recognition of hyperglycemic symptoms (20% of these patients have no history of diabetes) Clinical presentation: HHS is similar to DKA except ketosis is absent or minimal Ketosis. Absence of ketosis and acidosis delay seeking medical advice and therefore the patient presents with marked hyperglycemia and dehydration. Therefore patients with HHS compared to those with DKA have: 1. marked manifestations of dehydration 2. less GI symptoms 3. No Kussmaul respiration and no Acetone breath. 4. Mental status is more affected (altered level of consciousness due to hyperosmolarity), focal neurological deficits (hemianopia and hemiparesis) and seizures (focal or generalized) are more common. Laboratory Diagnosis Plasma glucose >600 mg/dl Effective serum osmolality > 320 mOsm/kg Effective serum osmolality = 2 [ serum Na+ (mEq/l) ] + glucose (mg/dl)/ 18 = mOsm/kg Arterial pH >7.3 HCO3> 15 mEq/l Absence of significant ketoacidosis (minimal or no ketosis) Treatment of DKA: Treatment Objectives 1. Improve circulatory volume and perfusion 2. Correct electrolyte disturbances 3. Provide adequate insulin to restore and maintain normal glucose metabolism and correct acidosis 4. Prevent complications resulting from treatment  5. Identification of precipitating conditions 6. Provide patient and family education and follow-up 1. Fluid Therapy First line. The aim is to correct ( intravascular , interstitial and intracellular) volume depletion, hypertonicity and renal perfusion. It usually started before insulin therapy especially in patients with severe volume contraction and hypokalemia. Type of fluid :0.9% NaCl 1 Liter of 0.9% NaCl per hour to avoid overcorrection that may lead to cerebral edema. 2. Insulin Therapy Insulin therapy is a cornerstone in management The aim of insulin therapy is to correct hyperglycemia (6 h) and reverse ketoacidosis (metabolic acidosis) (12 h) Regular insulin can be administered via continuous intavenous infusion protocol. It is preferable to postpone insulin therapy until the results of serum potassium are obtained Insulin should not be given if hypokalemia or severe volume contraction is present unless these conditions are corrected During treatment of DKA, hyperglycemia is corrected faster(~6 h) than ketoacidosis(~12h). When serum glucose reaches 200 mg/dl in DKA 5% dextrose should be added to allow continued insulin administration until ketonemia is controlled while at the same time avoiding hypoglycemia. 3. Potassium Therapy Mild-to-moderate hyperkalemia at presentation is usually corrected by insulin therapy, correction of acidosis, and volume expansion. To prevent hypokalemia, potassium replacement is initiated when serum level is less than 5.2mEq/l. The treatment goal is to maintain serum potassium levels within the normal range of 4–5 mEq/l.(20–30 mEq potassium in each liter of infusion fluid)  If serum K is less than 3.3 mEq/l , hold insulin treatment until serum K is restored to ≥ 3.3 mEq/l to avoid life-threatening arrhythmias and respiratory muscle weakness 4. Bicarbonate Therapy The use of bicarbonate in DKA is controversial because most experts believe that during the treatment, as ketone bodies decrease there will be adequate bicarbonate except in severely acidotic patients. So , the use of bicarbonate therapy is only indicated in severe metbolic acidosis (pH is < 6.9 ) The treatment goal is to maintain the pH ≥ 7 Side effects of bicarbonate therapy: Hypokalemia Decrease tissue oxygen uptake Cerebral edema Therefore the use of bicarbonate therapy is only indicated in severe acidosis (pH is 7.3 3- calculated anion gap ≤ 12 mEq/l. Criteria for resolution of HHS: 1- Normal osmolality and regain of normal mental status. 2- Blood glucose < 300 mg/dl Note That ❖ Monitoring of plasma ketones is not practical and monitoring urine acetone is misleading ❖ β-OHB direct measurement in the blood is the preferred method for monitoring DKA but it is not practical. ❖ β-OHB is the strongest , predominant and most prevalent acid in DKA.  ❖ β-OHB is not measured by the nitroprusside method (measures only acetoacetic acid and acetone in blood and urine) ❖ Most urine testing kits detect aceto-acetate only, not the predominant ketone β-OHB. ❖ It is possible for the test to be false negative with high levels of beta- hydroxybutyrate. ❖ It is possible for the test to be false positive :During therapy, β-OHB is converted to acetoacetic acid so the urine test becomes positive (to aceto-acetate). Therefore, assessments of urinary ketone levels should not be used as an indicator of response to therapy Transition to subcutaneous insulin ❖ To prevent recurrence of hyperglycemia or ketoacidosis during the transition period to SC insulin, stop IV insulin 1-2 h after the first SC dose due to very short half-life of IV insulin. ❖ Patients with known diabetes may be given insulin at the dosage they were receiving before the onset of DKA so long as it was controlling glucose properly. ❖ In insulin-naïve patients, a multidose insulin regimen should be started at a dose of 0.5– 0.8 units/kg/day by using either the conventional or Basal/Bolus regimens. Both regimens have similar glycemic control during transition. However, treatment with basal bolus is associated with lower rate of hypoglycemic events. Complications of DKA treatment ❖ Hypoglycemia and hypokalemia are two common complications with overzealous treatment of DKA with insulin and bicarbonaterespectively. ❖ Cerebral edema during treatment, esp in children ,presented by onset of headache, gradual deterioration in level of consciousness,seizures, sphincter incontinence, pupillary changes, papilledema, bradycardia, elevation in blood pressure, and respiratory arrest Mechanisms of cerebral edema include: A rapid fluid shift from extracellular to intracellular by rapid correction of osmolality and dehydration Prevention of cerebral edema: 1-Avoidance of excessive hydration. 2- Avoidance of Rapid reduction of plasma osmolarity. 3-Gradual decrease in serum glucose.  Hypoglycemia Prof. Yehia M. Ghanem Definition Blood glucose below 70 mg/dl accompanied by adrenergic or gastrointestinal manifestations. Clinical Picture: G.I.T. manifestations: Epigastric pain – nausea - vomiting Adrenergic manifestations: palpation – sweating – tremors – numbness– coma Neuroglycopenic manifestations Grades: Grade I: Mild when one can help himself. Grade II: Moderate needs help to reach the glucose. Grade III: Severe go to the hospital to receive glucose infusion and glucagon. Common Causes of Hypoglycemia in Adults: 1. Fasting hypoglycemia: A. 2ry causes Endocrine (hypopituitrism – Addison – Myxedema) Liver (Acute alcoholism - liver failure) Renal failure. B. 1ry causes: ▪ Hyperinsulinism, e.g., Pancreatic B-cell tumor ▪ Extra pancreatic Non-insulin secreting tumors ▪ Surreptitious administration of Insulin or HA 2. Postprandial (Reactive) hypoglycemia: A. Early hypoglycemia (Alimentary): i. Post gastrotomy ii. Functional vagal tone B. Late hypoglycemia occult DM i. Counter regulatory hormone deficiency ii. Idiopathic iii. Alcohol induced hypoglycemia iv. Immuno-pathogenic hypoglycemia: Early post prandial hypoglycemia (Alimentary): Rapid discharge of ingested CHO into small bowel followed by rapid glucose absorption and hyperinsulinism e.g. after gastric surgery (dumping syndrome). It might be functional: as it may represent over activity of parasympathetic nervous system Defective counter regulatory response as GH, cortisol, glucagon. Treatment: frequent feeding - small diet Alcohol induced hypoglycemia: Due to hepatic glycogen depletion combined with alcohol mediated inhibition of gluconeogenesis It is followed by gastritis and vomiting Immuno-pathogenic hypoglycemia: Idiopathic anti-insulin antibodies (release bound insulin) Antibodies to insulin receptors (agonist) Pantamidine induced hypoglycemia Factitious hypoglycemia: It is self-induced hypoglycemia due to surreptitious administration of insulin or OHA Diagnosis: High immuno-reactive insulin, Serum C-peptide, High level of insulin antibodies Hypoglycemia due to pancreatic β-cell tumor (Insulinoma): 90% benign adenoma of islet of Langerhans (single) If multiple >>> malignant It is associated with MEN syndrome Clinical picture: ✓ Whipple’s Triad "Characteristic of hypoglycemia": History of hypoglycemic symptoms, ↓FBG< 40 mg/dl and Immediate decay after ingestion of glucose. ✓ Symptoms: Fasting hypoglycemia; symptoms develop early in the morning, after missing meal or after exercise Subacute or chronic neuroglycopenia: blurred vision & diplopia, headache, slurred speech and weakness, personality and mental changes, coma Sweating & palpation may not occur Hypoglycemic Unawareness: Common in insulinoma; as patients adapt hypoglycemia Laboratory Investigations: ✓ Diagnostic Test: Prolonged fasting under hospital supervision ad Proinsulin determination. Elevated insulin and C-peptide levels at time of hypoglycemia ✓ Stimulation test: Glucagon is better than tolbutamide  Preoperative localization of β-cell tumor: MRI (hepatic metastasis), better than arteriography- Percutaneous transhepatic vein catheter insulin assay localizes the tumor Treatment: ✓ Surgical ✓ Diet ✓ Diazoxide 300-600 mg + diuretic therapy ✓ Octuritide ✓ Streptozetocal Hypoglycemia due to extra-pancreatic tumors: Rare Retroperitoneal sarcoma, Hepatocellular carcinoma, Adrenocortical carcinoma Prognosis: Poor  Chronic Diabetic Complications Prof. Eman Youssef I. Macrovascular disease Coronary heart disease Cerebrovascular disease Peripheral vascular disease Coronary heart disease Known risk factors: Non- modifiable: Age, Gender, Family history Modifiable: Lipid abnormalities, Hypertension, Smoking, Diabetes, Atherogenic diet and Physical inactivity Coronary heart disease in diabetes It is more common and occurs earlier than in people without diabetes. Women lose gender protection. Myocardial infarction is often painless (silent). Two- to three-fold higher risk of heart failure. Diabetic patients with myocardial infarction have poor prognosis even after adjustments of infarct size and risk factors. Cerebrovascular disease: Cerebrovascular disease in diabetes Strokes occur twice as often in diabetes and hypertension than those with hypertension alone Transient Ischaemic Attacks (TIAs) occur two to six times more often Prevention & Management of Macrovascular Complications: Intensive treatment of modifiable risk factors; Increase physical activity. Improve diet: reduce total and saturated fat, increase monounsaturated fat. Aggressive treatment of dyslipidaemia. aggressive treatment of hypertension. Smoking cessation. Antiplatelet therapy. Diabetic dyslipidemia  Main features of diabetic dyslipidemia: 1) Increased level of triglycerides more than150 mg/dl. 2) Low HDL-C less than 40 mg/dl in men and less than 50 mg/dl in women 3) Normal or increased level of LDL-C more than 100 mg/dl.  4) Increased number of small dense LDL particles 5) Normal or increased level of cholesterol more than 200 mg/dl.  Targets of therapy: 1) LDL-C < 100 mg/dl (optional 40 mg/dl (men), >50 mg/dl (women)  Lipid Lowering Drug Therapy: For LDL lowering, HMG-CoA Reductase Inhibitors (statins) are 1st line therapy. Cholesterol absorption inhibitors may provide additional LDL lowering in combination with a statin. Bile acid sequestrants may increase TG. Niacin is the best drug for increasing HDL, but may affect glucose homeostasis (increase insulin resistance). Glycemic control may significantly reduce triglycerides. Hypertension and Diabetes Hypertension may be linked to development and progression of nephropathy, retinopathy, and atherosclerosis In patients with Type 1 diabetes, persistent hypertension is often a manifestation of diabetic nephropathy (concomitant elevated levels of urinary albumin and, in later stages, by a decrease in the glomerular filtration rate) In patients with Type 2 diabetes, hypertension is often part of a syndrome that includes glucose intolerance, insulin resistance, obesity, dyslipidemia, and coronary artery disease  Initial Treatment and Goals for Adult Hypertensive Diabetic Patients: Systolic Diastolic Goal (mmHg) 80  Treatment options: ACE Inhibitors Angiotensin receptor blockers (ARB) Calcium channel blockers β-blockers Thiazide diuretics (low dose) α-blockers *** Many people require more than one drug to achieve the recommended target Antiplatelet Therapy Recommendations in Patients with Diabetes Use aspirin therapy 75-162 mg/dl as a primary prevention in diabetic patients (type 1&2) at increased cardiovascular risk. (C) Use aspirin therapy 75-162 mg/dl as a secondary prevention in diabetic patients (type 1&2) with cardiovascular disease. (A) Aspirin allergy, bleeding tendency, anticoagulant therapy, recent GI bleeding, under the age of 30 and clinically active hepatic disease are contraindications for aspirin therapy. Clopidogrel (75mg/day) should be used. Role of tight glycemic control in CVD outcomes The general goal of A1c < 7% is reasonable for macrovascular risk reduction. II. Microvascular Complications Tight glycemic control would prevent the development and/or ameliorate the progression of diabetes-associated microvascular complications (type 1&2). Pathogenic mechanism of the chronic microvascular complications Glucose induced cell injury: Advanced glycosylation end-products (AGEs) Accelerated of polyol pathway Others: 1.Activation of protein kinase C 2.Oxidative stress. Diabetic retinopathy It is the most frequent late complication of type 1 diabetes. Diabetes is the leading cause of blinding in persons aged 20 to 74 years in the United States. The incidence of retinopathy, it's progression and development of proliferative retinopathy were highest in patients with type 1, intermediate in insulin-treated patients with type 2 diabetes, and lowest in patients Stages of diabetic retinopathy: 1) Mild non proliferative diabetic retinopathy (Mild NPDR) These changes begin 3 to 5 years after diagnosis in type 1 diabetics. First signs are microaneurysms with subsequent retinal haemorrhages and hard exudates. Infarctions of nerve fiber layer, known as soft exudates. Visual acuity is generally unaffected. 2) Moderate NPDR Characterized by microvascular abnormalities such as: i. Venous beading, venous caliber changes.  ii. Increased capillary dilatation and permeability. 3) Severe or very severe NPDR Manifested by: 1. Progressive retinal ischemia. 2. Extensive hemorrhages, exudates and microaneurysms. ** At 5 years; mild, moderate and severe NPDR are associated with 15%, 30% and 60% risk of progression to PDR. 4) Proliferative diabetic retinopathy (PDR) Involves: I. Neovascularization in the retina "early PDR" II. Neovascularization in the vitreous body "High risk PDR" → Retinal detachment, Retinal hemorrhages, Blindness. ** Occasionally, new vessels can invade the iris and the anterior chamber, leading to sight threatening closed-angle glaucoma. Management of Diabetic Retinopathy: I. General Recommendations: To reduce the risk or slow progression of retinopathy A. Optimize glycemic control: 1) A1C should be lowered to below or around 7% 2) FPG (preprandial) should be lowered to (80-130 mg/dl) 3) 2h-PPG (peak postprandial) should be lowered to below or around 180 mg/dl B. Optimize blood pressure control: Diabetic patient should be treated; to a systolic BP