Diabetes Mellitus (DM) by Minwoldu

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Information about Diabetes Mellitus (DM) by Minwoldu

Published on February 27, 2014

Author: minwoldu

Source: authorstream.com

Diabetes Mellitus (DM): Diabetes Mellitus (DM) By Minyahil A Woldu Bpharm., MSc in Clincal Pharmacy Definition and Prevalence: Definition and Prevalence DM is a syndrome with disordered metabolism and inappropriate hyper- glycemia due to either an absolute deficiency of insulin secretion or a reduction in its biologic effectiveness ( insulin resistance ) or both. Classification of DM: Classification of DM I Type 1 diabetes (B cell destruction, usually leading to absolute insulin deficiency) A. Immune-mediated B. Idiopathic II Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance) Classification of DM: Classification of DM III Other specific types A. Genetic defects of B cell function Chromosome 20, HNF-4alpha (MODY 1) Chromosome 7, glucokinase (MODY 2) Chromosome 12, HNF-1alpha (MODY 3) B. Genetic defects in insulin action Lipoatrophic diabetes C. Diseases of the exocrine pancreas Pancreatitis Trauma, pancreatectomy Cystic fibrosis Hemochromatosis Classification of DM: Classification of DM III Other specific types D. Endocrinopathies Acromegaly Cushing’s syndrome Glucagonoma Pheochromocytoma Hyperthyroidism E. Drug- or chemical-induced Glucocorticoids Thiazides B-blockers Nicotinic acid Classification of DM: Classification of DM III Other specific types F. Infections Congenital rubella Cytomegalovirus G. Genetic syndromes associated with diabetes Down’s syndrome DIDMOAD (diabetes insipidus, DM, optic atrophy, nerve deafness) Friedreich’s ataxia Klinefelter’s syndrome Turner’s syndrome IV Gestational diabetes mellitus (GDM) Viruses implicated in the development of type I diabetes mellitus: Viruses implicated in the development of type I diabetes mellitus Pathogenesis of Type 1 Diabetes : Pathogenesis of Type 1 Diabetes Type 1 diabetes (DM1) probably results from an infectious or toxic environmental insult to pancreatic B cells of persons whose immune system is genetically predisposed to develop a vigorous autoimmune response against altered pancreatic B cell antigens. Extrinsic factors which may insult pancreatic B cells include viruses such as mumps or coxsackie B4 virus , toxic chemical agents and cytotoxins . Antibodies against bovine serum albumin may react against altered pancreatic B cells (increased incidence of DM1 in those who take cow’s milk before 2-3 months of age ) As a result of damage to the pancreatic B cells insulin becomes virtually absent from the circulation. Pathogenesis of Type 1 Diabetes: Pathogenesis of Type 1 Diabetes Lack of Insulin Increased secretion : Glucagon Cortisol Growth hormone Catecholamines Decreased anabolism Increased catabolism Hyperglycemia Glycosuria Osmotic diuresis Salt and water depletion Increased: glycogenolysis gluconeogenesis lipolysis Wt loss Wasting Hyperketonemia Diabetic ketoacidosis Peripheral vasodilatation Hyperventillation Death fatigue vulvitis balanitis polyuria polydipsia tachycardia hypotension Pathogenesis of Type 1 Diabetes: Pathogenesis of Type 1 Diabetes Diabetic ketoacidosis develops on average 2-4 weeks after the onset of symptoms The genetic predisposition to DM1 may be due to: 1. Possesion of HLA-DR3 or HLA-DR4 genes which are present in 95% of DM1 patients 2. Presence of a genetic defect on chromosome 11 relating to B cell replication or function However most patients with DM1 have no family history of diabetes and the concordance of diabetes in identical twins is only 30-50% An important evidence that DM1 is an autoimmune disease is the presence of circulating islet cell antibodies in 85% of patient s. Pathogenesis of Type I DM: Pathogenesis of Type I DM Insulin deficiency Type I / IDDM ß cell Destruction PS Glomerulonephritis Graves, Hashimoto thyroiditis. Rheumatic heart disease SLE, Collagen vascular disease Rheumatoid arthritis. Genetic HLA-DR3/4 Environment Viral infe ..? Autoimmune Insulitis Ab to ß cells/insulin Pathogenesis of Type 2 Diabetes: Pathogenesis of Type 2 Diabetes In type 2 diabetes (DM2) there is an element of tissue insensitivity to insulin attributed to several factors. These include a primary genetic factor which is aggravated in time by additional enhancers of insulin resistance such as aging , physical inactivity , and abdominal-visceral obesity . As time passes B cell failure ensues on top of the insulin resistance and hyperglycemia worsens In DM2 there is usually a positive family history and concordance in identical twins is almost 100% PowerPoint Presentation: Pathogenesis of Type II DM IDDM Genetic / ß cell defect ß cell exhaustion Type II NIDDM Obesity / Life style ? Abnor . Secretion Insulin Resistance Relative Insulin Def. Comparison between DM1 and DM2: Comparison between DM1 and DM2 DM1 DM2 % of all diabetics 10% 90% Usual age at onset <40 years >50 years Heredity HLA -DR3 or HLA-DR4 in 95% FH usually – ve c. 30-50% concordance in identical twins No HLA links FH usually +ve Almost 100% concordance in identical twins Pathogenesis Autoimmunity Islet cell antibodies in 85% Association with other autoimmune diseases Insulin resistance No islet cell antibodies No association with auto- immune diseases Body weight Usually lean Often overweight Comparison between DM1 and DM2: Comparison between DM1 and DM2 DM1 DM2 Clinical: a. Onset b. Ketosis c. Rapid death with- out Rx with insulin d. Diabetic compli- cations at Dx Abrupt Present Yes No Insidiuos Absent No Yes in 10-20% Treatment Insulin and diet Diet, exercise, pills, and later insulin RISK OF DIABETES…: RISK OF DIABETES… Usually extensive pancreatic damage or removal must occur for diabetes to emerge. Cystic fibrosis , hemochromatosis and fibrocalculous pancreatopathy may also cause diabetes. Diabetes may also be caused by other endocrine diseases particularly when there is over-secretion of hormones that antagonize the normal effect of insulin (including Cushing’s syndrome , acromegaly , pheochromocytoma ). Drugs that have a similar effect ( glucocorticoids , diazoxide , thiazides ) may also cause diabetes. Risk factors: Risk factors Family history of diabetes (i.e., parent or sibling with type 2 diabetes) Obesity (BMI> 25 kg/m 2 ) Habitual physical inactivity Race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander) Previously identified IFG or IGT History of GDM or delivery of baby >4 kg. Hypertension (blood pressure 140/90 mmHg) HDL cholesterol level <35 mg/ dL (0.90 mmol /L) and/or a triglyceride level >250 mg/ dL (2.82 mmol /L) History of vascular disease Risk Factor Defining Level: Risk Factor Defining Level Abdominal obesity: Waist circumference Men >102 cm (>40 in) Women >88 cm (>35 in) Triglycerides ≥150 mg/ dL High-density–lipoprotein C Men <40 mg/ dL Women <50 mg/ dL Blood pressure ≥130/≥85 mmHg Fasting glucose ≥110 mg/ dL PowerPoint Presentation: Diabetes occurs in 15–30% of patients with acromegaly and similarly with impaired glucose tolerance. About 10% of patients with Addison’s disease have diabetes, usually type 1. Diabetes is present in around 60% of young adults with Turner’s syndrome (45,XO karyotype) and is usually type 2. ADA recommendation: ADA recommendation The ADA recommends screening all individuals >45 years every 3 years and screening individuals at an earlier age if they are overweight [body mass index (BMI) > 25 km/m 2 ] and have one additional risk factor for diabetes Clinical Features of DM1: Clinical Features of DM1 Symptoms : onset could be either abrupt or subacute When the onset is abrupt the patient presents with: Polyuria due osmotic diuresis Polydipsia due to hyperosmolar state Blurred vision due to lens exposure to hyperosmolar fluids Dizziness and weakness due to plasma volume depletion Diabetic ketoacidosis ( DKA ): after an average of 2-4 weeks the above symptoms may progress to: Dehydration, anorexia, nausea, vomiting, Kussmaul respiration, reduced level of consciousness, circulatory collapse When the onset is subacute: in addition to above: Weight loss despite increased appetite Muscle wasting Paraesthesias Clinical Features of DM1: Clinical Features of DM1 Signs: 1. Usually no physical signs are found when onset is abrupt except for may be postural hypotension. 2. When the onset is subacute the patient may show: A. Loss of subcutaneous fat B. Muscle wasting Enlarged liver, eruptive xanthomas on the flexor surface of the limbs and on the buttocks and lipemia retinalis due to chylo- micronemia resulting chronic insulin deficiency 3. When DKA develops the patient will show: Signs of dehydration: loose dry skin, dry furred tongue, cracked lips, tachycardia, hypotension Fruity breath odor Kussmaul breathing Impaired consciousness, stupor, coma Clinical Features of DM2: Clinical Features of DM2 Symptoms : The onset is usually insiduous: 1. The patient may be asymptomatic and discovered by routine laboratory investigations 2. The patient may present with classical symptoms of DM: polyuria, polydipsia, recurrent blurring of vision, easy fatiguability 3. The patient may present with pruritus vulvae or balanitis due to infection of the external genitalia by fungi (Candida) which flourish on skin and mucous membranes contaminated by glucose 4. The patient may present with a complication of DM in 10-20% of cases Clinical Features of DM2: Clinical Features of DM2 Signs : The patient is usually obese The external genitalia may show signs of candidal infection Signs of atherosclerosis : diminished or impalpable pulses in the feet, bruits over the carotid or femoral arteries, gangrene of the feet Opthalmoscopy may show the typical appearances of diabetic retinopathy Signs of peripheral neuropathy : depression or loss of the tendon reflexes at the ankles, impaired perception of vibration sensation distally in the legs Signs of diabetic nephropathy : oedema of the lower limbs DIAGNOSIS OF DIABETES…: DIAGNOSIS OF DIABETES… The diagnostic criteria for DM have been modified in recent years by the American Diabetes Association ( ADA ) from previous recommendations made by the National Diabetes Data Group in 1979 and the World Health Organization ( WHO ) in 1985 . When symptoms of hyperglycemia exist ( thirst, polyuria , weight loss, etc.) a random plasma glucose concentration of ≥ 11.1mmol/l ( 200mg/dl ) or a fasting plasma glucose (FPG) of ≥ 7.0mmol/l ( 126mg/dl ) confirms the diagnosis. DIAGNOSIS OF DIABETES…: DIAGNOSIS OF DIABETES… Where diagnostic difficulty exists, the precise diagnosis can be established with an oral glucose tolerance test ( OGTT ) using a 75 g anhydrous glucose load dissolved in water: a 2 h value ≥ 11.1mmol/l ( 200mg/dl ) establishes the diagnosis of diabetes. A confirmatory test using one or other of the three methods should be employed. The OGTT is not recommended for routine clinical use , but may be an important test for epidemiologic purposes where using the FPG only may lead to lower prevalence rates than with the combined use of the FPG and OGTT. DIAGNOSIS OF DIABETES…: DIAGNOSIS OF DIABETES… The ADA recognizes an intermediate group of subjects whose FPG is ≥ 6.1mmol/l (110mg/dl) but < 7.0mmol/l (126mg/dl) and has defined this group as having impaired fasting glucose ( IFG ). It has recently been suggested by the ADA that the FPG level to diagnose IFG should be reduced from ≥ 6.1mmol/l (110mg/dl) to ≥ 5.6mmol/l (100mg/dl). A further abnormal category is defined as having a plasma glucose ≥ 7.8mmol/l (140mg/dl) but < 11.1mmol/l (200mg/dl) at 2 h when an OGTT is used and is described as impaired glucose tolerance ( IGT ). Mechanisms of glucose production: Mechanisms of glucose production Glucose is produced in the liver by the process of gluconeogenesis and glycogenolysis. The main substrates for gluconeogenesis are the glucogenic amino acids (alanine and glutamine), glycerol, lactate and pyruvate. Many factors influence the rate of gluconeogenesis; it is suppressed by insulin and stimulated by the sympathetic nervous system. Glycogenolysis (the breakdown of hepatic glycogen to release glucose) is stimulated by glucagon and catecholamines, but is inhibited by insulin The biochemical consequences of insulin deficiency: The biochemical consequences of insulin deficiency Insulin deficiency results in increased hepatic glucose production and, hence, hyperglycemia by increased gluconeogenesis and glycogenolysis . Insulin deficiency also results in increased proteolysis releasing both glucogenic and ketogenic amino acids. Lipolysis is increased, elevating both glycerol and non- esterified fatty acid levels which further contribute to gluconeogenesis and ketogenesis , respectively. The end result is hyperglycemia , dehydration , breakdown of body fat and protein , and acidemia The biochemical consequences of insulin deficiency: The biochemical consequences of insulin deficiency PowerPoint Presentation: Short term Complications: (metabolic) Hypoglycemia Diabetic Ketoacidosis Non Ketotic hyperosmolar diabetic coma Lactic acidosis Long term Complications :(Angiopathy) Microngiopathy - Retinopathy, Nephropathy, Neurophathy, dermatopathy. Macroangiopathy – Atherosclerosis. Complications: Chronic Complications of DM: Chronic Complications of DM Ocular complications: Diabetic cataracts : Premature cataracts occur due to nonenzymatic glycosylation of lens protein Diabetic retinopathy : Nearly 50% of all diabetics have retinopathy after 10 years of DM Retinopathy is due to retinal microangiopathy which leads to retinal vascular occlusion and leakage Diabetic retinopathy is the most common cause of blindness in the 20-65 age group Non-proliferative diabetic retinopathy: Non-proliferative diabetic retinopathy Non-proliferative diabetic retinopathy: Non-proliferative diabetic retinopathy Proliferative diabetic retinopathy: Proliferative diabetic retinopathy Advanced diabetic eye disease: Advanced diabetic eye disease Chronic Complications of DM: Chronic Complications of DM Other ocular complications: Glaucoma: either primary open angle glaucoma or neovascular glaucoma Rubeosis iridis Rubeosis iridis: Rubeosis iridis Chronic Complications of DM: Chronic Complications of DM Diabetic nephropathy: It results from microangiopathy (basement membrane thickening of capillaries) The kidneys become affected by glomerulo- sclerosis (Kimmelsteil Wilson’s disease) 50% of patients who develop diabetes before the age of 20 develop diabetic nephropathy after 20 years Diabetic nephropathy starts with microalbuminuria then it progresses to proteinuria (nephrotic syndrome), hypertension, and finally renal failure PowerPoint Presentation: Lower Limb Edema in a Patient with Diabetic Nephrotic Syndrome Chronic Complications of DM: Chronic Complications of DM Diabetic neuropathy Neuropathy results from the following changes induced by diabetes: Axonal degeneration of both myelinated and unmyelinated fibres Thickening of Schwann cell basal lamina Patchy, segmental demyelination Abnormalities of intraneural capillaries, thickening of basement membrane and microthrombi Diabetic neuropathy can occur in motor, sensory, and autonomic nerves Chronic Complications of DM: Chronic Complications of DM Classification of diabetic neuropathy I Somatic A. Polyneuropathy 1. Symmetrical (mainly sensory and distal): features a. Diminished perception of vibration, sense of position, pain & temperature distally (glove and stocking distribution) b. Paraesthesia in the feet and hands c. Lancinating pain in lower limbs d. Burning sensation in soles of feet e. Loss of ankle jerk f. There may be painless ulcers on the feet and painless distal arthropathy (Charcot joints) PowerPoint Presentation: Diabetic Foot Ulcer PowerPoint Presentation: Charcot’s Feet Chronic Complications of DM: Chronic Complications of DM Classification of diabetic neuropathy I Somatic A. Polyneuropathy 2. Asymmetrical (mainly motor and proximal)=diabetic amyotrophy Weakness and wasting of the proximal muscles of the lower limbs with severe pain felt on the anterior aspect of the leg B. Mononeuropathy Due to small vessel disease of the vasa nervorum Most commonly affected nerves: 3 rd and 6 th cranial nerves, ulnar and median nerves, femoral, sciatic and lateral popliteal nerves PowerPoint Presentation: Diabetic Amyotrophy Chronic Complications of DM: Chronic Complications of DM Classification of diabetic neuropathy II Visceral (autonomic) A. Cardiovascular: Postural hypotension B. Gastrointestinal: Dysphagia due to esophageal atony Abdominal fullness, nausea and vomiting due to delayed gastric emptying (gastroparesis) Nocturnal diarrhea +/- fecal incontinance, constipation due to colonic atony C. Genitourinary: Difficulty in micturition Urinary incontinance Impotence Retrograde ejaculation Chronic Complications of DM: Chronic Complications of DM Classification of diabetic neuropathy II Visceral (autonomic) D. Sudomotor: Gustatory sweating E. Vasomotor: Feet feel constantly cold Dependent oedema F. Pupillary: Decreased pupil size G. Hypoglycemia unawareness Chronic Complications of DM: Chronic Complications of DM Diabetic macroangiopathy = Disease of the large blood vessels It probably results from hyperlipidemia, hyperinsulinemia, hypertension, and increased arterial endothelial permeability Macroangiopathy (atherosclerosis) results in ischemic heart disease, cerebrovascular accidents, and peripheral vascular disease Gangrene of the feet Factors responsible for its development are ischemia, peripheral neuropathy and infection Chronic Complications of DM: Chronic Complications of DM Infection In diabetics there is increased susceptibility to infection particularly skin, urinary tract, and lung infections. Dermatological complications Necrobiosis lipoidica diabeticorum: Oval or irregularly shaped plaques with demarcated borders and yellow surface usually located on the anterior surface of the legs Ulcers Infections Pigmented scars over shins (diabetic dermopathy) PowerPoint Presentation: Necrobiosis Lipoidica Diabeticorum PowerPoint Presentation: Cellulitis in a Diabetic PowerPoint Presentation: Extensive Cellulitis in a Diabetic Acute Complications of DM: Acute Complications of DM Diabetic Ketoacidosis (DKA) DKA carries a mortality of 1-10% Nonketotic Hyperosmolar Hyperglycemia (NKHH) NKHH carries a mortality 10 times that of DKA Spectrum of DKA and NKHH: Spectrum of DKA and NKHH Pure Ketoacidosis Ketoacidosis- NKHH Pure NKHH Rapid Onset Marked Insulin Lack Intermediate Slow Onset Mild Insulin Lack Diabetic Ketoacidosis: Diabetic Ketoacidosis Pathophysiology: Insulin deficiency  Reduced peripheral utilization of glucose Protein breakdown amino acids to liver gluconeogenesis Increased glucagon secretion increased gluconeogenesis and ketogenesis Increased lipolysisincreased free fatty acids to liver conversion to ketones ketoacidosis Acute insulin deficiency and metabolic stress of ketosisincreased diabetogenic hormones (GH, cortisol, catecholamines) Electrolyte Loss: Electrolyte Loss Glucose Ketoacids Ketoacids draw out intravascular cations of Sodium and Potassium Intracellular exchange of potassium with hydrogen ions H + K + Phosphorous is also depleted in the osmotic diuresis K I D N E Y Diabetic Ketoacidosis: Diabetic Ketoacidosis Precipitating factors: Infection Acute stroke Pancreatitis Myocardial infarction Interruption of insulin therapy Trauma and stress Pregnancy Dietary indiscret ion Diabetic Ketoacidosis: Diabetic Ketoacidosis Clinical Features: P olyuria, polydipsia Nausea, vomiting, abdominal pain Clouding of sensorium, weakness, and coma Hyperventilation (Kussmaul pattern) “ Fruity ” breath odor Dehydration and shock (postural hypotension, tachycardia, dry axillae and mucous membranes) Diabetic Ketoacidosis: Diabetic Ketoacidosis Laboratory Findings: BG > 14 mmol/L (250 mg/dl) Arterial pH <7.30 Arterial bicarbonate <15 mEq/L Anion gap >1 2 [AG=Na-Cl-HCO3] Urine ketones positive Serum Na is generally reduced [For every 100mg/dl of plasma glucose above normal, serum Na decreases by 1.6meq/L] Diabetic Ketoacidosis: Diabetic Ketoacidosis Investigations to be done: Serum glucose initially then hourly Serum K initially then hourly if <3 or >5 or otherwise 2 hourly till stable Na, urea, creatinine initially then 4 hourly till stable ABG initially then as often as necessary Serum osmolality CBC with differential white count ECG, CXR Urine analysis Diabetic Ketoacidosis: Diabetic Ketoacidosis Contd Investigations to be done: Urine culture if pus cells or bacteria in U/A or patient is septic Blood culture if patient is febrile or WBC>12,000 Serum Mg and PO4 Cardiac enzymes if ECG abnormal initially and after 8 hours Throat swab culture if signs of pharyngitis present Sputum culture if purulent looking or infiltrate on CXR Serum amylase Diabetic Ketoacidosis: Diabetic Ketoacidosis Complications of DKA: Cerebral edema Hypoxia, ARDS Hypoglycemia Hypokalemia Venous and arterial thrombosis Questions to Ask Pts: Questions to Ask Pts Has insulin use been discontinued or a dose skipped for any reason? If an insulin pump is being used, is the tubing clogged or twisted? Has the catheter become dislodged? Has the insulin being used lost its activity? Is the bottle of rapid-acting/regular or basal insulin cloudy? Does the bottle of NPH look frosty? Have insulin requirements increased owing to illness or other forms of stress (infection, pregnancy, pancreatitis, trauma, hyperthyroidism, or MI)? What to Look For: What to Look For Signs and symptoms of hyperglycemia: thirst, excessive urination, fatigue, blurred vision, consistently elevated blood glucose concentrations (>300 mg/dL) Signs of acidosis: fruity breath odor, deep and difficult breathing Signs of dehydration: dry mouth; warm, dry skin; fatigue Others: stomach pain, nausea, vomiting, loss of appetite What to Do: What to Do Review “Sick Day Management” Test blood glucose ≥4 times daily Test urine for ketones when blood glucose concentration is >300 mg/dL Drink plenty of fluids (water, clear soups) Continue taking insulin dose Contact physician immediately DKA Treatment : DKA Treatment Treatment of patients with DKA is aimed at expansion of intravascular and extravascular volume, restoration of renal perfusions, correction of dehydration, fluid and electrolyte losses, and hyperosmolarity See the management of DKA Nonketotic Hyperosmolar Hyperglycemia (NKHH): Nonketotic Hyperosmolar Hyperglycemia (NKHH) Pathophysiology: Marked insulin resistance with partial insulin deficiency + increased diabetogenic hormones (GH, cortisol, catecholamines) due to stress of illness or infection  HYPERGLYCEMIA Hyperglycemia tends to be worse than in DKA: DKA patients are usually younger and have higher GFR DKA patients usually present earlier than pts with NKHH The small amount of insulin present prevents lipolysis and therefore ketogenesis usually does not occur Hyperglycemia osmotic diuresisvolume depletion impaired renal blood flow reduced kidney ability to to excrete glucose worsenning hyperglycemia Nonketotic Hyperosmolar Hyperglycemia (NKHH): Nonketotic Hyperosmolar Hyperglycemia (NKHH) Precipitating factors: Same as those for DKA ( i nfection , stroke , MI, noncompliance to DM therapy, t rauma , stress , d ietary indiscret ion ) NKHH often occurs in elderly patients who may have an impaired thirst mechanism. Inadequate water intake in such patients prevents partial correction of the hyperosmolality, which may be a particular problem in hot weather. Nonketotic Hyperosmolar Hyperglycemia (NKHH): Nonketotic Hyperosmolar Hyperglycemia (NKHH) Clinical Features: Similar to DKA but coma is more frequent Severe dehydration is the rule Focal neurologic deficits may be found at presentation Usually more elderly patients. Underlying renal insufficiency or CHF is common Kussmaul respiration, and abdominal pain are usually absent Nonketotic Hyperosmolar Hyperglycemia (NKHH): Nonketotic Hyperosmolar Hyperglycemia (NKHH) Laboratory Findings: Blood glucose greater than 33 mmol/L (600 mg/dl) Arterial pH >7.30 Arterial bicarbonate >15 mEq/L Anion gap <12 Urine ketones negative Serum osmolality >320 mOsm/Kg   How to calculate osmolality: Calculated serum osmolality= 2[Na+] + serum glucose in mg/dl /18 + urea in mg/dl / 2.8 OR = 2[Na] + [glucose] + [urea] all in mmol/L Treatment of NKHH: Treatment of NKHH 74 Fluid replacement should initially stabilize the hemodynamic status of the patient (1–3 L of 0.9% normal saline over the first 2–3 h). A reasonable regimen for HHS begins with an IV insulin bolus of 0.1 units/kg followed by IV insulin at a constant infusion rate of 0.1 units/kg per hour. If the serum glucose does not fall, increase the insulin infusion rate by twofold. Treatment cont…: Treatment cont… 75 As in DKA, glucose should be added to IV fluid when the plasma glucose falls to 13.9 mmol/L (250 mg/dL), and the insulin infusion rate should be decreased to 0.05–0.1 units/kg per hour. The insulin infusion should be continued until the patient has resumed eating and can be transferred to a SC insulin regimen. DM Management: DM Management 76 The goals of therapy for type 1 or type 2 DM (1) eliminate symptoms related to hyperglycemia, (2) reduce or eliminate the long-term microvascular and macrovascular complications, and (3) allow the patient to achieve as normal a lifestyle as possible. PowerPoint Presentation: 77 NONPHARMACOLOGIC THERAPY: NONPHARMACOLOGIC THERAPY 78 Diet: medical nutrition therapy w/c includes meals moderate in carbohydrates and low in saturated fat, with a focus on balanced meals is recommended. Exercise Has multiple positive benefits including cardiovascular risk reduction, reduced blood pressure, maintenance of muscle mass, reduction in body fat, and weight loss. In patients with diabetes, the ADA recommends 150 min/week (distributed over at least 3 days) of aerobic physical activity. PHARMACOLOGIC THERAPY: PHARMACOLOGIC THERAPY 79 Insulin Insulin is an anabolic and anticatabolic hormone. Endogenously produced insulin is cleaved from the larger proinsulin peptide in the β cell to the active peptide of insulin and C-peptide, which can be used as a marker for endogenous insulin production. Insulin cont… :  Insulin cont… 80 Characteristics that are commonly used to categorize insulins include source, strength, onset, and duration of action. Regular or Neutral Protamine Hagedorn (NPH) insulin is commonly injected in (from most rapid to slowest absorption): abdominal fat, posterior upper arms, lateral thigh area, superior buttocks area. PowerPoint Presentation: 81 PowerPoint Presentation: 82 Intensive Insulin Therapy Regimens: Intensive Insulin Therapy Regimens 83 Insulin cont….:  Insulin cont…. 84 It is recommended that unopened injectable insulin be refrigerated (2.2° to 7.7°C [36° to 46°F]) prior to use. Adverse Effects. The most common adverse effects reported with insulin are hypoglycemia and weight gain. Lipohypertrophy Lipoatrophy Treatment of hypoglycemia::  Treatment of hypoglycemia: 85 Glucose ( 10 to 15 g ) given orally is the recommended treatment in conscious patients. Dextrose IV may be required in individuals who have lost consciousness. Glucagon 1 g intramuscular, is the treatment of choice in unconscious patients when IV access cannot be established . Sulfonylureas: Sulfonylureas 86 The primary mechanism of action of sulfonylureas is enhancement of insulin secretion. First-generation and second-generation agents. Based on: Differences in relative potency, Relative potential for selective side effects, and Differences in binding to serum proteins (i.e., risk for protein-binding displacement drug interactions) . Sulfonylureas cont…: Sulfonylureas cont… 87 First generation agents consist of acetohexamide, chlorpropamide, tolazamide, and tolbutamide. Each of these agents is lower in potency relative to the second-generation drugs: glimepiride, glipizide, and glyburide All sulfonylureas are equally effective at lowering blood glucose when administered in equipotent doses. Sulfonylureas cont….: Sulfonylureas cont…. 88 Individuals at high risk for hypoglycemia (e.g., elderly individuals and those with renal insufficiency or advanced liver disease) should be started at a very low dose of a sulfonylurea with a short half-life. On average, HbA1c will decrease 1.5% to 2%, with FPG reductions of 60 to 70 mg/ dL . Patients who fail sulfonylurea usually fall into two groups: Those with low C-peptide levels and high (>250 mg/ dL ) FPG levels . Sulfonylureas cont….: Sulfonylureas cont…. 89 Factors that facilitate a positive response include; Newly diagnosed patients with no indicators of type 1 DM, High fasting C-peptide levels, and Moderate fasting hyperglycemia (<250 mg/dL). Sulfonylureas cont….: Sulfonylureas cont…. 90 Adverse Effects. The most common side effect of sulfonylureas is hypoglycemia Hyponatremia (serum sodium <129 mEq/L) is reportedly associated with tolbutamide Weight gain Short-Acting Insulin Secretagogues: Short-Acting Insulin Secretagogues 91 Nateglinide and repaglinide stimulate insulin secretion from the β cells of the pancreas, similarly to sulfonylureas. both require the presence of glucose to stimulate insulin secretion. are rapid acting insulin secretagogues that are rapidly absorbed (~0.5 to 1 hour) and have a short half-life (1 to 1.5 hours). Short-Acting Insulin Secretagogues…: Short-Acting Insulin Secretagogues… 92 The lower efficacy of these agents versus sulfonylureas should be considered when patients are >1% above their HbA1c goal. addition of either agent to a sulfonylurea will not result in any improvement in glycemic parameters. Adverse Effects. Weight gain of 2 to 3 kg has been noted with repaglinide, whereas weight gain with nateglinide appears to be <1 kg. Hypoglycemia Biguanides: Biguanides 93 Metformin is the only biguanide Enhances insulin sensitivity of both hepatic and peripheral (muscle) tissues Has approximately 50% to 60% oral bioavailability, low lipid solubility, and a volume of distribution that approximates body water. Is not metabolized and does not bind to plasma proteins. Metformin cont…: Metformin cont… 94 Metformin is eliminated by renal tubular secretion and glomerular filtration The average half-life of metformin is 6 hours , although pharmacodynamically, metformin’s antihyperglycemic effects last >24 hours . consistently reduces HbA1c levels by 1.5% to 2.0%, FPG levels by 60 to 80 mg/dL , and retains the ability to reduce FPG levels when they are extremely high (>300 mg/dL). Metformin cont….: Metformin cont…. 95 Decreases plasma triglycerides and LDL-C by approximately 8% to 15%, as well increasing HDL-C very modestly (2%). Metformin reduces levels of plasminogen activator inhibitor-1 and causes a modest reduction in weight (2 to 3 kg). Metformin should be included in the therapy for all type 2 DM patients, if tolerated and not contraindicated, as it is the only oral antihyperglycemic medication proven to reduce the risk of total mortality and is generic . Metformin cont…: Metformin cont… 96 Adverse Effects. GI side effects, including abdominal discomfort, stomach upset, and/or diarrhea in approximately 30% of patients. Anorexia and stomach fullness Rarely causes lactic acidosis. serum creatinine of 1.4 mg/dL in women and 1.5 mg/dL in men or greater, is contraindication , as it is renally eliminated If the GFR is less 70ml/min , contraindicated Metformin cont…: Metformin cont… 97 Metformin immediate-release is usually dosed 500 mg twice a day with the largest meals to minimize GI side effects. Metformin can be increased by 500 mg weekly until glycemic goals or 2,000 mg/day is achieved Approximately 80% of the glycemic -lowering effect can be seen at 1,500 mg, and 2,000 mg/day is the maximal effective dose . Thiazolidinediones (TZDs or glitazones): Thiazolidinediones (TZDs or glitazones) 98 Pioglitazone and rosiglitazone enhance insulin sensitivity at muscle, liver, and fat tissues indirectly. are well absorbed with or without food. Both are highly (>99%) protein bound to albumin The half-life is 3 to 7 hours and 3 to 4 hours, respectively have a duration of antihyperglycemic action of more than 24 hours. They are given for approximately 6 months, reduce HbA1c values ~1.5% and reduce FPG levels by approximately 60 to 70 mg/dL at maximal doses. Thiazolidinediones cont….: Thiazolidinediones cont…. 99 Glycemic-lowering onset of these drugs is slow, and maximal glycemic-lowering effects may not be seen until 3 to 4 months of therapy Thiazolidinediones cont….: Thiazolidinediones cont…. 100 Adverse Effects Elevated liver enzymes Patients with ALT levels >2.5 times the upper limit of normal should not start either medication, and if the ALT is >3 times the upper limit of normal the medication should be discontinued. Fluid retention- edema, dilutional anemia, c/I for pts with stage III and IV HF Wt gain , increase fracture rate in women (upper limb), resume ovulation Exenatide: Exenatide 101 glucagon-like peptide-1 agonist (GLP-1 agonist) Shares approximately 50% amino acid sequence with human glucagon-like peptide (GLP-1). Enhances glucose dependent insulin secretion while suppressing inappropriately high postprandial glucagon secretion in the presence of elevated glucose concentrations, resulting in a reduction in hepatic glucose production Exenatide cont….: Exenatide cont…. 102 Exenatide significantly decreases postprandial glucose excursions but has only a modest effect on FPG values. The average HbA1c reduction is approximately 0.9% with exenatide Weight loss ADR: N,V,D Pramlintide: Pramlintide 103 Is a synthetic analog of amylin (amylinomimetic), a neurohormone co-secreted from the β cells with insulin. Suppresses inappropriately high postprandial glucagon secretion, reduces food intake, which can result in weight loss, and slows gastric emptying Pramlintide cont….: Pramlintide cont…. 104 The average HbA1c reduction is approximately 0.6% with pramlintide, although optimization of the insulin and pramlintide doses can result in further drops in HbA1c. Results in 1.5 kg weight loss. Dipeptidyl peptidase IV enzyme (DPP-IV) inhibitors: Dipeptidyl peptidase IV enzyme (DPP-IV) inhibitors 105 Sitagliptin and vildagliptin prolong the half-life of an endogenously produced glucagon-like peptide-1 (GLP-1). The average reduction in HbA1c is approximately 0.7% to 1% at a dose of 100 mg a day α-Glucosidase Inhibitors: α- Glucosidase Inhibitors 106 Acarbose and miglitol α- Glucosidase inhibitors competitively inhibit enzymes (maltase, isomaltase, sucrase, and glucoamylase) in the small intestine, delaying the breakdown of sucrose and complex carbohydrates The net effect from this action is to reduce the postprandial blood glucose rise PowerPoint Presentation: 107 Postprandial glucose concentrations are reduced (40 to 50 mg/dL), whereas fasting glucose levels are relatively unchanged (~10% reduction). Efficacy on glycemic control is modest (average reductions in HbAlc of 0.3% to 1%), affecting primarily postprandial glycemic excursions. The GI side effects, such as flatulence, bloating, abdominal discomfort, and diarrhea, are very common and greatly limit the use of α-glucosidase inhibitors. THERAPEUTICS: THERAPEUTICS 109 Type 1 DM Type 1 DM patients generally require between 0.5 and 1 unit/kg per day. Empirically, patients can begin on ~0.6 unit/kg per day with basal insulin 50% of total dose and prandial insulin 20% of total dose prebreakfast, 15% prelunch, and 15% presupper. Type 2 DM: Type 2 DM 110 Patients with HbAlc ~7% or less are usually treated with therapeutic lifestyle measures and an agent that will not cause hypoglycemia. Those with HbAlc >7% but <8% could be initially treated with single oral agents, or low dose combinations. Patients with higher initial HbAlc can benefit from initial therapy with two oral agents, or even insulin. PowerPoint Presentation: 111 Obese patients (>120% ideal body weight) without contraindications should be started on metformin titrated to ~2,000 mg/day. Near normal weight patients can be treated with insulin secretagogues Failure of initial therapy should result in addition rather than substitution of another class of drug Initial oral combination therapy for patients with HbAlc >9% to 10% should be considered PowerPoint Presentation: 112 If the HbA1c is >8.5% to 9% on multiple therapies, insulin therapy should be considered first thiazolidinediones ( TZDs), exenatide, vildagliptin, and sitagliptin can potentially preserve β-cell function Sulfonylureas are often stopped when insulin is added, but continuing the sulfonylurea is permissible until multiple daily injections are started, at which time it should definitely be discontinued Gestational DM: Gestational DM 113 If FPG is >105 mg/dL, or 1-hour postprandial plasma glucose levels are >155 mg/dL, or if 2-hour postprandial plasma glucose levels are >130 mg/dL, insulin therapy is usually begun. One shot of NPH or a mixture of NPH and regular insulin in a 2:1 ratio given before breakfast may be adequate to reach glucose targets. PowerPoint Presentation: THANK YOU

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