1Diabetes Mellitus Dr: Wael H.Mansy, MD Assistant Professor College of PharmacyKing Saud University
2Diabetes Mellitus Study Objectives • List the effects of insulin and glucagon in the body.• List the factors that put an individual at risk for developing diabetes.• Discuss the possible etiology of type I and type II diabetes.• Define the three “ploys.” Why do they occur?• What are the manifestations of diabetic ketoacidosis? Why does it occur?• What is hyperosmolar -hyperglycemic syndrome? Why does it occur?• Discuss pharmacologic and nonpharmacologic treatment for diabetes .• Discuss possible mechanisms of tissue injury in diabetes mellitus.• List the major effects of chronic diabetes mellitus. Why does each occur?• Define gestational diabetes
3Diabetes MellitusGroup of metabolic disorders characterized by hyperglycemia resulting from either or both:insufficient insulin secretionresistance to the action of insulinAbnormalities in carbohydrate, fat, protein metabolism
4Effects of Insulin on Various Tissues Adipose TissueIncreased glucose entryIncreased fatty acid synthesisIncreased glycerol phosphate synthesisActivation of lipoprotein lipaseInhibition of hormone-sensitive lipaseIncreased K+ uptakeMuscleIncreased glycogen synthesisIncreased amino acid uptakeIncreased protein synthesis in ribosomesDecreased release of gluconeogenic amino acidsIncreased ketone uptakeLiverDecreased ketogenesisIncreased protein synthesisIncreased lipid synthesisDecreased glucose output due to decreased gluconeogenesis, increased glycogen synthesis, and increased glycolysisGeneralIncreased cell growth
5Insulin stimulates hepatic glucose storage as glycogen; in adipose tissue as triglycerides; and amino acid storage in muscle as protein; it also promotes utilization of glucose in muscle for energy. These pathways, which also are enhanced by feeding, are indicated by the solid blue arrows. Insulin inhibits the breakdown of triglycerides, glycogen, & protein and conversion of amino acids to glucose (gluconeogenesis), as indicated by the white arrows. These pathways are increased during fasting and in diabetic states. Conversion of amino acids to glucose & glucose to fatty acids occurs primarily in the liver.
7Diabetes Classification Majority of diabetics classified in 2 categories:type 1: absolute deficiency of insulintype 2: presence of insulin resistance with reduced insulin secretionGestational diabetestriggered by stress of pregnancyOther specific types:infections, drugs, endocrinopathies, pancreatic destruction, genetic defects7
9Type 1 DM Autoimmune destruction of pancreatic β-cells ~90% of patients have markers of immune β-cell destruction at diagnosischildren & adolescents often have rapid β-cell destruction & present with ketoacidosismay occur at any ageKnown as latent autoimmune diabetes in adults (LADA)slowly progressivesufficient insulin secretion to prevent ketoacidosis for many years9
10LADALatent Autoimmune Diabetes in Adults (LADA) is a form of autoimmune (type 1 diabetes) which is diagnosed in individuals who are older than the usual age of onset of type 1 diabetes.Alternate terms that have been used for "LADA" include Late-onset Autoimmune Diabetes of Adulthood, "Slow Onset Type 1" diabetes, and sometimes also "Type 1.5Often, patients with LADA are mistakenly thought to have type 2 diabetes, based on their age at the time of diagnosis.Autoimmune (type 1 diabetes)type 2 diabetes
12Type 1 DM Pathogenesis Preclinical period Hyperglycemia immune markers presentβ-cell destructionHyperglycemia80 to 90% of β-cells destroyedTransient remissionhoneymoon phaseEstablished disease12
13Type 2 DM Insulin resistance, relative lack of insulin secretion Usually presents with cluster of abnormalities known as metabolic syndrome:abdominal obesityhypertensiondyslipidemiaelevated PAI-1 (plasminogen activator inhibitor-1) levelsIncreased macrovascular complication risk13
14NCEP ATP III: Components of the Metabolic Syndrome (> 3 for diagnosis) Risk FactorDefining LevelAbdominal obesityaMen (waist circumference)b> 102 cm (> 40 in.)Women> 88 cm (> 35 in.)Triglycerides> 1.7 mmol/L (> 150 mg/dL)HDL cholesterolMen< 1.0 mmol/L (< 40 mg/dL)< 1.3 mmol/L (< 50 mg/dL)Blood Pressure≥ 130/≥ 85 mmHgFasting glucose> 6.1 mmol/L ( > 110 mg/dL)NCEP-ATP: National Cholesterol Education Program Adult Treatment Panel
15Screening Type 1 Type 2 not recommended low prevalence, acute symptoms fasting plasma glucose (FPG) recommendedalternative: oral glucose tolerance test (OGTT)more costly, less convenient, less reproducibleHbA1c (HbA1c reflects glucose levels for the previous 2 to 3 months)no gold standard assayuseful in monitoring glycemic control after diagnosis15
16Glucose Tolerance Test Blood glucose curves of a normal and a diabetic person after oral administration of 1 g of glucose/kg body weight.Note the initial raised concentration in the fasting diabetic.A criterion of normality is the return of the curve to the initial value within 2 hours.
17ADA Type 2 Diabetes Screening Recommendations Type 2 DM ScreeningADA Type 2 Diabetes Screening RecommendationsChildren & AdolescentsEvery 3 years at age 10 or onset of puberty if overweighta with two additional risk factorsbAdultsEvery 3 years in adults ≥ 45 years of age or earlier if overweightc & additional risk factors presentaBMI > 85th percentile for age & sex, > 85th percentile weight for height, or > 120% of ideal weight for height bFamily history of DM2 in 1st or 2nd degree relative; high risk ethnic group; signs of insulin resistance; maternal history of gestational diabetes during child’s gestation c BMI ≥ 25kg/m2American Diabetes Association. Standards of medical care in diabetes Diabetes Care 2009;32:S13-S61.
18Type 2 DM Risk Factors BMI ≥ 25 Physical inactivity 1st degree relative with DMHigh risk ethnic group (Latino, African American, Native American, Asian American, Pacific Islander)IFG, IGTHTN: ≥ 140/90 mmHg or on therapy for HTNCV diseaseHDL < 35 mg/dLTriglycerides > 250 mg/dLDelivery of > 9 lb babyHistory of GDMInsulin resistancePolycystic ovary syndromeAmerican Diabetes Association. Standards of medical care in diabetes Diabetes Care 2009;32:S13-S61.
19Screening for Gestational DM Risk assessment at 1st prenatal visitScreen high risk women as soon as possiblefamily history of DMhistory of GDMmarked obesitypresence of glycosuriadiagnosis of PCOSIf initial screening negative, retest high risk women at 24 to 28 weeks gestation19American Diabetes Association. Standards of medical care in diabetes Diabetes Care 2009;32:S13-S61.
20Gestational diabetes mellitus Any degree of glucose intolerance with onset or first recognition during pregnancy, most commonly seen during the third trimester of pregnancy (in about 1 to 6% of pregnancies).More common among obese women and women with a family history of diabetes.Resolves itself in most patients after birth but in certain percentage (50 to 60%) type 2 diabetes will develop within 10 yrs of initial diagnosis.May be associated with an increased risk of fetal abnormalities.Currently recommended that all pregnant women be screened for the presence of gestational diabetes.
22ADA Criteria for DM Diagnosis 1Fastinga plasma glucose (FBG) ≥ 126 mg/dL2Symptoms of diabetesb & casualc plasma glucose ≥ 200 mg/dL32-hour plasma glucose ≥ 200 mg/dL during OGTTdIn absence of unequivocal hyperglycemia: confirm on different daya Fasting: no caloric intake for at least 8 hoursb Classic symptoms: polyuria, polydipsia, unexplained weight lossc Causal: any time of day without regard to last meald Oral glucose tolerance test: equivalent to 75-g anhydrous glucose in H2O; not recommended for routine clinical useDiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:
24Clinical Presentation of Diabetesa Characteristic Type 1 DM Type 2 DM Age< 30 yearsb> 30 yearsbOnsetAbruptGradualBody habitusLeanObese or history of obesityInsulin resistanceAbsentPresentAutoantibodiesOften presentRarely presentSymptomsSymptomaticcOften asymptomaticKetones at diagnosisAbsentdNeed for insulin therapyImmediateYears after diagnosisAcute complicationsDiabetic ketoacidosisHyperosmolar hyperglycemic stateMicrovascular complications at diagnosisNoCommonMacrovascular complications at or before diagnosisRareaClinical presentation can vary widely. bAge of onset for type 1 DM is generally < 20 years of age but can present at any age. The prevalence of type 2 DM in children, adolescents, and young adults is increasing. This is especially true in ethnic and minority children. cType 1 can present acutely with symptoms of polyuria, nocturia, polydipisia, polyphagia, weight loss. dType 2 children and adolescents are more likely to present with ketones but after the acute phase can treated with oral agents. Prolonged fasting can also produce ketones in individuals.
25Diabetes Mellitus Manifestations: Symptoms of diabetes appear when the levels of glucose are either very high or very low.Many persons with diabetes and all those with pre-diabetes do not have symptoms.Children may also feel very tired all the time.
26Diabetes Mellitus Manifestations: Weight loss. The three “ploys” : Polydepsia (increased thirst),Polyphagia (increased appetite),Polyuria (increased urine output).Weakness and fatigue due to poor energy utilization and skeletal muscle catabolism .
27Diabetes Mellitus Why do the three “polys” occur? Polyuria :Excess blood glucose filtered by the kidneys cannot be reabsorbed and is eliminated at the expense of water.Polydepsia : Excessive thirst caused by the osmotic diuresis of glucose and subsequent tissue dehydration. The thirst response is mediated by the hypothalamus.Polyphagia: Poor utilization of carbohydrates (due to the lack of insulin) results in depletion of stored fats, proteins and carbohydrates.
28- INSULIN Fatty Acids INSULIN+ Diabetes MellitusManifestations:Diabetic ketoacidosisAccumulation of acidic ketone bodies in the blood due to a lack of insulin stimulated fatty acid utilization. Much more common in type I than type 2Ketone Bodies(β-hydroxybutyrate)(acetoacetate)(acetone)- INSULIN Fatty Acids INSULIN+Energy
29Diabetes Mellitus Manifestations: Manifestations of Diabetic KetoacidosisDecreased blood pH levels.Ketonuria — Appearance of excess ketones in the urine.Lethargy.Nausea and vomitingSevere dehydration.Markedly increased respiratory rate as an attempt to correct decreased blood pH.Acetone breath — Acetone is a volatile ketone body that is eliminated via the lungs; may be noticeable in the exhaled air during diabetic ketoacidosis.Coma and possible death.
30Diabetes Mellitus Manifestations: Hyperglycemic Hyperosmolar Syndrome A syndrome of type I diabetes mellitus that can result from acute insulin deficiency.It may often accompany diabetic ketoacidosis.The manifestations include:Severe dehydrationExtreme thirstSerum osmolarity over 300 mOsm due to excessive glucose in the bloodOsmotic diuresis of glucoseDepressed neurologic functionPossible shock, coma and death
31Diabetes: Complications MacrovascularMicrovascularStrokeDiabetic eye disease(retinopathy and cataracts)Heart disease and hypertension2-4 X increased riskRenal diseasePeripheralvascular diseaseErectile DysfunctionThe risk of CAD and stroke is increased two to four times in patients with diabetes. Cardiovascular disease is a major cause of morbidity and mortality in diabetes. Morbidity and mortality rates are two to four times higher than in age- and sex-matched groups in the population without diabetes.The eye and the kidney are common sites for microvascular complications of diabetes. Diabetic retinopathy is the leading cause of adult blindness in North America. Cataracts and glaucoma are also significantly more frequent in patients with diabetes, especially those over age 65. Diabetes is the leading cause of end-stage renal failure.Foot problems, a frequent consequence of neuropathy and peripheral vascular disease, constitute a major complication. Diabetes is the leading cause of non-traumatic lower-extremity amputations in North America.Peripheral NeuropathyFoot problemsMeltzer et al. CMAJ 1998;20(Suppl 8):S1-S29.
32Diabetes Mellitus Complication: 1.Vascular Diseases Chronic diabetes mellitus is associated with significant increases in the incidence of coronary artery disease, cerebrovascular disease and peripheral vascular disease.May be due to a number of factors including elevated serum lipid levels, vascular injury, and enhanced atherogenesis (formation of atherosclerotic lesions).Coronary artery disease and stroke are significant sources of mortality and morbidity in patients with diabetes. Peripheral vascular disease can lead to gangrene and amputations (particularly of the toes and feet) in people suffering from diabetes.
33Diabetes Mellitus Complication: 2.Diabetic neuropathy Abnormality of nerve conduction and function.Often affects peripheral nerves.Can involve sensory or motor neurons.May manifest as numbness, pain or sensory/motor impairment.Often progressive and irreversible.Although the exact cause is unknown, the neuropathy may be related to ischemia or altered nerve cell metabolism.
34Diabetes Mellitus Complication: 3.Diabetic Retinopathy Pathogenesis of DR:The most serious consequence of long-term diabetes in terms of the eye is retinal damage.The retina is a highly metabolic tissue that is especially vulnerable to the effects of chronic hypoxia and diabetes.Hemorrhage of eye capillaries and chronic inflammation is common and can lead to increases in intraocular pressure that scar the retina and impair vision. This phenomenon is usually progressive and can lead to blindness.Diabetes is also associated with an increased incidence of glaucoma and cataract formation.
36Diabetes Mellitus Complication: 4.Diabetic Nephropathy It is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli.The glomerular injury is characterized by thickening of the glomerular basement membrane and glomerulosclerosis.Although the exact etiology is unclear, trapping of glycosylated proteins in the glomeruli appears to be a key contributing factor.The appearance of protein (albumin) in the urine is an early indicator of altered glomerular permeability (Microalbuminuria).Renal function may continue to deteriorate as glomerular filtration decreases.Signs and symptoms of renal failure will appear as renal function continues to decline.
37Diabetes Mellitus Complication: 5. Impaired healing and increased infectionsAs a result of peripheral vascular disease, injuries in patients with diabetes do not heal properly. Poor blood flow limits the delivery of leukocytes and oxygen to the injured area while impairing removal of debris and infectious organisms.The high glucose levels serve as a nutrient to support the growth of microorganisms.Patients with diabetes might also be more susceptible to physical injuries as a result of impaired vision and sensory perception.
38Erectile dysfunctionErectile dysfunction (ED, "male impotence") is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance.Since penile erection is neurovascular process, diabetic patients usually suffer from vascular complications that affect penile blood flow as well as neuropathies that disturb the nervous control of penile erection.
39Diabetes Mellitus Complication: 6. Diabetic Foot Pathogenesis: Loss of protective sensation.Starts distally and migrates proximally in “stocking” distribution.Mostly affects forefoot ulceration.It results from repeated improper shoe ware, deformity or injury by glass or any other objects.
40Possible Mechanisms of Tissue Injury in Chronic D M Diabetes MellitusComplication:Possible Mechanisms of Tissue Injury in Chronic D MGlycosylation of proteins : Attachment of glucose to proteins in the eye, blood vessel walls, and kidney membranes will change their structure and may lead to altered function and eventual damage of these tissues. Circulating glycosylated proteins may also be trapped in the glomeruli of the kidney, leading to inflammation and injury.Formation of alcohol sugars e.g. sorbitol : Unlike glucose, alcohol sugars do not easily diffuse out of tissues. Because these alcohol sugars are osmotically active, they can lead to swelling and damage of tissues. The accumulation of other sugars such as galactose might also contribute to this phenomenonPoor blood flow and oxygen delivery to tissues :Glycosylation of hemoglobin alters its affinity for oxygen while progressive vascular disease can reduce overall blood flow to tissues, leading to ischemic injury
41Fasting Blood Glucose Test (FBG)* Glucose Tolerance Test (GTT) ** Diabetes MellitusDiagnosis :Diagnosis CriteriaNormalPre diabetesDiabetesFasting Blood Glucose Test (FBG)*Less than100BetweenMore than or equalto 126Glucose Tolerance Test (GTT) **140Equal to or more than 140 butless than 200More than or equal to 200* FBG blood test is done after fasting 8 hours.** GTT results are repeated after 2 hours. A person drinks a 75 mg glucose solution before test. 100 mg for Pregnant women.
42To maintain target blood glucose Diabetes MellitusTreatmentOptimal diabetes control is a careful balance of Diet, Exercise, and Insulin and/or oral medicationGOAL:To maintain target blood glucose
43Diabetes Self-management what a person with diabetes should do by her/himself to maintain controlmeal plan (always eating healthy)exercise moderately (eg. walking 30 minutes a day), Exercise may enhance glucose utilization and improve glucose control in patients with type II diabetes, thus reducing the risk of diabetic complications.
44Treatment of diabetes mellitus The key to optimal diabetes control is a careful balance or juggling of food, exercise, and insulin and/or oral medication.As a general rule, insulin/oral medication and exercise/activity makes blood glucose levels go down.Maintaining good blood glucose control is a constant juggling act, 24 hours a day, 7 days a week.
452 to 3 portions2 to 4 portionsLess than one portion2 to 3 portions3 to 5 portions6 to 11 portions
46Type I of diabetes mellitus Treatment:Insulin replacement.Insulin must be administered by injection because an oral form would be degraded in the gastrointestinal tract.Insulin is generally available in three preparations:Short-acting form : Peak action in 2–4 hours, duration 6–8 hours.Intermediate-acting form :Peak action in 6–12 hours, duration 12–24 hours.Long-acting form : Peak action 8–24 hours, duration 24–36 hours.
47Type II of diabetes mellitus Oral therapy: prescribed after dietary control has been proven insufficient or if the client is highly symptomaticClassifications:SulfonylureasMeglitnide analogsBiguanidesAlpha-glucosidse inhibitorsThiazolidinedione antidiabetic agents
48Monitoring of DM Frequent measurement of blood glucose levels Measurement of glycosylated hemoglobin (Hb A1c, hemoglobin that has glucose bound to it) that forms at a rate that increases with increasing blood glucose, which is a useful measure of blood glucose control in patients with diabetes.
49Why should we educate diabetics about diabetes? BECAUSE…Controlling Glucose Levels through Self Management Every 1% drop of A1C significantly reduces the risk of eye, kidney, and nerve complicationsControlling Blood Pressure Will reduce the risk of heart disease or stroke by 33% to 50%.Controlling Lipids (fats) Will reduce cardiovascular complications by 20% to 50%.Careful foot care Will reduce amputations rates by 45% to 85%.Careful eye care Will reduce the development of severe vision loss by 50% - 60%.Careful kidney care Will reduce the decline in kidney function by 30% - 70%.