Presentation on theme: "Biochemical Aspects of Diabetes Mellitus"— Presentation transcript:
1 Biochemical Aspects of Diabetes Mellitus ENDO 412
2 OverviewDM is a heterogeneous group of syndromes characterized by an elevation of fasting blood glucose caused by absolute or relative deficiency of insulinTwo types of DM:Type 1 (insulin-dependent DM)Type 2 (noninsulin dependent DM)Prevalence of type 2 is increasing as:Aging (increase in rate of life-age of population)Increasing prevalence of obesity
5 Type 1 Diabetes Mellitus about 10% of diabetics (in USA)Onset: usually during childhoodCaused by absolute deficiency of insulin :may be caused by autoimmune attack of b-cells of the pancreas, viral infection or toxinDestruction is enhanced by environmental factors as viral infection & a geneticelement (that allows b-cells to be recognized as nonself)In identical twins if one sibling has type 1 DM, the other twin has only % chance of developing DMRapid symptoms appear when 80-90% of the b-cells have been destroyedCommonly complicated by diabetic ketoacidosis (DKA)Treated only by insulin
7 Metabolic changes of type 1 DM 1- Hyperglycemia2- Diabetic Ketoacidosis (DKA)3- Hypertriacylglyceridemia & hypercholestrolemia
8 Metabolic changes of type 1 DM (cont.) 1- Hyperglycemia: increased glucose in bloodDue to:Decreased glucose uptake by muscles & adipose tissues (by GLUT-4)& Increased hepatic gluconeogenesis (& glycogenlysis)2- Diabetic Ketoacidosis (DKA):Increased ketone bodies in blood (ketonemia) leads to metabolic acidosisDKA occurs in untreated or uncontrolled cases of DM- In 25 – 40% of newly diagnosed type 1 DM (untreated & uncontrolled yet)- In stress states demanding more insulin (as during infection, illness or during surgery Uncontrolled DM)- No comply with therapy (intake of meals with no insulin medication i.e. Uncontrolled DM)Biochemical causes of diabetic ketoacidosis (DKA)Absence of insulin leads to increased mobilization of FFA from adipose tissuesin the liver, FFA are oxidized to yield excess acetyl CoA that will synthesize KETONE BODIES.
9 Carbohydrates Metabolism Metabolic changes of type 1 DM (cont.) Metabolic & Clinical Abnormalities in DKALow InsulinCarbohydrates MetabolismIn Sk. Ms. & Adipose In LiverGlucose Uptake GlycogenlysisGluconeogenesisLipids MetabolismLipolysisin Adipose TissueFatty Acidsin liverketone Bodies(KETOGENESIS)Protein MetabolismProteolysisUptake of AA by liverGluconeogenesisHyperglycemiaPlasmaOsmolalityComaPrerenal UremiaGlycosuriaMetabolicAcidosisLowRenal H+ExcretionOsmotic diuresisKetonemiaWith Loss of water & Na+& HypovolemiaLowBloodBicarbonateLow pCO2Nausea&VomitingAcetoneSmelton BreathIncreasedRespirationKetonuriaPolyuria,&DehydrationThirstLow GFR
10 Metabolic changes of type 1 DM (cont Metabolic changes of type 1 DM (cont.) Metabolic & Clinical Abnormalities in DKADiagnosis of DKA1- History (for a cause of DKA)2- Clinical Examination3- Lab Investigations: (to confirm the diagnosis & follow up of treatment)- Urine by dipstick: Glucose & Ketones +++ (RAPID TEST)- Blood Chemistry Analysis:* Blood Glucose: High* Blood Urea: High (due to dehydration)* Electrolytes: Low (or normal) sodiumHigh (or normal) potassium* Assessment of acid-base status: (metabolic acidosis)- Blood Bicarbonate: Low (usually below 5 mmol/L)- pCO2: Low (compensatory)
11 Biochemical Basis of Treatment of DKA Metabolic changes of type 1 DM (cont.) Metabolic & Clinical Abnormalities in DKABiochemical Basis of Treatment of DKAAIM: (EMERGENCY TREATMENT)1- Correction of dehydration (Hypovolemia): by IV fluids & Sodium2- Correction of acidosis: by IV bicarbonate3- Correction of metabolic abnormality: by insulin IV infusion4- Potassium is given with insulin treatment as insulin induces K+ entry into cells5- IV GLUCOSE SHOULD BE STARTED IN CASE GLUCOSE IN BLOOD FALLS BELOW 10 mmol/L (AVOID HYPOGLYCEMIA INDUCED BY INSULIN)6- FOLLOW UP is QUITE IMPORTANT to monitor*Blood glucose level*Electrolytes (Na+ & K+)*Acid-base status (blood bicarbonate level)
12 Metabolic changes of type 1 DM (cont.) 3- Hypertriacylglyceridemia & hypercholestrolemia:Released fatty acids from adipose tissues are converted to triacylglycerol & cholesterol in the liver.Triacylglycerol is secreted from the liver in VLDL to blood (with liver cholesterol)Chylomicrons (from diet fat) accumulates (due to low lipoprotein lipase activity as a result of low or absent insulin)Chylomicrons contain Triacyglycerols (mainly) & CholesterolIncreased VLDL & chylomicrons in blood results inhypertriacylglyceridemia & hypercholesterolemia
14 Diagnosis of type 1 DM Clinically: Laboratory diagnosis: Age: during childhood or puberty (< 20 years of age)With Abrupt (Sudden) appearance of :Polyuria (frequent urination)Polydepsia (excessive thirst)Polyphagia (excessive hunger)FatigueWeight lossComplication as ketoacidosis (common, may be the cause of diagnosis)Laboratory diagnosis:Fasting blood glucose: > or equal 126 mg/dl100 – 125 mg/dl is called impaired fasting blood glucoseHBA1c: High (more than 6% of normal hemoglobin)Insulin level in blood: lowCirculating islet-cell antibodies detection
15 Biochemical Aspects for Treatment & Control of Type 1 DM AIMExogenous insulin by subcutaneous injection is given to:1- Control Hyperglycemia (long run complications)&2- Prevent occurrence of Ketoacidosis (emergency case!!)Strategies of Treatment1- Standard Treatment2- Intensive Treatment (Tight Control)
16 Biochemical Aspects for Treatment & Control of Type 1 DM (cont.) 1- Standard Treatment:By one or two injections of insulin/dayAIM: Mean blood glucose level mg/dl (normal: 110 mg/dl)HbA1c level: 8-9 % of total Hb (normal: 6% of total hemoglobin)HbA1c:is proportional to average blood concentration over the previous several monthsSo, it provides a measure of how proper treatment normalized blood glucose in diabetic overseveral months
17 Treatment of type 1 DM (cont.) 2- Intensive Treatment: (Tight control)By more frequent monitoring & subsequent injection of insulin(i.e. 3 or more times / day)It will more closely normalize blood glucose to prevent chronic complications of existence of hyperglycemia for a long period.AIM: Mean blood glucose levels of 150 mg/dlHbA1c : approximately 7% of total hemoglobinAdvantage: Reduction in chances of occurrence of chronic complications of DM:e.g. retinopathy, nephropathy & neuropathy by about 60%
18 Biochemical Aspects for Treatment & Control of Type 1 DM (cont.) Complications of Treatment by InsulinHypoglycemia is a common complication of insulin treatment(in more than 90% of patients on insulin medication)More Common with intensive treatment strategyCauses of hypoglycemia due to insulin treatmentDiabetics cannot depend on glucagon or epinephrine to avoid hypoglycemia as:No glucagon (early in the disease)No epinephrine (with progression of the disease diabetic autonomic neuropathy with inability tosecrete epinephrine in response to hypoglycemia)So, patients with long-standing type 1 DM are particularly vulnerable to hypoglycemiaHypoglycemia can be caused by strenuous exercise.Exercise promotes glucose uptake into muscles & decrease the need for exogenous insulin.So, blood glucose level should be checked before & after exercise to avoid hypoglycemia.
19 Contraindications of Intensive Treatment Biochemical Aspects for Treatment & Control of Type 1 DM (cont.)Contraindications of Intensive TreatmentChildren: risk of episodes of hypoglycemia may affect thebrain developmentElderly people: as hypoglycemia can cause strokes & heartattacks in older people
21 Type 2 DM 90% of diabetics (in USA) Develops gradually may be without obvious symptomsmay be detected by routine screening testsBUT: many type 2 diabetics have symptoms of polyuria & polydepsiaIn type 2 DM: a combination of insulin resistance & dysfunctional b-cellsMetabolic changes in type 2: are milder than type 1as insulin secretion, although not adequate, restrains ketoacidosisDiagnosis: blood glucose concentration equal or more than 126 mg/dlTreatment : no requirement for insulin to sustain lifeBUT: insulin may be required to control hyperglycemia in some patients
22 Causes of Type 2 DM Insulin Resistance & Dysfunctional b-cell Insulin resistance is the decreased ability of target tissues, such as liver, adipose tissue & muscle to respond properly to normal circulating insulinObesity is the most common cause of insulin resistanceObesity causes insulin resistance as:- substances produced by fat cells as leptin and resistin may contribute todevelopment of insulin resistance- Free fatty acids elevated in obesity is involved in insulin resistance
23 Causes of type 2 DM (cont.) Insulin Resistance & Dysfunctional b-cell Obesity, Insulin Resistance & DMObesity is the most common cause for insulin resistance.HOWEVER, Most people with obesity & insulin resistance do not develop DM !!How insulin resistance leads to DM??1- In the absence of defect in b-cell function, nondiabetic, obese individuals can compensate for insulin resistance by secreting high amounts of insulin from b-cell (i.e. Hyperinsulinemia)So, glucose levels in blood remain within normal range2- In late cases, b-cell dysfunction with low insulin secretion occurs due to increased amounts of free fatty acids & other factors secreted by fat cells (as leptin & resistin) may end in development of type 2 DM (hyperglycemia).
24 Causes of type 2 DM (cont.) Insulin resistance & dysfunctional b-cell In Type 2 DMInitially (In early stages : with Insulin resistance)the pancreas retains b-cell capacityInsulin is secreted (may be higher than normal i.e. hyperinsulinemia)Normal blood glucose levels________________________________________________With time (late stages)b-cells become dysfunctional (low function)(due to harmful effects of FFAs & substances released by increased fat cells)b-cells fail to secrete enough insulin (low insulin)Increased blood glucose levels (hyperglycemia)
26 Metabolic changes in Type 2 DM Metabolic abnormalities of type 2 DM are the results of insulin resistance (in liver, muscle & adipose tissue)1- Hyperglycemia2- Hypertriacylglyceridemia3- Nonketotic hyperglycemic comaIn cases with severe hyperglycemia especially in older age diabetics type 2Hyperglycemia induces osmotic diuresis with loss of ECFThe osmotic diuresis causes loss of water in excess of sodiumleading to very high plasma osmolality (with hypernatremia)& marked dehydrationNo ketgenesis due to presence of sufficient insulin to prevent DKA(or sometimes there is minimal ketogenesis with minimal metabolicacidosis i.e. Bicarbonate is not much lowered as in DKA)Treatment:Fluid replacement + Insulin IV infusion + follow up (Emergency Case!!)
28 The long-standing hyperglycemia causes the chronic complications of DM Chronic Effects of DMThe long-standing hyperglycemia causes the chronic complications of DM1- Atherosclerosis :Diabetic RetinopathyDiabetic Nephropathy: glomerular proteinuriaDiabetic Neuropathy: peripheral neuritisCardiovascular Diseases (as MI) & strokes (as cereb. hge)2- Sorbitol accumulation in certain cells with its complications3- Glycated proteins formation with microvascular complicationsFor avoiding these complications, long-term control of hyperglycemia is recommended for all types of DM
29 Chronic Effects of DM (cont.) In cells where entry of glucose is not dependent on insulin(eye lens, retina, kidney, neurones)Intracellular Levels of GlucoseSORBITOL accumulation in these cellsCataractDiabetic RetinopathyDiabetic NephropathyDiabetic Neuropathy
30 Treatment of Type 2 DM AIM: Lines of treatment: 1- To maintain blood glucose concentrations within normal limits2- To prevent the development of long-term complications occurring dueto prolonged hyperglycemiaLines of treatment:1- Weight reduction (to control insulin resistance)2- Exercise3- Dietary modification4- Hypoglycemic agents5- Insulin (required in some cases)
31 Case Study What investigations were recommended for him?? Parents of a 15 years old boy was reported by his school that he was found drowsy & they havegot to take him to hospital according to the advice of his school doctor.In the hospital, his mother told the doctor that her son seemed unusually thirsty for the last 3months & she thought that he had lost weight. She admitted also that on the morningbefore leaving for school, he was complaining of abdominal pain & discomfort.On examination:SemiconsciousDeep & rapid respirationPulse rate 120 beats/minuteBP: 90/50Cold extremitiesWhat investigations were recommended for him??What is the diagnosis of this case??What is the treatment ??