Biochemical Aspects of Diabetes Mellitus ENDO 412

Biochemical Aspects ofBiochemical Aspects ofDiabetes MellitusDiabetes Mellitus

ENDO 412ENDO 412

OverviewOverview

• DM is a heterogeneous group of syndromes characterized by an DM is a heterogeneous group of syndromes characterized by an elevation of fasting blood glucose caused by absolute or relative elevation of fasting blood glucose caused by absolute or relative

deficiency of insulindeficiency of insulin

• Two types of DMTwo types of DM:: Type 1 (insulin-dependent DM)Type 1 (insulin-dependent DM) Type 2 (noninsulin dependent DMType 2 (noninsulin dependent DM)

• Prevalence of type 2 is increasing as:Prevalence of type 2 is increasing as: Aging (increase in rate of life-age of population)Aging (increase in rate of life-age of population) Increasing prevalence of obesityIncreasing prevalence of obesity

Comparison between type 1 & type 2 DMComparison between type 1 & type 2 DM

Type 1 Diabetes MellitusType 1 Diabetes Mellitus


• about 10% of diabetics 10% of diabetics (in USA)

• Onset: usually during childhood childhood

• Caused by absolute deficiency of insulin absolute deficiency of insulin : : may be caused by autoimmune attack of -cells of the pancreas, viral infection or toxin Destruction is enhanced by environmental factors as viral infection & a genetic element (that allows -cells to be recognized as nonself) In identical twins if one sibling has type 1 DM, the other twin has only 30- 50% chance of

developing DM

• Rapid symptoms appear when 80-90% of the 80-90% of the -cells -cells have been destroyed

• Commonly complicated by diabetic ketoacidosis (DKA)complicated by diabetic ketoacidosis (DKA)

• Treated Treated onlyonly by insulin by insulin

Onset of type 1 DMOnset of type 1 DM

1-1- HyperglycemiaHyperglycemia2-2- Diabetic Ketoacidosis (DKA)Diabetic Ketoacidosis (DKA)3- Hypertriacylglyceridemia & hypercholestrolemia3- Hypertriacylglyceridemia & hypercholestrolemia

Metabolic changes of type 1 DMMetabolic changes of type 1 DM

Metabolic changes of type 1 DMMetabolic changes of type 1 DM (cont.)(cont.)

1-1- HyperglycemiaHyperglycemia: increased glucose in bloodincreased glucose in blood Due to: Decreased glucose uptakeuptake by muscles & adipose tissues (by GLUT-4) & Increased hepatic gluconeogenesis gluconeogenesis (& glycogenlysis(& glycogenlysis))

2-2- DiabeticDiabetic Ketoacidosis (DKA)Ketoacidosis (DKA): IIncreased ketone bodies in blood (ketonemia) leads to metabolic acidosis ncreased ketone bodies in blood (ketonemia) leads to metabolic acidosis

DKA occurs in untreated or uncontrolled cases of DMDKA 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)Biochemical causes of diabetic ketoacidosis (DKA) Absence of insulin leads to increased mobilization of FFA from adipose tissues in the liver, FFA are oxidized to yield excess acetyl CoA that will synthesize KETONE BODIES.

Metabolic changes of type 1 DM Metabolic changes of type 1 DM (cont.)(cont.)

Metabolic & Clinical Abnormalities in DKAMetabolic & Clinical Abnormalities in DKA

Carbohydrates MetabolismCarbohydrates Metabolism

In Sk. Ms. & Adipose IIn Sk. Ms. & Adipose In n LiverLiver Glucose Uptake GlycogenlysisGlucose Uptake Glycogenlysis GluconeogenesisGluconeogenesis

Lipids MetabolismLipids Metabolism

LipolysisLipolysis in Adipose Tissuein Adipose Tissue

Fatty Acids Fatty Acids in liver in liver

ketone Bodiesketone Bodies (KETOGENESIS) (KETOGENESIS)

Protein MetabolismProtein Metabolism

Proteolysis Proteolysis Uptake of AA by liver Uptake of AA by liver

GluconeogenesisGluconeogenesis HyperglycemiaHyperglycemia

Low InsulinLow Insulin

GlycosuriaGlycosuria

Osmotic diuresisOsmotic diuresis

With Loss of water & Na+With Loss of water & Na+& Hypovolemia& Hypovolemia

KetonemiaKetonemia

Polyuria, Polyuria, &&

DehydrationDehydration

Acetone Acetone Smelt Smelt

on Breathon Breath

Metabolic Metabolic AcidosisAcidosis

Increased Increased RespirationRespiration

Low GFR Low GFR

LowLowRenal H+Renal H+ ExcretionExcretion

Prerenal UremiaPrerenal Uremia

PlasmaPlasmaOsmolalityOsmolality

ThirstThirst

ComaComa

Nausea Nausea & &

VomitingVomiting

LLow ow Blood Blood BicarbonateBicarbonate

Low pCO2Low pCO2

KetonuriaKetonuria

Diagnosis of DKADiagnosis of DKA1- HistoryHistory (for a cause of DKA)2- Clinical Examination Clinical Examination 3- Lab InvestigationsLab Investigations: (to confirm the diagnosis & follow up of treatment)

- UrineUrine by dipstick: Glucose & Ketones +++ (RAPID TEST)(RAPID TEST) - - BloodBlood Chemistry AnalysisChemistry Analysis::

* Blood GlucoseGlucose: High

* Blood UreaUrea: High (due to dehydration) * Electrolytes: Low (or normal) sodium High (or normal) potassium * Assessment of acid-base statusacid-base status: (metabolic acidosis) - Blood Bicarbonate: Low (usually below 5 mmol/L) - pCO2: Low (compensatory)



Biochemical Basis of Treatment of DKABiochemical Basis of Treatment of DKA

AIMAIM: (EMERGENCY TREATMENTEMERGENCY TREATMENT)1-1- Correction of Correction of dehydrationdehydration (Hypovolemia): (Hypovolemia): by IV fluids & Sodium

2- Correction of 2- Correction of acidosisacidosis: by IV bicarbonate

3- Correction of 3- Correction of metabolic abnormalitymetabolic abnormality: by insulin IV infusion

4- 4- PotassiumPotassium is given with insulin treatment as insulin induces K+ entry into cellsis given with insulin treatment as insulin induces K+ entry into cells

5-5- IV GLUCOSEIV GLUCOSE SHOULD BE STARTED IN CASE GLUCOSE IN BLOOD FALLS BELOW 10 mmol/L (AVOID SHOULD BE STARTED IN CASE GLUCOSE IN BLOOD FALLS BELOW 10 mmol/L (AVOID HYPOGLYCEMIA INDUCED BY INSULIN)HYPOGLYCEMIA INDUCED BY INSULIN)

6- FOLLOW UP is QUITE IMPORTANT FOLLOW UP is QUITE IMPORTANT to monitor to monitor **Blood Blood glucoseglucose level level *Electrolytes (*Electrolytes (Na+ & K+)Na+ & K+) *Acid-base status (blood *Acid-base status (blood bicarbonatebicarbonate level) level)




3- Hypertriacylglyceridemia & hypercholestrolemia:3- Hypertriacylglyceridemia & hypercholestrolemia: Released fatty acids from adipose tissues adipose tissues are converted to triacylglycerol & cholesterol

in the liver. Triacylglycerol is secreted from the liver in VLDL VLDL to blood (with liver cholesterol)

ChylomicronsChylomicrons (from diet fatdiet fat) accumulates (due to low lipoprotein lipase activity as a result of low or absent insulin)

Chylomicrons contain Triacyglycerols Triacyglycerols (mainly) & Cholesterol

Increased VLDL & chylomicrons in blood VLDL & chylomicrons in blood results in hypertriacylglyceridemia & hypercholesterolemiahypertriacylglyceridemia & hypercholesterolemia

Metabolic changes of type 1 DMMetabolic changes of type 1 DM

Diagnosis of type 1 DMDiagnosis of type 1 DM

• ClinicallyClinically::

Age: during childhood or puberty (< 20 years of age) With Abrupt (Sudden) appearance of : PolyuriaPolyuria (frequent urination) PolydepsiaPolydepsia (excessive thirst) PolyphagiaPolyphagia (excessive hunger) Fatigue Fatigue Weight lossWeight loss ComplicationComplication as ketoacidosis as ketoacidosis (common, may be the cause of diagnosis)

• Laboratory diagnosis:Laboratory diagnosis:

Fasting blood glucoseFasting blood glucose: > or equal 126 mg/dl: > or equal 126 mg/dl 100 – 125 mg/dl is called impaired fasting blood glucose HBA1cHBA1c: High (more than 6% of normal hemoglobin) Insulin level in bloodInsulin level in blood: low Circulating islet-cell antibodies detection Circulating islet-cell antibodies detection

Biochemical Aspects Biochemical Aspects for Treatment & Control of Type 1 DMfor Treatment & Control of Type 1 DM

AIMAIMExogenous insulin by subcutaneous injection is given to:Exogenous insulin by subcutaneous injection is given to:

1- Control 1- Control HyperglycemiaHyperglycemia (long run complications) (long run complications) & &

2- Prevent occurrence of 2- Prevent occurrence of KetoacidosisKetoacidosis (emergency case!!) (emergency case!!)

Strategies of TreatmentStrategies of Treatment

1- Standard Treatment1- Standard Treatment 2- Intensive Treatment (Tight Control)2- Intensive Treatment (Tight Control)

1- 1- Standard TreatmentStandard Treatment:: By one or two injections of insulin/dayBy one or two injections of insulin/day AIMAIM: Mean blood glucose levelMean blood glucose level 225-275 mg/dl 225-275 mg/dl (normal: 110 mg/dl) HbA1c levelHbA1c level: : 8-9 % of total Hb 8-9 % of total Hb (normal: 6% of total hemoglobin) HbA1c: HbA1c: is proportional to average blood concentration over the previous several months So, it provides a measure of how proper treatment normalized blood glucose in diabetic over several months

Biochemical Aspects Biochemical Aspects for Treatment & Control of Type 1 DM for Treatment & Control of Type 1 DM (cont.)

2- 2- Intensive TreatmentIntensive Treatment: : (Tight controlTight control) By more frequent monitoring & subsequent injection of insulin By more frequent monitoring & subsequent injection of insulin (i.e. 3 or more times / day)(i.e. 3 or more times / day) It will more closely normalize blood glucose to prevent It will more closely normalize blood glucose to prevent chronicchronic complications of complications of

existence of hyperglycemia for a long period.existence of hyperglycemia for a long period.

AIMAIM: Mean blood glucose levelsMean blood glucose levels of 150 mg/dl HbA1cHbA1c : approximately 7% of total hemoglobin

AdvantageAdvantage: Reduction in chances of occurrence of chronicchronic complications of DM: e.g. retinopathy, nephropathy & neuropathy by about 60%

Treatment of type 1 DM Treatment of type 1 DM (cont.)

Complications of Treatment by InsulinComplications of Treatment by Insulin

HypoglycemiaHypoglycemia is a common complication of insulin treatment is a common complication of insulin treatment (in more than 90% of patients on insulin medication)(in more than 90% of patients on insulin medication)

More Common More Common with intensive treatment strategywith intensive treatment strategy

Causes of hypoglycemia due to insulin treatmentCauses of hypoglycemia due to insulin treatment Diabetics cannot depend on glucagon or epinephrine to avoid hypoglycemia Diabetics cannot depend on glucagon or epinephrine to avoid hypoglycemia asas:: NoNo glucagon (earlyearly in the disease) NoNo epinephrine (with progressionprogression of the disease diabetic autonomic neuropathy with inability to secrete epinephrine in response to hypoglycemia) So, patients with long-standing type 1 DM are particularly vulnerable to hypoglycemiapatients with long-standing type 1 DM are particularly vulnerable to hypoglycemia

Hypoglycemia can be caused by strenuous exerciseHypoglycemia 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 hypoglycemiablood glucose level should be checked before & after exercise to avoid hypoglycemia.


Contraindications of Intensive TreatmentContraindications of Intensive Treatment

• ChildrenChildren: risk of episodes of hypoglycemia may affect the : risk of episodes of hypoglycemia may affect the brain developmentbrain development

• Elderly peopleElderly people: as hypoglycemia can cause strokes & heart as hypoglycemia can cause strokes & heart attacks in older peopleattacks in older people



Type 2 DMType 2 DM

• 90%90% of diabetics (in USA)• Develops gradually gradually • may be without obvious symptoms• may be detected by routine screening tests• BUT: many type 2 diabetics have symptoms of polyuria & polydepsia

• In type 2 DM: a combination of insulin resistance & dysfunctional insulin resistance & dysfunctional -cells-cells

• Metabolic changes in type 2Metabolic changes in type 2: are milder than type 1 as insulin secretion, although not adequate, restrains ketoacidosis • DiagnosisDiagnosis: blood glucose concentration equal or more than 126 mg/dl

• TreatmentTreatment : nono requirement for insulin to sustain life BUTBUT: insulin may be required to control hyperglycemia in some patients

Insulin resistance is the decreased ability of target tissues, such Insulin resistance is the decreased ability of target tissues, such as liver, adipose tissue & muscle to respond properly to as liver, adipose tissue & muscle to respond properly to

normal circulating insulinnormal circulating insulinObesityObesity is the most common cause of insulin resistance is the most common cause of insulin resistance

Obesity causes insulin resistance as:Obesity causes insulin resistance as: - substances produced by fat cells as leptin and resistin substances produced by fat cells as leptin and resistin may contribute to

development of insulin resistance - Free fatty acids elevated in obesity Free fatty acids elevated in obesity is involved in insulin resistance

Causes of Type 2 DM Causes of Type 2 DM Insulin Resistance & DysfunctionalInsulin Resistance & Dysfunctional-cell -cell

Obesity, Insulin Resistance & DMObesity, Insulin Resistance & DM

ObesityObesity is the most common cause for is the most common cause for insulin resistanceinsulin resistance.. HOWEVER, MostHOWEVER, Most people with obesity & insulin resistance do notnot develop

DMDM !!

How insulin resistance leads to DM??How insulin resistance leads to DM?? 1- In the absence of defect in -cell function, nondiabetic, obese individuals

can compensate for insulin resistance by secreting highhigh amounts of insulin from -cell (i.e. HyperinsulinemiaHyperinsulinemia)

So, glucose levels in blood remain within glucose levels in blood remain within normalnormal range range

2- In late cases, In late cases, -cell dysfunction with lowlow 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 of type 2 DM type 2 DM (hyperglycemiahyperglycemia).

Causes of type 2 DM Causes of type 2 DM (cont.)(cont.)Insulin Resistance & DysfunctionalInsulin Resistance & Dysfunctional-cell -cell

In Type 2 DMIn Type 2 DMInitially (In early stages : with Insulin resistance)Initially (In early stages : with Insulin resistance)

the pancreas the pancreas retainsretains -cell capacity -cell capacity

Insulin is secreted (may be higher than normal i.e. hyperinsulinemia) Insulin is secreted (may be higher than normal i.e. hyperinsulinemia)

Normal blood glucose levelsNormal blood glucose levels________________________________________________

With time (late stages)With time (late stages)

-cells become dysfunctional (low function) -cells become dysfunctional (low function) (due to harmful effects of FFAs & substances released by increased fat cells)(due to harmful effects of FFAs & substances released by increased fat cells)

-cells -cells failfail to secrete enough insulin (low insulin) to secrete enough insulin (low insulin)

Increased blood glucose levels (hyperglycemia)Increased blood glucose levels (hyperglycemia)

Causes of type 2 DM Causes of type 2 DM (cont.)(cont.)

Insulin resistance & dysfunctionalInsulin resistance & dysfunctional-cell -cell

Progression of Type 2 DMProgression of Type 2 DM

Metabolic changes in Type 2 DMMetabolic changes in Type 2 DM

Metabolic abnormalities of type 2 DM are the results of insulin resistance (in Metabolic abnormalities of type 2 DM are the results of insulin resistance (in liverliver, , musclemuscle & & adipose tissueadipose tissue) )

1- HyperglycemiaHyperglycemia 2- HypertriacylglyceridemiaHypertriacylglyceridemia3- Nonketotic hyperglycemic coma Nonketotic hyperglycemic coma In cases with In cases with severe hyperglycemia severe hyperglycemia especially in especially in older age older age diabetics diabetics type 2type 2 Hyperglycemia induces osmotic diuresis with loss of ECF Hyperglycemia induces osmotic diuresis with loss of ECF The osmotic diuresis causes loss of water in excess of sodiumThe osmotic diuresis causes loss of water in excess of sodium leading to very high leading to very high plasma osmolality plasma osmolality (with (with hypernatremiahypernatremia)) & marked dehydration& marked dehydration No ketgenesis No ketgenesis due to presence of sufficient insulin to prevent DKAdue to presence of sufficient insulin to prevent DKA (or sometimes there is (or sometimes there is minimal ketogenesis minimal ketogenesis with with minimal metabolic minimal metabolic acidosisacidosis i.e. Bicarbonate is not much lowered as in DKA) i.e. Bicarbonate is not much lowered as in DKA)Treatment:Treatment:Fluid replacement + Insulin IV infusion + follow up (Emergency Case!!)Fluid replacement + Insulin IV infusion + follow up (Emergency Case!!)

Metabolic changes in Type 2 DMMetabolic changes in Type 2 DM

Chronic Effects of DMChronic Effects of DM

The long-standing hyperglycemia causes the chronic The long-standing hyperglycemia causes the chronic complications of DMcomplications of DM

1- AtherosclerosisAtherosclerosis :Diabetic RetinopathyDiabetic Retinopathy

Diabetic Nephropathy: Diabetic Nephropathy: glomerular proteinuriaglomerular proteinuria Diabetic Neuropathy: Diabetic Neuropathy: peripheral neuritisperipheral neuritis Cardiovascular Diseases Cardiovascular Diseases (as MI) (as MI) & strokes & strokes (as cereb. hge)(as cereb. hge)

2- Sorbitol accumulation in certain cells Sorbitol accumulation in certain cells with its complications with its complications

3- Glycated proteins formationGlycated proteins formation with microvascular complicationswith microvascular complications

For avoiding these complications, long-term control of For avoiding these complications, long-term control of hyperglycemia is recommended for all types of DMhyperglycemia is recommended for all types of DM

Chronic Effects of DM Chronic Effects of DM (cont.)

In cells where entry of glucose is not dependent on insulin (eye lenslens, retinaretina, kidneykidney, neuronesneurones)

Intracellular Levels of Glucose

SORBITOL accumulation in these cells SORBITOL accumulation in these cells

CataractCataract Diabetic RetinopathyDiabetic Retinopathy

Diabetic NephropathyDiabetic Nephropathy Diabetic NeuropathyDiabetic Neuropathy

Treatment of Type 2 DM Treatment of Type 2 DM

• AIMAIM:

1- To maintain blood glucose concentrations within normal limits1- To maintain blood glucose concentrations within normal limits 2- To prevent the development of long-term complications occurring due 2- To prevent the development of long-term complications occurring due to prolonged hyperglycemiato prolonged hyperglycemia

• Lines of treatment:Lines of treatment: 1- Weight reduction Weight reduction (to control insulin resistance) 2- ExerciseExercise 3- Dietary modificationDietary modification 4- Hypoglycemic agents Hypoglycemic agents 5- Insulin (required in somesome cases)

Case StudyCase StudyParents of a 15 years old boy was reported by his school that he was found drowsy & they have got 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 3 months & she thought that he had lost weight. She admitted also that on the morning before leaving for school, he was complaining of abdominal pain & discomfort.

On examination:On examination: Semiconscious Deep & rapid respiration Pulse rate 120 beats/minute BP: 90/50 Cold extremities

What What investigationsinvestigations were recommended for him?? were recommended for him??What is the What is the diagnosisdiagnosis of this case?? of this case??What is the What is the treatmenttreatment ?? ??

Clinical Biochemistry Lab InvestigationsClinical Biochemistry Lab InvestigationsBlood ChemistryBlood Chemistry• Random Blood Glucose: 550 mg/dl • Urea: 160 mg/dl (N: 20 -40)• Na+: 127 mmol/L (N: 135 – 145)• K+: 6.9 mmol/L (N: 3.5 – 4.5)• pCO2: 2.9 kPa (N: 4.4 – 6.1)• HCO3- : 7 mmol/L (N: 21 – 27.5)• pO2: 14 kPa (N: 12 – 17)

Urine Analysis:Urine Analysis:• Urine Dipstick Test: - Glucose +++ - Ketone +++ - Albumin ++

Case Study Case Study cont.cont.

Documents

Biochemical Aspects of Diabetes Mellitus ENDO 412