Learning ObjectivesBy the end of this session you should be able to describe:• Hyperglycemia & diabetes mellitus including symptoms, diagnosis, classification, metabolic features, long-term and acute complications, and an easy guide for diabetic control.• Investigations in diabetic coma, definition, causes, and assessment of severity of coma. 2
If you are working in a pharmacyor a hospital, what complains orsigns a patient will have toindicate he might be diabetic ?? 3
HyperglycemiaIncrease in plasma glucose levels; most commonly due to diabetes mellitus.Diabetes Mellitus (DM):The term “diabetes” is derived from the Greek word diabeinein (“to go toexcess”). DM is caused by an absolute or relative insulin deficiency. It hasbeen defined by the World Health Organization (WHO), as a fasting venousplasma glucose concentration >126 mg/dl (7.0 mmol/l) or >200 mg/dl(11.1 mmol/l) two hours after a CHO meal or after the oral ingestion of 75gof glucose, even the fasting concentration is normal.The most obvious symptom of diabetes is hyperglycemia, caused byinadequate uptake of glucose from the blood. Because the kidney’scapacity to reabsorb glucose is limited, excessive amounts of bloodglucose (>180 mg/dl or ~ 11 mmol/l) results in glucosuria (glucose inurine). High urinary glucose concentrations produce an osmotic diuresisand therefore polyuria. Hyperosmolality due to water loss causes thirst &polydipsia. Diabetes is also Dr. Mohamed Z Gad increased appetite and food 16 March 2011 associated with 4consumption (polyphagia).
Diagnosis of DMDM should not be diagnosed unless high plasma glucose concentrationshave been found in at least two different occasions. If the plasma glucoseconcentrations are not within normal reference range and are not abovethat diabetic level, the patient is said to have impaired glucose tolerance.A) Plasma Glucose Concentration:Normal Level: 70-110 mg/dl (3.89-6.0 mmol/l) (true level) Plasma glucose estimation should be taken if a patient presents with symptoms of DM such as glucosuria or polyuria. The measurement of plasma glucose concentrations is preferable to that of whole blood. Blood sample must be mixed upon collection with an inhibitor of glycolysis, such as fluoride or iodoacetate, to prevent the in vitro fall of blood glucose as glycolysis continues. 16 March 2011is measured in Dr. Mohamed Z Gadspecific enzymatic methods Glucose the lab by 5 (hexokinase or glucose oxidase) to give “true” blood levels.
Blood samples may be taken according to any of thefollowing ways:I. Fasting: after about 10 h fastII. Postprandial: 2 h after a mixed mealIII. At RandomIV. Glucose Load test:By administration of a standard oral glucose load (~75 g)and determining plasma glucose conc. 2 h later. It is moreprecise than the postprandial glucose.*DM is usually present if :Fasting plasma glucose 126 mg/dl (7.0 mmol/l) on twooccasions or random plasma glucose > 200 mg/dl (11.1mmol/l) on two occasions or both a fasting >126 mg/dl andrandom >200 mg/dl. Also plasma glucose levels >200mg/dl 2 h after a meal or glucose load is indicative of DM.*DM is usually excluded if:Fasting < 110 mg/dl (6.0 mmol/l) Dr. Mohamed Z Gad 16 March 2011 on two occasions 6
*Confirmation tests for suspected DM patients:V. Oral Glucose Tolerance Test (OGTT):To avoid misleading responses, it is essential to place the patients on a dietcontaining adequate calories, protein and at least 150 g CHO/day for 3 daysbefore the test; this stimulates the production of inducible enzymes necessaryfor glycogenesis and glucose utilization. No alcohol, no drugs, no smoking andno exercise during the test. Not to be done during recovery from acute illness,emotional stress, surgery, trauma or pregnancy.Procedure:A blood sample is drawn from a patient after an overnight fast. 75 g of glucoseare ingested (in a solution ~250 g/L) over a 5 min period. Blood samples aredrawn 30, 60, 120, 180 min after the glucose ingestion.Use:GTT should be reserved principally for patients with “borderline” fasting plasmaglucose levels (i.e. fasting range 110-126 mg/dl).GTT is not indicated in:Persistent fasting hyperglycemia (>126 mg/dl), persistent fastingnormoglycemia (<110 mg/dl), patients with typical clinical findings of DM,secondary 2011 never be done to evaluate Gad 16 March DM, Dr. Mohamed Z reactive hypoglycaemia and rarely 7indicated for diagnosis of DM in children.
Interpretation:For diagnosis of DM in adults, at least two If the serum glucose conc. Isvalues of GTT should be increased. plotted against time, different types of curves are obtained for diabeticsA typical normal curve shows fasting glucose and normal.level is ~75mg/dl. Maximum concentration isreached 30-60 min after taking the glucose.Blood level then returns to the normal fastinglevel in 90 min (75-110 mg/dl). Sometimes aslight dip in the curve occurs at 120 min (65mg/dl) that returns to fasting level (75 mg/dl)thereafter WHY ??VI. Intravenous Glucose Tolerance Test:Poor absorption to oral glucose may result ina “flat” tolerance curve. Some patients areunable to tolerate a large CHO load orally(vomiting) or may have altered gastricphysiology (e.g. gastric resection). In thesecases an i.v glucose tolerance test may beperformed. The dose of glucose is 0.5 g/kgb.w 16given 2011 within 2-4 min. Mohamed Z is March i.v Dr. Blood Gad 8collected every 10 min for 1 h.
Criteria for the diagnosis of DMFasting blood glucoseNon-diabetic Impaired glucose tolerance Diabetes (IGT)<6.0 mmol/l (<110 mg/dl) 6.0-6.9 mmol/l (110-125 mg/dl) ≥7.0 mmol/l (≥126 mg/dl)Oral glucose tolerance test Fasting 2-hourIGT <7.0 mmol/l (<126 mg/dl) 7.0-11.0 mmol/l (126-200 mg/dl)Diabetes ≥7.0 mmol/l (≥126 mg/dl) ≥11.1 mmol/l (≥200 mg/dl)B) Glucosuria: Normal Level: Not detected in the urine by routine testsIn most normal persons, glucose in not detected in the urine below the level of180 mg/dl of blood glucose. This level is termed “renal threshold for glucose”,and reflects maximum capacity of kidneys for glucose reabsorption. Glucosuriais best detected by enzyme reagent strips & occurs in diabetes mellitus,glucose infusion, renal dysfunction and pregnancy.False Negative: if urine containsDr. Mohamed Z Gad of ascorbic acid. 16 March 2011 large amounts 9False Positive: if urine container is contaminated with detergent.
C) Microalbuminuria:Normal Level: <30 mg/day albumin in urine Strip Test for Glucose in UrineDefined as albumin excretion rateintermediate between normality andmacroalbuminuria (>300 mg/day). It is amarker of early (reversible) diabeticnephropathy and is thus used to screen forrenal damage.D) Ketone Bodies in serum & Urine:Normal Level: Blood <3 mg/dl (0.3 mmol/l), Urine <10 mg/dl (1 mmol/l).Usually detected by strips.Excessive formation of ketone bodies results in increased bloodconcentrations (ketonemia) and increased excretion in urine (ketonuria).Observed in conditions associated with a decreased intake of CHO such asstarvation, digestive disturbances, dietary imbalance and frequent vomiting.However, the most frequent cause is diabetic Ketoacidosis. 16 March 2011 Dr. Mohamed Z Gad 10
E) Glycohemoglobin (Glycated Hemoglobin): Normal Level: 4-8%In adults, circulating hemoglobin (Hb) consists of 97%Hb A, 2.5% Hb A2 and 0.5% Hb F. Glycated Hb (Hb A1c)is formed by non-enzymatic condensation of glucoseand N-terminal valine of b-chains of Hb & occurs overthe life span of he RBC (~120 days). It is expressed aspercentage of the total Hb concentration.Use:Monitor the long-term control of D.M. It depends on the glucose concentrationover the two or three months prior to the test.This is useful for judging control of diabetes in: (1) a new patient, (2) when urineglucose records are inadequate, (3) in patients during pregnancy.In known diabetics: 7% indicates good diabetic control, 10% indicates fairdiabetic control, 13-20% indicates poor diabetic control.F) Serum Fructosamine: Normal Level: 2.4-3.4 mmol/lMeasure concentration of glycated serum proteins, giving a reliable estimate ofmean blood glucose levels during preceding 1-3 weeks. It correlates with HbA1c 16 March not affected by abnormal Hb. However, it is affected by significant but is 2011 Dr. Mohamed Z Gad 11changes in serum albumin or protein concentrations.
Classification of DM Insulin-Dependent Diabetes Mellitus Non-insulin-Dependent Diabetes (IDDM) Mellitus (NIDDM)Also called type I diabetes or juvenile Also called type II diabetes oronset diabetes (usually occurs before maturity-onset diabetes (usuallythe age of 20). occurs after the age of 40).It represents 10-20% of diabetic It represents 80-90% of diabeticpatients. patients.Prone to ketosis Resistant to ketosisEndogenous insulin low/absent Endogenous insulin present but insufficientVery low serum C-peptide levels Normal or increased C-peptide levels<10mgLow/normal weight Mostly obeseTreatment by exogenous insulin Diet control and exercise. Oral 16 March 2011 hypoglycemics Dr. Mohamed Z Gad are used 12 when necessary.
IDDM NIDDMMost cases of IDDM result from the Most individuals with type II diabetesdestruction of the insulin producing b- have normal or even elevated bloodcells by the immune system. levels of insulin. For a variety ofDestruction of b-cells is initiated by the reasons, type II patients are resistantbinding of an antibody to a cell surface to insulin. The most common cause ofantigen. One of the most common insulin resistance is the down-autoantibodies found in IDDM is an regulation or defect of insulinantibody against glutamic acid receptors.decarboxylase (GAD) enzyme.HLA (histocompatibility antigens, which No HLA associationare found on the surface of most of thebody’s cells, play an important role indetermining how the immune systemreacts to foreign substances or cells)antigens are presentIslet cell antibodies are present Islet cell antibodies are absentPolygenic Strong genetic associationViruses and toxins might be implicated Obesity and physical inactivity13play 16 March 2011 Dr. Mohamed Z Gad role
Gestational Diabetes Mellitus (GDM)Diagnosed when hyperglycemiadevelops for the first time duringpregnancy. (This is not the same as aknown diabetic who becomespregnant.) Affects 2-3% of pregnantwomen. There is a high probability(30-60%) that a woman with GDM willdevelop DM later in life. Earlydiagnosis of GDM is important. Dr. Mohamed Z Gad 14
Metabolic Features of DMIn the absence ofinsulin, liver, adiposetissue and musclesbehaves as if the body isundergoing starvation. Dr. Mohamed Z Gad 15
Key Note: Easy Guide for Diabetic ControlA diabetic regimen has three cornerstones: nutrition, weightcontrol and exercise. Here are some guidelines issued bythe American Diabetes Association (ADA) that help indiabetic control:1. CHO (simple or complex) accounts for ~50% of calories.2. Protein 12-20% of calories.3. Cut the fat out of your diet as possible. It should not be >30% of calories.4. Eat food with fiber (e.g. wheat, barley, oat, legumes, vegetables, fruits). Fibers could lower cholesterol & fat levels and keep you not Hungary.5. Cut your cholesterol. It should not exceed 300 mg/day.6. Use alternative sweeteners if your diabetes is not well controlled.7. Have good care with your feet, as diabetic’s weakest link is the foot. Here are some useful guidelines: try to lose weight, inspect your feet 2-3 times/day for cuts, bruises, swelling .. keep your feet clean and dry, keep them warm in cold days, make sure your shoes fit well.8. Eat smaller meals more often. Less glucose -> less insulin -> more constant blood sugar. 16 March 2011 Dr. Mohamed Z Gad 16
9. Too much fish oil (usually taken to help prevention of atherosclerosis) is not advisable since it is of high calorie & may increase blood glucose levels. However, eating fish is encouraged.10. Try to lose weight. Remember that ~80% of type II diabetics are overweight. Do not be hard on yourself, just try to change eating habits and do exercise.11. Nutritional changes should be a family affair. It is hard for a diabetic person to do it alone.12. Reduce stress & anxiety, if possible.13. Test your blood glucose quite often.14. Testing urine glucose is an easy routine way to monitor blood glucose after control.15. Take care of your teeth. Diabetics are more susceptible to gum infections.16. Administer vitamin & mineral medications, if your diet is not balanced 17
Long-Term Complications of DMDiabetics (if uncontrolled!) are especially prone to developnephropathy, myocardial infarction, stroke, retinopathy, andneuropathy (nerve damage due principally to poor bloodcirculation causes the loss of various types of sensory &motor function). In addition, circulatory problems often resultin gangrene, which leads to tens of thousands ofamputations annually.Most diabetic complications are the result of the damage tothe vascular system. For example, damaged capillaries inthe eye and kidney lead to blindness and kidneys damage,respectively. It is now believed that most of the damage isinitiated by hyperglycemia which promotes the nonenzymaticglycosylation of protein molecules (a process referred to asthe Maillard reaction). Accumulation of glycosylation endproducts cause extensive damage throughout thecardiovascular system. 16 March 2011 Dr. Mohamed Z Gad 18
Acute Complications of DM NEED MEDICAL EMERGENCYA) Diabetic Ketoacidosis:Precipitating factors areinfection, vomiting, trauma,myocardial infarction orsevere insulin deficiency.Decreased glucose transportinto tissues leads tohyperglycemia, which givesrise to glycosuria. Increasedlipolysis causes over-production of fatty acids,some of which are convertedinto ketones, giving Dehydration, if severe, produces renal uraemiaketonemia, metabolic acidosis and may lead to hypovolemic shock.and ketonuria. Glycosuria Hyperventilation occurs to compensate forcauses an osmotic diuresis, severe metabolic acidosis. Odour of acetone iswhich leads to the loss of observed in the breath. Hyperosmolalitywater and electrolytes - Na, K, 16 March 2011 causes cellular dehydration, if in cerebral19 Dr. Mohamed Z Gad cellsCa, Mg, P, Cl. it may causes confusion and coma.
NEED MEDICALB) Hyperosmolar Non-Ketotic (HONK) EMERGENCYComa:Occurs mostly in elderly, NIDDM, anddevelops relatively slowly over days andweeks. The level of insulin is sufficient toprevent ketosis but does not preventhyperglycemia and osmotic diuresis.Precipitating factors include severe illness,dehydration, glucocorticoids, diuretics,dialysis, and surgery. Extremely high bloodglucose levels (above 600 mg/dl or 35mmol/l) accompany severe dehydrationresulting in impaired consciousness. 20
Key Note: Investigations in Diabetic ComaFor a patient in coma, blood samples should be taken and sent immediately to thelab for estimation of plasma: glucose, sodium and potassium, urea and/or creatinineand bicarbonate and/or arterial pH. Urine samples are taken (if possible) fordetection of glucose and acetone. A diabetic patient may be in coma due tohyperglycemia, hypoglycaemia or any of the causes shown in the following table:Diagnosis Clinical Features Laboratory Findings Plasma Urine Glucose Bicarbonate Glucose KetonesKetoacidosis Volume depletion High Low +++ +++ HyperventilatingHyperosmolar Volume depletion Very high N +++ NegComa No hyperventilationHypoglycemia Non-specific Low N Neg NegCerebrovascula Neurological May be May be low May be + AbsentAccident May be hyperventilating raisedN = Normal Neg = Negative 21
DefinitionIn medicine, a coma (from the Greek κῶμα koma, meaningdeep sleep) is a profound state of unconsciousness.What are the criteria for a person in coma ???1) cannot be awakened, 2) fails to respond normally to painor light, 3) does not have sleep-wake cycles, and 4) doesnot take voluntary actions.How ?Coma may result from a variety of conditions, includingintoxication, pharmaceutical agents, metabolicabnormalities, CNS diseases, acute neurological injuriessuch as stroke, and hypoxia. 23
SeverityThe depth of coma can be definedfollowing clinical examination usinga scale called Glasgow ComaScale (GCS). The GCS is a simple15-point scale used by medicalprofessionals to assess severity ofneurologic trauma, and establish aprognosis. 8 in GCS are in coma, at 6 h~50% will die. 9 in GSC not in coma.Contrary to popular belief, a patientin a coma does not always lay stilland quiet. They may talk, walk, andperform other functions that mayappear to be conscious acts but arenot.16 March 2011 Dr. Mohamed Z Gad 24
Guesswhat is The longest periodspent in coma according toGuinness World Records ? 25
Guinness World RecordsThe longest period spent in comaElaine Esposito(December 3, 1934 - November 25,1978) of Tarpon Springs, Florida, USA,holds the record for longest coma.Elaine never stirred after beinganaesthetized for an appendectomy on Sharon still in coma afterAugust 6, 1941, when aged 6. She died a massive stroke sinceaged 43 years 357 days, having been in 26 December 2005 !!!a coma for 37 years 111 days.Elaines coma evidenced statesbetween deep sleep and open-eyedunconsciousness. 16 March 2011 Dr. Mohamed Z Gad 26
References:• Clinical Biochemistry: An illustrated colour text, A. Gaw et al., Churchill Livingstone.• Clinical Chemistry, W.J. Marshall, Mosby.• Clinical Chemistry: Interpretation and Techniques, A. Kaplan & L.L. Szabo, Lea & Febiger, Philadelphia.• Fundamentals of Clinical Chemistry, N.W. Tietz, W.B., Saunders Company, Philadelphia, London, Tokyo ….• Clinical Biochemistry, A.F. Smith, G.J. Beckett, S.W. Walker & P.W. H Rae, Blackwell Science Ltd, London…• Interpretation of Diagnostic Tests, I. Wallach, Little, brown & Company, Boston, London …..• Practical Clinical Biochemistry, H. Varley, A.H. Gowenlock & M. Bell, William Heinemann Medical Books LTD, London 27
Learning ObjectivesBy the end of this session you should be able to describe:• Hypoglycaemia: clinical effects, causes, and investigations.• Mechanism of insulin secretion, mode of action of SUs, structure of insulin receptor, insulin signaling pathways, insulin role in regulation of blood glucose level, types of glucose transporters, insulin & carbohydrate metabolism.• Insulin resistance: definition, clinical presentation, and causes. 2
Hypoglycaemia Any condition in which plasma glucose concentration falls below 60 mg/dl (3.3 mmol/l) is called hypoglycaemia. In general, children and adults are not usually symptomatic unless the glucose falls below 40 mg/dl (2.2 mmol/l). Clinical effectsHypoglycaemia normally leads to suppression of insulin secretion, anincrease in catecholamine secretion and stimulation of glucagon, cortisol,and growth hormone. Catecholamine surge accounts for signs andsymptoms most commonly seen in hypoglycaemia i.e. sweating, shaking,tachycardia, feeling weak and nauseated.Since brain is dependent upon an adequate supply of glucose for its energy,clinical symptoms of hypoglycaemia resemble those of cerebral anoxia.They include confusion, poor concentration, detachment and, in moresevere instances, convulsions and coma. 3
Principal causes of HypoglycaemiaØ Insulinoma (b- cell tumour of pancreas) or pancreatic hyperplasia.Ø Advanced extrapancreatic malignancy, for example by producing insulin-like growth factors.Ø Hepatic and renal diseaseØ Deficiency of anti-insulin hormones e.g. in Addisons diseaseØ Sepsis, mechanism unclearØ Starvation, anorexia nervosa, lactic acidosis , and intense exercise.Ø Drug-induced, e.g. Inappropriate or excessive insulin, alcohol, sulphonylureas, and salicylates.Ø Accelerated gastric emptying (Dumping syndrome) following gastric resection, which result in rapid absorption of large 4 amounts of glucose with a resultant surge of insulin release.
Investigations in HypoglycaemiaThe diagnosis of hypoglycaemia is established when three criteria are satisfied: Symptoms consistent with hypoglycaemia Laboratory confirmation of hypoglycaemia Symptoms are relieved by glucose administration • The most important test is plasma insulin concentration. This differentiates hypoglycaemia due to high insulin level from other causes of hypoglycaemia. • If plasma insulin conc. is inappropriately high, plasma C-peptide concentrations should be assayed …… WHY ? • If plasma C-peptide is high, it suggests endogenous insulin secretion, or pancreatic stimulation e.g. by sulphonylureas. Undetectable plasma C-peptide concentration 5 suggests exogenous insulin administration.
Cause of Hypoglycaemia Plasma Insulin Plasma C-peptideInsulin administration High LowInsulinoma High HighSulphonylurea High HighadministrationAlcohol Low LowNon-pancreatic tumour Low LowPituitary or adrenal Low Low 6failure
Mechanism of Insulin Secretion Insulin was discovered in 1922 (Boyd, Diabetes, 1988)1. Glucose is transported through GLUT2, and its - + subsequent metabolism produces ATP.2. The increase in ATP closes KATP channels, which depolarizes the membrane and results in the opening of voltage-dependent Ca2+ channels. GLUT2: glucose transporter 2, VDCC: voltage-dependent calcium channel3. Ca2+ influx leads to an increase in intracellular Sulfonylureas (SUs) bind and close the KATP Ca2+ concentration, channels and subsequently stimulate insulin which triggers insulin secretion. granule exocytosis in 7 the beta cells.
Mode of Action of SUsSpecific blocker of ATP-sensitive K+ channel in pancreatic b-cell(Sturgers et al, Lancet, 1985; Trube et al, Pflugers Arch., 1986)KATP channel is the first exampleof a heteromultimeric complexassembled by a RECEPTOR(Sulphonylurea receptor,tetramer of SUR1, member ofthe ATP-binding cassette (ABC)protein superfamily) and aninwardly rectifying K+ CHANNEL(Kir6.2), that are structurallyunrelated to each other. 9
Structure of Insulin Receptor- It is a heterotetrameric membraneglycoprotein composed of two a- andtwo b-subunits, linked together bydisulfide bonds.- Insulin binds to the receptor’sextracellular subunit.- Insulin binding brings the two a-subunits closer together. Thisconformational change enables ATPbinding to the b-subunit’s intracellulardomain.- ATP binding activates receptorautophosphorylation, which, in turn,enables the receptor’s kinase activitytoward intracellular protein 10substrates.
• When insulin binds to itstyrosine kinase receptor, it Insulin Signalingactivates insulin receptorsubstrates (IRS), which in turn Pathwaysstimulates the lipid kinase activityof phosphatidylinositol 3-kinase.• Rapid rise in Tris-phosphorylatedinositol (PIP3) triggers a cascadeof PIP3-dependentserine/threonine kinases.• Among the latter, Akt (a productof the akt protooncogene) andatypical protein kinase C isoformsare thought to be involved ininsulin regulation of glucosetransport and oxidation; glycogen,lipid, and protein synthesis; andmodulation of gene expression. 11
Insulin & Carbohydrate Metabolism1) Insulin facilitates entry of glucose into muscle, adiposeand several other tissuesmainly by enhancing translocation of hexose transporters (GLUT4) fromthe cytoplasmic vesicles to plasma membrane for efficient uptake ofglucose.When blood levels of insulin decrease and insulin receptors are nolonger occupied, the glucose transporters are recycled back intocytoplasm. N.B: There are some tissues that do not require insulin for efficient uptake of glucose; important examples are brain and the lens. This is because these cells dont use GLUT4 for importing glucose, but rather, another transporter that is not insulin-dependent. 13
2) Insulin has several effectsin liver which stimulateglycogen synthesis It activates hexokinase, whichphosphorylates glucose, trapping itwithin the cell. Coincidently, it acts toinhibit activity of glucose-6-phosphatase. It activates glycogen synthaseresponsible for glycogen synthesis. Decreased activity in any of these steps could be responsible for insulin resistance 15
Definitions of Insulin Resistance (IRS)• A decrease in the sensitivity of tissues such as liver, skeletal muscle and adipose tissue to action of insulin.• A state in which a given concentration of insulin produces a less-than-expected biological effect 16
From Insulin Resistance to Type-II DiabetesThe first progressiontowards type-II diabetesis hyperinsulinemia andimpaired glucosetolerance (IGT), withincreases in post-prandialglucose concentrations.Most patients stay at thislevel for a considerabletime with excess insulinproduced just matchingthe blood glucose levels.However, in time b- cellsbegin to fail and areunable to produce Studies lean toward existence of both insulinsufficient insulin to resistance and insulin deficiency in most NIDDMstabilize the raised blood patients, because a moderate degree of insulinglucose, type-II diabetes resistance is not sufficient to cause NIDDM. 17is developed.
Clinical Presentation of Insulin ResistanceDepends on the type and stage of the IRS state:• Metabolic syndrome (syndrome X): clustering of atherosclerotic cardiovascular disease risk factors including obesity, IRS, low HDL, and systemic proinflammatory state.• Obesity• Type 2 diabetes mellitus: Chronic or acute.• Impaired glucose tolerance• History of hypertension• Symptoms of coronary artery disease or microvascular angina• Symptoms of other macrovascular disease e.g. peripheral vascular disease• Polycystic Ovary Disease (PCOD): Patients present with infertility associated with anovulation; menstrual irregularity. 18 Symptoms due to excess androgen.
Causes of Insulin ResistanceHereditary: includes mutations of insulin receptor, glucose transporter, andsignaling proteins.Acquired: includes physical inactivity, diet, medications, hyperglycemia(glucose toxicity), increased free fatty acids, and aging process.The underlying causes of insulin-resistant states can be categorized as follows:Prereceptor Abnormal insulin (mutations) Anti-insulin antibodiesReceptor Decreased number of receptors, mainly failure to activate tyrosine kinase Reduced binding of insulin Insulin receptor mutations Insulin receptor–blocking antibodiesPostreceptor Defective signal transductionCombinations of defects are common. Obesity is associated mainly withpostreceptor abnormality and also decreased number of insulin receptors. “Obesity is the most common cause of insulin resistance” 19
Adipocyte is no longer regarded as apassive depot for storing excess Obesity & NIDDMenergy in the form of TG, but as a Obesity alone doescell that actively regulates pathways not always lead to IRSresponsible for energy balance.Adipocyte modulates energy balancethrough secretion of peptide hormones andother signaling molecules e.g. leptin issecreted by TG-rich adipocytes, travelsthrough the circulation, crosses blood–brainbarrier, and reaches hypothalamus, where itmodulates a host of neuroendocrine andautonomic nervous system activities,resulting in decreased food intake andincreased energy expenditure.Resistin, tumor necrosis factor,adiponectin, free fatty acids are otherfactors released by adipocytes, act inperipheral tissues to influence sensitivity toinsulin and other cellular and metabolic 20processes.
References:• Clinical Biochemistry: An illustrated colour text, A. Gaw et al., Churchill Livingstone.• Clinical Chemistry, W.J. Marshall, Mosby.• Clinical Chemistry: Interpretation and Techniques, A. Kaplan & L.L. Szabo, Lea & Febiger, Philadelphia.• Fundamentals of Clinical Chemistry, N.W. Tietz, W.B., Saunders Company, Philadelphia, London, Tokyo ….• Clinical Biochemistry, A.F. Smith, G.J. Beckett, S.W. Walker & P.W. H Rae, Blackwell Science Ltd, London…• Interpretation of Diagnostic Tests, I. Wallach, Little, brown & Company, Boston, London …..• Practical Clinical Biochemistry, H. Varley, A.H. Gowenlock & M. Bell, William Heinemann Medical Books LTD, London 21