‫ﺑﻨﺎم ﺧﺪا‬

Disorders Di d off Carbohydrate Metabolism

CARBOHYDRATE • Complex Complex carbohydrates ‐ carbohydrates are digested into simple  are digested into simple sugars, principally glucose, which is used primarily as  an energy source or stored as glycogen an energy source or stored as glycogen • Disaccharides – carbohydrates that can be hydrolyzed  y y y into two monosaccharide units, Sucrose, which is  hydrolyzed into glucose and fructose y y g and lactose  (glucose and galactose) are important disaccharides. • Monosaccharides – carbohydrates that cannot be  hydrolyzed to simpler carbohydrates

CARBOHYDRATES • The most important dietary hexoses are, D‐Glucose,  D‐Galactose, D‐Fructose, but the principle sugar  circulating in the bloodstream is glucose. • Carbohydrates are needed for specific cellular  function(such as ribose in nucleic acids) and can  function(such as ribose in nucleic acids) and can modify protein and their function by glycosylation .

CARBOHYDRATES • The The concentration of glucose concentration of glucose in blood is  in blood is normally controlled within narrow limits by  many hormones, the most significant of  h th t i ifi t f which, insulin, is produced by the endocrine  pancreas.  • Diabetes Diabetes mellitus mellitus is the most common  is the most common disease of carbohydrate metabolism.

FUNCTIONs OF THE ENDOCRINE PANCREAS • The The pancreas pancreas function as both an  function as both an endocrine and an exocrine organ in  the control of carbohydrate the control of carbohydrate  metabolism. • Exocrine gland: produces and secretes  Exocrine gland: produces and secretes amylase for breakdown of ingested  carbohydrates. carbohydrates • The monosaccharide absorbed signal  endocrine pancreas d i which regulates  hi h l t hormones involved in energy  h hemostasis. t i

Hormones involved in Glucose homoestasis • • • • • •

Insulin (by the beta cell) G ucago ( y Glucagon (by the alpha cell) p ) Adrenaline (Epinepherine) Growth Hormone Growth Hormone Cortisol Incretins

INSULIN • Insulin is a peptid p p hormone with a mass of 5800  daltons. It has A 21 amino acid and a 30 amino  acid B chain that are linked by two disulfide  y bonds.  • Insulin is synthesized initially as a precursor  Insulin is synthesized initially as a precursor hormone , proinsulin.

PROINSULIN • Proinsulin (9000Da) is the immediate precursor of insulin, • It is processed into insulin in the beta cell by enzymatic removal of 31 amino acid peptide segment that connected the A and B chains, known as c-peptide tid . • The half half-life life of proinsulin is x3 > insulin. • The biological activity of proinsulin is 10%–15% of that insulin

Biosynthesis of Insulin

INSULIN • Approx 50% of insulin is rapidly removed by its initial passage through the liver. • In healthy individuals, the half life of both Cpeptide and proinsulin is approximately 30 min, min whereas it is only 4-9 min for insulin. • In cirrhosis, hyperinsulinemia is observed as the result l off ddecreasedd hhepatic i iinsulin li clearance. l

INSULIN & C‐PEPTIDE • C‐peptide level are measured in sera in hypoglycemic state to help identify the cause of the hypoglycemia. • Ç Insulin & Insulin & Ç C‐peptide  C peptide Æ insulinoma • Ç Insulin & È C‐peptide  p p Æ injected or exogenous  j g insulin • In hyperglycaemia Low C‐peptid Low C peptid levels are characteristic  levels are characteristic of the absolute insulin deficiency of type 1diabetes.

Insulin & Glucose • Disease states occur when insulin levels are inappropriate for f given blood bl d glucose l l l levels. • Insulin deficiency, either absolute or relative, leads to diabetes mellitus. • A high insulin level with low glucose level suggests inappropriate secretion or administration of insulin, • High insulin levels with normal glucose can be observed in insulin-resistant individuals who need to secrete additional insulin to keep blood glucose levels normal.

GLUCAGON • Synthesized in the pancreatic alpha cells as proglucagon. • Glucagon stimulates glucose production and It is an important p regulator g of hepatic p gglycogenolysis, y g y , gluconeogenesis, and ketogenesis. • IIn type t 1 diabetes, di b t over ti time, progressive i glucagon l ddeficiency fi i develops. This deficiency of glucagon results in increased glycemic l i fluctuations fl t ti andd difficulty diffi lt recovering i from f hypoglycemia. • Serum glucagon levels are rarely measured in clinical p practice.

INCRETINS • Oral nutrients stimulate the release of incretins from the intestines. • The incretin effect is to rapidly stimulate insulin secretion in response to a meal. meal • The most important incretins in the regulation of insulin secretion are : – glucagon-like peptide 1 (GLP-1) and – gglucose-dependent p insulinotropic p ppeptide p ((GIP). )

INCRETINS • GIP : originally called gastric inhibitory polypeptide.

The ratio of insulin to glucagon is important in the regulation of carbohydrate metabolism • Anabolism is favored when there is a relative  increase in the insulin‐to‐ increase in the insulin to glucagon ratio as in the  glucagon ratio as in the postprandial state . • Catabolism is favored with a relative decrease in  this ratio as in the fasting state.

DIABETES MELLITUS DIABETES MELLITUS

The International Diabetes Federation (IDF) symbol for diabetes.

DIABETES MELLITUS IA T S M ITUS • Diabetes mellitus is a group of diseases in which blood glucose level are elevated • Diabetes is the most common set of disorders of carbohydrate y metabolism,, affecting 382 million people in 2013 (90% type yp 2 diabetes)) • This is equal to 8.3% of the adults population l ti

DIABETES MELLITUS IA T S M ITUS • Worldwide in 2012 and 2013 diabetes

resulted in 1.5 to 5.1 million deaths per year making it the 8th leading cause of year, death

• The prevalence of diabetes is increasing, with the p prediction of an estimated 33% of males and 39% females born in 2000 in the US being g diagnosed g with diabetes during their lifetime

DIABETES MELLITUS • This chronic disease is responsible  f for significant i ifi morbidity, mortality  bidi li and cost. • Diabetes is the leading cause of: – treated end‐stage renal disease,  – the most common cause of  nontraumatic amputation ,and  – the foremost  cause of new blindness in  adult age 20‐74 years.

DIABETES MELLITUS • Nerve damege, known as diabetic neuropathy, occurs in  g , p y, 60%‐70% of people with diabetes.

DIABETES MELLITUS • Most diabetes‐related death however are related to  the increase risk of developing atherosclerotic  disease.  • People with diabetes are at least 2 to 4 times more  lik l t h likely to have heart disease and cerebrovascular h t di d b l disease than those without diabetes.

Criteria for the diagnosis of DM A American Diabetes Association (2010) i Di b A i i (2010)

• A Fasting plasma glucose level ≥ 126 mg/dl  ( ) on at least two occasions (after 8‐hours fast).

or • Symptoms of hyperglycemia (e.g., polyuria,  polydipsia, polyphagia, unexplained weight  l di i l h i l i d i ht loss) with a casual plasma glucose level ≥200  mg/dL (11.1 mM) or HbA1c ≥6.5% 

Symptoms of Diabetes

Pre‐DIABETES  • Pre‐ diabetes designates condition in which  glucose homeostasis is abnormal, but serum  gglucose level are not  high enough to be  g g classified as diabetes. • This group includes individual with impaired  gg ( ) p g fasting glucose (IFG) and impaired glucose  tolerance(IGT) . • They are also at increase risk for  cardiovascular and cerebrovascular disease.

Classification of DM I. Type 1 diabetes yp 2 diabetes II. Type III. Other specific types A. Genetic defects of β β-cell cell function

B. Genetic defects in insulin action C. Diseases of the exocrine pancreas eg. Pancreatitis, Cystic fibrosis D. Endocrinopathies (Acromegaly, Cushing’s syndrome, Hyperthyroidism) E. Drug- or chemical-induced F. Infections G. Other genetic syndromes sometimes associated with diabetes eg. Down’s syndrome Turner’s syndrome, Turner s syndrome

IV. Gestational diabetes mellitus (GDM) The glucose Th l iintolerance l that h ddevelops l dduring i approximately i l 7% off all ll pregnancies

Drugs and chemicals that induce DM 1. Vacor 2 P 2. Pentamidine idi 3. Nicotinic acid 4 Gl 4. Glucocorticoids ti id 5. Thyroid hormone 6 Diazoxide 6. Diazoxide 7. β‐Adrenergic agonists 8 Thiazides 8. Thiazides 9. Dilantin 10 γ‐Interferon 10. γ Interferon

insulin‐dependent” versus “non‐ i li d insulin dependent” DM d t” DM ti t ith f f di b t may  • P Patients with any form of diabetes require insulin treatment at some stage  of their disease Such use of insulin does of their disease. Such use of insulin does  not, of itself, classify the patient. • Therefore, the terms “insulin‐dependent”  or “non non‐insulin dependent insulin dependent” is confusing  is confusing and should not be utilized.

TYPE 2 DIABETES Risk factors

Oral Glucose Tolerance Test (OGTT) I di ti Indications: • Formal oral glucose test are not generally recommended  for routine clinical use in the diagnostic of diabetes. • Except : 1. when the results of fasting or random glucose are  g g equivocal 2. to detect gestational diabetes in high‐risk individuals, or  g g , 3. Clinical features of DM or its complications with normal  plasma glucose 

Oral Glucose Tolerance Test (OGTT) ( ) Befor an OGGT an OGGT is performed, individuals should:    is performed, individuals should: • Eat a normal diet with at least 250g/day of  carbohydrates for the 3days preceding the test carbohydrates for the 3days preceding the test  without limitation in physical activity • Fast overnight (8‐to 14h). F t i ht (8 t 14h) • Take blood sample for glucose determination • Give 75g glucose in water orally Take 2nd blood sample for glucose determination  blood sample for glucose determination • Take 2 after 120min

Screening for type 2 DM • Unlike undiagnosed type 1 diabetes, in which people  are usually symptomatic, people with new‐onset type 2  ll i l ih 2 diabetes can be free of symptom.  • An estimated 1 out of every 3 people with type 2  diabetes are not aware they have it.  y • The American Diabetes Association (2010) recommended  screening for type 2 DM in: for type 2 DM in: – Obese adults with one or more risk factor  – Obese children and adolescents with 2 risk factor (family history,  race, sign of insulin resistance)

Screening for type 2 DM • The preferred test is  a fasting plasma glucose or  HbA1c level. • If a random plasma glucose level is ≥ 160 mg/dl a  fasting glucose , HbA1c or 2 hours 75g OGTT should  be performed.

Treatment of type 2 DM f yp • Although many people with type 2 diabetes can be  effectively treated with diet, exercise, and oral  glycemic control agents, other require insulin therapy.

MEASURES OF GLYCEMIC CONTROL MEASURES OF GLYCEMIC CONTROL • It has been established that improved glycemic control is associated with preventing or delaying the  progression of microvascular complications in  diabetes . • It is also demonstrated that lowering glucose levels  in patients with type 1 diabetes slow or prevents the in patients with type 1 diabetes slow or prevents the  developing of RETINOPATHY, NEUROPATHY, and  NEPHROPATHY

BLOOD GLUCOSE MEASUREMENT • Whole blood capillary glucose values obtained b d withh point-of-care f d devices are useful for the detection of h hyperglycemia l andd hypoglycemia h l in individuals with diabetes, and help to monitor andd ddirect therapy. h • They should not be used to diagnose diabetes or hypoglycemic disorders. To establish these diagnoses, confirmation with laboratory measures of plasma glucose are essential because of their greater accuracy.

WHOLE BLOOD GLUCOSE • Error that may contribute to inaccurate reading: • • • •

Application of an insufficient blood, Milking the finger to acquire blood, The use of outdate test strip, Enviromental factor (humidity, heat)

• Some blood glucose monitoring devices are influenced by high level of: – Salicylate, – Acetaminophen, – levodopa, bilirubin, lipid…

Glycated Hemoglubin HbA1c

‫ﭼﮕﻮﻧﻪ ﺗﺸﻜﻴﻞ ﻣﻴﺸﻮد؟‬ ‫هﻤﻮﮔﻠﻮﺑﻴﻦ ‪ A1c‬ﭼ‬ ‫ﻫﻤﻮﮔﻠــﻮﺑﻴﻦ‪ ،‬ﮔﮔﻠــﻮﻛﺰ ﺑــﻪ ‪-N‬ﺗﺮﻣﻴﻨــﺎل زﻧﺠﻴــﺮه ﺑﺘــﺎي‬ ‫ﮔ‬ ‫در اﻳــﻦ‬ ‫ﻫﻤﻮﮔﻠﻮﺑﻴﻦ ﻣﺘﺼﻞ ﻣﻲ ﮔﺮدد‪.‬ﻫﻤﻮﮔﻠﻮﺑﻴﻦ ﮔﻠﻴﻜﻮزﻳﻠﻪ ﺑﻪ ﻃﻮر ﻏﻴﺮ‬ ‫آآﻧﺰﻳﻤﻲ و از ﻃﺮﻳﻖ واﻛﻨﺶ ‪ 2‬ﻣﺮﺣﻠﻪ اﻳﻲ اﺗﻔﺎق ﻣﻲ اﻓﺘﺪ‪:‬‬ ‫ﮔﻠـﻮﻛﺰ‬ ‫ﻮﻛﺰ‬ ‫‪(1‬اﻳﻦ واﻛﻨﺶ‪ ،‬ﺳﺮﻳﻊ‪ ،‬ﻗﺎﺑﻞ ﺑﺮﮔﺸﺖ و واﺑﺴﺘﻪ ﺑﻪ ﻏﻠﻈﺖ ﮔﻠ‬ ‫در ﻣﺤﻴﻂ ﺑﻮده و ﻳﻚ آﻟﺪﻳﻤﻴﻦ ﻧﺎﭘﺎﻳﺪار ﻳﺎ ﺑﺎز ﺷﻴﻒ ﺗﻮﻟﻴﺪ ﻣﻴﻜﻨﺪ‪.‬‬ ‫ﺑـﺎزآراﻳﻲ ﻣـﻲ ﺷـﻮدو ﺑـﻪ ﻳـﻚ‬ ‫‪(2‬آآﻟﺪﻳﻤﻴﻦ ﺑـﻪ آآﻫﺴـﺘﮕﻲ دﭼـﺎر آ‬ ‫ﻛﺘﻮآﻣﻴﻦ ﭘﺎﻳﺪار ﻛـﻪ ﻫﻤﻮﮔﻠـﻮﺑﻴﻦ ﮔﻠﻴﻜﻮزﻳﻠـﻪ اﺳـﺖ ﺗﺒـﺪﻳﻞ ﻣـﻲ‬ ‫ﺷﻮد‪.‬‬

MEASURES OF GLYCEMIC CONTROL Glycated hemoglubin (HbA1C)  ) • HbA1C testing provides an index of average blood  glucose level over the past 2‐4 months. • Although Although the life span of red blood cells is  the life span of red blood cells is approximately 120 days, HbA1c levels represent a  “weighted” weighted  average of glucose level .  average of glucose level Aprox 50% of HbA1c level is  50% of HbA1c level is determined by plasma  glucose levels over the glucose levels over the  previous months, and 75%  during the previous 2 months 

A graph of glucose A graph of glucose changes over 9 weeks.  changes over 9 weeks. The glucose (green line) changes between  7‐12. This results in an HbA1c level of 10%  at the end of the 9 weeks (red line). Poorly  ( ) y controlled

Here the glucose Here the glucose changes between 5‐9.  changes between 5 9 This results in an HbA1c level of 7% at  the end of the 9 weeks. Well  controlled controlled.

Estimation of [glucose] average from [HbA1c] HbA1c

eAG (estimated average glucose)

(%)

(mg/dL)

5

97 (76–120)

6

126 (100–152)

7

154 (123–185)

8

183 (147–217)

9

212 (170–249)

10

( ) 240 (193–282)

11

269 (217–314)

12

298 (240–347) 298 (240 347)

13

326 (260–380)

14

355 (290–410) 355 (290 410)

15

384 (310–440)

‫ي دارد؟‬ ‫ﭼﻪ آﺎرﺑﺮدي‬ ‫‪ HbA1c ‬ﭼ‬ ‫ﻧﺸﺎن ﻣﻲ‬ ‫ﻲ‬ ‫ﻲ ‪ 2‬ﺗﺎ ‪ 3‬ﻣﺎه ﮔﺬﺷﺘﻪ ررا ن‬ ‫ﻓﺮد ﻃﻲ‬ ‫ﻮن ﺮ‬ ‫ن ﻗﻨﺪ ﺧﻮن‬ ‫ﻣﻴﺰان‬ ‫• ‪ HbA1c ‬ﻴﺰ‬ ‫دﻫﺪوﺑﻪ دو دﻟﻴﻞ اﻧﺪازه ﮔﻴﺮي ﻣﻴﺸﻮد‪:‬‬ ‫‪-1‬ﺗﺸﺨﻴﺺ دﻳﺎﺑﺖ درﻓﺮدﻣﺸﻜﻮك ﺑﻪ دﻳﺎﺑﺖ‬ ‫‪-2‬ارزﻳﺎﺑﻲ اﺛﺮﺑﺨﺸﻲ درﻣﺎن در ﻓﺮد ﻣﺒﺘﻼ ﺑﻪ دﻳﺎﺑﺖ‬ ‫ﻣﻴـﺰان ﻛ ل‬ ‫ﻛﻨﺘـﺮل‬ ‫ا‬ ‫ﺑﺎﺷﺪ و ﭼﻪ‬ ‫ﺑﻴﻤﺎر ااز ﭼﻪ ﻧﻮﻋﻲ ﺎﺷ‬ ‫دﻳﺎﺑﺖ ﺎ‬ ‫اﻳﻨﻜﻪ ﺎ‬ ‫• ﺑﺴﺘﻪ ﺑﻪ ا ﻜ‬ ‫ﺷﺪه ﺑﺎﺷﺪ ﺑﻴﻦ ‪ 2‬ﺗﺎ ‪ 4‬ﺑﺎر در ﺳﺎل ﺑﺎﻳﺪ اﻧﺪاه ﮔﻴﺮي ﺷﻮد‪.‬‬ ‫• ﺑﺮاي اﻓﺮاد ﻣﺒﺘﻼ ﺑﻪ دﻳﺎﺑﺖ اﻧﺠﻤﻦ دﻳﺎﺑـﺖ آآﻣﺮﻳﻜـﺎ ﺗﻮﺻـﻴﻪ ﻛـﺮده‬ ‫اﺳﺖ ﺣﺪاﻗﻞ ‪ 2‬ﺑﺎر در ﺳﺎل اﻧﺠﺎم ﺷﻮد ‪.‬‬

Metabolic complication of diabetes Diabetic ketoacidosis (DKA)  • DKA is a serious and potentially fatal hyperglycemic condition  requiring urgent treatment. • It is frequently associated with : – Nausea – Vomiting – Acidosis – Abdominal pain – Hypotension – Circulatory failure – Drowsiness, Coma ,

Pathogenesis of diabetic ketoacidosis

HYPOGLYCEMIA • Definition: Plasma glucose <50 mg/dl • Hypoglycemia Hypoglycemia result from an imbalance between  result from an imbalance between and  • Unregulated excess insulin secretion cause  hypoglycemia. This is seen in insulin‐secreting  tumors, especially insulinomas where patient have  low serum glucose and ↑ insulin with hypoglycemic  symptom

Hypoglycaemia Symptoms

Example of drugs that may cause hypoglycaemia • Insulin • Sulfonylureas • Benzoic acid derivatives  ( (repaglinide) l d ) • Nateglinide • Alcohol • Pentamidine • Beta‐blockers • Quinine • Salicylates • Sulfonamides • Haloperidol

• • • • • • • • • • •

Propoxyphene Para‐aminobenzoic acid Cibenzoline Gatifloxacin Indomethacin Lithium Clinafloxacin Artesunate Artemisin Artemether Chloroquineoxaline q sulfonamide

‫ﻣﻨﺎﺑﻊ درس‬ • Clinical diagnosis & management by lab  y nd ed, 2011. Chapter 16 p methods, Henry 22 • Clinical Chemistry, Marshall, 6th ed. 2008.  Chapter 11