Disorders of Carbohydrate Metabolism (2024) PDF

Presented by: Assoc. Prof. Abdullah Gibriel Glucose Homeostasis Addition of glucose Fructose & galactose Glycogenolysis Gluconeogenesis Diet Blood glucose Fasting: 65-110 mg/dl (3.6-6.1 mmol/l) 1 mg/d...

Presented by: Assoc. Prof. Abdullah Gibriel Glucose Homeostasis Addition of glucose Fructose & galactose Glycogenolysis Gluconeogenesis Diet Blood glucose Fasting: 65-110 mg/dl (3.6-6.1 mmol/l) 1 mg/dL = 0.0555 mmol/L Normal: 80-120 mg/ dl (4.4-6.6 mmol/l) HMP Lipogenesis Glycogenesis Oxidation Glycolysis Kreb’s Removal of glucose Tissue Regulation: 1- Gastrointestinal tract: After meals, GIT prevents hyperglycemia through: A- Slow evacuation of food through stomach. B- Slow digestion and absorption by intestine. 2-Liver: Liver prevents hyperglycemia by increasing tissue uptake and utilization by activating glycogenesis, glycolysis and kreb’s cycle. In case of fasting and hypoglycemia, Liver activates glycogenolysis and gluconeogenesis. 3- Muscles: The muscles convert glucose to glycogen (glycogenesis) in case of hyperglycemia. In case of hypoglycemia, glycogenolysis occurs. * NB: Fasting depletes liver glycogen but decreases muscle glycogen while exercises depletes muscle glycogen but decreases liver glycogen. 4- Adipose tissues: The adipose tissues convert glucose to fats (triacylglycerols) through glycerol-3-P. 5- Kidneys: 1- Kidney maintains blood glucose by preventing its loss in urine (If not exceeding normal threshold value: 180 mg/dl. 2- If blood glucose level exceeds 180 mg/dl, it will be excreted in urine 3- In prolonged fasting, glucose is generated by gluconeogenesis Renal threshold of glucose: is the blood glucose level above which glucose appears in urine. Normal renal glucose threshold is 180 mg/dl (9.9 mmol/l). In some cases glucose appears in urine even when blood glucose level is 100 mg/dl or normal. This may occur in:- 1- Renal glucosuria due to congenital or renal damage. (Diabetes innocence). 2- Defect in tubular enzymes for glucose reabsorption. 3- Pregnant females: due to change in hormonal cycle Renal threshold value might reach 220 mg/dl in; A- Diabetic patients due to renal damage. B- Elderly people due to the decrease in glomerular filtration rate. NB: Diabetes insipidus: Caused by defect in action of antidiuretic hormone (ADH) cause polyuria > 5 L/day, without hyperglycemia nor glucose in urine.  Hormonal Regulation: Thyroid hormone Epinehrine & NE (Thyroid gland) (Adrenal medulla) Growth Hormone (GH) Pituitary gland Glucocorticoids Insulin effect: (Adrenal cortex) A- Carbohydrate metbalsm: Glucagon (α cells of Isle of ↑glucose cellular uptake. Langerhans in pancreas) ↑glucose oxidation (glycolysis & Hyperglycemic hormones Krebs). ↑ glycogenesis (glycogen storage). Blood glucose ↓ glycogenolysis (glycogen break Fasting: 70-110 mg/dl down). Normal: 80-120 mg/ dl ↓ gluconeogenesis. B- Lipid metabolism:- ↑ Lipogenesis. Hypoglycemic hormones ↓ Lipolysis. C- Protein metabolism:- ↑ Protein synthesis. Insulin (β cells of Isle of Langerhans in pancreas) Remember the following chronological mechanisms for maintaining blood glucose levels: * Glucose from the diet may be stored as glycogen (5%), converted into fat (30 -40%) or metabolized in muscle & tissues to yield energy. ** After 2-3 hours of fasting, stored glycogen begins to be degraded & glucose is released into blood. Liver stores would be depleted first followed by muscle stores. The overall glycogenolysis occurs only for 10-18 hours. *** After 18 hours of fasting, gluconeogenesisbecomes the only source of blood glucose. Triglycerides in adipose tissue are degraded into fatty acid (used as alternative fuel) & glycerol (converted into glucose in the liver), amino acids released from muscles are converted into glucose in the liver. Lactic, pyruvic and oxalates are also converted to glucose.  Hyperglycemia (When fasting blood glucose level is > 150 mg/dl or if postprandial glucose level is > 200 mg/dl) Symptoms: hypeglycemia, glucosuria, polyuria, polyphagia (hunger), polydipsia (thirst), dehydration. Causes: I- Primary causes:- Due to defects in pancreas (-cells of Langerhans) as in diabetes mellitus. II- Secondary cause:-  Alimentary hyperglycemia due to heavy diets.  Stresses (↑ E, NE & ↑ thyroxin).  Chronic pancreatitis, pancreatic surgery.  Increased secretion of antagonistic hormones to insulin (anti-insulin hormones). ◦ Acromegaly (excess growth hormone). ◦ Thyroiditis, goiter (excess thyroxine). ◦ Cushing's syndrome (excess glucocorticoids). ◦ Pheochromocytoma (excess E & NE).  Pregnancy (especially at late trimester stages).  Andresen disease (Deficiency of liver glycogen branching enzyme)  Hypoglycemia (When blood glucose level is < 60 mg/dl) Symptoms: Fatigue, nausea, dizziness, headache, sweating, dilated pupil and tachycardia Causes: I. Fasting hypoglycemia: Due to prolonged fasting II.Reactive hypoglycemia: Due to excessive secretion of insulin after a heavy carbohydrate meal. This is usually temporary and insulin level return back to normal quickly. It is not a pathological case. III.Insulin or drug induced hypoglycemia: Overdose of insulin, oral antidiabetics or Aspirin poisoning in Children.  Excessive exercise  Excessive alcohol drinking  Insulinoma: A tumor in β cells of pancreas resulting in excessive production of insulin.  Hepatic disease (liver damage)  Addison disease (adrenal insufficiency in production of glucocorticoids = hypocortisolism)  Insufficiency in NE, GH, and thyroid hormones.  Glycogen storage diseases (Von Gierke’s disease = deficiency of glucose -6-phospatase) (McArdle disease = deficiency of phosphorylase enzyme) (Pompe’s disease = deficiency of lysosomal α-1,4- glucosidase enzyme), characterized by delayed motor skills, Cardiomegaly, heart falure (Cori’s disease = deficiency of α-1,6- glucosidase enzyme)  Galactose intolerance Excess galactose is reduced by aldose reductase into galactitol which accumulates in the: *Eye leading to hydration of the lens and cataract. ** Liver causing liver damage. *** Brain leading to severe mental retardation.  Classical Galactose intolerance (Deficiency of galactose-1 phosphate Uridyl transferase enzyme which converts galactose into glucose)  Non-Classical Galactose intolerance (Deficiency of galacto-kinase enzyme  Fructose intolerance * Hereditary fructosuris (deficiency of aldolase B) ** Essential fructosuris (deficiency of fructokinase)  Diabetes = excess production of urine Mellitus = sweet (refers to sugar in urine) DM is a spectrum of inherited and acquired disorders that is characterized by elevated circulating blood glucose levels. Inherited condition is characterized by an absolute deficiency of insulin while acquired condition results from either relative deficiency of insulin or increasing insulin resistance. DM does not affect only carbohydrate metabolism but also fat and protein metabolism. DM is a leading cause of blindness and renal failure and is a major cause of heart attacks and stroke. DM can be controlled and the patients with this disease can lead a productive life. Nutrition plays a key role in the management of disease.  When fasting blood glucose level is > 150 mg/dl or if postprandial glucose level is > 200 mg/dl on two different occasions these indicate DM. Classic symptoms include hyperglycemia, glucosuria, polyuria, polyphagia, polydipsia and dehydration. P.O.D Type I Type II Abbreviation IDDM NIDDM Age of onset Juvenile (< age of 20 years) Mature (> age of 40 years) Prevalence Less than 6% of all diabetics About 95% of all diabetics Disorder Inherited (genetic) Acquired (non-genetic) Reasons Complete destruction of β Insulin resistance or partial cells of pancreas destruction of β cells of (Autoimmune disease) pancreas Insulin level Absent or very low Low or normal Treatment Insulin injection Oral anti-diabetic drugs Ketosis Common (Starvation in the Rare middest of plenty) Nutritional Generally malnourished Mostly obese 3 - DM complications: Acute complications: Short term complications include; Hyperglycemia (increased blood glucose level) , glucosuria (glucose in urine) , polyuria (increased urine volume) & frequent urination, polydepsia (thirst), polyphagia (hunger), lack of energy and blurred vision. If hyperglycemia persists, the person might develop coma. Persons with type 1 diabetes have common ketoacidosis which is fatal as it leads to diabetic coma. ↓insulin →↑lipolysis →↑fattyacids →liver → ketosis, ketonuria, and ketonemia (Acidic = low pH + acetone breath) Ketone bodies (acetone+ acetoacetate+ β-hydroxy butyrate) Chronic complications: Long term complications include; Retinopathy (retinal damage), Nephropathy (kidney nephron damage), Neuropathy (nerve damage) with Tingling & numb sensation in feet and hand (should be prevented with vitamin B complex supplements), Atherosclerosis, Micro and macro albuminuria Coronary heart disease, Cerebrovascular disease, Chronic complications occur through the following mechanisms; A- glycosylation (glycation) of proteins such as hemoglobin and albumin. This occurs in two stages: (1) the aldehyde group of glucose links to the amino group of an amino acid forming an aldimine (Schiff base), and (2) the unstable aldimine undergoes rearrangement to form the stable ketoamine linkage. This process, occurring spontaneously without enzyme action, is termed nonenzymatic glycosylation. B- convertion of glucose into sorbitol and fructose which degrade slowly and accumulate in the cell causing cell distention and toxicity. *** Long-term complications cannot be prevented, but risks can be lowered with good diabetic control. NB; Excess glucose accumulates in the lens, retina, kidney & nerves and is then reduced by aldose reductase to sorbitol which causes strong osmotic pressure leading to water retention and cell swelling which will ultimately lead to; - Cataract for the Lens of the eye. - Retinopathy (damage to retina) of the eye. - Nephropathy (damage of the nephron) of the kidney. - Neuropathy (damage to the neurons) of the peripheral nerves Gestational DM: It develops during pregnancy. Glucose metabolism is altered due to change of insulin sensitivity, hormonal secretions, eating habits, exercise pattern and emotional state. Although most of these women return to normal glucose tolerance after delivery, 40 to 60% of them may develop Type II DM. Those who maintain a reasonable body weight and exercise on a regular basis have been shown to have a decreased incidence of developing NIDDM. In diabetic women and during the first half of pregnancy, insulin requirements may decrease by 20 to 30% because of decreased food intake and increased glucose uptake by the fetus and placenta. During the second half of pregnancy, insulin requirements often increase by 60 to 100% above pre-pregnancy levels because of placental hormone production and insulin resistance. After delivery insulin requirements decrease slowly but it increases gradually after 6 weeks from delivery date. This requires careful blood glucose monitoring.  Chemical Determination of glucose level in blood and urine (Chemical Nature) There are specific and non-specific tests for glucose determination. Higher values are obtained for non specific tests as they are based on the reducing properties of glucose and many other compounds in the blood such as glutathione, uric acid, ascorbic acid and glucouronic acid possess such properties too. The value measured by non specific tests is called apparent glucose. Non specific tests include o-toluidine, Bendict and phosphomolybdic acid methods. True glucose is measured by specific methods which depends on the use of enzymes such as glucose oxidase and hexokinase. Glucose level in blood decreases rapidly on standing due to rapid conversion of glucose to lactic acid (glycolysis) by RBC’s. This can be prevented by adding sodium fluoride and potassium Oxalate to the anticoagulant in a proportion of 1:3 parts. This will inhibit Enolase enzyme in glycolysis and hence prevent any loss of glucose for 2 to 3 days. Patients are said to be diabetic if they have a fasting plasma glucose concentration > 150 mg/dl (7.8 mmol/l) or > 200 mg/dl (11.1 mmol/l) two hours after a CHO meal or after the oral ingestion of 75g of glucose, even if the fasting concentration is normal.  Phosphomolybdic acid method (non-specific) Glucose reduces cupper in an alkaline solution and the produced cuprous ion reacts with phosphomolydic acid to produce molybdenum blue that is estimated colorimetrically. 2  B.W.B Glucose  Cu  Reduced cupper (Cuprous ion) Alkaline medium  Cu+ + phosphomolybdic acid Cu2+ + molybdenum Blue. O-Toluidine method (non-specific)  It is a specific method for glucose determination in the absence of other aldo-sugars since it depends on the reaction with the aldehydic group of glucose as follows:  O-toluidine reacts quantitatively with the aldehyde group of glucose to form glycosylamine then Schiff base which has a color that can be measured colorimetrically.   Glucose oxidase method (Specific test) Glucose  O2  H2O GlucoseoxidaseGluconic acid  H2O2 H2O2  dianisidin e PeroxidaseOxidized dianisidin e (Color)  H2O The produced colored complex is measured colorimetrically and is proportional to glucose concentration.  Hexokinase method (Specific test) Glucose-6-PO4 Glucose HexokinaseGlucose - 6 - phosphatedehydrogenase6  phosphogluconolacton e ATP ADP NADP NADPH H+  NADPHH+ can be measured colorimetrically and is proportional to glucose concentration.  Biochemical lab tests/ways for glucose measurement (Clinical Nature) Blood samples may be taken according to the following ways:  1. Random blood glucose (RBG) test: is required in case of emergency and/or random check. Values higher than 200 mg/dl (11 mmol/l) usually indicate DM.  2. Fasting blood glucose (FBG) test: is measured after an overnight fast (at least 10 hours). It is better than RBG for diagnostic purposes. In non-diabetics it is ≤ 110 mg/dl. Borderline is 110-150 mg/dl. Any person with blood glucose level ≥150 mg/dl on two different occasions is considered to have D.M. 3.Postprandial: 2 hours after a CHO meal or oral ingestion of 75 g glucose. Normal person have ≤120 mg/dl. Borderline is 120-200 mg/dl. DM have ≥ 200 mg/dl. 4. Oral glucose tolerance test (OGTT):  It is used to measure the ability of body to utilize glucose without appearance of hyperglycemia & glucosuria. A baseline blood sample is first taken after an overnight fast. The patient is then given 75 gm of glucose orally, in about 300 ml of water, to be drunk within 5 minutes. Plasma glucose levels are measured every 30 minutes for 2-3 hours. Urine may also be tested for glucose at time 0 and after 2 hours. The patient should be sitting comfortably throughout the test, should not smoke or perform any exercise activity, no alcohol or drugs and should have been on a normal diet for at least 3 days prior to the test.  Values recorded across the first 2 hr (every 30 minutes) are generally the most informative and indicative for the OGTT. Normal and diabetic responses to an oral glucose load are shown in the next figure:  Normal glucose tolerance curve:  Diabetic curve: - Fasting range: 70-110 mg/dl -Fasting range: > than normal (140 – 200 mg/dl). - Peak (1 hr): 120-150 mg/dl - Peak (1 hr): > 200 mg/dl. - Levels return to the fasting range after 2 hr. - Levels become slower or do not return to normal - No glucosuria. fasting level. - Glucosuria. 5. Intravenous Glucose Tolerance Test (IGTT): Some individuals are unable to tolerate a large CHO load orally due to malabsorption, vomiting or a surgical gastroctomy. Poor absorption of oral glucose will result in a 'flat' tolerance curve. This is overcome by intravenous (i.v) glucose tolerance test. The dose of glucose is 0.5g/kg Blood is collected every 10 minutes for 1 Hr. Other common/routine screening tests for diabetics; 1. Glucose in urine: Glycosuria allows for a good first-line screening test for D.M; most occupational health checks and hospital admissions will include a urinary glucose test. Normally glucose does not appear in the urine until the BG rises above 180 mg/dl (Renal threshold). However, in some healthy individuals, glucose may spill over into the urine at much lower plasma concentrations (such as Diabetes Innocence). These individuals are said to have a low renal threshold for glucose and have glucosuria without having D.M. Conversely, the renal glucose threshold increases with age and DM and as a result many diabetics will not have glycosuria. It is important when interpreting urinary glucose measurements to remember that urine glucose level is a reflection of integrated glycemia over the time of the formation of the urine and does not reflect the exact level of BG at the time of testing. Therefore, presence or absence of glucose in urine is not an absolute indication of impaired glucose metabolism???? 2. Ketones in urine/ plasma: Ketone bodies (acetone, acetoacetate and - hydroxybutyrate) may accumulate in the plasma of a diabetic patient. Their presence is by no means diagnostic of ketoacidosis, a serious condition. Ketones may be present in a normal subject as a result of simple prolonged fasting.  3. Plasma Insulin level: Insulin measurements can lead to the diagnosis or exclusion of of insulinoma and also could distinguish between hypoglycemic conditions that are due to insulinoma or excessive insulin dose injection. They do not play critical role in diagnosis of DM. It is carried out by radioimmunoassay (RIA) or (ELISA). Normal range is 0-20 U/ml Insulin is a peptide hormone with 84 amino acids. It is secreted by the β cells of Islet of Langerhans has two chains (α and β) that are connected to each others through peptide C (Connecting peptide (A, B & C) and also possess three disulfide bonds. This is the inactive form of insulin and is called proinsulin. A chain has 21 aa, B chain has 30 aa, C chain has 33 aa. C-peptide is then cleaved to produce active insulin with 51 aa. Active form of insulin does not have the C-peptide. Exogenous insulin administered by injection also does not have the C-peptide. Measurement of plasma C-peptided level can differentiate between hypoglycemia due to insulinoma (high C-peptide) and that due to excessive dose of insulin injection (low C-peptide). This test is carried out by radioimmunoassay (RIA) or (ELISA)  Long-Term Indices of Diabetic Control: The presence of glucose in high concentration in the blood for prolonged times leads to its non-enzymatic attachment to the lysine residues of a variety of proteins through covalent bonds. This is termed glycation. The extent of this process depends on the glucose level. It is irreversible (ketoamine stage) and therefore the glucose molecule will remain attached until the protein molecule is degraded. The concentration of glycated protein is therefore a reflection of a mean blood glucose level prevailing in the extracellular fluid (ECF) during the life of that protein. The biochemical tests below are therefore used in long term monitoring of diabetic control and also in diabetic drug monitoring. 1. Hemoglobin A1c : glycated hemoglobin or glycosylated hemoglobin:  Glucose attaches haemoglobim in RBC’s. The life span of RBC’s is 120 days (4 months). Glycated hemoglobin reflects the mean glycemia over 3 months prior to its measurement.  Not indicative in case of haemolytic anaemia and short RBC’s life span.  Normal level: 4-6%, less than 8% indicates good control, 8-10% indicates fair diabetic control, >10% indicates poor diabetic control. 2. Fructosamine: Normal level: 2.4-3.4 mmol/l Many other proteins especially albumin are glycated when exposed to glucose in the blood.An indication of the extent of this glycation can be obtained by measuring fructosamine, the ketoamine product of non-enzymatic glycation. Albumin has a shorter half-life than hemoglobin, fructosamine measurements are complementary to HbAlc providing an index of glucose control over the 3 weeks prior to its measurement 3. Microalbuminuria & Macroalbuminuria: Defined as an albumin excretion rate intermediate between normality (2.5-25 mg/day) and macroalbuminuria (> 250 mg/day). The small increase in urinary albumin excretion is not detected by simple albumin stick tests and requires confirmation by careful quantitation in a 24 hr urine specimen. The importance of microalbuminuria in the diabetic patient is that it is a signal of early reversible renal damage. Macroalbuminuria is a sign for irreversible renal damage prior to End Stage Renal Disease (ESRD). Microalbuminuria and Macroalbuminuria are recognized as indicative markers for nephropathy and are predictive chronic kidney diseases (CKD) and also macrovascular disease risk. They are currently being updated/replaced by Urinary Albumin creatinine Ratio (UACR) marker. NB; OGTT and HbA1c are used to screen for short & long term indices of diabetic control respectively. 4. Urine Albumin Creatinine ration (UACR) (ACR) Albumin is a high molecular weight protein and is a major plasma protein that performs various functions such as maintaining osmotic pressure to prevent edema and ascites, carries drugs, bilirubin (indirect = unconjugated) and steroidal hormones and others. In heathy individuals with no diabetes or renal defect, albumin is never passed to urine as the nephron can not filter such high molecular weight molecule. Creatinine is a normal waste product that is excreted at almost steady concentration into urine. That’s is why health care provider can more accurately measure the amount of albumin by comparing it to the amount of creatinine in urine. The urine sample requested in the lab could be a 24-hour urine sample (gold standard) or a random urine sample. In this test, Albumin in urine is measured in milligram while creatinine is measured in urine in grams. This test is also very useful in determining damage occur in the kidney because of impaired glucose metabolism (Nephropathy). The results are classified as follows; Normal individuals (Category A1) will have UACR 300 mg/g  Case 1 A 30-year-old registered nurse was admitted for unconsciousness and found to be hypoglycemic. She had a history of recurrent hypoglycemic episodes occurring about once a month for the past year. Initially, they were characterized by confusion and lethargy but were relieved by eating. However, the last one resulted in coma. Her blood sugar level was found to be 20 mg/dl. She was treated with intravenous glucose and admitted to the hospital. After she regained consciousness, the patient stated that just before the episodes occurred she felt very hungry, shaky and sweaty and could feel heart pounding. If she ate immediately, she could have prevented the attack. Physical examination revealed a thin anxious woman with normal blood pressure and pulse. No skin lesions or hepatomegaly (enlarged liver) was present. Laboratory examination, including liver and kidney tests, were normal. However, insulin levels drawn during two hypoglycemic episodes were 82 and 74 µU/ml (normal fasting 0 to 29 ). Simultaneous C-peptide levels in both samples were detectable. Q- Which causes are the most likely ones affecting this patient? Dr. Abdullah Gibriel  Case 2 A 37-year-old lady performed the OGTT and the following results were obtained: Q1- Draw the OGTT curve. From the curve, does this lady seem to be diabetic? Q2- In addition to the OGTT, what are the other tests that can be performed? Q3- If this lady was having a malabsorption or gastroctomy, what will be the most convenient way to replace OGTT? Q4- Is the presence of glucose in urine is an absolute indication of DM? Q5- What are the acute and chronic complications of DM? and what are the long term indices for DM? Dr. Abdullah Gibriel