1. Pentose phosphate pathway p.p.p. (hexose monophosphate shunt)
This is an alternative pathway for glucose metabolism, it does not generate ATP but has two major functions :

2. Formation of NADPH for reduction processes and for synthesis of fatty acids and steroids. Synthesis of ribose 5 phosphate for nucleotides and nucleic acid synthesis.

3. The reactions of ppp occur in the cytoplasm, and have two pathways:
1.Oxidative nonreversible reactions 2.Non oxidative reversible reactions

4. Oxidative pathway
Oxidation of glucose 6 phosphate into ribulose 5 phosphate is achieved through dehydrogenation (oxidation) of glucose 6 phosphate into 6 phosphogluconolactone catalyzed by glucose 6 phosphate dehydrogenase enzyme in the presence of NADP˖, then hydration of 6 phosphogluconolactone into 6 phospho gluconate by the action of hydrolase enzyme

5. Both enzymes require co factors which are calcium or magnesium.
Now oxidation and decarboxylation of 6 phospho gluconate into a keto pentose known as ribulose 5 phosphate a reaction catalyzed by 6 phosphoguconate dehydrogenase in the presence of NADP˖ and calcium or magnesium

6. Glucose 6 phosphate NADP NADPH 6 phoshogluconolactone H2O
6 phosphogluconate NADP NADPH+ CO2 Ribulose 5 phosphate

7. Ribulose 5 phosphate is the substrate for two enzymes which are A
Ribulose 5 phosphate is the substrate for two enzymes which are A . Ribulose 5 phosphate 3 epimerase that alters the configuration about C3,forming another ketopentose known as xylulose 5 phosphate B . Ribulose 5 phosphate ketoisomerase that converts Ribulose 5 phosphate which is a keto sugar to the corresponding aldosugar known as ribose 5 phosphate which is the precursor of ribose required for nucleotides and nucleic acid synthesis.

9. Transketolase enzyme catalyzes the conversion of a ketose sugar into an aldose sugar with two carbon less and simultaneously converts an aldose to ketose with two carbon more. Therefore, transketolase catalyzes the transfer of two carbon from the five carbon ketose (xylulose 5 phosphate) to the five carbon aldose(ribose 5 phosphate) ,producing seven carbon ketose (sedoheptulose 7 phosphate) and three carbon aldose (glyceraldehyde 3 phosphate)

11. Two molecules of glyceraldehyde 3 phosphate may condense into one molecule of glucose 6 phosphate i.e. the reversal of glycolysis ,this need a series of enzymes as follows :

12. In summery pentose phosphate shunt is markedly different from glycolysis by:
*Oxidation utelizes NADP insteed of NAD. *CO₂ which not produced in glycolysis is a characteristic product in PPP *No ATP is generated in PPP where as ATP is produced in glycolysis.

13. The main reductive function of NADPH is found in erythrocytes in which NADPH + H˖ share in the reduction of oxidized glutathione in a reaction catalyzed by glutathione reductase enzyme. The reduced glutathione removes H₂O₂ in a reaction catalyzed by glutathione peroxidase enzyme to be back into the oxidized form. This is important since H₂O₂ decreases the life span of RBC by causing oxidative damage to the cell leading to hemolysis.

15. Clinical aspects of pentose phosphate pathway
Glucose 6 phosphate dehydrogenase deficiency (G6PD Deficiency) or Favism :it is the main clinical aspect of pentose phosphate pathway in which there is genetic deficiency of glucose 6 phosphate dehydrogenase enzyme with consequent impairment of the generation of NADPH+H⁺, this disease is common in population of Mediterranean and afro Caribbean origin.

16. The defect is manifested as red cell hemolysis (hemolytic anemia) when susceptible individual is subjected to an oxidant that contain H₂O₂ because glutathione peroxidase which removes H₂O₂ is dependent upon a supply of NADPH, which in RBC can be formed only via the pentose phosphate shunt. These oxidants that contain H₂O₂ INCLUDE MAINLY DRUGS AS PRIMAQUINE ,ASPIRIN , SULFONAMIDES or when they have eaten fava beans (hence the term favism)

17. Uronic ACID
Uronic acid is an alternative for glucose metabolism. it does not generate ATP. It catalyzes the conversion of glucose into glucoronic acid ,pentoses and in animal ascorbic acid. Glucuronic acid is incorporated into proteoglycans, and conjugated with bilirubin ,steroids hormones and number of drugs to be excreted from the body in urine or bile. while the pentoses are mainly xylulose 5 phosphate which enter the petose shunt.

18. Fructose metabolism
Fructose in the liver is converted mainly to glucose or to a less extent into the intermediates of glycolysis and minor amount is converted into fatty acids. Major pathway for fructose metabolism occurs in liver and kidney initiated by fructokinase ,which catalyzes the irreversible phosphorylation into fructose 1 phosphate in expense of ATP .

19. This enzyme is not acting on glucose and its activity is not affected by fasting or by insulin, this may explain why fructose is cleared from the blood of diabetics at normal rate. Fructose 1 phosphate is cleaved by aldolase into glyceraldehyde and dihydroxyacetonphosphate , then phosphorylation of glyceraldehyde to glyceraldehyde 3 phosphate by triokinase enzyme in expense of ATP.

20. Now the two triose may be degraded by glycolysis ,or may be substrates for gluconeogenesis. Fructose is degraded more rapidly than glucose, because it bypass first few steps of glycolysis .

21. Clinical aspects
Essential fructosuria: is an inborn error of metabolism due to lack of hepatic fructokinase ,however the condition is benign. Hereditary fructose intolerance : inborn error of metabolism due to absence of hepatic fructose 1 phosphate aldolase which leads to the following presentations at infancy when the baby start to eat fructose containing diet.

22. 1.fructose induced hypoglycemia because accumulation of fructose 1 phosphate inhibits the activity of liver phosphorylase causing hypoglycemia despites the presence of glycogen reserve. 2.Liver impairment due to accumulation of fructose 1 phosphate in the liver. 3.Hyper uricemia because of sequestration of inorganic phosphate by the accumulated of fructose 1 phosphate ,therefore, there is less inhibition of DE novo synthesis of purine synthesis and uric acid is increased. 4.Failure to thrive.

23. Diagnosis by detection of fructose in urine, and measuring enzyme activity. Treatment by fructose abstinence (also sorbitol and sucrose).

24. Galactose metabolism
Galactose is readily converted to glucose in the liver by the following steps: 1.Galactose is phosphorylated by galactokinase enzyme to galactose 1 phosphate in presence of Mg ⁺⁺ and ATP . 2.Galactose 1 phosphate reacts with uridine diphosphate glucose to form uridine diphosphate galactose and glucose 1 phosphate, this reaction catalyzed by galactose 1 phosphate uridyl transferase.

25. 3. UDP galactose is converted to UDP glucose by epimerase enzyme
3.UDP galactose is converted to UDP glucose by epimerase enzyme.(reversible reaction). 4.Glucose is liberated from UDPglucose after it enters the glycogenesis followed by glycogenolysis. Since epimerase reaction is reversible ,glucose can be converted into galactose ,so that galactose is not essential in diet.

27. Clinical aspects
Galactosemia is an inborn error of metabolism characterized by the inability to metabolize galactose, caused mainly by inherited defect of galactose 1 phosphate uridyl transferase and to less extent by a defect in galactokinase or UDP galactose epimerase.the clinical features of galactosemia usually start early after the baby start suckling milk which contain lactose,and they include:

28. 1.cataract the excess galactose in the lense is reduced to galacticol, which accumulate causing cataract due to its osmotic effect. 2.Liver impairment especialy in galactose 1 phosphate uridyl transferase defeciency due to the accumulated galactose 1 phosphate. 3.hypoglycemia. 4. Failure to thrive..

29. Diagnosis by detection of galactose in urine
Diagnosis by detection of galactose in urine. Treatment by galactose free diet .as UDP galactose epimerase is present in adequate amount in most cases ,the patient can still form UDP galactose from glucose and has normal growth and development regardless of the galactose free diet.

30. gluconeogenesis
It is the term used to define all the pathways responsible for converting noncarbohydrate precursors to glucose or glycogen. These non carbohydrate precursors include glucogenic aminoacids,lactate and glycerol. Gluconeogenesis takes place in liver and kidney.

31. Gluconeogenesis meets the need of the body for glucose to supply energy especially for nervous system and erythrocytes. It clears lactate produced by RBC and muscle. Also it is important to drain glycerol produced by adipose tissues. Failure of gluconeogenesis is fatal.

32. Pathways of gluconeogenesis
Reversal of glycolysis Three reactions provides pathways for inversion of glycolysis 1.the mitochondrial pyruvate carboxylase convert pyruvate to oxaloacetate this is irreversible reaction expends ATP in the presence of biotin as a coenzyme. Oxaloacetate does not cross the mitochondrial inner membrane and is converted to malate in the mitochondria by kreps cycle catalyzed by malate dehydrogenase ,malate is transported to the cytosol where it is converted back to oxaloacetate by the same enzyme!

33. Phosphoenolpyruvate carboxylase catalyzes the carboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate this is irreversible reaction requires GTP(guanosine triphosphate) as phosphate donner. 2.The conversion of fructose 1 ,6 bisphosphate to fructose 6 phosphate this is catalyzed by fructose 1,6 bisphosphatase .

34. 3.Conversion of glucose 6 phosphate to glucose via the action of glucose 6 phosphatase. By the reversal of glycolysis and citric acid cycle glucose can be formed from the following non carbohydrate precursors : 1. Glucogenic aminoacids after transamination or deamination they yield either pyruvate or intermediates of citric acid as αketoglutarate ,oxaloacetate,or fumerate. Alanine is the most important aminoacid transported from the muscle to the liver during fasting ,it will be converted to pyruvate by transamination and enter into gluconeogenesis this cycle is called glucose –alanine cycle.

35. 2. Lactate can be converted to pyruvate by the lactate dehydrogenase
2.Lactate can be converted to pyruvate by the lactate dehydrogenase . Lactate formed in RBC and skeletal muscle (anaerobicaly) transported to liver and kidney for gluconeogenesis,this prossess known as Cori cycle 3.Glycerol from fatty acid oxidation ,can enter the gluconeogenesis through its conversion into dihydroxyactone phosphate through the following pathways:

37. Hormonal control of carbohydrate metabolism
1.Glycolysis is stimulated by insulin and inhibited by glucagon and epinephrine. 2.Glycogenesis is stimulated by insulin and inhibited by glucagon and epinephrine. 3.Glcogenolysis is stimulated by glucagon and epinephrine and inhibited by insulin. 4.Gluconeogenesis is stimulated by growth hormone ,glucocorticoids,glucagon and epinephrine,it is inhibited by insulin.

38. Blood glucose level
The concentration of blood glucose is regulated within narrow limits ranging from 3.3 mmol/L(60 mg/dl)in starvation ,up to 7.2 mmol/L(130 mg/dl) after the ingestion of a carbohydrate meal. A sudden decrease in blood glucose will cause convulsion due to the immediate brain dependence on a supply of glucose.

39. glucosuria
Normally glucose is continuously filtered by the glomeruli but its completely reabsorbed in the renal tubules, therefore, normally there is no glucose in urine. This happen when venous blood glucose concentration is exceeding the renal threshold for glucose ( mg/dl).

40. The presence of glucose in urine (glucosuria) suggest : 1
The presence of glucose in urine (glucosuria) suggest : 1.Hyperglycemia when venous blood glucose concentration exceeds the renal threshold for glucose as occurs in diabetes mellitus. 2.Reduction of renal threshold for glucose as occur in renal glucosuria which is harmless condition with no obvious cause for it. Also it could happen in normal pregnancy due to hypervolemia that occur during pregnancy.

41. Diabetes mellitus
It is a family of disorder that is characterized by hyperglycemia. These disorders differ in their etiology ,symptoms and complications. In Mosul % of population have diabetes.

42. Classification of diabetes
Type 1 diabetes Type 2 diabetes Gestational diabetes Other specific types

43. Type 1
It usually represents about 5-10% of diabetes and is due to lack of insulin production by beta cell of pancreas. It manifests itself usually in childhood and adolescents. Treatment by insulin so it is called insulin dependent ,together with diet and exercise. It could be immune mediated in which there is auto antibodies that destruct the β cells. And it could be ideopathic in which there is no obvious cause .

44. Type 2
It forms the most common cases and it is either due to insulin insufficiency or insulin resistance i.e decrease responsiveness to insulin by the cells. It is poly genic which mean that hereditary and environmental factors precipitate the disease (obesity , sedentary life style, over stress, increasing age, hypertension ,hyperlipidemia and others) usually affects obese people older than 40 years old treatment by oral drugs ,reducing body weight, diet, exercise ,if fail then insulin is used.

45. Gestational diabetes
It is defined as diabetes diagnosed first time during pregnancy it affects about 4% of pregnant women . during pregnancy there is reduction of cellular response (insulin resistance). Most pregnant women compensate with increasing secretion of insulin , those who are unable to compensate may develop diabetes. It fades away after delivery ,but the woman becomes at risk at future of diabetes.

46. Other types of diabetes
Disease of exocrine pancreas such as cystic fibrosis. Endocrinopathies as cushing´s syndrome. Drug triggered as glucocorticoids .

47. Impaired glucose tolerance and impaired fasting glucose ….prediabetes
They represent a borderline stage in which blood glucose is higher than normal and lower than diabetes. It is a risk factor for cardiovascular disease.20-30% of those people will have overt diabetes within 10 years.

48. Diagnosis of diabetes mellitus
Fasting plasma glucose test measure glucose after at least 8 hours without eating.
Fasting plasma glucose mg%
Diagnosis
70-100
Normal
Pre diabetes impaired fasting
And above
Diabetes

49. Oral glucose tolerance test OGTT
Measure plasma glucose after 8 hours fasting and two hours after oral glucose load of 75 grams in 300 ml water . It is more precise .

50. Random plasma glucose measure glucose any time post prandial, if level of glucose exceeds 200mg% it is consider diabetes mellitus.