Dr Kameel Mungrue

1. Dr Kameel Mungrue Primary Care and Public Health The implications of Carbohydrate metabolism Kmungrue@fms.uwi.tt 645-2018 Ext 2887

3. Human happiness is not merely the province of isolated individuals. ... The better connected are one's friends and family, the more likely one will attain happiness in the future. ... People's happiness depends on the happiness of others with whom they are connected.(happiness contagion) This provides further justification for seeing happiness, like health, as a collective phenomenon."James H Fowler and Nicholas A Christakis, "Dynamic spread of happiness in a large social network: longitudinal analysis over 20 years in the Framingham Heart Study,"British Medical Journal, 4 December 2008.

4. carbohydrates • Substances manufactured from the conversion of C02 and H20 by plants using sunlight and chlorophyll • C02 + H20 carbohydrates Sunlight, chlorophyll soil AIR

5. monosacharides • Glucose, galactose, fructose. dextrose hexoses

6. disacharides • Two sugars • One glucose + one glucose =maltose • One glucose + one galactose = lactose • One glucose + one fructose = sucrose

7. oligosacharides • 3-10 glucose molecules

8. Polysacharides • Starch • Glycogen (animal starch)

9. Polysacharides • Starch • Glycogen (animal starch)

10. Why are carbohydrates important? • They provide energy • Storage in the form of glycogen • Protein sparing action • Antiketogenic effect

11. Why need for energy? • Brain consumes glucose at a rate of 110gm/day • brain tissue requires 22 times the food energy that skeletal muscle does • Homo erectus would have had to chew raw food for six hours each day to obtain enough food energy to sustain its brain size. • fire and cooking allowed for the evolution of larger brains. • It has no storage • Muscle contraction • Heat production

12. coma convulsions glycosuria hypoglycaemia hyperglycaemia 20 50 70 100 126 170 Hepatic gluconeogenesis Normal Range lipogenesis Liver glycogen Glucose….Fats….adipose tissue Carbs protein fat Glycogenesis in muscle

17. Quiz • Which one of the following substances will cause the release of Insulin : • Free fatty acid • Amino acids • Glycogen • α1antitrypsin

18. The discovery of Insulin Banting Best Collip Macleod

19. Banting was a struggling young physician • he took a job at London's Western University as a demonstrator in surgery and anatomy • He was required to give a lecture on the pancreas on Nov. 1, 1920.

20. In preparing his lecture he stumbled across a paper “The Relation of the Islets of Langerhans to Diabetes by Dr. Moses Barron.” blocked pancreatic ducts would make the pancreas shrivel, but its cell system the islets of Langerhans did not He also noted that diabetes didn't appear to develop unless the islets were damaged.

21. External secretion • Internal secretion • Could the islets carry the secret of the mysterious internal secretion? • "Tie off the pancreatic duct of dogs. Wait six to eight weeks for degeneration. Remove residue and extract."

22. he discussed his idea with Dr. Miller at Western University • Miller suggested that Banting talk to J. J. R. Macleod (an expert on carbohydrate metabolism) • He threw him out • Banting keep insisting

23. Eventually MacLeod offered Banting the use of an aging unused lab • Macleod included the help of two summer assistants. A coin toss decided that Charles Best, who had just completed a degree in biochemistry and physiology, would work with Banting

24. removed the pancreas from dogs which made them diabetic • Used extract from the pancreas • injected it into the diabetic dogs which restored them to normalcy. • An expert biochemist J.B. Collip worked feverishly in the fall of 1921 to purify insulin or isletin

25. On Feb. 26, 1923, the Nobel Prize for medicine and physiology was jointly awarded to Banting and Macleod. • Banting was furious, he shared his reward equally with Best • While Macleod shared his with Collip

26. Chromosome Gene Introns IVS-2 IVS-1 Exons E2 E3 E1 1430 bp

27. Insulin gene transcription insulin C-peptide Translation/ Translocation Protease cleavage Folding & cleavage Golgi transport/vesicle packaging

28. band centromere Short arm p Long arm chromosome Insulin gene 11 p 15

29. No insulin • hyperglycaemia

30. hyperglycaemia • Advanced glycosolation end products • Protien kinase C • Transforming growth factor β • ↑ release of proinflamatory cytokines • Elevated oxidative stress • Retinopathy • neuropathy

31. AGE’s • Protein alteration resulting from a nonenzymatic reaction between ambient glucose and primary amino groups on proteins to form glycated residues called Amadori products is termed the Maillard reaction. By dehydration and fragmentation reactions, Amadori products are transformed to stable covalent adducts called advanced glycosylation end products (AGEs).

32. In diabetes, accelerated synthesis and tissue deposition of AGEs is proposed as a contributing mechanism in the pathogenesis of clinical complications. • Uremia in diabetes is associated with both a high serum level of AGEs and accelerated macro- and microvasculopathy.

33. Protein Kinase C • PKC is an enzyme that phosphorylates protein substrates on serine (Ser) or threonine (Thr) residues. • In the edothelium glucose can freely enter the cell and can be metabolised resulting in an increase intracellular concentrations of the lipid diacylglycerol (DAG). • Of 10 known mammalian PKC isoforms, 8 are activated by DAG

34. PKC activation in diabetes leads to microvascular complications • but increasing evidence supports that PKC plays a role in several mechanisms promoting atherosclerosis.

35. Transforming growth factor β extracellular signalling molecules (ligands), eg TGFβ, cytokines External receptor Second messenger Cellular response

36. TGF-β • TGF-β is produced by a wide variety of cells and tissue types e.g. platelets, bone and placenta. • Essentially all cels have a receptor for TGF-β • In hyperglycaemia there is ↑ TGF-β, which is associated with arteriosclerosis

44. Diabetic hyperglycemia is partially due to glucagon-stimulated hepatic glucose synthesis which occurs in spite of the high blood glucose levels that follow the loss of insulin or insulin resistance.  Inhibition of hepatic gluconeogenesis with metformin is an important component of treatment for type 2 diabetes.

46. Insulin resistance • When a defect in insulin action results in fasting hyperinsulinaemia to maintain euglycaemia • Postprandial hyperglycaemia • The major contributing factors • Is an overabundance of circulating fatty acids(adipose tissue) • Upon reaching insulin sensitive tissue fatty acids create insulin resistance by modifying downstream signaling • Eg protein kinase C-/protein kinase C-

47. The mechanisms responsible for insulin resistance syndromes include genetic or primary target cell defects, autoantibodies to insulin, and accelerated insulin degradation.

48. Obesity, the most common cause of insulin resistance, is associated with a decreased number of receptors and with postreceptor failure to activate tyrosine kinase.