Carbohydrate metabolism. Topics in Metabolism Overview of glucose homeostasis Glucose metabolic pathways and their regulation Glycolysis Citric acid cycle

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  • Carbohydrate metabolism

  • Topics in Metabolism Overview of glucose homeostasis Glucose metabolic pathways and their regulation Glycolysis Citric acid cycle Gluconeogenesis Glycogen metabolism Pentose phosphate pathway Carbohydrate metabolism

  • CarbohydratesCarbohydrates are called carbohydrates because they are essentially hydrates of carbon (i.e. they are composed of carbon and water and have a composition of (CH2O)n.

    The major nutritional role of carbohydrates is to provide energy and digestible carbohydrates provide 4 kilocalories per gram. No single carbohydrate is essential, but carbohydrates do participate in many required functions in the body.

  • Clinical exampleR.D., a 6-week-old girl, was born after a normal pregnancy and weighed 3.2 kg at birth . Her parents and two older siblings were in good health. She was breast fed for 4 wk, and her weight gain had been normal. At 4 wk of age, breastfeeding was discontinued and a common baby formula was substituted. As a result of poor initial formula preparation, the child develop a viral gastroenteritis and after several days exhibited fussiness, watery diarrhea, and vomiting. At age of 6 wk she was admitted to the hospital. Urinalysis yielded a +1 reaction for reducing substance.

  • Pediatric gastroenteritisWas there any significant difference between the breast milk and the baby formulas?How did the gastroenteritis affect the digestion of carbohydrates? was the gastroenteritis related to diarrhea? What might have caused the explosive, acid, watery stool containing reducing substances?

  • DigestionPre-stomach Salivary amylase : a 1-4 endoglycosidase

    GGGGGGGGa 1-4 linkGGGGa 1-6 linkGGGGGGGGGGGGGGGmaltoseGGGisomaltoseamylasemaltotrioseGGGGa Limit dextrins

  • StomachNot much carbohydrate digestionAcid and pepsin to unfold proteinsRuminants have forestomachs with extensivemicrobial populations to breakdown andanaerobically ferment feed

  • Small IntestinePancreatic enzymesa-amylaseGGGGGGGGGGGGGGGGamyloseamylopectinGGGGGa amylase+GGGGGmaltotriosemaltosea Limit dextrinsG

  • Oligosaccharide digestion..contGGGGGGGGGGGGGlucoamylase (maltase) ora-dextrinaseGGGGGa-dextrinaseGGGGGGGmaltasesucrasea Limit dextrinsG

  • Small intestinePortal for transport of virtually all nutrients

    Water and electrolyte balanceEnzymes associated with intestinal surface membranesSucrasea dextrinaseGlucoamylase (maltase)Lactasepeptidases

  • Carbohydrate absorptionHexose transporterapicalbasolateral

  • Carbohydrate malabsorptionLactose intolerance (hypolactasia).Decline lactase with ageLactose fermented in LI Gas and volatile FAWater retention diarrhea/bloatingNot all populationsNorthern European low incidenceAsian/African Americans High

    b 1-4 linkage

  • Glucose metabolism: Breakfast Eat cereal, bread, skimmed milk, fruit - mixture of monosaccharides (glucose, fructose), disaccharides (lactose, sucrose), complex carbohydrates (starch). Carbohydrates are broken down to monosaccharides for absorption in the small intestine. Glucose enters circulation through portal vein and increased blood glucose is detected 15 min after and peaking at 30-60 min after meal

  • Efficiency of glucose disposition after a meal The amount of glucose in a meal (~100 g) is enough to raise the blood glucose level 8-fold, but in a healthy person, glucose level rises only 60%! Insulin level exhibits a much greater increase, from 60 to 400-500 pmol/l (6-8-fold!). By the end of the post-absorptive period (~5 hrs), about 25 g of the carbohydrate ingested will have been stored as glycogen, and 75 g oxidized.

  • Plasma glucose(mmol/l)Time of dayPlasma insulin(pmol/l)mealsBlood glucose levels are relatively constant

  • Breakfast: Action of glucose in the b-cellInsulin secretion is stimulated as the glucose concentration rises above 5 mmol/l (the normal baseline concentration of glucose in the plasma).

  • Breakfast: Fate of glucose in muscleGLUT4GlucoseGlucoseGlucose-6-PHexokinaseGlycogensynthesisGlycolysisInsulin+

  • Breakfast: Fate of glucose in adipocytesGLUT4GlucoseGlucoseInsulin+Glucose-6-PHexokinaseLPLInsulin+Glycerol-3-PTriglyceridesFatty acidsInsulin-Lipoproteins

  • Intracellular pool of GLUT4 in membranous vesicles translocate to the cell membrane when insulin binds to its receptor. The presence of more receptors increases the Vmax for glucose uptake (does not affect Km). When insulin signal is withdrawn, GLUT4 proteins return to their intracellular pool. GLUT4 is present in muscle and adipose tissue. GLUT4 activity is regulated by insulin-dependent translocation

  • GluconeogenesisGlucoseGlycogenadipocyteslivermuscleFood consumptionControl of blood glucose requires cooperation between organsliverliver

  • ************************************************************ Definitions:

    Catabolism = the breakdown ofcomplex substances.Anabolism = the synthesis of complex substances from simpler ones. ***********************************************************

  • GlucoseGlucose-6-PPyruvateHexokinasePentosePhosphateShuntglycolysisCarbohydratesServe as primary source of energy in the cellCentral to all metabolic processesGlc-1- phosphateglycogenCytosol - anaerobic

  • PyruvatecytosolAceytl CoAmitochondria (aerobic)KrebscycleReducingequivalentsOxidativePhosphorylation(ATP)AMINOACIDSFATTY ACIDS

  • No mitochondriaGlucoseGlucoseGlucoseThe FullMontyGlucoseGlycogenLactate

  • Carbohydrate Metabolism/ Utilization- Tissue SpecificityMuscle cardiac and skeletalOxidize glucose/produce and store glycogen (fed)Breakdown glycogen (fasted state)Shift to other fuels in fasting state (fatty acids)Adipose and liverGlucose acetyl CoAGlucose to glycerol for triglyceride synthesisLiver releases glucose for other tissuesNervous systemAlways use glucose except during extreme fastsReproductive tract/mammaryGlucose required by fetusLactose major milk carbohydrateRed blood cellsNo mitochondriaOxidize glucose to lactateLactate returned to liver for Gluconeogenesis

  • Breakfast: Fate of glucose in the liverGLUT2GlucoseGlucoseGlucose-6-PGlucokinaseGlycogensynthesisPentose phosphateGlycolysis

  • Breakfast: Fate of glucose in muscleGLUT4GlucoseGlucoseGlucose-6-PHexokinaseGlycogensynthesisGlycolysisInsulin+

  • Breakfast: Fate of glucose in adipocytesGLUT4GlucoseGlucoseInsulin+Glucose-6-PHexokinaseLPLInsulin+Glycerol-3-PTriglyceridesFatty acidsInsulin-Lipoproteins

  • Glucokinase vs. HexokinaseGlucokinase: Km = 10 mM, not inhibited by glucose 6-phosphate. Present in liver and in pancreas b cells. Hexokinase: Km= 0.2 mM, inhibited by glucose 6-phosphate. Present in most cells.

  • Glucokinase vs. Hexokinase Glucokinase is also found in b-cells of pancreas Glucokinase allows liver to respond to increasing blood glucose levels At low blood glucose levels, very little is taken up by liver, so that it is spared for other tissues. Glucokinase is not inhibited by glucose 6-phosphate, allowing accumulation in liver for storage as glycogen Glucokinase has a high Km, so it does not become saturated till very high levels of glucose are reached Hexokinase has a low Km and therefore can efficiently use low levels of glucose. But is quickly saturated.

  • Clinical exampleD.M., a 24-year-old, complaints were fatigue, weight loss, and increase in appetite, thirst, and frequency of urination. At 6 month before his visit he tired easily and tended to fall asleep in class, he had lost approximately 6.8 kg. His grandfather had had diabetes mellitus and his older sister was obese and had recently been diagnosed as having diabetes.

  • Diabetes mellitus and obesityWhat is the basis for the symptoms of the patient?Glucose tolerance test demonstrated in ability to handle a normal glucose loadGlocoseuriaFamilial history of diabetesIncreased appetite and excessive fluid intake and fluid loss means his energy stores were being wasted and frequent urination was required for elimination of catabolic end products.

  • Glucose and insulin response in bloodHow does the response to insulin of the obese diabetic person compare with that of the nonobese diabetic person?

  • Polyol pathwayWhat role does the polyol pathway play in disturbance of carbohydrate metabolism?Glucose reduced to sorbitol and can oxidase to fructoseSorbotol stay in high concentration in lens epithelium, the Schwann cell in peripheral nerve, the papillae in kidney and the islets of Langerhans in the pancreas make cataract and neuropathy

  • Summary: Glucose metabolism after a carbohydrate breakfastNet glycogen storage in liver and muscle

    In muscle, insulin enhances glucose uptake.

    In adipose tissue, insulin prevents lipolysis, enhances glucose uptake, promotes fat storage

  • Glycolysis Conversion of 6-carbon glucose to 3-carbon pyruvate. Pyruvate is converted to lactate when oxygen is low.

    Glycolysis is anaerobic; aerobic metabolism of pyruvate takes place in the TCA cycle.

    Requires some investment of energy to produce ATP. ATP is produced to a much lesser extent than in oxidative phosphorylation. ATP produced can be important, especially in muscle.

    Occurs in cytosol, so resulting compounds must be transported to mitochondria for subsequent metabolism by TCA cycle.

  • Glycolysis requires investment of energyThe two phosphorylation steps require 2 ATP.

  • Glycolysis, continuedTwo 3-carbon fragments are produced from one 6-carbon sugar.Thus far, 2 ATPs consumed, 0 ATPs produced.Not directly in the glycolysis pathway; must be salvaged by isomerization t