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1. Diabetes mellitus What’s in a name? 1. Diabetes: “Marching through” – urine is produced incessantly 2. mellitus: honey-sweet – as opposed to diabetes insipidus (insipid – without ﬂavour) What does the adjective tell us about a traditional method of diagnosis? Notes: The traditional method of diagnosis was exactly as suggested by the nomenclature. It was eﬀective, even if not entirely quantitative. For those of you who aspire to medical school, it may be comforting to know that it is no longer in use.
2. Forms of diabetes mellitus • Type I, II, and secondary/symptomatic diabetes • Type I and II are somewhat similar: Lack of insulin eﬀect – lack of the hormone (type I), or lack of functional response to the hormone (type II) • Symptomatic diabetes diﬀerent; insulin still present, but antagonistic hormones drive up glucose production. Typically acute clinical symptoms Notes: Type I diabetes is the form typically observed in the young, whereas the type II is more frequent overall and is typically observed in the elderly. MODY – maturity type onset diabetes of the young – is type II diabetes in young people. While the causation of diabetes type I is well understood and straightforward— destruction of the insulin-producing β-cells of the pancreatic islets—our understanding of type II diabetes is lagging behind. We will look at some recent science addressing this question. Symptomatic diabetes is diverse. A straightforward example is the excessive secretion of glucagon by a glucagonoma, that is a benign tumor derived from glucagonsecreting α-cells in pancreatic islets. More commonly though it is caused by treatment with high dosages of glucocorticoid hormones in the treatment of auto-immune diseases.
3. Why is glucose lost through the kidneys? Stages of urine production in the kidneys: • Filtration – small molecules and ions are ﬁltrated from the blood plasma at 150 liters/day • Salts and major metabolites reabsorbed by speciﬁc transporters • Capacity for glucose reuptake only slightly above the range of physiological blood glucose values – elevated levels of blood glucose will result in overﬂow
Kidney tissue structure and function: Glomerulus and tubuli Notes: The tissue slice shows a single glomerulus. as is the case in an autoimmune disease called glomerulonephritis. 5. Therefore. This explains the extraordinarily large ﬂow rate of ﬁltration. all small molecules and ions are ﬁltrated.Kidney structure: Glomerulus and tubuli 4. Primary ﬁltration occurs in the glomerulus Primary filtration in the glomerulus Bowman’s capsule afferent arteriole proximal tubule efferent arteriole Notes: The blood pressure remains high throughout the glomerulus. 2 . The ﬁltration has a molecular weight cutoﬀ of about 10 kDa.or longitudinal sections. whereas large proteins such as proteins are retained in the blood plasma. The appearance in the urine of proteins in signiﬁcant amounts indicates that the ﬁltration apparatus is damaged. meaning that there is a driving force for ﬁltration across the blood vessel walls. and various tubular segments in cross.
The capacity for glucose reuptake is saturated slightly above the physiological Urine glucose secretion in diabetes mellitus plasma concentration range Reabsorption maximum Amount filtrated Normal range Pathological range Amount excreted Plasma glucose concentration Notes: The normal range of glucose in the blood is approximately 4–8 mM. The distal segments are concerned with ﬁne-tuning the concentration of the urine and the secretion or retention of salt ions and protons according to the metabolic situation. 7. Glucose starts to appear in the urine when the plasma level exceeds 10 mM. Reuptake and secretion occur in the tubular segments Active secretion of uric acid. bicarbonate. organic bases Segments of the nephron and their functions Reuptake of weak organic acids and bases Filtration Reuptake of glucose. including glucose. and most of the water are taken up again in the proximal tubule of the nephron.6. organic acids. … Reuptake / exchange of ions. amino acids. 3 . reuptake of water Notes: The bulk of the metabolites.
SGLT occurs at the luminal side of intestinal and kidney epithelia 2 Na+ Glucose 2 Na+ Glucose SGLT1 Glucose GLUT2 Notes: The occurence of SGLT at the intestinal and kidney epithelia ensures a virtually complete uptake of glucose. the sodium is secreted by the pancreas and the glands underneath the mucosa of the small intestines. a low intracellular glucose conSequential transport of glucose across the apical and centration is maintained through the phosphorylation of glucose by hexokinase. basolateral membranes of the intestinal epithelia gut lumen cytosol blood 9. Types of glucose transporters Active and facilitated transport of glucose Na+ Glc Na+ Glc SGLUT Glc Glc GLUT Notes: The sodium-coupled SGLT transporter is an example of secondary active transport. In the intestinal. 4 . In most tissues. it enables the uptake of glucose even against its concentration gradient. which always occurs downhill the concentration gradient. The simpler GLUT transporter enables facilitated diﬀusion.8.
As stated before. its uptake into most other cell types occurs is restricted by its dependence on insulin. The role of insulin in glucose transport Active transport Insulin-sensitive never Facilitated transport Muscle Fat Most other tissues Insulin-insensitive Intestine Kidney tubules Liver Brain Blood cells Lens and cornea of eye Notes: The brain must keep working and can take up glucose with or without insulin. the brain will still experience shortages. Insulin promotes sugar uptake by increasing the number of surface-exposed glucose transporters of surface-exposed glucose transporters Glucose Glucose transporter 4 exposed on cell surface cytoplasmic membrane High insulin Glucose Low insulin Glucose transporter 4 stored intracellularly in vesicles Notes: This scheme only applies to those cell types in which glucose uptake is insulindependent. If blood glucose drops too low. and unconsciousness will result. a state called hypoglycemia. 5 .Modes of glucose transport 10. Insulin promotes sugar uptake by increasing the number 11. the brain and some other cell types are exempt. To preserve glucose when supply is low.
If you lack a textbook for doing so. Do you understand it? Can you identify the pathways responsible for these conversions? If not. Synthesized via gluconeogenesis 4. . Converted from other carbohydrates: Fructose. . Triacylglycerol synthesis 13. Overview of glucose metabolism Starch. you may want to look at my Chem 333 metabolism course notes (available through the web). Digested starch 2. Recovered from glycogen stores 3.12. it is advisable to repeat them. and where does it go? Sources: 1. Biosynthesis (amino acids. nucleotides. sugars Glucose glycolytic intermediates Amino acids NH3 UC Urea Pyruvate Acetyl-CoA TCA H2 H2 O ADP + P ATP Triacylglycerol Glycogen Ribulose-5-P Notes: Looking at this slide is an opportunity for self-assessment. Glycogen synthesis 4. . galactose Destinations: 1. ATP production 2. Where does glucose come from. ) 3. 6 .
14. Digestion of amylose/amylopectin CH2OH C H OH O CH H C OH OH CH2OH HC HC OH H C OH O H C O HC CH2OH HC OH C H H C OH O CH OH HC OH C H OH C H Glucose Maltose It is in turn cleaved by the ‘brush-border’ enzyme Notes: In type II maltase. Maltose: glucosyl-α(1→4). which results in a decreased rate of glucose uptake. Can you imagine what kind of side eﬀects this would have? Think of lactose tolerance. α(1→4) glycosidic bonds. which is the major storage carbohydrate of plants. the molecule is called amylose. Structure ofAmylose and amylopectin amylose/amylopectin CH2OH … 2OH CH2OH O OH O O OH CH2OH O OH OH O OH CH2OH O OH O OH CH2OH O OH O OH CH2OH O OH O OH CH2OH O OH O OH OH O CH2 O OH CH2 O OH HO OH CH2OH O OH O O OH O OH Amylopectin is polyglucose. 7 . branches formed by α(1→4) glycosidic bonds. If no branches are present.glucose • Amylase cleaves amylose and amylopectin to the disaccharides maltose and isomaltose Maltose is produced by amylase cleaving amylose • The brush border enzymes maltase and isomaltase produce monomeric glucose and amylopectin. • Uptake occurs through the luminal SGLT transporter with the drug acarbose. one therapeutic strategy is to inhibit the maltase enzyme diabetics. Amylose and amylopectin are the two main components of starch. Glucose and maltose 15.
The portal circulation 17. The liver plays a key role in metabolic regulation. The brush border of the small intestine Notes: The rate of substrate uptake from the intestine is proportional to its surface. The surface is maximized at each level of organization: Length of the organ. The portal circulation Systemic circulation Liver vein Liver Portal vein Notes: The perfusion of the intestinal organs is organized diﬀerently from most other organs. it also protects the organism from ingested poisons.and microvilli. decorated with macro. in that the blood drained from them is passed through the liver before being fed back into the general circulation. 8 . folded surface.Villi and microvilli in the small intestine 16.
This usage is promoted by glucagon and epinephrin 19. Glycolysis and gluconeogenesis Gluconeogenesis uses the reversible reactions from glycolysis and bypasses the irreversible ones Glucose Glucose-6-P Fructose-6-P Fructose-1. particularly the brain. This is promoted by insulin • If free glucose is in high demand. both immediate utilization and conversion for storage are enhanced. pentose phosphate shunt 2. Conversion for storage: Glycogen synthesis.18. Immediate utilization: Glycolysis. utilization is restricted to “preferred customers”. triacylglycerol synthesis The distribution of glucose between these destinations depends on our metabolic state: • If free glucose is plentiful.6-bis-P Dihydroxyacetone-P + Glyceraldehyde-P 1. Metabolic fates of glucose 1.3-Bis-P-glycerate Glycolysis only Shared Gluconeogenesis only Oxaloacetate 3-P-glycerate 2-P-glycerate P-enolpyruvate Pyruvate 9 .
Glycolysis and gluconeogenesis: Allosteric regulation of key enzymes Pi Fructose-6-P ATP + Fructose-1. the allosteric regulation of PFP-1 and fructose-1. lysine and the aromatic amino acids are degraded to acetyl-CoA and/or acetoacetate. ATP and AMP reﬂect the metabolic situation of the cell itself. Thus. Substrate sources for gluconeogenesis Carbon sources for gluconeogenesis P-enolpyruvate Pyruvate CO2 Acetyl-CoA Glucose Lactate. these amino acids are called phosphofructokinase I and Fructose-bisphosphatase (1) 21. In contrast.6-bis-P + Fructose-1. or Regulation of gluconeogenesis (1): Allosteric control of ketogenic.6-bisphosphate is controlled by hormones (see below).20. can be converted to ketone bodies. Leucine.6-bis-P ADP Glycolysis ↑ H 2O Gluconeogenesis ↑ Notes: The regulatory molecule fructose-2. 10 .6-bisphosphatase strikes a compromise between the needs of the individual cell and those of the organism as a whole. Hormones communicate the metabolic demands of the entire organism (see below).6 bisphosphatase ATP AMP + PFK 1 - Fructose-2. Since the latter are. amino acids Oxaloacetate Malate Citrate Isocitrate CO2 α-Ketoglutarate CO2 Succinyl-CoA Fumarate Succinate Amino acids Notes: Amino acids that are converted to pyruvate or TCA intermediates and therefore can serve as substrates for gluconeogenesis are called glucogenic.
glucagon + cAMP + Protein kinase A P PFK-2/bis-P’ase PFK-2/bis-P’ase Fructose-2.22.6-bisphosphatase enzyme activities are located on the same bifunctional enzyme molecule.6-bisphosphate Notes: Fructose-2.6-bis-P Glycolysis ↑ Fructose-6-P Gluconeogenesis ↑ Insulin Notes: The phosphofructokinase 2 (PFK-2) and fructose-2.6-bisphosphate is under hormonal control Epinephrin. Regulation of gluconeogenesis (2): cAMP controls the level of PFK-2 / fructose-2. The phosphorylation by protein kinase A activates the phosphatase activity and at the same time inhibits the kinase activity. Fructose-bisphosphates compared Fructose bisphosphates compared O O OH O P O OH CH2 O H2C OH OH OH OH O HO P O O OH O O P O OH CH2 O O H2C OH P O Fructose-1. Regulation by phosphorylation is best thought of as allosteric regulation.6-bisphosphate Fructose-2. where the allosteric eﬀector happens to be covalently bound to the enzyme.6-bisphosphate is present at much lower levels than the 1.6bisphosphate and only exists for the purpose of regulation. 11 .6-bisphosphatase 23. The level of Fructose-2.
branched by α(1→6)-glycosidic bonds O O O O O CH2 O O O O O O O O O O O CH2 CH2 O O O O O O O O-Tyr Glycogenin 6-8 glc residues total: > 105 glc residues Notes: The structure of glycogen is essentially the same as that of amylopectin. . glycogen accounts for up to 10% of wet weight. the density of branches is greater..) molecules of glucose divides the osmotic eﬀect by 2 (3. The number of free ends determine the possible rates of synthesis and breakdown.. . and the higher density in glycogen reﬂects the metabolic rate that is higher in humans than in plants.) and makes storage of large amounts of glucose compatible with physiological osmolarity. Glycogen metabolism Why store glucose in polymeric form? In the liver. Structure of glycogen Structure of glycogen Linear polymers of α(1→4)-linked glucose residues.24. According to pV = nRT or p = n RT V this would roughly triple the osmotic activity of the liver cytosol – cells would swell and burst. which means that a glycogen molecule has a greater number of free ends than an amylopectin molecule of the same molecular weight. Linking 2 (3. 25. Notes: The proportionality of concentration and osmotic activity does not strictly apply at very large molecular weights. which corresponds to 600 mM of glucose. However. 12 .
The glycogen synthase reaction CH2OH O OH OH OH O Tyr Glycogenin UDP-glc UDP-glc UDP-glc UDP-glc UDP-glc HO O O O O O O-Tyr Glycogenin UDP UDP UDP UDP UDP Notes: Glycogenin is a small protein that serves as the starter substrate for glycogen synthesis. move along. The glycogen phosphorylase reaction Pi glc–glc–glc–glc–glc–glc–glc–glc glc-1-P Pi glc–glc–glc–glc–glc–glc–glc–glc–glc–glc–glc–glc–glc–glc glc-1-P glc-6-P glucose 13 .Glycogen synthesis (4): elongation 26. This is just to remind you what glycogen synthase does – nothing new here. Glycogen degradation (1): Glycogen phosphorylase successively cleaves single glucose subunits and converts them to glucose-1-phosphate 27.
whereas the eﬀect of insulin in both cases is the opposite. The conversion of glucose-1-phosphate to UDP-glucose by glucose-1phosphate uridyltransferase requires UTP and releases pyrophosphate.Regulation of glycogen metabolism (2): Allosteric regulation 28. Glucagon Glycogen synthase (active) Phosphorylase kinase (inactive) Glycogen synthase–P (inactive) Phosphorylase kinase–P (active) Phosphorylase-P (active) Phosphorylase (inactive) Notes: The upper part of this regulatory cascade is the same as in shown before for gluconeogenesis. Allosteric regulation of glycogen synthase and phosphorylase Glycogen glycogen synthase + Glc-6-P ATP AMP + phosphorylase UDP-glucose Glucose-1-P Glucose-6-P Notes: Glucose-1-phosphate is reversibly converted to glucose-6-phosphate by phosphoglucomutase. 29. Regulation of glycogen metabolism (2) Regulation of glycogen metabolism (3): Regulation by phosphorylation in response to hormone action ATP cAMP Protein Kinase A Insulin Epinephrine. In both cases. the eﬀect of glucagon is to increase the rate of glucose synthesis and to reduce the rate of consumption. Glycogen metabolism and gluconeogenesis are therefore regulated in parallel. 14 .