Carbohydrate Metabolism

CARBOHYDRATE METABOLISM By Dr. Aisha Eid

METABOLISM OF FOODSTUFFS Ptns, CHO, lipids carbon compounds

CO2 & H2O excretion

Dietary Carbohydrates: Monosaccharides: glucose, fructose and galactose in fruits and honey & obtained by hydrolysis of oligo- & polysacs.  Disaccharides: sucrose, lactose, maltose (by hydrolysis of starch).  Polysaccharides: starch (in potatoes, rice, corn and wheat) Cellulose (in cell wall of plants) not digested by humans due to absence of cellulase 

Digestion of Carbohydrates: In the mouth: Salivary amylase hydrolyzes starch into dextrin +maltose In the stomach: due to drop of pH salivary amylase acts for a very short time In the small intestines: Pancreatic and intestinal enzymes hydrolyze the oligo- and polysaccharides as follows: Pancreatic amylase Starch maltose + isomaltose Maltase Maltose 2 glucose Lactase Lactose glucose + galactose Sucrase Sucrose

glucose + fructose

Absorption of monosaccharides: 1. Simple diffusion: Depending on the concn gradient of sugars between intestinal lumen and mucosal cells. e.g. Fructose and pentose 2. Facilitated transport: It requires a transporter. e.g. Glucose, Fructose and galactose 3. Active transport (cotransport): It needs energy derived from the hydrolysis of ATP. glucose & galactose are actively transported against their concentration gradients by this mechanism.

Fate of absorbed monosaccharides: In the liver, fructose and galactose are converted to glucose. Fate of glucose: A. Uptake by different tissues (by facilitated diffusion) B. Utilization by the tissues: in the form of: 1. Oxidation to produce energy: - Major pathways (glycolysis & Krebs' cycle). - Minor pathways (hexose monophosphate pathway & uronic acid pathway) 2. Conversion to other substances: Carbohydrates: ribose (RNA,DNA), galactose (in milk), fructose (semen) Lipids: Glycerol-3 P for formation of triacylglycerols. Proteins: Non-essential amino acids which enter in formation of proteins. C. Storage of excess glucose: as glycogen in liver and muscles, when these reserves are filled it is converted to TAG & deposited in adipose tissue. D. Excretion in urine If blood glucose exceeds renal threshold (180 mg/dL), it will be excreted in urine.

Glucose Oxidation Extracting Energy from Glucose: There are 3 major biochemical processes that occur in cells to progressively breakdown glucose with the release of various packets of energy: Glycolysis (occurs in the cytoplasm and is only moderately efficient). Krebs' cycle (takes place in the matrix of the mitochondria and results in a great release of energy). Electron transport chain.

GLUCOSE OXIDATION

GLYCOLYSIS Series of biochemical reactions by which glucose is converted to: -Pyruvate (in aerobic conditions)or -Lactate (in anaerobic conditions). Site: cytosol of every cell. Physiologically it occurs in: -muscles during exercise (lack of oxygen) -RBCs (no mitochondria).

Steps: Phase one: 1 molecule of glucose (C6) is converted to 2 molecules of glyceraldehyde 3-phosphate (C3) as follows: ATP Glucose (C6) 3 P (C3)

ATP 2 Glyceraldehyde

Phase two: in this phase the 2 molecules of glyceraldehyde 3-P are converted to 2 molecules of pyruvate (aerobic) or lactate (anaerobic): 4 ATP 2 Glyceraldehyde-3 P (C3) (C3)

2 Pyruvic Acid

2 NADH + 2 H+ 2 NAD+

2 Lactic Acid

Overall, glycolysis can thus be summarized as follows:

Glucose ATP

2 Pyruvic Acid + 2 net +4 hydrogens (2 NADH2) 2 Lactic Acid + 2 net ATP

Regulation of Glycolysis: It can be noted that all reactions of glycolysis are reversible except those catalyzed by:  Glucokinase (or hexokinase) (GK)  Phosphofructokinase (PFK)  Pyruvate kinase (PK) Glycolysis is regulated by factors which control the activity of the key enzymes which catalyze the 3 irreversible reactions.

Activity of these enzymes increase during CHO feeding, and decreases during starvation: 

Regulation according to energy requirements of cell



Regulation by hormones

Regulation according to energy requirements of cell: Each cell regulates glycolysis according to the rate of utilization of ATP: i) High levels of AMP (indicating high ATP utilization): +++ PFK (i.e. activates glycolysis). ii)High levels of ATP (indicating little utilization of ATP): - - -PFK and PK (i.e. inhibits glycolysis).

Regulation by hormones: Postprandial hyperglycemia causes: +++ of insulin --- glucagon & adrenaline (anti-insulin hormones) i) Insulin: +++ all pathways of glucose utilization. +++ glycolysis by inducing synthesis, activation of all the glycolytic key enzymes (GK, PFK, PK). ii) Glucagon: Inhibits glycolysis by acting as repressor & inactivator of the glycolytic key enzymes.

Importance of Glycolysis: 1. Glycolysis provides mitochondria with pyruvic a oxaloacetate which is the primer of the Krebs' cycle. 2. Glycolysis provides dihydroxyacetone P glycerol 3-P that is important for lipogenesis (TAG synthesis) 3. Energy production: Glycolysis liberates only a small part of energy from glucose, however: a. Important during severe muscular exercise, where oxygen supply is often insufficient to meet the demands of aerobic metabolism. b. Provides all energy required by the R.B.Cs. (due to lack of mitochondria).

Energy yield of glycolysis: In absence of oxygen: 2 ATP are consumed for conversion of glucose to Fructose 1,6 P. 2 ATP are produced during conversion of glyceraldehydes 3-P to pyruvate. Since 1 glucose molecule gives 2 molecules of G 3-P, then total number of ATP produced is 4. net gain of ATP in absence of oxygen is: 4-2=2 ATP.

Energy yield of glycolysis: In presence of oxygen: 2 ATP are produced directly (as in absence of oxygen), 6 ATP are produced indirectly: from oxidation of 2 NADH2 through ETC net gain of ATP in presence of oxygen is: 2+6= 8 ATP.

Reactions These link glycolysis to the Krebs Cycle

Alternate Fates of Pyruvate A. Oxidative Decarboxylation

B. Carboxylation

forms Acetyl CoA

forms Oxaloacetate

Oxidative decarboxylation of pyruvate: Puruvate dehydrodenase complex irreversibly converts pyruvate into acetyl CoA: Pyruvic acid (3C)+NAD++Coenzyme A Acetyl CoA(2C)+CO2+ NADH+ H+ Acetyl CoA can also be produced by breakdown of:  lipids or  certain (ketogenic) amino acids. -NAD+ is converted into NADH+H+. Those hydrogens go through oxidative phosphorylation and produce 3 more ATP.

Oxidative decarboxylation of pyruvate:

NADH+H

2 CoA

NADH+H

Carboxylation of pyruvate to oxaloacetate:

Pyruvate carboxylase converts pyruvate to oxaloacetate. Pyruvic acid (3C) + CO2 + ATP Oxaloacetic acid (4C) + ADP + Pi

Finally, comes the Krebs' Cycle Krebs' Cycle (Citric Acid Cycle) (Tricarboxylic Acid Cycle) "TCA"

Site: mitochondria of every cell Series of biochemical reactions that are responsible for complete oxidation of CHO, fats and Ptns to form : CO2 + H2O + Energy

Steps:

acetyl-CoA + oxaloacetate citrate

+H+ Acetyl CoA

×2

oxaloacetate +H+

+H+

+H+

During this process the following is produced:

   

3x2=6 NADH+H+ 1x2=2 FADH2 1x2=2 ATP 2x2=4 CO2

Each glucose molecule that goes through Krebs cycle + the preparatory conversion to Acetyl CoA gives:

   

8 2 2 6

NADH FADH2 ATP CO2

N.B.: glycolysis produced 2 ATP + 2 NADH, so there is a net production of:  

4 ATP 10 NADH

Energy yield of Krebs' cycle: Glucose

2 puruvate 2 NADH

6 ATP

2 oxaloacetate

6 ATP 6 ATP 4 ATP 6 ATP

Energy yield of Krebs' cycle: 1 mole of acetyl CoA through Krebs' cycle produces 12 ATPs: 1 ATP (substrate level oxidative phosphorylation). 1 FADH2 → 2 ATP (respiratory chain oxidative phosphorylation). 3 NADH+H+→9 ATP(respiratory chain oxidative phosphorylation) oxidative decarboxylation of pyruvate gives 1 NADH+H+ → 3 ATP Thus net ATP gain is: 12 + 3 = 15 ATP Since 1 glucose molecule by undergoing glycolysis gives 2 pyruvate Thus 1 glucose molecule yields 15 × 2 = 30 ATP.

Thus complete oxidation of glucose (in presence of oxygen) gives:

 

Glycolysis: 8 ATP Total ATP yield = 30+8 = 38 ATP.

2 Acetyl CoA

Reduced coenzymes (e-) 10 NADH + 2 FADH2

38

Regulation of Krebs' cycle: 1. Regulation according to energy status of the cell: +++NADH/NAD and ATP/ADP (thus no need for further energy production) inhibit the cycle, and vice versa. Krebs' cycle is only aerobic, since under anaerobic conditions the respiratory chain is inhibited leading to increased NADH/NAD ratio which inhibits the cycle. 2. Regulation according to availability of substrate: +++ acetyl CoA and oxaloacetate +++ cycle. +++ intermediate products of cycle (citrate & succinyl Co A) ---feedback inhibition of the cycle.

Importance of Krebs' cycle: 1. Energy production: 1 acetyl CoA yields 12 ATP. 2. It is the final common metabolic pathway for complete oxidation of acetyl CoA which results from the partial oxidation of CHO, fats and proteins (amino acids). 3. Interconversion of carbohydrates, fats and proteins (gluconeogenesis, lipogenesis, and formation of non-

Minor Pathways of Glucose Oxidation:



Hexose monophosphate pathway (HMP shunt).



Uronic acid pathway.

Hexose Monophosphate Pathway (HMP shunt) Pentose Phosphate Pathway Pentose Shunt

Site: cytoplasm of cells e.g. liver, adipose tissue, adrenals, gonads, RBCs and retina. Steps: Glucose-6-P dehydrogenase

G-6-P P NADP+ NADPH+H+

R-5CO2

Importance of HMP shunt R-5-P

NADPH

Importance for RBCs

Importance of HMP shunt: 2. It is the main source of NADPH: coenzyme for reductases, hydroxylases and NADPH oxidase which catalyze several important biochemical reactions, e.g.: i) Fatty acid synthesis lipogenesis: HMP is active in liver, adipose tissue & lactating memory gland. ii) Steroid synthesis: HMP is active in adrenal cortex, testis, ovaries and placenta. iii) Important for vision: NADPH

retinal

retinol (important for

3) Importance of HMP in RBCs: -H2O2 (powerful oxidant) produces damage of:  cellular DNA,  Ptns  phospholipids of cell membrane. -RBCs are liable to oxidative damage by H2O2 due to their role in O2 transport. -H2O2 produces oxidative damage in the form of:  Oxidation of Fe2+ to Fe3+ (metHb can’t carry O2)  Lipid peroxidation which increases cell membrane fragility.

HMP in RBCs produces NADPH, which provides reduced GSH to remove H2O2 protects cell from oxidative damage GSH reductase & GSH peroxidase remove

glutathione peroxidase

H2O2 H2O

2

2 G-SH

G-S-S-G

NADP+ NADPH, H+ glutathione reductase

Favism: 





Genetic condition due to deficiency of (G6PD), There is impaired HMP in the RBCs, and RBC capacity to protect itself from oxidative damage is markedly decreased (--- NADPH) Eating Fava beans (which contain oxidizing agents), or administration of certain drugs (e.g. aspirin, sulfonamides or primaquin) which stimulate production of H2O2, produce lysis of the fragile red cells.

Regulation of HMP: NADPH produces feedback (-) G6PD.  Insulin produces (+) G6PD. N.B: Insulin produced in response to hyperglycemia increase glucose oxidation by HMP ( acts as inducer of synthesis of 

Uronic Acid Pathway This pathway converts glucose to glucuronic acid. Site: cytosol of liver cells. Importance of Uronic Acid Pathway: enters in different biological reactions, e.g.: 1. Synthesis of glycosaminoglycans (GAGs). 2. Conjugation with certain compounds rendering them more water soluble, thus helping in their excretion, e.g.:  Steroid hormones.  Bilirubin, which is excreted in bile in the form of bilirubin diglucuronide.

Glycogen Metabolism Glycogenesis Glycogenolysis Gluconeogenesis

Glycogen Metabolism 1. Liver glycogen: -Forms 8-10% of the wet weight of the liver. -Maintains blood glucose (especially between meals). -Liver glycogen is depleted after 12-18 hours fasting. 2. Muscle glycogen: -Forms 2% of the wet weight of muscle. -Supplies glucose within muscles during contraction. -Muscle glycogen is only depleted after prolonged exercise.

Glycogen metabolism includes:







Glycogenesis: synthesis of glycogen from glucose. Glycogenolysis: breakdown of glycogen to glucose-1-phosphate. Gluconeogenesis: synthesis of glucose or glycogen from non-CHO precursors.

Glycogenesis & Glycogenolysis Site: cytoplasm of liver and muscles. The key enzyme of glycogenesis is glycogen synthase. The key enzyme of glycogenolysis is glycogen phosphorylase. In muscles: G-6-P is oxidized by glycolysis to provide energy during muscle contraction. In liver: G-6-Phosphatase G-6-P G

Glucose + Pi

Blood

N.B: Muscles cannot supply blood glucose due to their lack of the enzyme G-6-phosphatase.

hexokinase

Glycogenolysis

Glycogen Phoshorylase

Glycogenesis Glycogen Synthase + Branching Enzyme

Mechanism of glycogen synthesis (glycogenesis): A. Synthesis of UDP-glucose. B. Synthesis of a primer to initiate glycogen synthesis: A fragment of glycogen (present in cells whose glycogen stores are not totally depleted) can serve as a primer. C. Elongation of glycogen chains by glycogen synthase: -Glycogen synthase uses UDP-glucose to add glucose to glycogen primer (1,4 link), and the process is repeated. D. Formation of branches in glycogen: -When the chain becomes about 6-11 glucose units long, the branching enzyme transfers 5-8 glucosyl residues of α-1,4-chain to a neighboring chain attaching it by α1,6- glucosidic linkage

Mechanism of glycogen degradation (glycogenolysis) A. Shortening of chains: Glycogen phosphorylase acts on the 1,4-glucosidic linkage of glycogen G-1-P residues until each branch contains only 4 glucose units. B. Removal of branches: -The transferring enzyme transfers 3 glucose units from one end of the short branch to the end of another branch. -The debranching enzyme cleaves 1,6-glucosidic linkage releasing free G , and the process is repeated. C. Conversion of G-1-P to G-6-P: This is done by phosphoglucomutase enzyme.

Regulation of Glycogen Synthesis vs. Degradation Glycogen synthase & glycogen phosphorylase: key enzymes Regulation of these enzymes occurs via:  Covalent modification (phosphorylation & dephosphn.)  Allosterics  Hormones -Reciprocal control of the two pathways is hormonally mediated through phosphorylation and dephosphorylation of synthase and phosphorylase. -Phosphorylation of enzymes : turns synthesis off (--- glycogenesis), and turns degradation on (+++ glycogenolysis).

Covalent modification : Phosphorylation/dephosphorylat ion I. Glycogen synthase is present in two forms: a-form: it is the active form and it is dephosphorylated. b-form: it is the inactive form and it is phosphorylated. -Conversion of a- to b-form by protein kinase: ++ by cAMP -Conversion of b- to a-form by protein phosphatase. II. Glycogen phosphorylase is present in two forms: a-form: it is the active form and it is phosphorylated. b-form: it is the inactive form and it is dephosphorylated. -Conversion of a- to b-form by the enzyme protein phosphatase. -Conversion of b- to a-form by phosphorylase kinase:+by c-AMP

Allosteric regulation: Conformational changes in the enzyme ptns affecting activity and regulation:  Glucose-6-phosphate ++ synthase (+) glycogenesis (excess substrate). - - phosphorylase (-) glycogenolysis & (+) glycogenesis. ATP + + synthase - - phosphorylase . 

(+) glycogenesis (-) glycogenolysis

Ca+2 ++ phosphorylase kinase (+) glycogen phosphorylase glycogenolysis -Muscle contraction ---> Ca+2 release (+) phosphorylase glycogenolysis (+) glucose ATP generation for ensuing cycles of muscle contraction.  

Hormonal regulation

Insulin: ++ phosphodiesterase - cAMP - protein kinase ++ protein phosphatase A. stimulates glycogenesis: ba-form of glycogen synthase (activation) activation of glycogenesis in both liver and muscle. B. inhibits glycogenolysis: ab-form of glycogen phosphorylase (inactivation) This leads to inactivation of glycogen phosphorylase (conversion of active to the inactive form) decrease glycogenolysis in both liver and muscle.

Insulin +++Glycogenesis ----Glycogenolysis

B. Glucagon (in liver) and epinephrine (in liver and muscles): Both hormones produce activation of adenyl cyclase thus increasing cAMP This produces activation protein kinase.This converts: 1. Active a- to inactive b-form of glycogen synthase (phosphorylated), thus inhibiting synthase. Accordingly glucagon & epinephrine --glycogenesis. 2.Inactive b- to active a-form of glycogen phosphorylase, thus activating glycogen phosphorylase. Accordingly glucagon & epinephrine +++glycogenolysis.

C. Growth hormone and glucocorticoids: +++ gluconeogenesis +++ G-6-P G-6-P allosterically +glycogen synthase-b

++glycogenesis. Thus growth hormone & glucocorticoids

Regulation according to nutritional status: A. In the well fed state: Glycogen synthase is allosterically (+) by G6P (which is present in high concentrations). Glycogen phosphorylase is (-) by G6P & ATP, i.e. (-)glycogenolysis & (+)glycogenesis stores bl glucose B. During starvation: There are decreased levels of G6P & ATP, thus (-)glycogenesis & (+)glycogenolysis to supply blood glucose.

Muscle glycogen and blood glucose Muscle glycogen can be converted to Bl glucose via indirect pathways: Cori's cycle: during muscle exercise Glucose- alanine cycle: during starvation

Cori's cycle:

Glycogen

gluconeogenesis

glycolysis

Glucose- alanine cycle: Glycogen

gluconeogenesis transamination

Glycogen storage diseases: Inherited deficiencies of specific enzymes of glycogen metabolism. Von Gierke's disease (most common) Cause: deficiency of G-6-phosphatase. It is characterized by: -enlargement of liver and kidneys -hypoglycemia -hyperlipemia -hypercholestorelemia.

Gluconeogenesis

Gluconeogenesis Synthesis of glucose from noncarbohydrate precursors. These precursors are metabolic intermediates. Importance: Supply blood glucose in case of CHO deficiency >18 hrs. (fasting, starvation and low CHO diet). Site: Cytosol of liver cells

Steps: By reversal of glycolysis. 3 glycolytic key enzymes are reversed by 4 key enzymes of gluconeogenesis as follows:

Glucogenic Precursors: They give directly or indirectly pyruvate, oxaloacetate or any intermediates of glycolysis or Krebs' cycle. They include: 1. Lactate: It is released by R.B.Cs. and by skeletal muscles during exercise, then transferred to the liver to form pyruvate then glucose. 2. Glycerol: It is produced from digestion of fats and from lipolysis.

3. Glucogenic amino acids: Ptns are the main sources of blood glucose especially after 18 hrs due to depletion of liver glycogen. -Some amino acids by deamination directly form pyruvic acid or oxaloacetic. -Others may give intermediates of Krebs' cycle which go through the cycle eventually yielding oxaloacetic acid.

4. Propionyl CoA: Many amino acids may give propionyl CoA through their catabolism. Also the last 3 carbons of odd chain fatty acids form propionyl CoA and thus give glucose. This is uncommon in humans.

Regulation of gluconeogenesis: Gluconeogenic regulatory key enzymes are those which reverse the glycolytic key enzymes. Glycolysis and gluconeogenesis are reciprocally controlled: Insulin: (secreted after carbohydrate meal) --- gluconeogenic key enzymes (at the same time it acts as inducer of glycolytic key enzymes) decrease bl. Glucose. Anti-insulin hormones (glucagon, epinephrine, glucocorticoids & growth hormone): (secreted during fasting, stress or severe muscular exercise) increased blood glucose. +++ gluconeogenic key enzymes, thus increasing gluconeogenesis

Blood Glucose Concentration of bloog glucose: fasting blood glucose (8-12 hrs. after the last meal) is 70-110 mg/dL. It increases after meals but returns to fasting level within 2 hrs. Sources of blood glucose: Dietary carbohydrates. Glycogenolysis (during fasting for less than 18 hrs.). Gluconeogenesis (during fasting for more than 18 hrs.).

Regulation of Blood Glucose: Four factors are important for regulating blood glucose level: I. Gastrointestinal tract. II. Liver III. Kidney. IV.Hormones.

I. Gastrointestinal tract: 1. It controls the rate of glucose absorption. The maximum rate of glucose absorption is 1 gm/kg body weight/ hour. An average person weighing 70 gm will absorb 70 gm glucose/ hour. 2. Glucose given orally stimulates more insulin than intravenous glucose. This may be due to secretion of glucagonlike substance by intestines. This stimulates B-cells of pancreas to secrete more insulin. This is called anticipatory action.

II. Liver: The liver is the main blood glucostat Maintains blood glucose level within normal as follows: A. If blood glucose level increases, the liver controls this elevation and decreases it through: 1. Oxidation of glucose via major and minor pathways. 2. Glycogenesis. 3. Lipogenesis. B. If blood glucose level decreases, the liver controls this drop and increases it through: 1. Glycogenolysis. 2. Gluconeogenesis.

III. Kidney: All glucose in blood is filtered through the kidneys, it then completely returns to the blood by tubular reabsorption. If blood glucose exceeds a certain limit (called renal threshold), it will pass in urine causing glucosuria. Renal threshold: it is the maximum rate of reabsorption of glucose by the renal tubules. Normally the renal threshold for glucose is 180 mg/100mL.

IV. Hormones: A. Insulin (the only hypoglycemic hormone): Action of insulin: Insulin decreases bl glucose level by: 1. +++ oxidation of glucose 2. +++ glycogenesis 3. --- glycogenolysis 4. --- glyconeogenesis 5. +++ lipogenesis

B. Anti-Insulin Hormones: (hyperglycemic hormones): 1. Growth Hormone: It elevates the blood glucose level by stimulating gluconeogenesis. 2. Thyroxine: It elevates the blood glucose level by: Increasing the rate of absorption of glucose from intestines. Stimulating gluconeogenesis and glycogenolysis. Inhibiting glycogenesis. 3. Epinephrine (adrenaline): It increases the blood glucose level by increasing glycogenolysis in both liver and muscles. 4. Glucagon: It increases the blood glucose level by increasing glycogenolysis in liver only.

Mechanism of Blood Glucose Regulation (Glucose Homeostasis) The blood glucose level is regulated by the balance between the action of insulin and anti-insulin hormones (hyperglycemic hormones). After a carbohydrate meal: Bl glucose increases, stimulating the secretion of insulin which tends to decrease the blood glucose level by its various actions. During fasting: Bl glucose is low; this stimulates the secretion of the antiinsulin hormones (hyperglycemic hormones) which by their various mechanisms lead to increasing the blood glucose level. The net result is a condition of glucose equilibrium, or what we call the homeostatic mechanism.

Abnormalities of Blood Glucose Level These may be in the form of:  Hyperglycemia  Hypoglycemia Hyperglycemia: (Diabetes Mellitus): It is due to: decreased insulin secretion and/or hypersecretion of anti-insulin

Hypoglycemia: -It is the decrease in blood glucose level below the fasting level. At a level of 50mg/100 mL convulsions occur At a level of 30 mg/100 mL coma and death result. -Hypoglycemia is more dangerous than hyperglycemia because glucose is the only fuel to the brain. Causes: i. Excess insulin: a) Overdose of insulin. b) Tumor of B-cells of pancreas (insulinoma). ii. Hyposecretion of anti-insulin hormones: (hypo-functions of the pituitary gland, adrenals & thyroid gland). insulin acts unopposed causing lowering of blood glucose iii. Liver disease: hypoglycemia is due to decreased glycogen stores and

Glucosuria Presence of detectable amounts of glucose in urine (>30 mg/dL). Causes: A. Hyperglycemic glocusuria: Bl glucose exceeds the renal threshold (180mg/dL). It is caused by: 1. Diabetes mellitus. 2. Emotional or stress glucosuria (epinephrine glucosuria) 3. Alimentary glucosuria;It is due to increased rate of glucose absorption as in cases of gastrectomy or gastrojejunostomy. B. Normoglycemic or renal glucosuria: 1. Congenital renal glucosuria (diabetes innocens): due to congenital defect in renal tubular reabsorption of glucose. 2. Acquired renal disease (e.g. nephritis).