Thomas O. Henderson, Ph.D.

Professor Emeritus Department of Biochemistry & Molecular Genetics Office: 321 CMW Phone: 312 996-5978 email: revtotis@uic.edu

Outline of Topics for Hendersons Lectures Will generally use Marks Basic Medical Biochemistry, 2nd ed., 2005
Overview of fuel metabolism in humans during absorptive and fasting phases Insulin and Glucagon Organ relationships Fuels for specific tissues as function of feeding cycle Metabolism of Glucose and related carbohydrates Overview of digestion & absorption of carbs Metabolic fates of glucose

Outline of Topics for T. Hendersons Lectures (continued) Glycolysis Tricarboxylic Acid Cycle Brief Overview of Oxidative Phosphorylation Gluconeogenesis Glycogen Synthesis and Degradation

Blood Glucose Concentration:

In normal (i. e., nondiabetic) people, the concentration of glucose in the blood is maintained in a rather tightly controlled range. Post-absorptive Phase: 4.5 - 5.5 mMole/L (80 -100 mg/dL) Absorptive Phase: 6.5 - 7.2 mMole/L (115 - 130 mg/dL) Fasting (3-4 days): 3.3 - 3.9 mMole/L (60 - 70 mg/dL)

Glucose Homeostasis
 Glycolysis  Gluconeogenesis  Glycogen  Roles  Role

metabolism

of Insulin & Glucagon

of fat & protein as energy sources or carbon skeletons for glucose synthesis

Fuel Metabolism

Introduction and Overview

Marks 2nd ed., Chapter 1, p. 1 - 7

Outline of topics for TOHs lectures on Fed and Fasting state

Marks 2nd ed., Chapters 2 & 3 - All Overview of metabolism in humans during absorptive (fed) and fasting states Insulin and Glucagon Organ relationships Fuels for specific tissues as a function of feeding cycle

 We

require sources of fuel to survive, since we are not able to carry out photosynthesis are used to drive the chemical reactions of the body

  Fuels

These chemical reactions involved in:

 moving  growth

& development

 reproduction  nerve

transmission of specialized biochemicals

 production

Obviously, we obtain fuel in our diets. What are the fuel sources in between meals, during the overnight fast while we sleep, or during an extended fast (starvation or semi-starvation)?

We will deal with these situations in a generalized fashion over the next few lectures.
We will briefly look at:  dietary fuel sources and processing  basic patterns of fuel metabolism in major organs in the body  changes in these patterns as a function of feeding pattern  the biological signals which modulate these changes

Major Dietary Fuels Carbohydrates Proteins Lipids (Fats)

When these fuel molecules are oxidized to CO2 and H2O in cells, energy is released by the transfer of electrons (e-) to O2

The oxidation of fuels to generate ATP is called respiration.

TCA = Tricarboxylic acid cycle

Electron transport system & Oxidative phosphorylation

Generation of ATP from fuels at cellular level

The energy released in this oxidative process is released in the form of heat and also captured in high-energy compounds which can be used in a host of cellular activities.
The most important high energy compound

(i. e., most widely used) is adenosine triphosphate (ATP)

Main purpose of fuel oxidation is generation of ATP. ATP is used for most of energy-requiring reactions and activities of the cell. ATP provides energy for: biosynthetic reactions  nerve transmission  transport of solutes across cell  muscle contraction


membranes

As ATP-utilizing activities proceed, ATP is converted back to ADP + inorganic phosphate (Pi)

Caloric content of dietary components kcal/g Carbohydrates 4 Proteins 4 Fat 9 Alcohol (ethanol) 7

Fuel composition of average 70-kg man following 12 hour fast

Energy reserves of humans following 12 hour fast

Stored fuel __ Tissue (g)_ Glycogen Liver 70 Glycogen Muscle 120 Glucose Body Fluids 20 Fat Adipose 15,000 (Protein)* (Muscle) 6,000

(kcal) 280 480 80 135,000 24,000

*NOTE: No specific storage form of protein

The Fed State or Absorptive Phase Marks 2nd ed. Chpt 2

Fig. 2.1 Major fates of fuel in the fed state

Glucose Storage (Glycogen, TAG)

Oxidation (Energy)

Synthesis (Many compounds) Amino acids

Protein synthesis

Oxidation (Energy) Fats

Synthesis of Nitrogen-containing compounds

Storage (TAG)

Synthesis (Membrane lipids)

Oxidation (Energy)

 Omnivorous

diet of most Americans is a mixture of carbohydrates, fats, proteins, plus a variety of micronutrients of both animal and plant origin. is ingested, digested, taken up into the general circulation, then absorbed by cells in the various tissues.

 This

The period of time from ingestion to absorption into tissues constitutes the absorptive state

or phase

Following ingestion, complex macromolecules digested mainly in small intestine to yield constituent building blocks by digestive enzymes which catalyze addition of water to bonds holding them together.

Digestive Enzymes

(Glucose)n Protein+ (H2O)n-1 (Amino Acids)n

Starch + (H2O)n-1

The end products are water soluble and are absorbed into the hepatic portal system and transported to the liver and the rest of the body

Digestive Enzymes

Triacylglycerol (TAG) + 2 H2O Monoacylglycerol + 2 Fatty Acids

Transport of digested fat more complicated than monosaccharides and amino acids.

 Monoacylglycerol (MAG) + 2 fatty acids reconverted to TAG in intestinal mucosal cells and secreted into lymph in form of a large complex lipoprotein called chylomicrons. chylomicrons Chylomicrons in lymph dumped into general circulation at thoracic duct TAG then delivered to various tissues where fatty acids in TAG are oxidized for energy or stored as TAG in adipose cells

 Some of absorbed glucose, amino acids, and fats oxidized for ATP production Some of glucose stored as glycogen Most of amino acids used for protein synthesis Fuel absorbed in excess of these needs is converted to TAG in liver and transported as Very Low Density Lipoproteins (VLDL) and (mainly) stored in adipose cells

Following a typical relatively high carbohydrate meal:

blood glucose concentration increases this leads to secretion of insulin (from the pancreas) into blood stream insulin is a peptide hormone secreted by -islets of pancreas in direct response to [glucose]blood

Diabetic

Blood glucose (mmol/L)

Normal

Time (hours)

Insulin Glucagon

Insulin is powerful hormonal signal

increases rate of uptake of blood glucose, especially by adipose and skeletal muscle promotes conversion of glucose to glucose-6-P in liver promotes synthesis of fuel storage molecules, glycogen and TAG promotes synthesis of proteins Simplistically, insulin signals the well-fed state

Fig. 2.1 The fed state

Ingested food

Glucose (6C)

Glycolysis
2 Pyruvate 2 X (3C)

2 Acetyl-CoA (2C)

TCA cycle CO2

OO Pyruvate CH3-C-OO Acetyl CH3-C-O-

Glucose (6C)

Fatty Acids

Pyruvate (3C)

Acetyl-CoA (2C)

TCA cycle CO2

Glucose (6C)

Fatty Acids

Pyruvate (3C)

Amino Acids

Acetyl-CoA (2C)

TCA cycle CO2

+I

Glucose entry into skeletal muscle requires insulin bound to its receptor

+I

Glucose entry into adipose cell requires insulin bound to its receptor i Intermediate in Glycolysis converted to glycerol An intermediate in Glycolysis -P

Fate of Fuels in Exercising Skeletal Muscle

Recap of Absorptive Phase

Summary of Fed State
Ingested fuels are oxidized to meet immediate energy needs Excess fuels stored mainly as TAG in adipose and lesser amounts of glycogen in muscle and liver Amino acids used in protein synthesis, especially in muscle

Recap of Absorptive Phase

Fate of Glucose in Liver During Absorptive Phase

Recap of Absorptive Phase

Fate of Glucose in Brain All of the Time

Recap of Absorptive Phase

Fate of Glucose in RBCs All of the Time

Current evidence suggests that during the first 3 - 4 hours after a carbohydrate - containing meal:
about 1/3 of the glucose is taken up by the liver 1/3 by the muscle, and 1/3 by the rest of the tissues (notably nervous system and adipose). glucose taken up by the liver can be utilized for glycogen synthesis efficiently. conversion of glucose to TAG for net increase in body fat begins after ~500(?) grams of glucose are converted to liver and muscle glycogen.

Excess glucose is converted to fatty acids and triacylglycerol (TAG) mainly in liver and adipose
TAG synthesized in liver is packaged in very low density lipoproteins (VLDL) VLDL are released into blood and transported to nonhepatic tissues TAG in VLDL hydrolyzed to free fatty acids + glycerol by lipoprotein lipase by these tissues In case of adipose, fatty acids converted back to TAG and stored

Fasting State

Marks 2nd ed., Chpt. 3

Basal State (Overnight Fast)

At end of absorptive state:

[glucose]blood get insulin secretion is reduced [glucose]blood leads to glucagon secretion (from pancreas) into the blood stream glucagon is peptide hormone secreted by -islet cells of pancreas in direct response to [glucose]blood

Diabetic

Blood glucose (mmol/L)

Normal

Insulin Glucagon

Time (hours)

Glucagon
Promotes breakdown of liver glycogen to glucose Promotes gluconeogenesis from amino acids, lactate, glycerol, etc., in the liver Promotes breakdown of TAG in adipose to fatty acids + glycerol

Primary function of glucagon is to increase the supply of glucose in the blood in post-absorptive phase to support energy needs of central nervous system and other glucosedependent cells (such as erythrocytes)

Major energy source for liver and muscle (skeletal and heart) in post-absorptive phase is fatty acids (or derivatives).

NOTE: glucagon promotes breakdown of triacylglycerol (TAG) in adipose to fatty acids plus glycerol

Fig. 3.1 Basal state (12-hr fast)

Figure 7.47
From Devlin, Textbook of Biochemistry with Clinical Correlations, Wiley -Liss, 4/e, (1997)

KB = Ketone bodies AA = Amino acids FA = Fatty acids

Ketone bodies
OH -Hydroxybutyrate Acetoacetate CH3-C-CH2-COOO CH3-C-CH2-COOO Acetone CH3-C-CH3

LIVER Acyl-CoA

BLOOD FFA

EXTRAHEPATIC TISSUES Acyl-CoA Glucose

Acetyl-CoA

Urine Ketone bodies Ketone bodies

Acetyl-CoA

Ketone bodies

TCA cycle Lungs

TCA cycle

O H2N-C-NH2

Urea
A neutral uncharged compound

Fasting State

Starved State

Fig. 3.3 Starved state

Sources of glucose during prolonged fast

Origin of blood glucose:

(I) Exogenous; (II) Glycogen, Liver gluconeogenesis; (III) Liver gluconeogenesis, Glycogen; (IV & V)Liver and Kidney gluconeogenesis

Major fuel of brain:

(I) - (III) Glucose; (IV) Glucose, ketone bodies; (V) Ketone bodies, glucose

Fig. 3.4. Changes in plasma fuel concentration during prolonged fast

Fig. 3.5. Changes in urea excretion during prolonged fast