Integration of Metabolism(Chapter 23)

o       Types of hypoglycemia

The Feed / Fast Cycle

-    Overview

-     Enzymic changes in the fed state :

  - Allosteric effects

- Regulation of enzymes by covalent modification

- Induction and repression of enzyme synthesis

4th Lecture: Pages : 314 - 320

Types of hypoglycemia:

Hypoglycemia may be divided into 3 groups :

1-Insulin induced hypoglycemia :

• Hypoglycemia occurs frequently in patients with DM receiving insulin treatment.

• Mild hypoglycemia in fully conscious patients is treated by oral administration of carbohydrate.

• More commonly, patients with hypoglycemia are unconscious or have lost the ability to coordinate swallowing.

• In these cases: glucagon, administered SC or IM, is the treatment of choice (Figure .23.14)

2-Postprandial hypoglycemia:

• The 2nd most common form of hypoglycemia.

• Caused by an exaggerated insulin release following a meal a transient hypoglycemia with mild adrenergic symptoms.

• The blood glucose level returns to normal even if the patient is not fed.

• The only treatment usually needed is that the patient eat frequent small meals instead of the usual three large meals.

3- Fasting hypoglycemia:

- It is rare neuroglycopenic symptoms.

- It may be due to:

a) rate of glucose production by the liver (in hepatocellular damage or adrenal insufficiency or in fasting persons who have consumed large quantities of ethanol )

gluconeogenesis and the risk of hypoglycemia in patients using insulin.

b) rate of glucose utilization by the peripheral tissues, most

commonly due to insulin resulting from a pancreatic B-cell tumor. If untreated, a patient with fasting hypoglycemia may lose consciousness and develop convulsions and coma.

Hypoglycemia and alcohol intoxication:• Alcohol is metabolized in the liver by 2 oxidation reactions

(Figure 23.15)

• Ethanol is first converted to acetaldehyde by Alcohol Dehydrogenase.

• Acetaldehyde is oxidized to Acetate by Aldehyde Dehydrogenase enzyme

• This enzyme is inhibited by “ Disulfiram - a drug used by patients to stop alcohol ingestion” accumulation of Acetaldehyde in the blood Flushing, tachycardia, Hyperventilation and nausea

• The metabolism of Ethanol cytosolic NADH in the liver

• The Ethanol – mediated in NADH Diversion of gluconeogenesis intermediates into alternate reaction pathways glucose synthesis Hypoglycemia Behavioral effects ( agitation, impaired judgement & combativeness)

• Alcohol consumption Hypoglycemia in patients using insulin

Metabolism in the well –fed state• The absorptive state is the 2 to 4 hours period after

ingestion of a normal meal.

• Transient in plasma glucose, A.A. and triacylglycerols occur during this period.

glucose and A.A. levels stimulate Islet tissue of the pancreas insulin and glucagon.

• It is an anabolic period ( synthesis of glycogen, triacylglycerols and protein).

• During this absorptive period, all tissues use glucose as a fuel.

A-Enzymic changes in the fed state:

The flow of intermediates through metabolic pathways is controlled by four mechanisms:

(1)  the availability of substrates

(2)  allosteric activation and inhibition of enzymes

(3)  covalent modification of enzymes and

(4)  induction-repression of enzyme synthesis.

(Figure: 24.1 )

Allosteric effects:

• The allosteric changes usually affect the rate- determining reactions For Example:

• Glycolysis in the liver is stimulated following a meal by in fructose 2, 6 – bisphosphate (an allosteric activator of phosphofructokinase. I ).

• Gluconeogenesis is inhibited by fructose 2, 6-bisphosphate ( an inhibitor of fructose 1,6-bisphosphatase).

• Allosteric effects work within minutes.

B- Regulation of enzymes by covalent modification

• Many enzymes regulated by covalent modification which takes minutes to hours (phosphorylation and dephosphorylation).

• In the fed- state most of the enzymes regulated by covalent modification are in the dephosphorylated state and active e.g.

- Pyruvate kinase - Pyruvate dehydrogenase complex - Glycogen synthase - HMG – CoA reductase - Acetyl –CoA carboxylase.

Three exceptions :

• Active phosphorylated forms are: - Glycogen phosphorylase - Fructose bisphosphate phosphatase-2 - Hormone-sensitive lipase of adipose tissue.

( Figure 24.2)

C) Induction and repression of enzyme synthesis:

• The key enzymes are usually regulated by hormones that affect their synthesis:

e.g. insulin stimulates the synthesis of ;

- glucokinase - phosphofructokinase I - pyruvate kinase (the key enzyme of glycolysis)

• Regulation of enzyme synthesis takes hours to days

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 -         Liver : Nutrient Distribution Center :       - Carbohydrate metabolism       - Fat metabolism     - Amino acid metabolism

-         Adipose tissue : Energy Storage Depot :       - Carbohydrate metabolism       - Fat metabolism

-         Resting skeletal muscle :       - Carbohydrate metabolism       - Fat metabolism

       - Amino acid metabolism

-         Brain :       -Carbohydrate metabolism       - Fat metabolism

5th Lecture: Pages : 320 - 326

LIVER : THE NUTRIENT DISTRIBUTION CENTER

• After a meal, the liver receives portal blood containing absorbed nutrients and high levels of insulin secreted by the pancreas.

• It controls the following:

A) Carbohydrate metabolism

B) Fat metabolism

C) Amino acid metabolism

A) Carbohydrate metabolism:

Liver is normally a glucose-producing rather than glucose-using tissue.

Liver becomes a net consumer of glucose after a carbohydrate meal.

Hepatic metabolism of glucose is by the following mechanisms: (Figure 24.3)

 1. phosphorylation of glucose:

• High levels of intra cellular glucose in the hepatocyte glucokinase which phosphorylates glucose glucose 6-phosphate.

• Glucokinase has low affinity (high Km for glucose).  

2- glycogen synthesis:

• Inactivation of glycogen phosphorylase and activation of glycogen synthase ( the key enzyme of glycogenesis) Conversion of glucose –6- phosphate to glycogen. (Figure 24.3)

3- activity of the hexose monophosphate pathway (HMP):

The availability of glucose 6-phosphate in the well-fed state, combined with the active utilization of NADPH in hepatic lipogenesis HMP.

(Figure 24.3)

 4- Glycolysis:

The conversion of glucose pyruvate acetyl-CoA is stimulated by the insulin / glucagon ratio that activates the key enzymes of glycolysis e.g. (phosphofructokinase)

•Acetyl-CoA is used either to provide energy by oxidation in the TCA cycle or as a building block for fatty acid synthesis. (Figure 24.3)

 5- gluconeogenesis:

insulin / glucagon ratio inhibits enzymes of gluconeogenesis, such as fructose 1,6-bisphosphatase.

Also, inactivation of Pyruvate carboxylase due to low levels of acetyl-CoA gluconeogenesis

B) Fat metabolism:

1. fatty acid synthesis:

Liver is the primary tissue for de novo synthesis of fatty acids . (Figure 24.3)

de novo synthesis of fatty acids is favored by the following:

1) in acetyl-CoA and NADPH (the substrates derived from the metabolism of glucose).

2) Activation of acetyl CoA carboxylase (the rate-limiting reaction in fatty acid synthesis)

2. Triacylglycerol synthesis:

- Triacylglycerol synthesis is favored due to :

(a) de novo synthesis of FA from acetyl CoA.

(b) hydrolysis of the triacylglycerol component of chylomicron remnants removed from the blood by

hepatocytes. (Figure 24.3)

- availability of glycerol 3-phosphate is favored by the glycolytic metabolism of glucose:

Glucose Dihydroxyacetone phosphate glycerol 3-phosphate

TG formed by the liver lipoprotein (VLDL) extrahepatic tissues especially adipose tissue and muscles.

C) Amino acid metabolism:

 1- protein synthesis:

A transient in the synthesis of hepatic protein occurs in the absorptive state.

2- A.A. degradation:

• In the absorptive period, more A.A. are present than the liver can use in the synthesis of proteins and other nitrogen-containing compounds.

(Figure 24.3)

• The excess A.A. are either :

• Released into the blood for all tissues to use in protein synthesis

• Deaminated to produce energy.

• The liver has limited capacity to degrade the branched-chain amino acids ( leucine, isoleucine, and valine) which are metabolized in the muscle.

Adipose Tissue: Energy Storage Depot

Adipose tissue comes after the liver in its ability to distribute fuel molecules.

• In a 70 kg man, adipose tissue weighs about 14 kg or about half as much as the total muscle mass.

• In obese individuals, adipose tissue can constitute up to 70% of body weight.

(Figure 24.4)

A. Carbohydrate Metabolism:

1. glucose transport : Glucose influx into adipocyte is stimulated by insulin

(Figure 24.5)

2. gIycolysis : To provide glycerol phosphate for triacylglycerol synthesis

3. activity in the HMP: To supply NADPH (essential for fat synthesis).

 

B. Fat Metabolism:

 1. synthesis of fatty acids:

• De novo synthesis of fatty acids from acetyl CoA in adipose tissue is nearly undetectable in humans, except when refeeding a previously fasted individual.

• Most of the fatty acids added to the lipid stores of adipocytes is provided by dietary fat (in the form of chylomicrons), and a lesser amount is supplied by VLDL from the liver.

• Dietary fat can be converted to body fat .So, When caloric intake exceeds energy expenditure, dietary fat can be converted to triacylglycerol in the adipose tissue. (Figure 24.5)

2. triacylglycerol synthesis:

Fatty acid + glycerol 3 - ph triacylglycerol (TG).

- Because adipocytes lack glycerol kinase used in triacylglycerol synthesis, so that glycerol 3- phosphate must come from the metabolism of glucose.

- In the well-fed state, elevated levels of glucose and insulin favor storage of TG. (Figure 24.5)

 3. triacylglycerol degradation:

Insulin inhibits the hormone-sensitive lipase (dephosphorylated form).

Triacylglycerol degradation is inhibited in the well-fed state.

Resting Skeletal Muscle• At rest, muscle accounts for about 30% of the

oxygen consumption of the body.

• During vigorous exercise, it is responsible for up to 90% of the total oxygen consumption.

• Skeletal muscle despite its potential for transient periods of anaerobic glycolysis, is an oxidative tissue.

• Heart muscle differs from skeletal muscle in three important ways:

1 -The heart is continuously active, whereas skeletal muscle contracts intermittent on demand.

2 - The heart has completely an aerobic metabolism.

3 - The heart contains negligible energy stores such as glycogen or lipid; thus , any interruption of the vascular supply, e.g. as occurs during a myocardial infraction, results in rapid death of myocardial cells.

• Heart muscle uses glucose, free fatty acid & ketone bodies as fuels.

A) Carbohydrate Metabolism:

1. glucose transport:

• Due to insulin (glucose transporter).

• Glucose is phosphorylated glucose 6-phosphate and metabolized produce the energy needed for the muscle.

• This contrasts with the post- absorptive state in which ketone bodies and fatty acids are the major fuels of resting muscle.

  (Figure 24.6)

2. glycogen synthesis:

• The insulin /glucagon ratio and the availability of glucose 6-phosphate stimulate glycogenesis, especially if glycogen stores have been depleted as a result of exercise.

(Figure 24.6)

B) Fat Metabolism:

Fatty acids are of secondary importance as a fuel for muscle in the well- fed state in which glucose is the primary source of energy. (Figure 24.6)

C) Amino Acid Metabolism:

 1. protein synthesis:

in A.A. uptake and protein synthesis occurs in the absorptive period after ingestion of a meal containing protein (stimulated by insulin). (Figure 24.6)

2. uptake of branched-chain amino acids:

• Muscle is the principal site for degradation of

branched-chain amino acids.

• The branched –chain A.A. ( Leucine, isoleucine,

and valine) are taken up by muscle, where they

are used for : - protein synthesis

- sources of energy.

The Brain• Although forming only 2% of the adult weight, the

brain accounts for 20% of the basal oxygen consumption of the body at rest.

• Brain uses energy at a constant rate.

• Normally, glucose is the primary fuel to the brain, because in the fed-state the concentration of ketone bodies is too low to be an energy source.

• If the blood glucose levels fall below approximately 30 mg /dl (normal blood glucose is 70-90 mg/dl), cerebral function impairment.

• If hypoglycemia occurs for short time, severe & potentially irreversible brain damage may occur .

A. Carbohydrate Metabolism:

•  In the well-fed state, the brain uses glucose exclusively as a fuel, completely oxidizing about 140 g /day glucose to CO2 and water.

• The brain contains no stores of glycogen, and is therefore, completely dependent on the availability of blood glucose.

(Figure 24.7)

B. Fat Metabolism:

• Brain has no significant stores of triacylglycerols.

• Blood fatty acids do not efficiently cross the blood-brain barrier. So, the oxidation of fatty acids is of little importance to the brain.

(Figure 24.8)

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6th Lecture: Pages : 327 - 333

     - Overview of fasting : o Fuel stores

o  Enzymic changes in fasting-   Liver in fasting :

o  Carbohydrate metabolismo  Fat metabolism

-   Adipose tissue in fasting :o  Carbohydrate metabolismo  Fat metabolism

-   Resting skeletal muscle in fasting :o  Carbohydrate metabolismo  Lipid metabolismo   Protein metabolism

-   Brain in fasting .

Metabolism in FastingOverview

•  Fasting may result from an inability to obtain food, from the desire to lose weight rapidly, or in clinical situations in which an individual cannot eat because of trauma, surgery, neoplasm and burns.

• In the absence of food, plasma levels of glucose, A.A., and triacylglycerols fall glucagon secretion and insulin secretion.

• Fasting is a catabolic period characterized by degradation of glycogen, triacylglycerol and protein for:

1) Maintaining sufficient plasma levels of glucose for energy metabolism of the brain and other glucose – requiring tissues.

2) Mobilizing fatty acids from adipose tissue and ketone bodies from liver to supply energy to all other tissues

1-Fuel Stores:• The metabolic fuels available in a normal 70 Kg man at the beginning of a fast are: (Figure 24.9)

• 15 Kg fat

• 0.2 Kg glycogen

• 6 Kg protein

• Only about 1/3 of the body protein can be used for energy production without affecting the vital functions.

• The metabolic changes in fasting are opposite to those in the well fed -state.

2-Liver in Fasting :

A) Carbohydrate Metabolism.

The liver first uses glycogen degradation, then gluconeogenesis to maintain blood glucose levels needed for the brain and tissues

1-Increased glyconeolysis:

The sources of glucose after ingestion of 100g glucose(Figure 24.10)

• Several hours after a meal, blood glucose levels glucagon and insulin secretion.

glucagon / insulin ratio glyconeolysis (Adult's liver contains 100 g of glycogen in the well -fed state). (Figure 24.11)

• Liver glycogen is nearly depleted after 10 – 18 hours of fasting.

• Hepatic glyconeolysis is a transient response to early fasting.

2-Increased Gluconeogenesis:

• Gluconeogenesis begins 4 –6 hours after the last meal and becomes fully active as liver glycogen stores are depleted. (Figure 24.11)

• Gluconeogenesis plays an essential role in maintaining blood glucose during both overnight and prolonged fasting.

• The main sources for gluconeogenesis are A.A., glycerol and lactate.

B) Fat Metabolism:

 1-Increased fatty acid oxidation: The oxidation of fatty acids derived from adipose tissue is the major source of energy in hepatic tissue in the post absorptive state. (Figure 24.11)

2-Increased Synthesis of Ketone bodies:

• Ketone bodies are important in fasting because they can be used as fuel by most tissues including brain. This the need for gluconeogenesis from A.A., thus slowing the loss of essential protein. (Figure 24.12)

• Ketone body synthesis is favored when the concentration of acetyl CoA, (produced from F.A. oxidation) exceeds the oxidative capacity of the tricarboxylic acid (TCA) cycle.

• Unlike fatty acids, Ketone bodies are water –soluble, and appear in the blood and urine by the second day of a fast.

3-Adipose Tissue in Fasting:

 A) Carbohydrate Metabolism:

Glucose transport into the adipocytes and its metabolism are depressed due to low levels of blood insulin .This leads to a decrease in fatty acid and triacylglycerol synthesis.

B) Fat Metabolism:

1- Increased degradation of triacylglycerols:

The activation of hormone – sensitive lipase and subsequent hydrolysis of stored triacylglycerol are stimulated by high levels of catecholamines (epinephrine and particularly norepinephrine). (Figure 24.13)

2- Increased release of fatty acids:

Fatty acids resulting from the hydrolysis of stored triacylglycerol are released into the blood.

Bound to albumin, they are transported to other tissues for use as fuel. Part of the fatty acids is oxidized in the adipose tissue to produce energy.

The glycerol produced from triacylglycerol degradation is used by the liver for gluconeogenesis.

3- Decreased uptake of fatty acids:

In fasting, lipoprotein lipase activity of adipose tissue is low. Thus, circulating triacylglycerol of lipoproteins is not available for triacylglycerol synthesis in adipose tissue .

4-Resting Skeletal Muscle in Fasting: Resting muscle uses fatty acids as its major fuel

source.

• By contrast, exercising muscle initially uses its glycogen stores as a source of energy.

• During intense exercise, glucose -6-phosphate derived from glycogen is converted to lactate by anaerobic glycolysis.

• As these glycogen reserves are depleted, free fatty acids provided by the mobilization of triacylglycerol from adipose tissue become the major sources.

A) Carbohydrate Metabolism:

Glucose transport and subsequent glucose metabolism are depressed because of low blood insulin.

B) Lipid Metabolism:

• During the first 2 weeks of fasting, muscle uses fatty acids from adipose tissue and ketone bodies from the liver as fuels.

• After about 3 weeks of fasting, muscle decreases its utilization of ketone bodies and oxidizes only fatty acids.

• This leads to further increase in the already elevated level of blood ketone bodies. 

C) Protein Metabolism:

• On starvation, there is rapid breakdown of muscle protein A.A. used by the liver for gluconeogenesis.

• Alanine and glutamine are quantitatively the most important glucogenic amino acids released from muscle. (Figure 24.14)

• After several weeks of fasting, the rate of muscle proteolysis due to need for glucose as a fuel for brain.

5- Brain in Fasting :

• During the first days of fasting, the brain continues to use only glucose as a fuel.

• In prolonged fasting (greater than 2-3 weeks), plasma ketone bodies and are used, in addition to glucose, as a fuel by the brain. (Figure 24.15)

• This the need for protein catabolism for gluconeogenesis. (Figure 24.16)

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