INTEGRATION OF METABOLISM METABOLISM - eGyanKosh

Block 4 Lipid Metabolism II

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UNIT 13

INTEGRATION OF INTEGRATION OF INTEGRATION OF INTEGRATION OF METABOLISMMETABOLISMMETABOLISMMETABOLISM

StructureStructureStructureStructure

13.1 Introduction

Expected Learning

Outcomes

13.2 Well-Fed State

13.3 Early Fasting State

13.4 Fasting State

13.5 Early Re-Fed State

13.6 Energy Requirements,

Reserve and Calorie

Homeostasis

13.7 Five Stages of Glucose

Homeostasis

13.8 Metabolic Adaptations in

Special Physiological

States

13.9 Summary

13.10 Terminal Questions

13.11 Answers

13.1 INTRODUCTION

Metabolism encompasses all the biochemical processes to obtain energy, and

to synthesize different structural and functional constituents in an organism. In

order to understand integration of metabolism, you should refresh the basic

metabolic pathways (anabolic, catabolic and amphibolic) and how they are

regulated. However, it is important to keep in mind that metabolism is not just

a collection independently existing sequences of enzyme catalyzed reactions

in a cell. Rather, these pathways are highly interconnected. They proceed in a

coordinated and very well regulated manner as per the cell needs. The

nutritional and hormonal status play significant role in modulation of metabolic

processes in human body. The alteration/adaptation of metabolism under

starvation and fed states termed as ‘Starved-Fed cycle’ helps us to understand

the integration of metabolism. In this context, the role of different hormones

e.g., insulin, glucagon, epinephrine, and key enzymes will be discussed.

Physical and mental activity in humans is powered essentially by the energy

captured from food, and body’s fat and carbohydrate reserves between meals.

ATP is universal energy currency of the cell. The amount of ATP required to

Unit 13 Integration of Metabolism

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meet energy needs for various activities of is striking. However, there is

enormous cycling of ADP back to produce ATP (ATP-ADP cycle). The process

of calorie homeostasis will also be discussed in the present unit.

Nature has not equipped human body with an abundant quantity of glucose

reserve. Different physiological processes modulate metabolism such that

blood glucose level is maintained within limits. Glucose homeostasis is very

important for maintenance of healthy condition of an individual. Evidently, you

will also learn about the five stages of glucose homeostasis. In this unit,

discussion on metabolism will be in the context of mammals keeping in view

the unique metabolic profile of different organs and how it is integrated in the

organism. The central role of liver in these processes will also be emphasized.

Expected Learning OutcomesExpected Learning OutcomesExpected Learning OutcomesExpected Learning Outcomes

After studying this unit, you should be able to:

� describe the metabolic processes under different nutritional states viz.,

well-fed state, early fasting, fasting, and early refed state;

� explain the energy requirements of humans, energy stores and calorie

homeostasis; and

� delineate the five stages of glucose homeostasis - sequence of events

that maintains blood glucose level.

13.2 WELL FED STATE

The diet consumed by a person determines the type of metabolism. The fate

of glucose, amino acids and fat under well-fed conditions is illustrated in Fig.

13.1.

Fig. 13.1: Metabolic fate of carbohydrates, lipids and proteins under well fed

state.


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After consumption of calorie rich food, glucose produced in gastrointestinal

tract passes from intestinal epithelial cells via portal vein to the liver. Insulin

signals the fed state. It is released from β-cells of pancreas in response to high

blood glucose level and stimulates the uptake of glucose by different tissues.

The fate of glucose in the liver may be one or more of the following:

(i) Insulin activates glycogen synthase and inactivates glycogen

phosphorylase which results in conversion of glucose 6-phosphate to

glycogen (glycogenesis);

(ii) Degradation of glucose to form pyruvate and lactate (glycolysis);

(iii) Glucose-6-phosphate can be diverted towards pentose phosphate

pathway for the production of NADPH to support reductive biosynthesis;

(iv) Pyruvate produced from glucose can be converted to acetyl-CoA by

oxidative decarboxylation (pyruvate dehydrogenase complex catalyzed

reaction). Further, acetyl-CoA may be oxidized completely to CO2 and

water by citric acid cycle.

(v) If not oxidized for energy production, the excess acetyl-CoA can be used

for synthesis of fatty acids. These fatty acids are transported from liver

as triacylglycerol by very low density lipoproteins (VLDLs) to adipose

tissue.

You should understand that although liver is recognized as the major organ for

gluconeogenesis but in well-fed state it uses glucose and does not engage in

gluconeogenesis.

Much of the dietary glucose passes through liver to other organs including

brain, red blood cells and renal medulla. Here, it should be noted that under

the influence of insulin, excess of blood glucose is converted to two storage

forms: (i) glycogen in liver & muscle, and (ii) triacylglycerol in adipose tissue.

Dietary fat is carried from intestine via lymphatic system as chylomicrons

which are ultimately delivered to blood by the thoracic duct. These

chylomicrons are acted upon by extracellular lipoprotein lipase attached to

the endothelial cells lining the capillaries of tissues, particularly adipose tissue.

The lipoprotein lipase hydrolyzes a large portion of triacylglycerol present in

chylomicrons (and VLDL). The free fatty acids released are picked up by

adipocytes and re-esterified with glycerol 3-phosphate (made from glucose) to

triacylglycerols and stored as fat droplets. Chylomicrons remaining after

digestion by lipoprotein lipase are removed from bloodstream by liver tissue.

These are hydrolysed with a lysosomal lipase and the free fatty acids released

are used to form triacylglycerols. The triacylglycerols produced from dietary fat

in this way and those produced by de novo synthesis from glucose and amino

acids are packed into very low density lipoproteins (VLDLs) and released in

the blood stream. VLDL is also acted upon by lipoprotein lipase in adipocytes,

and the free fatty acids are used in synthesis of triacylglycerols.

The intestinal cells transport most of amino acids into the portal blood. Liver

removes some of these amino acids while most pass through it. This is

important for providing essential amino acids needed by all cells for synthesis

of proteins. Excess of amino acids may be completely oxidised or converted to

intermediates which can be used for lipid synthesis. Amino acids that escape


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from liver tissue are used for protein synthesis or to provide energy in other

tissues

13.3 EARLY FASTING STATE

At this stage, blood glucose level begins to decline. Glucagon secretion rises

and it signals the starved state. Liver glycogen is mobilized by

glycogenolysis which plays an important role in maintenance of blood

glucose level. Glucagon hormone is released from α-cells of pancreas in

response to lowered blood glucose level and plays a pivotal role in

mobilization of glycogen by activating glycogen phosphorylase and inactivating

glycogen synthase. Lactate, pyruvate and alanine are also utilized by liver to

produce glucose. This happens through the Cori cycle (Refer Unit 2,

glycolysis) and Glucose-Alanine cycle (details in amino acid catabolism).

In glucose-alanine cycle (Fig. 13.2), glucose is transported from liver to muscle

where it is degraded to produce pyruvate. Pyruvate is transaminated to

alanine and transported through blood to liver where its carbon skeleton is

converted to glucose by gluconeogenesis and nitrogen is detoxified to urea.

Fig. 13.2: Metabolic state during early fasting stage such as during night.

13.4 FASTING STATE

The metabolic adaptations during fasted state are illustrated in Fig. 13.3. If

fasting is prolonged, no dietary fuel enters from gut, and the store of glycogen

is almost depleted after 10-12 hours of fasting. At this stage gluconeogenesis

in liver using lactate, glycerol and alanine becomes important. It should also

be noted that brain cannot carry out gluconeogenesis, and is constantly


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dependent on glucose supply through blood. If blood glucose level falls

significantly below a critical level, severe and sometimes irreversible changes

may occur in brain function(s).

Fig. 13.3: Intermediary metabolism during fasting.

During fasting, insulin / glucagon ratio is low. This favors lipolysis in adipose

tissue through the cAMP-dependent phosphorylation of perilipin and hormone

sensitive lipase. The free fatty acids released are transported to liver and other

tissues as fuel, sparing glucose for the brain. Glycerol produced on lipolysis in

adipose tissue serves as an important precursor for gluconeogenesis in liver.

Fatty acid oxidation in liver provides most of ATP required for

gluconeogenesis.

Excess of acetyl-CoA generated from fatty acid oxidation is diverted to

synthesis of ketone bodies (acetoacetate and β-hydroxybutyrate) in liver

mitochondria. Ketone bodies are released into the blood stream and serve as

source of energy for extrahepatic tissues. It is important to note that fatty acids

are not oxidized by brain because they cross the blood-brain barrier poorly.

However, as the levels of ketone bodies in blood are high enough, these enter

the brain to serve as an alternative fuel. Still, ketone bodies are not a complete

replacement for of glucose.

During fasting, proteins are hydrolyzed in muscle cells. Alanine and glutamine

are produced in the largest amounts. The other amino acids are metabolized

to produce certain intermediates such as pyruvate and α-ketoglutarate which

can also be converted to alanine and glutamine. Branched chain amino acids

(valine, leucine, and isoleucine) serve as major source of nitrogen for

production of alanine and glutamine in muscle. The synthesis of glucose from

the carbon skeletons of amino acids is linked to the detoxification of the amino

nitrogen to urea. Initially the nitrogen from these amino acids is channeled into

glutamate which is oxidatively deaminated to ammonia and then to urea.


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Here, it will be relevant to understand the role of catecholamines (epinephrine

and norepinephrine) also which elicit responses similar to those of glucagon.

You know that catecholamines are released from adrenal medulla during

stress such as during fight or flight response. Epinephrine promotes the

release of glucagon from pancreas, and binding of glucagon to receptor on

liver cells results in stimulation of glycogen degradation. Epinephrine also

binds directly to α- as well as β-adrenoreceptors present on liver cell surface.

Binding of epinephrine to β-adrenoreceptors increases intracellular cAMP

which results in increased glycogen breakdown and gluconeogenesis. Binding

of epinephrine to α- adrenoreceptors stimulates an increase in intracellular

concentration of calcium ions [Ca2+] which reinforces the cellular response to

cAMP (Recall from Unit-6, glycogen metabolism, that phosphorylase kinase,

the enzyme responsible for activation of glycogen phosphorylase and

inactivation of glycogen synthase is fully active in the phosphorylated form.

Binding of epinephrine to β-adrenoreceptors on muscle cells also promotes

glycogen breakdown, thereby releasing glucose which can be metabolized by

glycolysis to produce ATP for muscle activity. In adipose tissue, epinephrine

binding activates hormone sensitive lipase which results in mobilization of

stored fat and fatty acids, thus released can be used as fuel by other tissues.

13.5 EARLY RE-FED STATE

During this phase triacylglycerol is metabolized the same way as you have

studied under well-fed phase. The uptake of glucose by the liver is inefficient,

and it continues to remain in the gluconeogenic phase for a few hours after

feeding. In peripheral tissues glucose is incompletely degraded to lactate

which is picked up from circulation by liver and converted into glycogen (Cori

cycle). Thus following fasting liver glycogen is replenished by an indirect

route. Even gluconeogenesis using amino acids coming from gut is another

source of glycogen. Once gluconeogenesis declines, synthesis of liver

glycogen occurs using blood glucose made available through diet. Excess

glucose is diverted to fat synthesis or glycolytic breakdown. The metabolic

effects of insulin, glucagon and epinephrine are summarized in Table 13.1.

SAQ 1SAQ 1SAQ 1SAQ 1

Fill in the blanks with suitable word(s): i) After eating calorie rich meal, glucose produced in gastrointestinal tract

is passed from the intestinal epithelial cells via ___________vein to the

liver.

ii) Glucagon is released from _______ of pancreas in response to low

blood glucose levels.

iii) The enzyme which hydrolyzes TAG present in chylomicrons is

__________.

iv) Liver glycogen is mobilized by a process called ______________.

v) Insulin ___________ glycolysis in liver.

vi) Under the influence of epinephrine, fatty acid mobilization from adipose

tissue is __________.

vii) Ketone bodies are synthesized from acetyl-CoA in

_________mitochondria.


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Table 13.1: Metabolic effects of insulin, glucagon and epinephrine

(Source: Adapted from David L. Nelson & Michael M. Cox (2017) Ch. 23 Hormonal

regulation and integration of mammalian metabolism In: Lehninger Principles of

Biochemistry, W.H. Freeman and Company: NY)

13.6 CALORIC HOMEOSTASIS

As per Dietary Guidelines for Indians (National Institute of Nutrition, ICMR,

http://ninindia.org/DietaryGuidelinesforNINwebsite.pdf), an adult man

(sedentary work), weighing 60 Kg requires 2320 Kcal/day while a woman

Metabolic effect Target enzyme/Overall effect

Insulin

Glucose uptake (muscle, adipose

tissue)

Glucose uptake (liver)

Glycogen synthesis (liver, muscle)

Glycogen degradation (liver, muscle)

Glycolysis, acetyl-CoA production

(liver,muscle)

Fatty acid synthesis (liver)

Triacylglycerol synthesis (adipose

tissue)

Glucose transporter (GLUT4)

Glucokinase expression

Glycogen synthase

Glycogen phosphorylase

PFK1 (through PFK2 action),

Pyruvate dehydrogenase complex

Acetyl-CoA carboxylase

Lipoprotein lipase

Glucagon

Glycogen degradation (liver)

Glycogen synthesis (liver)

Glycolysis (liver)

Gluconeogenesis (liver)

Fatty acid mobilization (adipose tissue)

Ketogenesis

Glycogen phosphorylase

Glycogen synthase

Phosphofructokinase-1(PFK-1)

Fructose 2,6-bisphosphatase-2

(FBPase-2)

Pyruvate kinase

PEP carboxykinase

Hormone-sensitive lipase

PKA (perilipin-P)

Acetyl-CoA carboxylase

Epinephrine

Glycogen breakdown (muscle, liver)

Glycogen synthesis (muscle, liver)

Gluconeogenesis (liver)

Glycolysis (muscle)

Fatty acid mobilization (adipose tissue)

Glucagon secretion

Insulin secretion

Increased production of glucose for

fuel

Increases ATP production in muscle

Increase in availability of fatty acids as

fuels

Reinforces metabolic effects of

epinephrine


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(sedentary work), weighing 55 Kg requires 1900 Kcal/day. The recommended

allowances go up with increase in physical activity (Moderate, Heavy work);

state of pregnancy and lactation. Catabolism is responsible for extraction of

energy through degradation of foodstuffs or stored fuels such as

carbohydrates, lipids and proteins. The energy obtained on oxidation of food is

captured as high energy phosphate bonds in ATP. This ATP is consumed to

perform different activities of the body e.g. muscle contraction, active

transport, synthesis of macromolecules. The proportion of different types of

fuels used as energy source depends on the tissue/organ and the hormonal

state of the organism. The energy reserves of a normal man weighing 70 Kg

are shown below in Table 13.2.

Note that fat reserves are much higher than glycogen. However, glycogen can

be mobilized rapidly. Fat reserves are used in times of prolonged fasting.

Proteins can provide amino acids for release of energy by oxidation, but as

you have studied in Section 13.4 these are generally spared and utilized for

energy only when other choices are exhausted.

Table 13.2: Fuel reserves in a normal 70 Kg man

Type of Fuel reserve Weight (g) Energy (Kcal)

Liver Glycogen 70 280

Muscle glycogen 120 480

Fat (adipose tissue) 15,000 135,000

Protein (muscle) 6,000 24,000

Glucose(body fluids) 20 80

(Source: Adapted from Table 21.1, Ch. 21 Metabolic interrelationships In:

Text book of biochemistry with clinical correlations, T.M. Devlin (Ed.), 7th

edition)

The regulation of energy status of an organism is important for normal

functioning and survival. The ability to maintain adequate concentration of

energy fuels in blood under different conditions is caloric homeostasis or

energy homeostasis. Among the energy fuels the levels of glucose are

carefully regulated whereas fatty acids and ketone body concentrations tend

do vary. Overall, under well-fed conditions, insulin/glucagon ration is high and

storage of glycogen as well as triacylglycerol is higher. Conversely, under

starvation conditions there is low insulin/glucagon ratio which leads to

stimulation of glycogenolysis, gluconeogenesis, proteolysis, lipolysis and

increased production of ketone bodies.

By now you have understood that we consume different sources of energy as

foods, trap energy from oxidation as ATP to power activities of life. If we

consume more energy over time than we expend, there will be imbalance and

we will become overweight or obese. Obesity, a perturbation of caloric

homeostasis, has become a major health concern in developed as well as


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developing countries. You have already learnt under sections 13.2- 13.5, and

Table 13.1, actions of insulin and glucagon linked with organismal energy

regulation. Obesity is defined in terms of body mass index (BMI) which is

calculated as (weight in Kg)/ (height in m2). It is an estimate of fat in your body.

According to WHO for adults, BMI in the range of 18.5 to 24.9 is normal; 25 –

29.9 is overnight and > 30 is obese. In case of Asian Indians, the consensus

guidelines gives the optimal cut-offs as BMI of 18.5 to 22.9 for normal; 23.0 –

24.9 Kg/m2 are considered overweight, and >25 Kg/m2 is an indicator of

obesity (Mishra et al. (2009) JAPI 57:163-70).

The mechanisms involved in regulation of mammalian fuel metabolism are

complex and permit the body to respond efficiently to changes in demands of

energy and also accommodate the changes encountered in availability of

different types of fuels. Some hormonal signals originate in digestive tract,

muscle and adipocytes (fat cells) and are sent to hypothalamus where these

are integrated to produce a neuronal or hormonal response. AMP-activated

protein kinase (AMPK) plays a crucial role in summing up different inputs

reaching the hypothalamus in order to regulate fuel metabolism. In this unit,

we will discuss only some important hormonal signals known to the ever

growing list.

Leptin (Greek leptos meaning ‘thin’) is a peptide hormone (167 amino acids)

secreted from adipocytes in direct proportion to the amount of fat. It is

considered a ‘satiety signal’ that suppresses appetite by acting on

anorexigenic (appetite suppressing) neurosecretory cells in arcuate nucleus of

hypothalamus. These neurons in turn stimulate the production of anorexigenic

peptide hormones such as α -MSH (α-melanocyte stimulating hormone). They

produce neuronal signals that reduces fuel intake and enhances energy

expenditure. .

In adipose and other tissues leptin also stimulates increased synthesis of

thermogenin resulting in dissipation of useful energy as heat. Even insulin acts

on anorexigenic neurons. Obesity in humans is the result of leptin resistance

probably due to the decrease in the level of a leptin receptor in brain or the

saturation of receptor that transports leptin across the blood-brain barrier into

the central nervous system.

Adiponectin is a peptide hormone of 247 amino acid residues that is

produced almost exclusively in adipose tissue and sensitizes other organs to

the effects of insulin. It acts by controlling the activity of AMP-activated

protein kinase (AMPK). The binding of adiponectin to its receptor (G-protein

coupled receptor, GPCR) on the surface of muscle and liver cells results in

increase in phosphorylation and activation of AMPK. It increases the uptake

and degradation of fatty acids by muscle cells. In the liver it blocks fatty acids

synthesis and gluconeogenesis and stimulates glucose uptake and

catabolism. Deceased adiponectin levels are linked with insulin resistance.

The adiponectin receptors in the brain stimulate feeding behaviour.

AMPK is recognized as ‘Fuel Gauge’ of cells and a major regulator of

metabolic homeostasis. It monitors the energy and nutrient status in individual

cells and shifts the metabolism toward energy generation. By responding to


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various hormonal signals, AMPK in hypothalamus acts to keep the whole

organism in energy balance.

You know that many energy consuming reactions in cells convert ATP to ADP

or AMP. Further, adenylate kinase converts AMP + ATP to 2ADP. AMP

functions as a sensitive measure of energy status of cell. AMPK is activated

allosterically by AMP while ATP prevents binding of AMP to AMPK. Thus,

AMPK is activated at high [AMP] / [ATP] ratio and inactivated when energy

status of the cell is high (high [ATP]/[AMP]). It responds to energy needs of an

organism by working through another mode also which involves its activation

by phosphorylation catalysed by liver kinase B1 (LKB1). The latter is regulated

by many components including adiponectin. The activated AMPK

phosphorylates specific enzymes in metabolic pathways which are crucial to

energy homeostasis.

Neuropeptide Y (NPY) is produced in hypothalamus and adrenal glands. The

orexigenic (appetite stimulating) neurons stimulate eating by producing and

releasing NPY. Both leptin and insulin on binding to their respective receptors

in hypothalamus inhibit the secretion of NPY.

Incretins are a group of metabolic peptide hormones secreted from gut within

minutes after eating. Glucagon like peptide-1 (GLP-1) and glucose dependent

insulinotropic polypeptide (GIP) are examples of incretins. They share

common action on pancreas as both are insulinotropic (induce insulin

secretion). The incretin effect can be observed in response to oral as well as

intravenous glucose. In diabetics GIP no longer modulates glucose dependent

insulin secretion.

Ghrelin is an appetite stimulating peptide secreted by cells lining the stomach.

It is works on a shorter time scale (between meals). The concentration of

ghrelin in blood fluctuates throughout the day, increasing before meals and

decreasing sharply after meals.

PYY3-36 is a peptide hormone (34 amino acid residues), secreted by endocrine

cells in the lining of small intestine and colon. Its level in blood increases after

a meal and remains high for some hours. The hormone acts on orexigenic

neurons (appetite stimulating) and inhibits release of NPY resulting in

reduction of hunger.

Overall, in context of appetite regulation, you may note that ghrelin stimulates

appetite while leptin, insulin, and PYY3-36 suppress appetite by regulating the

secretion of NPY from the hypothalamus.


In the following statements choose the correct option from those given in

bracket:

i) The energy harnessed from oxidation of food is captured largely as

__________ (ATP/CTP).

ii) Liver stores_____________ (more/less) quantity of glycogen than

muscle.


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iii) Under starvation conditions, insulin level is _______

(increased/decreased).

iv) After prolonged starvation, the brain can adapt to utilization of

_________ (triacylglycerol/ketone bodies) as source of energy.

v) The primary target organ of glucagon is _____________ (liver/brain).

vi) Ghrelin _____________ appetite (stimulates /suppresses).

vii) PYY3-36 is secreted from lining of ___________ (small

intestine/stomach).

viii) The target organ of incretins is _____________ (adipose

tissue/pancreas).

13.7 FIVE STAGES OF GLUCOSE HOMEOSTASIS

It has been mentioned in the introduction that maintenance of blood glucose

level is of utmost importance for healthy state of an individual. The glycogen

stores in the liver are constantly utilised to replenish blood glucose levels. The

two hormones that are important regulators of fuel metabolism are insulin and

glucagon. Insulin signals body tissues that blood glucose is higher than the

necessary level and needs to be converted to glycogen and triacylglycerols.

On the other hand, glucagon signals a fall in blood levels and stimulates

glycogen breakdown and gluconeogenesis in the liver. Cahill and his

colleagues while working on obese patients undergoing long-term starvation

described the sequence of events of glucose homeostasis and arbitrarily

divided them into five phases (Table 13.3).

Phase I

It is the well-fed or post absorptive state in which dietary carbohydrates are

broken down in the GI tract to glucose and other sugars. The digested

carbohydrates and other nutrients are then released into blood. Insulin signals

the fed state. The secretion of insulin by the pancreatic β-cells is stimulated by

glucose. Insulin increases the rate of glucose uptake by glucose transporter

(GLUT2) into liver cells, activating glucokinase (high Km) and diverting

glucose 6-phosphate for glycogen synthesis. This is further complimented by

glucose itself; it binds to phosphorylase a and converts it to less active

phosphorylase b.

Insulin also promotes the entry of glucose into muscle and adipose tissue; it

stimulates glycogen synthesis in muscle and fat storage in adipose tissue.

The other effects include increased glycolysis in the liver and uptake of branch

chain amino acids by muscle.


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Table 13.3: Five stages of glucose homeostasis

Feature I II III IV V

Stage

description

Well-fed Post

resorption

Early

starvation

Prolonged

starvation

Extreme

starvation

Time

intervala

0-4h 4-16 h 16-30 h 2-24 d Over 24 d

Origin of

Glucose in

blood

Food Liver

glycogen

gluconeogen

esis

Gluconeo

genesis

Liver

glycogen

Gluconeo

genesis

Gluconeogene

sis

Utilization

of Glucose

All

tissuesb

All tissuesb

muscle,

adipose

tissues

All

tissuesb

muscle,

adipose

tissues

Brain,

RBCs,

Kidney

RBCs, Kidney,

Brain-limited

Energy of

Brain

Glucose Glucose Glucose Glucose,

ketone

bodies

Ketone bodies,

Glucose

aApproximate values, time 0=any main meal (e.g.lunch)

bExcept of liver.

Phase II

After exogenous glucose is exhausted, contribution from stored glycogen

through glycogenolysis in liver becomes important in maintenance of blood

glucose level. When the supply of glucose through this process starts to

decline, gluconeogenesis in liver using lactate, glycerol and alanine becomes

increasingly important to add glucose in blood stream.

Phase III

In this phase, gluconeogenesis becomes the major source of blood glucose.

This stage is reached generally within ~ 20 hours of fasting depending on well-

fed state before fasting, quantity of liver glycogen available, and the type of

physical activity during fast. The brain depends solely on supplied glucose.

Phase IV

After several days of fasting, gluconeogenesis also decreases. Ketone bodies

(acetoacetate and β-hydroxybutyrate), produced in liver, reach high

concentrations in blood. The brain uses both glucose and ketone bodies.

Gluconeogenesis in kidney also becomes important in Phase IV.

Phase V

This stage is reached after a very long period of starvation in obese individual.

Dependence on gluconeogenesis decreases even further and energy needs of

almost all organs are met by fatty acid oxidation or utilization of ketone bodies.


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After all of the fat has been exhausted and when level of ketone bodies falls,

degradation of muscle protein starts to maintain the blood glucose level.


Fill in the blanks with correct word(s):

i) Glucagon is released in response to ________ blood glucose level.

ii) Glycogen is mainly stored in liver and __________.

iii) During prolonged starvation, the level of ketone bodies in blood

__________.

iv) On binding to its receptor in hypothalamus, leptin _____ the secretion of

NPY.

v) AMP acts as a ___________ of AMPK.

13.8 METABOLIC ADAPTATIONS IN SPECIAL PHYSIOLOGICAL STATES

Based on understanding of these metabolic adaptations, let us discuss about

these interrelations in some normal but special physiological states such as

during exercise, pregnancy and lactation.

Exercise: It is of two types; anaerobic such as weight lifting or aerobic such as

running. Two modes differ in the source of energy. During anaerobic exercise,

as the blood vessels within involved muscles are compressed, therefore, these

are isolated from rest of the body. These muscles use their own glycogen

stores and phosphocreatine for ATP synthesis.

However, in case of aerobic exercise such as long distance running, there

aren’t enough glycogen stores to provide glucose. Cori’s cycle kicks in. Once

glycogen stores are exhausted, lipolysis increases as happens in case of

fasting. However, unlike fasting, concentration of ketone bodies does not rise

much as there is a balance between their synthesis in liver and oxidation by

muscles.

Pregnancy: During pregnancy, priority is supply of energy and nutrients for

growth and development of foetus as a result starved- fed cycle is perturbed.

Placenta secretes hormones such as lactogen, estrogen and progesterone.

Lactogen stimulates lipolysis in adipose tissue, while estrogen and

progesterone induce insulin resistance. As a result of increased use of

nutrients such as glucose and amino acids by foetus, mother enters starved

phase earlier than the normal condition causing hyproglycemia. Rapid fall in

level of these nutrients results in increased glucagon secretion, thereby

promoting lipolysis and ketogenesis.

Lactation: During later stage of pregnancy, placental hormones induce

lipoprotein lipase activity in the mammary glands and prepare them for

lactation. Consumption of glucose increases in breasts for synthesis of lactose

and triglycerides for energy and building of the tissue. Amino acids are taken

up for protein synthesis and chylomicrons and VLDL provide triacyl glycerides.


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If these nutrients are not available in sufficient amounts through diet, these are

taken up by enhanced proteolysis, gluconeogenesis and lipolysis depleting

mother of her nutrients and production of poor quality milk.

13.8 SUMMARY

Let us summarize what we have learnt so far.

• Metabolic pathways are not independent, but highly interconnected. The

nutritional and hormonal status play significant role in modulation of

metabolic processes in human body.

• In well-fed state, insulin released from pancreatic β-cells in response to

high blood glucose level stimulates the uptake of glucose by tissues.

Dietary fat is carried from intestine via lymphatic system as chylomicrons

which are ultimately delivered to blood by the thoracic duct. TGs are

hydrolysed by extracellular lipoprotein lipase and the products are made

available to the close by tissues. The intestinal cells transport most of

amino acids into the portal blood for distribution. Amino acids that

escape from liver tissue are a source of essential amino acids for protein

synthesis or to provide energy in other tissues.

• During the early fasting state, liver glycogen is mobilized by

glycogenolysis which plays an important role in maintenance of blood

glucose levels. Glucagon hormone released from α-cells of pancreas in

response to lowered blood glucose level stimulates mobilization of

glycogen from liver.

• During fasting state, gluconeogenesis in liver using lactate, glycerol and

alanine becomes important. The brain cannot carry out

gluconeogenesis, and is constantly dependent on glucose supply

through blood.

• In an adult, fat reserves are much higher than glycogen; however,

glycogen can be mobilized rapidly. Fat reserves are used in times of

prolonged fasting.

• The ability to maintain adequate but not excessive energy stores is

called caloric homeostasis or energy homeostasis. Obesity is a

perturbation of caloric homeostasis.

• Under well-fed conditions, insulin/glucagon ratio is high and storage of

glycogen as well as triacylglycerol is higher. Conversely, under

starvation conditions there is low insulin/glucagon ratio which leads to

stimulation of glycogenolysis, gluconeogenesis, proteolysis, lipolysis and

increased production of ketone bodies.

• The mechanisms involved in regulation of mammalian fuel metabolism

are complex. These permit the body to respond efficiently to changes in

demands of energy and also accommodate the changes encountered in

availability of different types of fuels.


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• Various hormonal signals originating in digestive tract, muscle and

adipocytes are sent to hypothalamus; where they are integrated to

generate a neuronal or hormonal response to regulate the energy

consumption/expenditure.

• Glucose homeostasis is very important for maintenance of healthy

conditions. As human body is not equipped with an abundant glucose

reserve therefore physiological processes modulate the metabolism in

such a way that blood glucose levels are maintained within limits.

• Metabolic inter relations are altered during certain physiological

conditions such as exercise, pregnancy and lactation so that body is

able to meet the special requirements. These adaptations are in

response to the nutritional and hormonal changes during these

conditions.

13.9 TERMINAL QUESTIONS

1. Name:

i) The hormone which stimulates glycogenesis in liver under

conditions of plenty.

ii) The compound produced on lipolysis in adipose tissue that can

serve as a precursor for synthesis of glucose.

2. Explain the effect(s) of fall in blood glucose level on Insulin/glucagon

ratio.

3. Describe the metabolic changes occurring during fasting state of an

adult man.

4. What are ketone bodies? Mention two conditions that lead to their

increased production.

5. Arrange the following energy reserves (adult man) in a decreasing order:

Glucose (body fluids), Protein (muscle), Fat (adipose Tissue), Muscle

glycogen, liver glycogen.

6. Indicate the effect of glucagon hormone on following metabolic

processes: (a) Glycogen synthesis (liver), (b) Glycolysis (liver), (c) Fatty

acid mobilization (adipose tissue), (d) Gluconeogenesis (liver).

7. Give an account of different phases (phase I- V) of glucose homeostasis

as categorized by Cahill and his colleagues.

8. Discuss the crucial role of AMPK (AMP-activated protein kinase) in

energy homeostasis.

9. Write a short note on significance of leptin.

13.10 ANSWERS

Self-Assessment Questions

1. i) portal ii) α-cells iii) lipoprotein lipase iv) glycogenolysis

v) stimulates vi) increased vii) liver


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2. i) ATP

ii) less

iii) decreased

iv) ketone bodies

v) liver

vi) Stimulant

vii) small intestine

viii) pancreas

3. i) low

ii) muscle

iii) rises

iv) inhibits

v) activator

Terminal Questions

1. i) Insulin is released from β-cells of pancreas which stimulates

glycogenesis in liver under conditions of plenty (well fed state).

ii) Glycerol is one of the products of lipolysis .Through blood it is

transported to liver where it serves as a precursor of

gluconeogenesis.

2. When blood glucose levels fall during fasting, glucagon is released from

α-cells of pancreas. Insulin is secreted from pancreas under well fed

conditions. Hence, Insulin/glucagon ratio will be decreased when blood

glucose level is decreased.

3. Glucose is used as the important source of energy for most organs.

Much of the dietary glucose passes through liver to other organs

including brain (completely dependent on glucose), red blood cells &

renal medulla (both dependent on glycolysis). A number of metabolic

adaptations occur during fasting. Refer Section 13.4 for details.

4. Acetoacetate, β-hydroxybutyrate and acetone are collectively referred to

as ketone bodies. They are normally synthesized in small amounts in the

liver from acetylCoA but are overproduced during conditions like

fasting/starvation, diabetes. These are used as source of energy by

extrahepatic tissues and even brain adapts to using these when the

supply of glucose is significantly diminished. (Refer to section 13.4).

5. The order of energy reserves of a normal adult man in decreasing order

is: Fat (adipose Tissue) > Protein (muscle) > Muscle glycogen> liver

glycogen > Glucose (body fluids). Refer to table 13.2.


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6. Glucagon is secreted from α-cells of pancreas when the blood glucose

level goes down such as fasting. The effect of glucagon release on the

following processes is:

(a) Glycogen synthesis in the liver will be inhibited as glycogen synthase

will be phosphorylated and less active.

(b & d) Liver is major organ for gluconeogenesis and it will be stimulated

as enzymes linked with gluconeogenesis; PEP carboxykinase, FBPase-

2 will be active and those linked with glycolysis like pyruvate kinase and

PFK-1 will be inhibited.

(c) Fatty acid mobilization: lipolysis and ketogenesis dominates.

7. Refer Section 13.7 for the different phases (phase I- V) of glucose

homeostasis as categorized by Cahill and his colleagues.

8. AMPK is recognized as ‘Fuel Gauge’ of cells and a major regulator of

metabolic homeostasis. It monitors the energy and nutrient status in

individual cells and shifts the metabolism toward energy generation.

Refer Section 13.6 for details.

9. Leptin is considered as an important regulator of appetite/body mass. It

suppresses appetite; considered as a ‘satiety signal’. Refer to section

13.6 for more information.

INTEGRATION OF METABOLISM METABOLISM - eGyanKosh

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