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Chapter-06 Carbohydrates–III: Regulation of Blood Glucose: Diabetes Mellitus



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Regulation of Blood Glucose;
Insulin and Diabetes Mellitus
Chapter 11
Chapter at a Glance
The learner will be able to answer quesons on the following topics:
Factors maintaining blood glucose
Normal plasma glucose level
Eects of hormones on glucose level
Oral glucose tolerance test (OGTT)
Diagnosc criteria for diabetes mellitus
Impaired glucose tolerance
Reducing substances in urine
Benedict's test
Insulin, synthesis and secreon
Physiological acon of insulin
Diabetes mellitus types
Metabolic derangements in diabetes
Clinical aspects of diabetes mellitus
Laboratory invesgaons in diabetes
Glycated hemoglobin
Glucose level in blood is maintained within narrow
limits. This is a very nely and efciently regulated
system. It is essential to have continuous supply of
glucose to the brain. It can utilize ketone bodies to
some extent, but brain has an obligatory requirement
for glucose. Factors maintaining the blood glucose
are shown in Box 11.1 and Figures 11.1 and 11.3.
Post-prandial Regulation
Following a meal, glucose is absorbed from the
intestine and enters the blood. The rise in the blood
glucose level stimulates the secretion of insulin by
the beta cells of islets of Langerhans of pancreas.
The uptake of glucose by extrahepatic tissues, except
brain is dependent on insulin. Moreover, insulin helps
in the storage of glucose as glycogen or its conversion
to fat (Fig. 11.2A).
1. The plasma glucose level at an instant depends on the balance
between glucose entering and leaving the extracellular uid
2. Hormones maintain this balance (Fig. 11.1)
3. The major factors which cause entry of glucose into blood are:
a. Absorption from intestines
b. Glycogenolysis (breakdown of glycogen)
c. Gluconeogenesis
d. Hyperglycemic hormones (glucagon, steroids)
4. Factors leading to depletion of glucose in blood are:
a. Utilization by tissues for energy
b. Glycogen synthesis
c. Conversion of glucose into fat (lipogenesis)
d. Hypoglycemic hormone (insulin)
Box 11. 1. Factors maintaining blood sugar
Chapter 11: Regulation of Blood Glucose; Insulin and Diabetes Mellitus
Regulation in Fasting State
Normally, 2 to hours after a meal, the
blood glucose level falls to near fasting levels. It may
go down further; but this is prevented by processes
that contribute glucose to the blood. For another 3
hours, hepatic glycogenolysis will take care of the
blood sugar level. Thereafter, gluconeogenesis
will take charge of the situation (Figs 11.2A and B).
Liver is the major organ that supplies the glucose for
maintaining blood glucose level (Fig. 11.1). Hormones
like glucagon, epinephrine, glucocorticoids, growth
hormone, ACTH and thyroxine will tend to increase the
blood glucose level. They are referred to as anti-insulin
hormones or hyperglycemic hormones. An overview of
the regulatory mechanism is shown in Figure 11.3. Effects
of hormones are shown in Box 11.2.
Determination of Glucose in Body Fluids
Estimation of glucose is the most common analysis
done in clinical laboratories. The blood is collected
using an anticoagulant (potassium oxalate) and an
inhibitor of glycolysis (sodium uoride).
Fluoride inhibits the enzyme, enolase, and so
glycolysis on the whole is inhibited. If uoride is not
added, cells will utilize glucose and false low value
may be obtained. Capillary blood from nger tips may
also be used for glucose estimation by strip method.
Enzymatic Method
This is highly specic, giving ‘true glucose' values
(fasting 70–110 mg/dL). In the medical laboratory,
the GOD-POD (glucose oxidase peroxidase) method
Fig. 11.1: Homeostasis of blood glucose
Fig. 11.2A: Blood glucose regulation during fasting state (high
Glucagon). In fasting state, blood glucose level is maintained
by glycogenolysis and gluconeogenesis; further, adipose
tissue releases free fatty acids as alternate source of energy.
Red arrows indicate activation; blue arrow indicates inhibition
Fig. 11.2B: Blood glucose regulation during post-prandial state
(high Insulin). In post-prandiall state, glucose level is high; then
blood glucose level is lowered by tissue utilization, glycogen
syntheis and lipogenesis. Red arrows indicate activation; blue
arrow indicates inhibition
144 Textbook of Biochemistry
instrument is named as glucometer. It is useful
for patients to have self-analysis at home. But the
instrument is less accurate.
Commonly Employed Terms Regarding
1. Blood sugar analyzed at any time of the day,
without any prior preparations, is called random
blood sugar.
2. Glucose estimated in the early morning, before
taking any breakfast is called fasting blood
glucose. Fasting state means, glucose is
estimated after an overnight fast (12 hours after
the food) (post-absorptive state).
3. The test done about 2 hours after a good meal
is called post-prandial blood glucose (Latin =
after food).
4. When blood glucose level is within normal
limits, it is referred to as normoglycemia. When
values are above the normal range, it is known
as hyperglycemia. When values are below the
normal range, it is called hypoglycemia.
(Greek, hyper =above; hypo = below).
5. When the blood glucose is below 50 mg/dL, it is a
very serious condition. Hyperglycemia is harmful
in the long run; while hypoglycemia even for a
short while is dangerous, and may even be fatal.
6. The ability of a person to metabolize a given load
of glucose is referred to as glucose tolerance.
Fig. 11.3: Overview of regulation of blood sugar
A. Eect of insulin (hypoglycemic hormone)
1. Lowers blood glucose
2. Favors glycogen synthesis
3. Promotes glycolysis
4. Inhibits gluconeogenesis
B. Glucagon (hyperglycemic hormone)
1. Increases blood glucose
2. Promotes glycogenolysis
3. Enhances gluconeogenesis
4. Depresses glycogen synthesis
5. Inhibits glycolysis (Details given below)
C. Cortisol (hyperglycemic hormone)
1. Increases blood sugar level
2. Increases gluconeogenesis
3. Releases amino acids from the muscle
D. Epinephrine or Adrenaline (hyperglycemic)
1. Increases blood sugar level
2. Promotes glycogenolysis
3. Increases gluconeogenesis
4. Favors uptake of amino acids
E. Growth hormone (hyperglycemic)
1. Increases blood sugar level
2. Decreases glycolysis
3. Mobilizes fatty acids from adipose tissue
Box 11.2: Eects of hormones on glucose level in blood
is most commonly used to assess the blood glucose
level. The reaction generates a colour, which is read
in a photometer. The newer automated systems use
hexokinase method.
The above GOD reaction mixture is immobilized
on a plastic lm (dry analysis). The intensity of the
colour is measured by reectance photometry. The
Chapter 11: Regulation of Blood Glucose; Insulin and Diabetes Mellitus
Conducting the Glucose Tolerance Test
At about 8 am, a sample of blood is collected
in the fasting state. Urine sample is also obtained.
This is denoted as the "0" hour sample.
Glucose load dose: The dose is 75 g anhydrous
glucose (82.5 g of glucose monohydrate) in 250–300
mL of water. This dose is xed for an adult, irrespective
of body weight. (When the test is done in children, the
glucose dose is adjusted as 1.75 g/kg body weight).
In order to prevent vomiting, patient is asked to drink
it slowly (within about 5 minutes). Flavoring of the
solution will also reduce the tendency to vomit.
Sample collection: As per current WHO
recommendations, 2 samples are collected, one
at fasting ("0" hr sample) and 2-hour post-glucose
load. Urine samples may also be collected along with
these blood samples. This is sufcient to get a correct
assessment of the patient.
Normal Values and Interpretations
As per WHO recommendation, In a normal person,
fasting plasma glucose is 70–110 mg/dL. The present
day tendency is to view values above 100 mg/mL as
suspicious. Value more than 100 mg/dL is one of the
criteria for the metabolic syndrome.
Following the glucose load, in normal persons,
the level rises and reaches a peak within 1 hour
and then comes down to normal fasting levels by 2
to hours. This is due to the secretion of insulin
in response to the elevation in blood glucose. None
of the urine sample shows any evidence of glucose.
Diagnostic criteria for diabetes mellitus are given in
Table 11.1 and Box 11.3.
Classical Oral Glucose Tolerance Test (OGTT)
Glucose tolerance test is articial, because in day to
day life, such a large quantity of glucose does not enter
into blood. However, the GTT is a well-standardized
test, and is highly useful to diagnose diabetes mellitus
in doubtful cases.
Indications for OGTT
1. Patient has symptoms suggestive of diabetes
mellitus; but fasting blood sugar value is
inconclusive (between 100 and 126 mg/dL).
TABLE 11.1: The plasma sugar levels in OGTT in normal persons
and in diabetic patients
Normal persons Criteria for
Criteria for
Fasting < 110 mg/dL > 126 mg/dL 110 to 126
1 hr (peak)
after glucose
< 160 mg/dL Not prescribed Not
2 hr after
< 140 mg/dL > 200 mg/dL 140 to
199 mg/dL
1. If the fasting plasma sugar is more than 126 mg/dL, on more
than one occasion (Table 11.1)
2. Or, if 2-hr post-glucose load value of OGTT is more than 200
mg /dL (even at one occasion)
3. Or, if both fasting and 2-hr values are above these levels, on
the same occasion
4. If the random plasma sugar level is more than 200 mg/dL, on
more than one occasion. Diagnosis should not be based on a
single random test alone; it should be repeated
5. Glycated hemoglobin (Glyco-Hb) or HbA1c level more
than 6.5% at any occasion. As per the recommendations of
American Association of Clinical Chemistry and American
Diabetes Association, HbA1c level is the preferred method for
initial diagnosis of diabetes mellitus.
Box 11.3: Diagnostic criteria for diabetes mellitus
2. During pregnancy, excessive weight
gaining is noticed, with a past history of big
baby (more than 4 kg) or a past history of
mis carriage.
3. To rule out benign renal glucosuria.
4. GTT has no role in follow-up of diabetes. It is
indicated only for the initial diagnosis.
Preparation of the Patient
The patient is instructed to have good carbohydrate
diet for 3 days prior to the test. Patient should not take
food after 8 PM the previous night. Should not take
any breakfast. This is to ensure 12 hours fasting.The
patients are advised to remain in the hospital during
the waiting period of two hours without any active
exercise. Figure 11.4 represents the graph, when
plasma glucose values are plotted on the vertical axis
against the time of collection on the horizontal axis.
Causes for Abnormal GTT Curve
Impaired Glucose Tolerance (IGT)
146 Textbook of Biochemistry
It is otherwise called as Impaired Glucose Regulation
(IGR). Here blood sugar values are above the normal
level, but below the diabetic levels (Table 11.1).
In IGT, the fasting plasma glucose level is between
110 and 126 mg/dL and 2-hour post-glucose value is
between 140 and 200 mg/dL (Fig. 11.4).
Such persons need careful follow-up because IGT
progresses to frank diabetes at the rate of 2% patients
per year.
Impaired Fasting Glycemia (IFG)
In this condition, fasting plasma sugar is above normal
(between 110 and 126 mg/dL); but the 2-hour post-
glucose value is within normal limits (less than 140
mg/dL). These persons need no immediate treatment;
but are to be kept under constant check up.
Gestational Diabetes Mellitus (GDM)
This term is used when carbohydrate intolerance
is noticed, for the rst time, during a pregnancy. A
known diabetic patient, who becomes pregnant,
is not included in this category.
Women with GDM are at increased risk for
subsequent development of frank diabetes. GDM is
associated with an increased incidence of neonatal
mortality. Maternal hyperglycemia causes the fetus to
secrete more insulin, causing stimulation of fetal growth
and increased birth weight. After the child birth, the
women should be reassessed.
Alimentary Glucosuria
Here the fasting and 2-hour values are normal; but
an exaggerated rise in blood glucose following
the ingestion of glucose is seen. This is due to an
increased rate of absorption of glucose from the
intestine. This is seen in patients after a gastrectomy
or in hyperthyroidism.
Renal Glucosuria
Normal renal threshold for glucose is 175–180 mg/
dL. If blood sugar rises above this, glucose starts to
appear in urine.
Generally, the increased blood sugar level is
reected in urine. But when renal threshold is
lowered, glucose is excreted in urine. In these cases,
the blood sugar levels are within normal limits. This is
called renal glycosuria.
Renal threshold is lowered physiologically in
pregnancy. Renal glucosuria is associated with renal
diseases with renal tubular transport defects; e.g.
Fanconi's syndrome. In these cases glucosuria is
seen along with amino aciduria and phosphaturia.
In some cases, renal threshold may be increased
when glucose will not appear in urine, even though
blood sugar is elevated. Here GFR is decreased with
minimal or no impairment of tubular reabsorption. This
is seen in old age (arteriosclerosis) and in Kimmelsteil-
Wilson Syndrome (diabetic nephrosclerosis).
Factors Affecting GTT
In acute infections, cortisol is secreted, and so curve
is elevated and prolonged. In hyperthyroidism there
will be steep rise in curve. A at curve is seen in
Normally glucose is not excreted in urine. But if
blood sugar is more than 180 mg/dL, urine contains
glucose. The blood level of glucose above which
glucose is excreted is called renal threshold.
The excretion of reducing substances in urine is
detected by a positive Benedict's test. (See Chapter
7). About 0.5 mL of urine is boiled with 5 mL Benedict's
reagent for 2 minutes (or kept for 2 minutes in water
bath which is already boiling). The formation of a
precipitate is observed on cooling. The test is semi-
Fig. 11.4: Oral glucose tolerance test (OGTT)
Chapter 11: Regulation of Blood Glucose; Insulin and Diabetes Mellitus
quantitative and the color of the precipitate roughly
parallels the concentration of reducing sugar. Blue
color indicates the absence of sugar in urine. The
green precipitate means 0.5%; yellow (1%); orange
(1.5%) and red indicates 2% or more of sugar (1%
means 1 g per 100 mL). Nowadays, strips are
available, which when dipped in urine will give the
color, if it contains sugar.
Any reducing sugar will give a positive
Benedict's test. So differentiation of various
sugars, which may be present in urine has practical
importance. Such conditions together are sometimes
called as "mellituria". The substances in urine
answering Benedict's test are enumerated in Table
11.2. Differential diagnosis of a positive Benedict's test
is shown in Box 11.4.
When reducing sugars are excreted in urine, the
condition is referred to as glycosuria. To denote the
excretion of specic sugars the sufx ‘uria' is added
to the name of the sugar, e.g. glucosuria, fructosuria,
lactosuria. Glucosuria means glucose in urine;
glycosuria means any sugar in urine. Since glucose
is the most common reducing sugar excreted in urine,
the term glycosuria is often (though incorrectly) used
to denote the excretion of glucose.
When blood glucose level exceeds the renal
threshold (175–180 mg/dL), glucose is excreted in
urine. Diabetes mellitus is the most common cause.
Transient glucosuria may occur in some people
due to emotional stress. Excessive secretion of anti-
insulin hormones like cortisol (anxiety) and thyroid
hormone may cause glucosuria. Once the stress is
removed, the glucosuria disappears.
It is the second most common reducing sugar
found in urine. It is observed in the urine of normal
women during 3rd trimester of pregnancy and
lactation. The condition is harmless. In pregnancy, it
is important to distinguish lactosuria from glucosuria
when gestational diabetes mellitus is suspected.
Fructosuria, Galactosuria and pentosuria are
described in Chapter 12.
Historical Perspectives
The word "insulin" is derived from Latin, insula,
meaning island (islet). In 1869, Langerhans identied
the alpha and beta cells in islets of pancreas. In 1889,
von Mering and Minkowski produced experimental
diabetes by pancreatectomy. In 1922, Banting and
Best extracted insulin from pancreas. Insulin was
the rst hormone to be isolated in a pure form. They
injected the extract to a diabetic dog, Marjorie, who
was kept alive by regular insulin injections. For this
work Banting was awarded Nobel prize in 1923. But
Best was deleted in the list. As a compensation,
Banting declared that half his share of the prize will
go to Best. In 1954, Sanger studied the amino acid
sequence of insulin. For this work Sanger got Nobel
prize in 1958.
Structure of Insulin
Insulin is a protein hormone with 2 polypeptide chains.
The A chain has 21 amino acids and B chain has 30
amino acids. These two chains are joined together by
two interchain disulde bonds, between A7 to B7 and
A20 to B19. There is also an intrachain disulde link
in A chain between 6th and 11th amino acids (See
Chapter 4, Fig. 4.4).
Biosynthesis of Insulin
Insulin is a protein synthesized and secreted
by the beta-cells of the islets of Langerhans of the
pancreas. The insulin is synthesized as a larger
precursor poly peptide chain, the pre-pro-insulin. It
has 109 amino acids. It is rapidly converted to pro-
insulin in the endoplasmic reticulum by removal of
leader sequence of 23 amino acid residues. The pro-
insulin with 86 amino acids is transported to Golgi
apparatus where it is cleaved by a protease (Fig. 11.5).
Thus C-peptide or connecting peptide with 33 amino
acids is removed. (The number of amino acids in C
peptide may vary according to species). Insulin with
TABLE 11.2: Reducing substances in urine
Sugars Noncarbohydrates
Glucose Homogentisic acid
Fructose Salicylates
Lactose Ascorbic acid
Galactose pentoses Glucuronides of drugs
148 Textbook of Biochemistry
51 amino acids is thus formed.
Secretion of Insulin
Insulin secretion is in response to an elevation of
glucose level. The GLUT2 allows the entry of glucose
into the beta cell. Glucose is further metabolized
producing ATP. This closes potassium channels
and calcium channels. The inux of calcium causes
release of insulin into the blood. The insulin in turn
lowers glucose level. Insulin and C-peptide are
synthesized and secreted in equimolar quantities.
Therefore, measurement of C-peptide is an index of
rate of secretion of insulin.
Factors Increasing Insulin Secretion
1. Glucose: As blood glucose level increases, the
insulin secretion also correspondingly increases.
The mechanism has been described in previous
paragraph. Please see Fig.11.6.
2. Gastrointestinal hormones: Insulin secretion is
enhanced by secretin, pancreozymin and gastrin.
After taking food, these hormones are increased.
3. Proteins and amino acids: Leucine and arginine
are stimulants.
4. Drug: Tolbutamide.
5. Incretin hormones: The incretins are hormones
that work to increase insulin secretion.
Nutrient intake stimulates the secretion of the
gastrointestinal incretin hormones, glucagon-
like peptide-1 (GLP-1) and glucose-dependent
insulinotropic polypeptide (GIP). Glucose in the
small intestine stimulates incretin release. Incretin
stimulation of beta cells causes them to secrete
more insulin in response to the same amount of
blood glucose. Decreased responsiveness to
GIP and markedly reduced GLP-1 concentration
occur in individuals with type 2 diabetes mellitus
(DM). In such cases, administration of GLP-1
improves glycemic control.
Degradation of Insulin
Insulin is rapidly degraded by the liver. Plasma
half-life is less than 5 minutes. An insulin specic
protease (insulinase) is involved in the degradation
of insulin.
Mechanisms of Action of Insulin
Insulin Receptors
Insulin acts by binding to a plasma membrane
receptor on the target cells. Insulin receptor is
a glycoprotein with 4 subunits; 2 alpha and 2 beta
subunits. The alpha units (135 kD) are located on the
extracellular side, to which insulin binds. The beta
subunits (95 kD) are exposed on the cytoplasmic side
(Fig. 11.7). Beta subunit has tyrosine kinase activity
(receptor tyrosine kinase). In obesity, the number of
receptors are decreased and target tissue becomes
less sensitive to insulin (diabetes mellitus type 2).
Signal Transduction
Insulin binds to the alpha subunit of the receptor.
Oligomerization of alpha units would trigger the
tyrosine kinase activity of the beta subunit. The
phosphorylated sites act as docking sites for insulin
receptor substrates IRS1 and IRS2. This recruits
GLUT4 to cell surface and stimulate glycogen
Gene Transcription (New Enzyme Synthesis)
Insulin acts at the transcriptional level to regulate
synthesis of more than 100 proteins.
A. Insulin induces the following enzymes:
i. Glucokinase
ii. Pyruvate kinase
Frederick Banting
(Right) NP 1923
Charles Best
(left) 1899–1978
Marjorie (middle)
NP 1923
1918 - 2013
NP 1958
and 1980
von Mering
John Abel
Chapter 11: Regulation of Blood Glucose; Insulin and Diabetes Mellitus
iii. Phosphofructokinase
iv. Acetyl CoA carboxylase
B. Insulin represses the following enzymes:
i. Glucose-6-phosphatase
ii. Phosphoenolpyruvate carboxykinase
iii. Fructose-1,6-bisphosphatase
Activation of Enzymes
Insulin activates the existing molecules of enzymes
by covalent modication (phosphorylation or dephos-
phorylation). There are more than 50 enzymes ac-
tivated by this mechanism. A small selected list is
shown in Table 11.3.
Other effects
Insulin increases DNA synthesis, cell
growth and anabolism. Insulin inhibits glycogen
phosphorylase (see Chapter 10). Insulin
increases the recruitment of GLUT4 in cells.
Physiological Actions of Insulin
(Metabolic Effects of Insulin)
Insulin plays a central role in regulation of the
metabolism of carbohydrates, lipids and proteins
(Table 11.4).
Uptake of Glucose by Tissues
Insulin facilitates the membrane transport of
glucose. Facilitated diffusion of glucose in muscle
is enhanced by insulin. In diabetes mellitus, the
transporter, GLUT4 is reduced (see Chapter 10).
However, glucose uptake in liver (by GLUT2) is
independent of insulin.
Utilization of Glucose
Glycolysis is stimulated by insulin. The
activity and amount of key glycolytic enzymes
(glucokinase, phosphofructokinase and pyruvate
kinase) are increased. Glycogen synthase
enzyme is activated, and so insulin favors
glucose storage as glycogen (see Chapter 10).
Hypoglycemic Effect
Insulin lowers the blood glucose level by promoting
utilization and storage. Gluconeogenesis is inhibited
by insulin by repressing the key enzymes, pyruvate
carboxylase (PC) phosphoenolpyruvate carboxykinase
(PEPCK) and glucose-6-phosphatase (see Chapter
10). Insulin inhibits glycogenolysis by favoring the
inactivation of glycogen phosphorylase and inhibiting
glucose-6-phosphatase. The net effect of all these
three mechanisms, blood glucose level is lowered.
Lipogenesis is favored by providing more acetyl
CoA by pyruvate dehydrogenase reaction. Insulin
increases the activity of acetyl CoA carboxylase and
provides glycerol for esterication of fatty acids to TAG
(see Chapter 13). Insulin also provides NADPH by
increasing the GPD activity of the HMP shunt pathway.
Anti-lipolytic Effect
Insulin inhibits lipolysis in adipose tissue
due to inhibition of hormone sensitive lipase.
The increased level of FFA in plasma in diabetes is
due to the loss of this inhibitory effect on lipolysis.
Other General Effects
i. Insulin depresses HMG CoA synthase and so
ketogenesis is decreased. Insulin also favors
fatty acid synthesis from acetyl CoA. All these
factors reduce the availability of acetyl CoA, so
that production of ketone bodies reduced.
ii. Protein synthesis is promoted and degradation is
retarded. Insulin is an anabolic hormone.
Fig. 11.5: Insulin biosynthesis
150 Textbook of Biochemistry
iii. Insulin is an essential growth factor for all
mammalian cells. These effects are summarized
in Table 11.4.
1. Glucagon
2. Epinephrine or Adrenaline
3. Glucocorticoids
4. Adrenocorticotropic hormone (ACTH)
5. Growth hormone
6. Thyroxine
All these are anti-insulin hormones.
It is a polypeptide hormone with 29 amino acids.
It is secreted by the alpha cells of pancreas.
Enteroglucagon is a peptide hormone secreted by
duodenal mucosa, having same immunological and
physiological properties of glucagon. Glucagon is
synthesized as a longer proglucagon precursor. The
major regulator of secretion of glucagon is glucose.
An increase in blood glucose level inhibits secretion
of glucagon.
Physiological Actions of Glucagon
Glucagon is the most potent hyperglycemic hormone.
It is anti-insulin in nature. Therefore, the net effect
is decided by the insulin-glucagon ratio (Fig. 11.8).
Glucagon is mainly glycogenolytic. The active
form of glycogen phosphorylase is formed under the
inuence of glucagon. Liver is the primary target for
the glycogenolytic effect of glucagon. It depresses
glycogen synthesis. Gluconeogenesis is favored by
glucagon by inducing enzymes like PEPCK, glucose-
6-phosphatase and fructose-1,6-bisphosphatase.
Glucagon increases plasma free fatty acid level. In
adipose tissue glucagon favors beta-oxidation, as it
activates carnitine acyl transferase. The mitochondrial
acetyl CoA level increases. Ketogenesis is favored.
Mechanism of Action
Glucagon combines with a membrane bound receptor.
This activates G protein and adenylate cyclase
(See Chapter 45). Thus ATP is converted to cAMP.
Cyclic AMP activates glycogen phosphorylase, and
inactivates glycogen synthase.
Anti-insulin Hormones
Regulation of carbohydrate metabolism in
general depends on the balance between insulin and
anti-insulin hormones. A summary is given in Box 11.2.
See also Table 11.5. Glucocorticoids act mainly by
stimulating gluconeogenesis. But growth hormone
antagonizes insulin in many key metabolic reactions
(Table 11.5). Bernado Houssey demonstrated that in
pancreatectomised animals, the requirement of insulin
was about 100 units per day. When anterior pituitary
was also ablated in such animals, the requirement of
insulin came down to 10 units or so. This shows that
growth hormone antagonizes insulin. Houssay was
awarded Nobel prize in 1947.
Historical Perspectives
The term is derived from the Greek words dia
(=through), bainein (=to go) and diabetes literally
means pass through. The disease causes loss of
weight as if the body mass is passed through the
urine. The Greek word, mellitus, means sweet, as it
is known to early workers, that the urine of the patient
contains sugar. Diabetes mellitus is a disease known
from very ancient times. Charaka in his treatise (circa
400 BC) gives a very elaborate clinical description
Fig. 11.6: Mechanism of insulin secretion
Chapter 11: Regulation of Blood Glucose; Insulin and Diabetes Mellitus
of madhumeha (= sweet urine). He had the vision
that carbohydrate and fat metabolisms are altered
in this disease. In Western literature, Thomas Willis
in 1670 noticed the sweet taste of diabetic urine. In
1838, Bouchardt and Peligot proved that the sugar
of diabetic urine is the same as that present in grape
sugar. A crude test for urine sugar was rst developed
by Trommer in 1841. Qualitative test for urine sugar
was perfected by Hermann Fehling (1848) and semi-
quantitative test by Stanley Benedict (1908). Folin in
1919 identied a method for quantitative determination
of sugar in blood.
Diabetes mellitus is a metabolic disease due to
absolute or relative insulin deciency. Diabetes
mellitus is a common clinical condition. About 10% of
the total population, and about 1/5th of persons above
the age of 50, suffer from this disease. It is a major
cause for morbidity and mortality. Insulin deciency
leads to increased blood glucose level. In spite of this
high blood glucose, the entry of glucose into the cell is
inefcient. Hence all cells are starved for glucose.
Criteria for diagnosis of diabetes mellitus are
shown in Table 11.1, under glucose tolerance test.
The disease may be classied as follows (WHO
recommendation, 1999):
Type 1 Diabetes Mellitus
(formerly known as Insulin-dependent diabetes
mellitus; IDDM). About 5% of total diabetic patients
are of type 1. Here circulating insulin level is decient.
It is subclassied as:
a. Immune mediated and
b. Idiopathic.
Type 2 Diabetes Mellitus
(Formerly known as non-insulin dependent diabetes
mellitus; NIDDM). Most of the patients belong to this
type. Here circulating insulin level is normal or mildly
elevated or slightly decreased, depending on the
stage of the disease. This type is further classied as:
a. Obese
b. Non-obese
Diabetic Prone States
a. Gestational diabetes mellitus (GDM);
b. Impaired glucose tolerance (IGT);
c. Impaired fasting glycemia (IFG)
d. Metabolic syndrome (described below)
Secondary to Other Known Causes
a. Endocrinopathies (Cushing's disease,
thyrotoxicosis, acromegaly);
b. Drug induced (steroids, beta blockers, etc.);
c. Pancreatic diseases (chronic pancreatitis, bro-
calculus pancreatitis, hemochromatosis, cystic
d. Anti-insulin receptor autoantibodies (Type B
insulin resistance)
e. Mutations in the insulin gene or insulin receptor
gene (acanthosis nigricans)
Fig. 11.7: Insulin receptor
TABLE 11.3: Insulin acting through covalent modication
Enzyme Activity Mechanism
Glycogen synthase Increase Dephosphorylation
Pyruvate dehydrogenase Increase Dephosphorylation
Pyruvate kinase Increase Dephosphorylation
Acetyl CoA carboxylase Increase Dephosphorylation
HMG CoA reductase Increase Dephosphorylation
152 Textbook of Biochemistry
f. MODY (Maturity Onset Diabetes of Young).
MODY was previously considered to be a
third form of type 2 diabetes. However, with the
discovery of specic mutations leading to MODY, it
is now classied under secondary diabetes. MODY
is characterized by onset prior to age 25, impaired
beta cell function and insulin resistance. Mutations of
about 10 different genes have been correlated with
the development of MODY.
Type 1 Diabetes Mellitus (T1DM)
It is due to decreased insulin production. Circulating
insulin level is very low. These patients are dependent
on insulin injections. Onset is usually below 30 years
of age, most commonly during adolescence. They are
more prone to develop ketosis.
An autoimmune basis is attributed to most of
these cases. Circulating antibodies against insulin is
seen in 50% cases. Type 1 diabetes mellitus is an
autoimmune disease in which pathologic, autoreactive
T cells of the immune system attack the insulin-
secreting pancreatic islets of Langerhans. There is
excessive secretion of glucagon in IDDM patients.
Type 2 Diabetes Mellitus (T2DM)
95% of the patients belong to this type. The disease
is due to the decreased biological response to insulin,
otherwise called insulin resistance. So, there is a
relative insulin deciency. Type 2 disease is commonly
seen in individuals above 40 years. These patients are
less prone to develop ketosis. About 60% of patients
are obese. These patients have insulin resistance
and high/normal plasma insulin levels.
Insulin resistance develops as a consequence
of excess accumulation of fat in liver and skeletal
muscle. The free fatty acid level increases, exceeds
the capacity of mitochondrial oxidation and spills over
to cytoplasm where it is re-esteried. The consequent
increase in diacylglycerol (DAG), a second
messenger, leads to reduced signal transduction by
insulin leading to insulin resistance.
A high-caloric diet coupled with a sedentary
lifestyle are the major contributing factors in the
development of the insulin resistance. A major
susceptibility locus for type 2 diabetes, named as
NIDDM1, is located on chromosome 2. Lipoprotein
(a) or Lp(a) (see Chapter 15) is associated inversely
with risk of type 2 diabetes.
TABLE. 11.4: Biological eects of insulin
Metabolism Key enzyme Action of insulin on the enzyme Direct eect Overall eect
Carbohydrate Translocase
Pyruvate kinase
Pyruvate carboxylase
Glycogen synthase
Glycogen phosphorylase
Glycogen deposition
Generation of NADPH
Lipid Acetyl CoA carboxylase
Glycerol kinase
Hormone sensitive lipase
HMG CoA reductase
Lipogenesis favored
Lipolysis inhibited
Cholesterol synthesis
Glucose is used for lipogenesis;
glucose lowered Decreased
Protein Transaminases
Ornithine transcarbamoylase
RNA polymerase
and ribosome assembly
Catabolism inhibited
Protein synthesis
General anabolism
Chapter 11: Regulation of Blood Glucose; Insulin and Diabetes Mellitus
Metabolic Syndrome (MetS)
It is a combination of abdominal obesity,
atherogenic dyslipidemia (hypertriglyceridemia and
low HDL cholesterol), elevated blood pressure and
elevated plasma glucose. The characteristic features
are abdominal obesity, insulin resistance and
decreased glucose tolerance (Box 11.4). The body
cannot properly use glucose even in presence of
normal insulin level. In other words, body cannot use
insulin efciently. Therefore, the metabolic syndrome
is also called the insulin resistance syndrome.
People with MetS are at increased risk of coronary
heart disease and type 2 diabetes. The MetS has
become increasingly common in the developing
countries. Diagnostic criteria are shown in Box 11.4.
Abdominal obesity is the most prevalent
manifestation of metabolic syndrome. Obesity and
adipocytokines are discussed in Chapter 35.
Metabolic Syndrome (MetS) and Polycystic Ovary
Syndrome (PCOS)
They have overlapping features. The common
factors are insulin resistance and obesity. In PCOS
there is hyperandrogenism. Those with PCOS have
an increased risk for coronary vascular disease as
in patients with MetS. Overweight adolescents with
PCOS are at increased risk of developing impaired
glucose tolerance and type 2 diabetes mellitus.
Pathological Alterations in Diabetes
Derangements in Carbohydrate Metabolism
Insulin deciency decreases the uptake of glucose
by cells. The insulin dependent enzymes are also
less active. Net effect is an inhibition of glycolysis
and stimulation of gluconeogenesis leading to
Derangements in Lipid Metabolism
Enhanced lipolysis leads to high FFA levels
in plasma and consequent accumulation of fat in liver
leading to NAFLD (Non alcoholic fatty liver disease).
More acetyl CoA is now available, which cannot
Fig. 11.8: Combined action of insulin and glucagon will keep
the blood sugar level within normal limits. High blood sugar
stimulates insulin secretion (yellow pathway). Low blood sugar
causes glucagon secretion (blue pathway)
NP 1947
von Fehling
Otto Olof
Stanley Rossiter Benedict (1884–1936) discovered
the Benedict's Reagent in 1908, while working as
a PhD student at Yale University. He was Profes-
sor of Physiological chemistry in Cornell University
Medical College from 1912 till death.
i. Elevated waist circumference: (For men >90 cm and for
women, >80 cm).
ii. Elevated triglycerides: >150 mg/dL
iii. Reduced HDL (“good”) cholesterol: For men, <40 mg/dL; for
women, < 50 mg/dL
iv. Elevated blood pressure: >130/85 mm Hg
v. Elevated fasting glucose: >100 mg/dL
vi. Insulin resistance (hyperinsulinemia)
vii. Additional parameters include coagulation abnormalities,
hyperuricemia, microalbuminuria non-alcoholic steato-
hepatitis (NASH) and increased CRP
viii. Diagnosis is made, if the rst criterion and any two of other
criteria are present.
Box 11. 4. Criteria for diagnosis of metabolic syndrome
154 Textbook of Biochemistry
be efficiently oxidized by TCA cycle, because the
availability of oxaloacetate is limited. The stimulation
of gluconeogenesis is responsible for the depletion of
oxaloacetate. The excess of acetyl CoA therefore, is
diverted to ketone bodies, leading to ketogenesis (see
Chapter 13). This tendency is more in type 1 disease.
There is hyperlipi demia, especially an increase in
NEFA, TAG and cholesterol in plasma.
Derangement in Protein Metabolism
Increased breakdown of proteins and amino acids
for providing substrates for gluconeogenesis is
responsible for muscle wasting.
Clinical Presentations in Diabetes
The cardinal symptoms of diabetes mellitus are
glucosuria, polyuria, polydypsia and polyphagia.
When the blood glucose level exceeds the renal
threshold glucose is excreted in urine (glucosuria).
Due to osmotic effect, more water accompanies
glucose (polyuria). To compensate for this loss of
water, thirst center is activated, and more water is
taken (polydypsia). To compensate the loss of glucose
and protein, patient will take more food (polyphagia).
The loss and ineffective utilization of glucose
leads to breakdown of fat and protein. This would lead
to loss of weight. Important differential diagnosis for
weight loss are diabetes mellitus, tuberculosis, hyper-
thyroidism, cancer and AIDS. Often the presenting
complaint of the patient may be chronic recurrent
infections, such as boils, abscesses, etc. Any person
with recurrent infections should be investigated for
diabetes. When glucose level in extracellular uid is
increased, bacteria get good nutrition for multiplication.
At the same time, macrophage function of the host is
inefcient due to lack of efcient utilization of glucose.
In India, tuberculosis is commonly associated with
Diabetic Keto Acidosis
Ketosis is more common in type 1 diabetes mellitus.
Ketone body formation and explanations for ketosis
are described in Chapter 13. Normally the blood level
of ketone bodies is less than 1 mg/dL and only traces
are excreted in urine (not detectable by usual tests).
But when the rate of synthesis exceeds the ability
of extrahepatic tissues to utilize them, there will be
accumulation of ketone bodies in blood. This leads
to ketonemia, excretion in urine (ketonuria) and
smell of acetone in breath. All these three together
constitute the condition known as ketosis.
TABLE 11.5: Comparison of action of insulin and anti-insulin hormones
Metabolism Key enzymes Insulin Glucagon Glucocorticoids Growth hormone
Glycolysis GK, PFK and PK Stimulation Inhibition
Gluconeogenesis PEPCK, G6 Pase,
Inhibition Stimulation Stimulation Stimulation
Glycogen synthesis Glycogen
Activation Inhibition
Glycogenolysis Phosphorylase Inactivation Activation
Lipolysis Hormone
sensitive lipase
Inhibition Stimulation Stimulation Stimulation
Ketogenesis Carnitine acyl
Inhibition Stimulation Stimulation
Protein breakdown Transaminases Inhibition Stimulation
Protein synthesis Anabolism Catabolism Anabolism
Blood sugar level Decreases Increases Increases Increases
Chapter 11: Regulation of Blood Glucose; Insulin and Diabetes Mellitus
Diagnosis of Ketosis
Ketone body formation, causes of ketosis, clinical
features and management of ketosis are elaborted in
Chapter 13.
Lactic Acidosis
It is another acute complication. It occurs due to
over- production and or under-utilization of lactic
acid. Overproduction can result from an increased
rate of anaerobic glycolysis due to hypoxia. Under-
utilization may be due to impairment of TCA cycle.
Lactic acidosis is seen when diabetic patients are
treated with biguanides. This drug inhibits TCA cycle
and gluconeogenesis (Box 11.5).
Chronic Complications of Diabetes
When there is hyperglycemia, proteins in the body
may undergo glycation. It is a non-enzymatic process.
Glucose forms a Schiff base with the N-terminal
amino group of proteins. The glycation rst occurs
in circulating proteins like hemoglobin, albumin and
LDL and then to extracellular proteins. The advanced
glycation end products (AGE) deposition in tissues
and endothelium lead to all the chronic complications
of diabetes mellitus.
Vascular diseases: Atherosclerosis in medium
sized vessels, plaque formation and consequent
intravascular thrombosis may take place. If it occurs
in cerebral vessels, the result is paralysis. If it is in
coronary artery, myocardial infarction results. In the
case of small vessels, the process is called micro-
angiopathy, where endothelial cells and mural
(cement) cells are damaged. Microangiopathy may
lead to diabetic retinopathy and nephropathy.
Complications in eyes: Early development of
cataract of lens is due to the increased rate of
sorbitol formation, caused by the hyper glycemia.
Retinal mic ro vascular abnormalities lead to
retinopathy and blindness.
Neuropathy: Peripheral neuropathy with paresthesia
is very common. Decreased glucose utilization and
its diversion to sorbitol in Schwann cells may be one
cause for neuropathy. Another reason proposed is
the production of advanced glycation end products.
Neuropathy may lead to risk of foot ulcers and
gangrene. Hence, care of the feet in diabetic patients
is important.
Kimmelsteil-Wilson syndrome is another
complication of diabetes, resulting from
nephrosclerosis, characterized by proteinuria and
renal failure. Persistent hyperglycemia leading to
glycation of basement membrane proteins may be
the cause of nephropathy.
Lactate is the normal end product of anaerobic glycolysis. All
tissues can produce lactate and liver can metabolise it. The
blood level seldom exceeds 1.5 mmol/L. Under conditions of
decreased oxygen availability, as in vigourous excercise, the
rate of lactate production increases. Te term lactic acidosis
denotes a pathological state, when the lactate level in blood is
more than 5 mmol/L. So blood pH is low, with decreased levels
of bicarbonate. Collection of blood for lactate estimation has
to be done avoiding tissue hypoxia, so that falsely elevated
values are not obtained.
Box 11.5. What is lactic acidosis?
Fig. 11.9: Metabolic derangements in diabetes mellitus
156 Textbook of Biochemistry
Pregnancy: Diabetic mothers tend to have big babies,
because insulin is an anabolic hormone. Chances of
abortion, premature birth and intrauterine death of
the fetus are also more, if the diabetes is not properly
Hyperosmolar Nonketotic Coma
It can result due to elevation of glucose to very high
levels (900 mg/dL or more). This would increase
the osmolality of extracellular uid (ECF). Osmotic
diuresis leads to water and electrolyte depletion. The
coma results from dehydration of cerebral cells due to
hypertonicity of ECF.
Laboratory Investigations in Diabetes
Random blood sugar estimation and oral glucose
tolerance tests are used for the diagnosis (Table 11.1).
Blood Glucose Level
For monitoring a diabetic patient, periodic check
of fasting and post-prandial blood glucose are to
be done. Blood glucose level has to be maintained
within the normal limits. Persistent hyperglycemia
is the most important factor, which leads to chronic
Glycated Hemoglobin
The best index of long-term control of blood glucose
level is measurement of glycated hemoglobin or
glycohemoglobin. Enzymatic addition of any sugar
to a protein is called "glycosylation", while non-
enzymatic process is termed "glycation". When once
attached, glucose is not removed from hemoglobin.
Therefore, it remains inside the erythrocyte, throughout
the lifespan of RBCs (120 days) (Fig. 11.10). The
glycated hemoglobins are together called HbA1
fraction. Out of this 80% molecules are HbA1c, where
glucose is attached to the N-terminal valine of beta
chain of hemo globin.
Interpretation of Glycohemoglobin
The determination of glycated hemoglobin is not for
diagnosis of diabetes mellitus; but only for monitoring
the response to treatment. The Hb A1c level reveals
the mean glucose level over the previous 10–12
weeks. It is unaffected by recent food intake or recent
changes in blood sugar levels. The estimation should
be done at least every 3 months in all diabetic patients;
however, it is better to do once in every month, so
as to analyze the effectiveness of the treatment.
Normally the level of Hb A1c
is less than 5.5%. The value 5.5% denotes very good
control of diabetes by treatment measures; 7% means
adequate control; 8% inadequate control and 9%
means very poor control. Any value above 5.5% is to
be closely watched and values between 5.6 and 6.4
are to be considered as impaired glucose tolerance.
6.5% and above means the person is diabetic. An
elevated glycohemoglobin indicates poor control of
diabetes mellitus. The risk of retinopathy and renal
complications are proportionately increased with
elevated glycated hemoglobin value. Reduction in 1%
of glycoHb will decrease long-term complications to
an extent of 30%.
Advantages of HbA1c over fasting blood sugar
estimation are (1) For HbA1c, fasting sample is not
required; the test may be done at any time. This adds
convenience to the patient . ( 2) HbA1c sampl e
is stable; while blood sugar level is lowered during
transportation to laboratory, unless precautions are
taken. (3) HbA1c reects long-term glucose control,
while blood sugar estimation will show the result of
a particular time only. (4) HbA1c is a better index for
predicting complications. Because of all these reasons,
HbA1c has become the preferred test nowadays.
Disadvantage of HbA1c estimation
Any type of anemia, (e.g., abnormal hemoglobins,
hemoglobinopathies) where RBC life span is reduced,
will reect in lowered HbA1c value, because the time
averaged value is less.
How frequently the estimation to be done?
Fig. 11.10: Glycation is parallel to the blood glucose
Chapter 11: Regulation of Blood Glucose; Insulin and Diabetes Mellitus
HbA1c estimation indicates the average blood
glucose concentration for the past 120 days (life span
of RBCs). However, the value is weighted towards the
younger RBCs. About half of the value is contributed
by the RBCs of the age of 1 month or less. Therefore,
it is ideal to repeat the test every month. This will give
an idea to the physician that the treatment is effective
or not.
Along with other proteins, albumin is also glycated in
diabetes mellitus. Glycated albumin is more correctly
called as fructosamine albumin. As half-life of albumin
is about 20 days, gluco-albumin concentration reects
the glucose control over a recent past, for a period
of last 2–3 weeks. Estimation of serum fructosamine
is preferred in gestational diabetes mellitus. It is
also useful in cases of decreased life span of RBCs
(e.g., anemias), where HbA1c estimation will give
erroneous answer.
Complete Lipid Prole
Total cholesterol, triglycerides, HDL and LDL cholesterol
levels may be done once in 6 months (see Chapters 14
and 15).
Kidney Function Tests
Blood urea and serum creatinine may be done at
least twice an year (see Chapter 25).
Micro-albuminuria and Frank Albuminuria
Presence of albumin (50 to 300 mg/day) in urine is
known as micro-albuminuria (see Chapter 25). It is
a predictor of progressive renal damage. Albumin
more than 300 mg/day indicates overt diabetic
nephropathy. Micro-albuminuria is to be checked at
least once in an year.
Management of Diabetes Mellitus
Diet and exercise: This is the rst line of treatment. A
diabetic patient is advised to take a balanced diet with
high protein content, low calories, devoid of rened
sugars and low saturated fat, adequate PUFA, low
cholesterol and sufcient quantities of ber. Vegetables
are the major sources of minerals, vitamins and ber.
Alpha glucosidase inhibitor, acarbose inhibits the
alpha-glucosidases present in the small intestinal
brush border. So absorption of glucose is reduced.
This allows the pancreas to more effectively regulate
insulin secretion.
Oral hypoglycemic agents: There are several types
of oral hypoglycemic agents (OHA) now in use. The
conventional types are sulfonylurea and biguanides
(Metformin) used in type 2 DM. Other groups include
glitazones, dipeptidyl peptidase inhibitors, which are
often combined with the conventional drugs.
Insulin injections: Insulin is the drug of choice
in type 1 disease. It is also used in type 2 disease, where
oral drugs are not sufcient. The availability of human
insulin prepared by recombinant DNA technology
has markedly improved the response of patients.
Prevention of complications.
Hyperglycemia causes harm; but hypoglycemia is
fatal. A fall in plasma glucose less than 50 mg/dL is
life-threatening (Fig. 11.11). Causes of hypoglycemia
1. Overdose of insulin: This is the most common
cause. The differentiation of hypoglycemic coma
from hyperglycemic coma (ketosis) is important,
since treatment is exactly opposite. The diagnosis
is mainly based on blood glucose estimation.
Fig. 11.11: Hypoglycemia is fatal
158 Textbook of Biochemistry
2. Post-prandial hypoglycemia: 2–3 hours after
a meal, transient hypoglycemia is seen in some
persons. This is due to over-secretion of insulin.
3. Insulinoma: Insulin secreting tumors are rare.
4. Von Gierke's disease (see Chapter 10).
Clinical Case Study 11.1
A 45-year-old obese male had a tooth infection. Prior
to extraction he was advised to have a routine blood
and urine examination. The results were:
Total WBC count: 35,000/cmm
Differential count: P70, L20, E7, M2, B1
ESR: 45 mm/hr
Urine albumin: Trace
Urine sugar: Orange precipitate
Urine ketone bodies: Nil
Urine bile salts: Nil
Urine bile pigments: Nil.
A. What are the further investigations to be done in
this patient? Explain the rationale behind each
B. When the diagnosis is conrmed and treatment
started, how will you monitor the patient?
C. What are the possible complications that can be
avoided by proper monitoring of the patient?
Clinical Case Study 11.2
A person is brought to the Emergency Department
in a comatose state. The following test results were
obtained Blood sugar – 400 mg%, Benedict’s test
(Urine) – Red precipitate, Rothera’s test (Urine) –
Positive, Serum Bicarbonate – 12 mEq/L, Plasma pH
– 7.14. What is your probable diagnosis?
Clinical Case Study 11.3
A person is brought to the Emergency Department
in a comatose state. The following test results were
obtained Blood sugar – 40 mg%, Benedict’s test
(Urine) – Negative, Rothera’s test (Urine) – Negative,
Serum Bicarbonate 12 mEq/L, Plasma pH 7.14.
What is your probable diagnosis?
Clinical Case Study 11.4
A 19-year-old with 4 year history of juvenile diabetes
mellitus was brought to the Emergency Department
in state of coma. The following laboratory results
were obtained Blood sugar 1300 mg%, Plasma
pH – 7.1, pCO2 13 mm Hg, Pulse rate – 120/min,
Respiratory rate – 28/min. What is your probable
diagnosis? What is the pathophysiology of the above
Clinical Case Study 11.5
A 55-year-old man with long standing diabetes
mellitus presented with fever, pruritis, delirium and
low urine output. His blood urea level was 135 mg%
and urea clearance was 35 mL/min. What is the most
likely diagnosis?
Clinical Case Study 11.6
A 52-year-old woman with a medical history of
hepatitis B, hyperlipidemia, hypertension and
anemia, presented to the medicine department
for a routine visit. Laboratory tests 3 months
previously had revealed an impaired fasting
glucose concentration of 118 mg/dL) [reference
interval, 70–110 mg/dL]. Therefore, a hemoglobin
HbA1c analysis was performed. The initial HbA1c
evaluation by HPLC showed an HbA1c value of
12.8% (reference interval, 4.0–5.5.0%). What are
the various types of methods used for measuring
HbA1c? How do Hb variants interfere with each of
these HbA1c methods? What actions should be
taken when a spurious HbA1c result is present?
Clinical Case Study 11.7
A 40-year-old male was brought to the emergency
room complaining of dizziness and weakness. History
revealed that he had skipped breakfast. Random
blood sugar value was 40 mg%. What is the probable
Clinical Case Study 11.8
A 40-year-old man presented with complaints of
frequent episodes of dizziness and numbness in
legs. On examination, he is obese, leads a sedentary
lifestyle, has a BP of 200/120 mm Hg, has fasting
hyperglycemia, hyperinsulinemia, dyslipidemia and
glucose intolerance. What is the diagnosis? What is
the pathogenesis involved?
Chapter 11: Regulation of Blood Glucose; Insulin and Diabetes Mellitus
Clinical Case Study 11.9
A 30-year old woman during her second pregnancy
had a glucose tolerance test and the results are:
Fasting glucose level: 125 mg/dL
1 hr glucose level: 210 mg/dL
2 hr value: 170 mg/dL.
A. Plot a GTT graph with these results.
B. Comment on the GTT results.
C. What will be the result of Benedict’s test with the
urine sample collected along with each blood
D. How will you follow up the patient?
E. What is the importance of assessing the glucose
tolerance in a pregnant lady?
F. How do you rule out lactosuria in this case?
Clinical Case Study 11.10
An apparently healthy man, on a routine checkup,
was found to have fasting blood sugar of 80 mg/dL,
and urine showed no abnormal constituents. After
a heavy breakfast of one-and-half hours, his blood
sugar was 140 mg/dL and urine sample at that time
was positive for Benedict’s test.
A. What is the diagnosis?
B. How do you further investigate?
C. What is the line of treatment?
D. What is the course of this disease?
Clinical Case Study 11.1 Answer
Likely diagnosis is uncontrolled diabetes mellitus.
Often, diabetes is noticed by a routine urine
examination. Fasting and postprandial blood sugar
should be estimated on this patient (See chapter 24
for further details).
Clinical Case Study 11.2 Answer
Diabetic ketoacidosis (DKA).
Clinical Case Study 11.3 Answer
Starvation ketosis.
Clinical Case Study 11.4 Answer
Diabetic ketoacidosis (DKA).
Clinical Case Study 11.5 Answer
Diabetic nephropathy.
Clinical Case Study 11.6 Answer
In an effort to determine if the unusual HbA1c result
was due to potential hemoglobinopathies, Hb variant
analysis was done and presence of HbS and HbF
identied. In this particular case, increased HbF
caused the abnormal HbA1c value. HbA1c assays
can be divided into methods that use molecular
charge (HPLC and electrophoresis) and methods
that use molecular structure (immunoassays). Hb
variants (or their glycated forms) may interfere with
HbA1c assays based on HPLC and electrophoresis
by coeluting/comigrating with Hb A and/or HbA1c.
When a spurious HbA1c result is obtained, the
possibility of interference by Hb variants should
be considered, Fructosamine and daily testing of
glucose may be used to monitor glycemic control.
These alternative tests may also be used for
patients who have an altered erythrocyte lifespan
and changes in the degree of glycation. HbA1c
testing cannot be used for these individuals.
Clinical Case Study 11.7 Answer
Patient has hypoglycemia, probably due to fasting.
Under physiological conditions, brain derives fuel
from glucose. Hypoglycemia is considered when
blood glucose falls to below 60 mg%. Symptoms
begin at this concentration of glucose; brain
symptoms appear when glucose level falls below 50
mg%. CNS symptoms include behavioral changes,
confusion, fatigue, seizures, loss of consciousness,
and if severe and prolonged, death.
Spontaneous hypoglycemia may be (1) fasting,
and (2) postprandial. Fasting hypoglycemia may
be subacute or chronic and usually presents with
neuroglycopenia. Post-prandial hypoglycemia is
usually acute and symptoms of neurogenic autonomic
discharge like sweating, palpitations, anxiety and
tremulousness are seen.
There are many causes for hypoglycemia. Fasting
hypoglycemia may be due to drugs (e.g. insulin),
critical illness (hepatic, renal and cardiac, sepsis),
endocrine problems, insulinoma, endogenous
hyperinsulinism, other β cell disorders, autoimmune
160 Textbook of Biochemistry
disorders and certain inborn errors of metabolism.
Post-prandial hypoglycemia may be due to alimentary
(post-gastrectomy), galactosemia, hereditary fructose
intolerance and idiopathic.
Treatment of hypoglycemia is oral glucose or IV
Clinical Case Study 11.8 Answer
The patient has “insulin resistance syndrome” or
metabolic syndrome. Metabolic syndrome is multi-
factorial in origin; there are 6 major factors involved,
abdominal obesity, atherogenic dyslipidemia,
hypertension, insulin resistance (with or without the
presence of glucose intolerance), proinammatory
state and prothrombotic state.
The defect may be due to; (1) Prereceptor
pathology —mutations in insulin molecule, anti-
insulin antibodies, (2) receptor defects—decreased
number of receptors, reduced insulin binding,
insulin receptor mutations, insulin receptor blocking
antibodies, (3) postreceptor defects— defective signal
transduction, mutations in GLUT4, (4) combination of
defects, (5) other pathologies—Werner syndrome,
ataxia telangiectasia, lipodystrophic states, etc. (6)
increased production of insulin antagonists, and (7)
glucose intolerance.
Other laboratory tests helpful are apoB, hs-CRP,
brinogen, uric acid, urine microalbumin and liver
function tests. Treatment includes treating insulin
resistance, lipid abnormalities, prothrombotic state,
hypertension, impaired fasting glucose and lifestyle
modications. Diet and exercise are the keystones to
the clinical management.
Clinical Case Study 11.9 Answer
Gestational diabetes mellitus (see Chapter 24).
Clinical Case Study 11.10 Answer
Renal glycosuria. Normal renal threshold for glucose
is 180 mg/dL, (see Chapter 24).
1. Major factors that cause entry of glucose
into blood are; absorption from intestines,
glycogenolysis and gluconeogenesis.
2. Major factors that cause depletion of glucose in
blood are; utilization by tissues, glycogenesis
and conversion to fat.
3. Hyperglycemic hormones are Glucagon, Cortisol,
Adrenaline and Growth hormone. Insulin is a
hypoglycemic hormone.
4. Indications for an oral glucose tolerance test
(OGTT) are; patient with symptoms suggestive
of diabetes mellitus, excess weight gain during
pregnancy and to rule out benign glycosuria.
5. Contraindications for an OGTT are; known
case of diabetes mellitus, to follow prognosis of
diabetes mellitus and performing on acutely ill
6. Conditions that can be assessed by OGTT are
impaired glucose tolerance, impaired fasting
glycemia, gestational diabetes, alimentary
glucosuria and renal glucosuria.
7. Reducing substances in urine other than glucose
are fructose, lactose, galactose, pentoses,
homogentisic acid, salicylates, glucuronides and
ascorbic acid.
8. Insulin has the following biochemical effects:
increases uptake of glucose by cells, enhances
utilization of glucose, hypoglycemic, antilipolytic,
antiketogenic and favors lipogenesis.
9. Insulin acts via a specic insulin receptor present
on cells of insulin responsive tissues. This affects
a signal transduction pathway, which leads to
regulation of gene transcription, DNA synthesis
and activation of enzymes.
10. Diabetes mellitus is of two types, Type 1 and Type
2. Type 1 is also known as insulin dependent
(IDDM), while the type 2 was previously known
as non-insulin dependent diabetes mellitus
11. Secondary diabetes mellitus can be; manifested
in endocrine disorders (Cushing’s syndrome,
Thyrotoxicosis), drug induced (beta blockers,
steroids), seen in pancreatic diseases (chronic
12. Diabetic ketoacidosis (DKA), lactic acidosis and
hypoglycemia are acute metabolic complications
of diabetes mellitus.
13. Retinopathy, neuropathy and vascular diseases
are chronic complications of diabetes mellitus.
14. Glycated hemoglobin (HbA1c) is used as an
index for long-term control of blood glucose level.
L’hyperglycémie chronique est impliquée dans le développement de complications associées au DT2 et la variabilité glycémique (VG) apparait comme une composante à part entière de l'homéostasie du glucose. Les mesures hygiéno-diététiques, en première ligne dans la prise en charge du DT2, passent entre autres par une modification de l’alimentation, dans laquelle les glucides occupent une place prépondérante. Au-delà de la quantité, la qualité des glucides a été mise en avant comme ayant un impact déterminant sur les excursions glycémiques. Notamment, la digestibilité des produits à base d’amidon pourrait alors avoir un impact sur le contrôle glycémique chez les patients atteints de DT2. Mais il y a aujourd’hui un réel besoin d’apporter une caractérisation des produits plus complète sur cet aspect et de mener des études de faisabilité et d’efficacité de tels régimes modulant la digestibilité de l’amidon. Mes travaux de thèse montrent qu’il est possible de concevoir un régime riche en amidon lentement digestible (SDS), grâce à des choix de produits amylacés disponibles dans le commerce, des conseils de cuisson et des recommandations adaptées. Pour la première fois, nous avons montré que le contrôle de la digestibilité de l'amidon de produits amylacés avec des instructions de cuisson appropriées dans une population atteinte de DT2 augmentait la consommation de contenu en SDS dans un contexte de vie réelle et que ce type de régime était bien accepté dans telle population. De plus, nous avons montré que l’augmentation du rapport SDS/glucides était associée à une amélioration du contrôle glycémique postprandial et qu’il existait une corrélation linéaire inverse entre les paramètres de VG et la teneur en SDS. La mise en œuvre d’un régime riche en amidon lentement digestible dans une population atteinte de DT2, a montré une différence significative sur le profil de variabilité glycémique, mais également sur les excursions glycémiques postprandiales, évalués par le CGMS, en comparaison avec un régime pauvre en amidon lentement digestible. Ce type de régime a également permis aux patients d’atteindre des cibles glycémiques postprandiales plus appropriées. Grâce à un travail de revue de la littérature, nous avons mis en évidence que la déviation standard (SD), le coefficient de variation (CV), l’amplitude moyenne des excursions glycémiques (MAGE) et la moyenne glycémique (MBG) étaient les paramètres de VG les plus étudiés en termes de relation avec les paramètres de diagnostic du DT2 et les complications liées au DT2 et qu’ils montraient des relations fortes, en particulier avec l’HbA1c. Dans les études interventionnelles, nous avons pu voir que la SD, le MAGE et le temps dans la cible (TIR) étaient les paramètres les plus utilisés comme critères d’évaluation, montrant des améliorations significatives suite aux interventions pharmacologiques ou nutritionnelles, souvent en lien avec des paramètres de contrôle glycémique comme l’HbA1c, la glycémie à jeun ou en postprandial. La VG apparaît donc comme une composante clé de la dysglycémie du DT2. Au-delà de son utilisation par le patient comme support du contrôle glycémique, le CGMS apparait comme un outil pertinent en recherche clinique pour évaluer l’efficacité des interventions même si à ce jour, il reste encore très peu utilisé pour les interventions nutritionnelles. Des études plus approfondies seront cependant nécessaires pour confirmer l'impact bénéfique de telles interventions alimentaires à long terme. Nous avons conçu une étude à plus grande échelle pour étudier l'impact à long terme d’un régime riche en SDS sur la variabilité et le contrôle glycémiques (CGMS) et les complications et comorbidités associées chez le patient atteint de DT2. La modulation de la digestibilité de l'amidon dans l'alimentation pourrait alors être utilisée comme un outil nutritionnel simple et approprié pour améliorer l'homéostasie glucidique au quotidien dans le DT2.
Full-text available
Glycemic variability (GV) appears today as an integral component of glucose homeostasis for the management of type 2 diabetes (T2D). This review aims at investigating the use and relevance of GV parameters in interventional and observational studies for glucose control management in T2D. It will first focus on the relationships between GV parameters measured by continuous glucose monitoring system (CGMS) and glycemic control and T2D-associated complications markers. The second part will be dedicated to the analysis of GV parameters from CGMS as outcomes in interventional studies (pharmacological, nutritional, physical activity) aimed at improving glycemic control in patients with T2D. From 243 articles first identified, 63 articles were included (27 for the first part and 38 for the second part). For both analyses, the majority of the identified studies were pharmacological. Lifestyle studies (including nutritional and physical activity-based studies, N-AP) were poorly represented. Concerning the relationships of GV parameters with those for glycemic control and T2D related-complications, the standard deviation (SD), the coefficient of variation (CV), the mean blood glucose (MBG), and the mean amplitude of the glycemic excursions (MAGEs) were the most studied, showing strong relationships, in particular with HbA1c. Regarding the use and relevance of GV as an outcome in interventional studies, in pharmacological ones, SD, MAGE, MBG, and time in range (TIR) were the GV parameters used as main criteria in most studies, showing significant improvement after intervention, in parallel or not with glycemic control parameters’ (HbA1c, FBG, and PPBG) improvement. In N-AP studies, the same results were observed for SD, MAGE, and TIR. Despite the small number of N-AP studies addressing both GV and glycemic control parameters compared to pharmacological ones, N-AP studies have shown promising results on GV parameters and would require more in-depth work. Evaluating CGMS-GV parameters as outcomes in interventional studies may provide a more integrative dimension of glucose control than the standard postprandial follow-up. GV appears to be a key component of T2D dysglycemia, and some parameters such as MAGE, SD, or TIR could be used routinely in addition to classical markers of glycemic control such as HbA1c, fasting, or postprandial glycemia.
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