15 disorders of carbohydrate metabolism

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Disorders of Carbohydrate Metabolism (1)

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Learning Objectives

By the end of this session you should be able to

describe:

• Hyperglycemia & diabetes mellitus includingsymptoms, diagnosis, classification, metabolicfeatures, long-term and acute complications, andan easy guide for diabetic control.

• Investigations in diabetic coma, definition, causes,and assessment of severity of coma.

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If you are working in a pharmacyor a hospital, what complains orsigns a patient will have toindicate he might be diabetic ??

16 March 2011 Dr. Mohamed Z Gad 4

Hyperglycemia

Increase in plasma glucose levels; most commonly due to diabetes mellitus.

Diabetes Mellitus (DM):

The term “diabetes” is derived from the Greek word diabeinein (“to go to

excess”). DM is caused by an absolute or relative insulin deficiency. It has

been defined by the World Health Organization (WHO), as a fasting venous

plasma glucose concentration >126 mg/dl (7.0 mmol/l) or >200 mg/dl

(11.1 mmol/l) two hours after a CHO meal or after the oral ingestion of 75g

of glucose, even the fasting concentration is normal.

The most obvious symptom of diabetes is hyperglycemia, caused by

inadequate uptake of glucose from the blood. Because the kidney’s

capacity to reabsorb glucose is limited, excessive amounts of blood

glucose (>180 mg/dl or ~ 11 mmol/l) results in glucosuria (glucose in

urine). High urinary glucose concentrations produce an osmotic diuresis

and therefore polyuria. Hyperosmolality due to water loss causes thirst &

polydipsia. Diabetes is also associated with increased appetite and food

consumption (polyphagia).


Diagnosis of DM

DM should not be diagnosed unless high plasma glucose concentrations

have been found in at least two different occasions. If the plasma glucose

concentrations are not within normal reference range and are not above

that diabetic level, the patient is said to have impaired glucose tolerance.

A) Plasma Glucose Concentration:

Normal Level: 70-110 mg/dl (3.89-6.0 mmol/l) (true level)

Plasma glucose estimation should be taken if a patient presents with

symptoms of DM such as glucosuria or polyuria.

The measurement of plasma glucose concentrations is preferable to

that of whole blood.

Blood sample must be mixed upon collection with an inhibitor of

glycolysis, such as fluoride or iodoacetate, to prevent the in vitro fall of

blood glucose as glycolysis continues.

Glucose is measured in the lab by specific enzymatic methods

(hexokinase or glucose oxidase) to give “true” blood levels.


Blood samples may be taken according to any of the

following ways:

I. Fasting: after about 10 h fast

II. Postprandial: 2 h after a mixed meal

III. At Random

IV. Glucose Load test:

By administration of a standard oral glucose load (~75 g)

and determining plasma glucose conc. 2 h later. It is more

precise than the postprandial glucose.

*DM is usually present if :

Fasting plasma glucose 126 mg/dl (7.0 mmol/l) on two

occasions or random plasma glucose > 200 mg/dl (11.1

mmol/l) on two occasions or both a fasting >126 mg/dl and

random >200 mg/dl. Also plasma glucose levels >200

mg/dl 2 h after a meal or glucose load is indicative of DM.

*DM is usually excluded if:

Fasting < 110 mg/dl (6.0 mmol/l) on two occasions


*Confirmation tests for suspected DM patients:

V. Oral Glucose Tolerance Test (OGTT):

To avoid misleading responses, it is essential to place the patients on a diet

containing adequate calories, protein and at least 150 g CHO/day for 3 days

before the test; this stimulates the production of inducible enzymes necessary

for glycogenesis and glucose utilization. No alcohol, no drugs, no smoking and

no exercise during the test. Not to be done during recovery from acute illness,

emotional stress, surgery, trauma or pregnancy.

A blood sample is drawn from a patient after an overnight fast. 75 g of glucose

are ingested (in a solution ~250 g/L) over a 5 min period. Blood samples are

drawn 30, 60, 120, 180 min after the glucose ingestion.

GTT should be reserved principally for patients with “borderline” fasting plasma

glucose levels (i.e. fasting range 110-126 mg/dl).

GTT is not indicated in:

Persistent fasting hyperglycemia (>126 mg/dl), persistent fasting

normoglycemia (<110 mg/dl), patients with typical clinical findings of DM,

secondary DM, never be done to evaluate reactive hypoglycaemia and rarely

indicated for diagnosis of DM in children.

Procedure:

Use:


For diagnosis of DM in adults, at least two

values of GTT should be increased.

A typical normal curve shows fasting glucose

level is ~75mg/dl. Maximum concentration is

reached 30-60 min after taking the glucose.

Blood level then returns to the normal fasting

level in 90 min (75-110 mg/dl). Sometimes a

slight dip in the curve occurs at 120 min (65

mg/dl) that returns to fasting level (75 mg/dl)

thereafter WHY ??

Interpretation:

If the serum glucose conc. Is

plotted against time, different types

of curves are obtained for diabetics

and normal.

VI. Intravenous Glucose Tolerance Test:

Poor absorption to oral glucose may result in

a “flat” tolerance curve. Some patients are

unable to tolerate a large CHO load orally

(vomiting) or may have altered gastric

physiology (e.g. gastric resection). In these

cases an i.v glucose tolerance test may be

performed. The dose of glucose is 0.5 g/kg

b.w given i.v within 2-4 min. Blood is

collected every 10 min for 1 h.


Criteria for the diagnosis of DM

Fasting blood glucose

Non-diabetic Impaired glucose tolerance

(IGT)

Diabetes

<6.0 mmol/l (<110 mg/dl) 6.0-6.9 mmol/l (110-125 mg/dl) ≥7.0 mmol/l (≥126 mg/dl)

Oral glucose tolerance test

Fasting 2-hour

IGT <7.0 mmol/l (<126 mg/dl) 7.0-11.0 mmol/l (126-200

mg/dl)

Diabetes ≥7.0 mmol/l (≥126 mg/dl) ≥11.1 mmol/l (≥200 mg/dl)

B) Glucosuria:In most normal persons, glucose in not detected in the urine below the level of

180 mg/dl of blood glucose. This level is termed “renal threshold for glucose”,

and reflects maximum capacity of kidneys for glucose reabsorption. Glucosuria

is best detected by enzyme reagent strips & occurs in diabetes mellitus,

glucose infusion, renal dysfunction and pregnancy.

False Negative: if urine contains large amounts of ascorbic acid.

False Positive: if urine container is contaminated with detergent.

Normal Level: Not detected in the urine by routine tests


D) Ketone Bodies in serum & Urine:Normal Level: Blood <3 mg/dl (0.3 mmol/l), Urine <10 mg/dl (1 mmol/l).

Usually detected by strips.

Excessive formation of ketone bodies results in increased blood

concentrations (ketonemia) and increased excretion in urine (ketonuria).

Observed in conditions associated with a decreased intake of CHO such as

starvation, digestive disturbances, dietary imbalance and frequent vomiting.

However, the most frequent cause is diabetic Ketoacidosis.

C) Microalbuminuria:

Defined as albumin excretion rate

intermediate between normality and

macroalbuminuria (>300 mg/day). It is a

marker of early (reversible) diabetic

nephropathy and is thus used to screen for

renal damage.

Normal Level: <30 mg/day albumin in urine Strip Test for Glucose in Urine


E) Glycohemoglobin (Glycated Hemoglobin): Normal Level: 4-8%

In adults, circulating hemoglobin (Hb) consists of 97%

Hb A, 2.5% Hb A2 and 0.5% Hb F. Glycated Hb (Hb A1c)

is formed by non-enzymatic condensation of glucose

and N-terminal valine of b-chains of Hb & occurs over

the life span of he RBC (~120 days). It is expressed as

percentage of the total Hb concentration.

Use:

Monitor the long-term control of D.M. It depends on the glucose concentration

over the two or three months prior to the test.

This is useful for judging control of diabetes in: (1) a new patient, (2) when urine

glucose records are inadequate, (3) in patients during pregnancy.

In known diabetics: 7% indicates good diabetic control, 10% indicates fair

diabetic control, 13-20% indicates poor diabetic control.

F) Serum Fructosamine: Normal Level: 2.4-3.4 mmol/l

Measure concentration of glycated serum proteins, giving a reliable estimate of

mean blood glucose levels during preceding 1-3 weeks. It correlates with Hb

A1c but is not affected by abnormal Hb. However, it is affected by significant

changes in serum albumin or protein concentrations.


Classification of DM

Insulin-Dependent Diabetes Mellitus

(IDDM)

Non-insulin-Dependent Diabetes

Mellitus (NIDDM)

Also called type I diabetes or juvenile

onset diabetes (usually occurs before

the age of 20).

Also called type II diabetes or

maturity-onset diabetes (usually

occurs after the age of 40).

It represents 10-20% of diabetic

patients.

It represents 80-90% of diabetic

patients.

Prone to ketosis Resistant to ketosis

Endogenous insulin low/absent Endogenous insulin present but

insufficient

Very low serum C-peptide levels

<10mg

Normal or increased C-peptide levels

Low/normal weight Mostly obese

Treatment by exogenous insulin Diet control and exercise. Oral

hypoglycemics are used when

necessary.


IDDM NIDDM

Most cases of IDDM result from the

destruction of the insulin producing b-

cells by the immune system.

Destruction of b-cells is initiated by the

binding of an antibody to a cell surface

antigen. One of the most common

autoantibodies found in IDDM is an

antibody against glutamic acid

decarboxylase (GAD) enzyme.

Most individuals with type II diabetes

have normal or even elevated blood

levels of insulin. For a variety of

reasons, type II patients are resistant

to insulin. The most common cause of

insulin resistance is the down-

regulation or defect of insulin

receptors.

HLA (histocompatibility antigens, which

are found on the surface of most of the

body’s cells, play an important role in

determining how the immune system

reacts to foreign substances or cells)

antigens are present

No HLA association

Islet cell antibodies are present Islet cell antibodies are absent

Polygenic Strong genetic association

Viruses and toxins might be implicated Obesity and physical inactivity play

role

Dr. Mohamed Z Gad 14

Diagnosed when hyperglycemia

develops for the first time during

pregnancy. (This is not the same as a

known diabetic who becomes

pregnant.) Affects 2-3% of pregnant

women. There is a high probability

(30-60%) that a woman with GDM will

develop DM later in life. Early

diagnosis of GDM is important.

Gestational Diabetes Mellitus (GDM)

Dr. Mohamed Z Gad 15

Metabolic Features of

DMIn the absence of

insulin, liver, adipose

tissue and muscles

behaves as if the body is

undergoing starvation.


Key Note: Easy Guide for Diabetic Control

1. CHO (simple or complex) accounts for ~50% of calories.

2. Protein 12-20% of calories.

3. Cut the fat out of your diet as possible. It should not be >30% of calories.

4. Eat food with fiber (e.g. wheat, barley, oat, legumes, vegetables, fruits).

Fibers could lower cholesterol & fat levels and keep you not Hungary.

5. Cut your cholesterol. It should not exceed 300 mg/day.

6. Use alternative sweeteners if your diabetes is not well controlled.

7. Have good care with your feet, as diabetic’s weakest link is the foot. Here

are some useful guidelines: try to lose weight, inspect your feet 2-3

times/day for cuts, bruises, swelling .. keep your feet clean and dry, keep

them warm in cold days, make sure your shoes fit well.

8. Eat smaller meals more often. Less glucose -> less insulin -> more

constant blood sugar.

A diabetic regimen has three cornerstones: nutrition, weight

control and exercise. Here are some guidelines issued by

the American Diabetes Association (ADA) that help in

diabetic control:

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9. Too much fish oil (usually taken to help prevention

of atherosclerosis) is not advisable since it is of

high calorie & may increase blood glucose levels.

However, eating fish is encouraged.

10. Try to lose weight. Remember that ~80% of

type II diabetics are overweight. Do not be hard on

yourself, just try to change eating habits and do

exercise.

11. Nutritional changes should be a family affair. It

is hard for a diabetic person to do it alone.

12. Reduce stress & anxiety, if possible.

13. Test your blood glucose quite often.

14. Testing urine glucose is an easy routine way

to monitor blood glucose after control.

15. Take care of your teeth. Diabetics are more

susceptible to gum infections.

16. Administer vitamin & mineral medications, if

your diet is not balanced


Long-Term Complications of DMDiabetics (if uncontrolled!) are especially prone to develop

nephropathy, myocardial infarction, stroke, retinopathy, and

neuropathy (nerve damage due principally to poor blood

circulation causes the loss of various types of sensory &

motor function). In addition, circulatory problems often result

in gangrene, which leads to tens of thousands of

amputations annually.

Most diabetic complications are the result of the damage to

the vascular system. For example, damaged capillaries in

the eye and kidney lead to blindness and kidneys damage,

respectively. It is now believed that most of the damage is

initiated by hyperglycemia which promotes the nonenzymatic

glycosylation of protein molecules (a process referred to as

the Maillard reaction). Accumulation of glycosylation end

products cause extensive damage throughout the

cardiovascular system.


Acute Complications of DM NEED MEDICAL

EMERGENCY

A) Diabetic Ketoacidosis:Precipitating factors are

infection, vomiting, trauma,

myocardial infarction or

severe insulin deficiency.

Decreased glucose transport

into tissues leads to

hyperglycemia, which gives

rise to glycosuria. Increased

lipolysis causes over-

production of fatty acids,

some of which are converted

into ketones, giving

ketonemia, metabolic acidosis

and ketonuria. Glycosuria

causes an osmotic diuresis,

which leads to the loss of

water and electrolytes - Na, K,

Ca, Mg, P, Cl.

Dehydration, if severe, produces renal uraemia

and may lead to hypovolemic shock.

Hyperventilation occurs to compensate for

severe metabolic acidosis. Odour of acetone is

observed in the breath. Hyperosmolality

causes cellular dehydration, if in cerebral cells

it may causes confusion and coma.

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NEED MEDICAL

EMERGENCYB) Hyperosmolar Non-Ketotic (HONK)

Coma:

Occurs mostly in elderly, NIDDM, and

develops relatively slowly over days and

weeks. The level of insulin is sufficient to

prevent ketosis but does not prevent

hyperglycemia and osmotic diuresis.

Precipitating factors include severe illness,

dehydration, glucocorticoids, diuretics,

dialysis, and surgery. Extremely high blood

glucose levels (above 600 mg/dl or 35

mmol/l) accompany severe dehydration

resulting in impaired consciousness.

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Key Note: Investigations in Diabetic ComaFor a patient in coma, blood samples should be taken and sent immediately to thelab for estimation of plasma: glucose, sodium and potassium, urea and/or creatinineand bicarbonate and/or arterial pH. Urine samples are taken (if possible) fordetection of glucose and acetone. A diabetic patient may be in coma due tohyperglycemia, hypoglycaemia or any of the causes shown in the following table:

Diagnosis Clinical Features Laboratory Findings

Plasma Urine

Glucose Bicarbonate Glucose Ketones

Ketoacidosis

Hyperosmolar

Coma

Hypoglycemia

Cerebrovascula

Accident

Volume depletion

Hyperventilating

Volume depletion

No hyperventilation

Non-specific

Neurological

May be hyperventilating

High

Very high

Low

May be

raised

Low

N

N

May be low

+++

+++

Neg

May be +

+++

Neg

Neg

Absent

N = Normal Neg = Negative

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What is Coma ?

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DefinitionIn medicine, a coma (from the Greek κῶμα koma, meaning

deep sleep) is a profound state of unconsciousness.

What are the criteria for a person in coma ???

Coma may result from a variety of conditions, including

intoxication, pharmaceutical agents, metabolic

abnormalities, CNS diseases, acute neurological injuries

such as stroke, and hypoxia.

How ?

1) cannot be awakened, 2) fails to respond normally to pain

or light, 3) does not have sleep-wake cycles, and 4) does

not take voluntary actions.


SeverityThe depth of coma can be defined

following clinical examination using

a scale called Glasgow Coma

Scale (GCS). The GCS is a simple

15-point scale used by medical

professionals to assess severity of

neurologic trauma, and establish a

prognosis.

8 in GCS are in coma, at 6 h

~50% will die.

9 in GSC not in coma.

Contrary to popular belief, a patient

in a coma does not always lay still

and quiet. They may talk, walk, and

perform other functions that may

appear to be conscious acts but are

not.

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Guess

what is The longest period

spent in coma according to

Guinness World Records ?


Guinness World Records

The longest period spent in coma

Elaine Esposito

(December 3, 1934 - November 25,

1978) of Tarpon Springs, Florida, USA,

holds the record for longest coma.

Elaine never stirred after being

anaesthetized for an appendectomy on

August 6, 1941, when aged 6. She died

aged 43 years 357 days, having been in

a coma for 37 years 111 days.

Elaine's coma evidenced states

between deep sleep and open-eyed

unconsciousness.

Sharon still in coma after

a massive stroke since

26 December 2005 !!!

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References:

• Clinical Biochemistry: An illustrated colour text, A. Gaw et al., Churchill

Livingstone.

• Clinical Chemistry, W.J. Marshall, Mosby.

• Clinical Chemistry: Interpretation and Techniques, A. Kaplan & L.L. Szabo, Lea

& Febiger, Philadelphia.

• Fundamentals of Clinical Chemistry, N.W. Tietz, W.B., Saunders Company,

Philadelphia, London, Tokyo ….

• Clinical Biochemistry, A.F. Smith, G.J. Beckett, S.W. Walker & P.W. H Rae,

Blackwell Science Ltd, London…

• Interpretation of Diagnostic Tests, I. Wallach, Little, brown & Company, Boston,

London …..

• Practical Clinical Biochemistry, H. Varley, A.H. Gowenlock & M. Bell, William

Heinemann Medical Books LTD, London

1

Disorders of Carbohydrate Metabolism (2)

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Learning Objectives

By the end of this session you should be able to

describe:

• Hypoglycaemia: clinical effects, causes, and

investigations.

• Mechanism of insulin secretion, mode of action of SUs,

structure of insulin receptor, insulin signaling pathways,

insulin role in regulation of blood glucose level, types of

glucose transporters, insulin & carbohydrate metabolism.

• Insulin resistance: definition, clinical presentation, and

causes.

3

Hypoglycaemia

Any condition in which plasma glucose concentration falls

below 60 mg/dl (3.3 mmol/l) is called hypoglycaemia. In

general, children and adults are not usually symptomatic

unless the glucose falls below 40 mg/dl (2.2 mmol/l).

Clinical effects

Hypoglycaemia normally leads to suppression of insulin secretion, an

increase in catecholamine secretion and stimulation of glucagon, cortisol,

and growth hormone. Catecholamine surge accounts for signs and

symptoms most commonly seen in hypoglycaemia i.e. sweating, shaking,

tachycardia, feeling weak and nauseated.

Since brain is dependent upon an adequate supply of glucose for its energy,

clinical symptoms of hypoglycaemia resemble those of cerebral anoxia.

They include confusion, poor concentration, detachment and, in more

severe instances, convulsions and coma.

4

Principal causes of Hypoglycaemia

Ø Insulinoma (b- cell tumour of pancreas) or pancreatic

hyperplasia.

Ø Advanced extrapancreatic malignancy, for example by

producing insulin-like growth factors.

Ø Hepatic and renal disease

Ø Deficiency of anti-insulin hormones e.g. in Addison's disease

Ø Sepsis, mechanism unclear

Ø Starvation, anorexia nervosa, lactic acidosis , and intense

exercise.

Ø Drug-induced, e.g. Inappropriate or excessive insulin, alcohol,

sulphonylureas, and salicylates.

Ø Accelerated gastric emptying (Dumping syndrome) following

gastric resection, which result in rapid absorption of large

amounts of glucose with a resultant surge of insulin release.

5

Investigations in Hypoglycaemia

The diagnosis of hypoglycaemia is established when three criteria are satisfied:

Symptoms consistent with hypoglycaemia

Laboratory confirmation of hypoglycaemia

Symptoms are relieved by glucose administration

• The most important test is plasma insulin

concentration. This differentiates

hypoglycaemia due to high insulin level from

other causes of hypoglycaemia.

• If plasma insulin conc. is inappropriately

high, plasma C-peptide concentrations

should be assayed …… WHY ?

• If plasma C-peptide is high, it suggests

endogenous insulin secretion, or pancreatic

stimulation e.g. by sulphonylureas.

Undetectable plasma C-peptide concentration

suggests exogenous insulin administration.

http://www1.istockphoto.com/file_thumbview_approve/3068088/2/istockphoto_3068088_mad_scientist_series_green_flask_and_friends_isolated_on_white.jpg

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Cause of Hypoglycaemia Plasma Insulin Plasma C-peptide

Insulin administration High Low

Insulinoma High High

Sulphonylurea

administration

High High

Alcohol Low Low

Non-pancreatic tumour Low Low

Pituitary or adrenal

failure

Low Low

7

Insulin was discovered in 1922 (Boyd, Diabetes, 1988)

Mechanism of Insulin Secretion

1. Glucose is transported

through GLUT2, and its

subsequent metabolism

produces ATP.

2. The increase in ATP

closes KATP channels,

which depolarizes the

membrane and results

in the opening of

voltage-dependent Ca2+

channels.

3. Ca2+ influx leads to an

increase in intracellular

Ca2+ concentration,

which triggers insulin

granule exocytosis in

the beta cells.

GLUT2: glucose transporter 2, VDCC: voltage-dependent

calcium channel

Sulfonylureas (SUs) bind and close the KATP

channels and subsequently stimulate insulin

secretion.

-+

8

Insulin Secreation.swf

Insulin Secretion.swf

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Specific blocker of ATP-sensitive K+ channel in pancreatic b-cell(Sturgers et al, Lancet, 1985; Trube et al, Pflugers Arch., 1986)

KATP channel is the first example

of a heteromultimeric complex

assembled by a RECEPTOR

(Sulphonylurea receptor,

tetramer of SUR1, member of

the ATP-binding cassette (ABC)

protein superfamily) and an

inwardly rectifying K+ CHANNEL

(Kir6.2), that are structurally

unrelated to each other.

Mode of Action of SUs

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- It is a heterotetrameric membrane

glycoprotein composed of two a- and

two b-subunits, linked together by

disulfide bonds.

- Insulin binds to the receptor’s

extracellular subunit.

- Insulin binding brings the two a-

subunits closer together. This

conformational change enables ATP

binding to the b-subunit’s intracellular

domain.

- ATP binding activates receptor

autophosphorylation, which, in turn,

enables the receptor’s kinase activity

toward intracellular protein

substrates.

Structure of Insulin Receptor

11

• When insulin binds to its

tyrosine kinase receptor, it

activates insulin receptor

substrates (IRS), which in turn

stimulates the lipid kinase activity

of phosphatidylinositol 3-kinase.

• Rapid rise in Tris-phosphorylated

inositol (PIP3) triggers a cascade

of PIP3-dependent

serine/threonine kinases.

• Among the latter, Akt (a product

of the akt protooncogene) and

atypical protein kinase C isoforms

are thought to be involved in

insulin regulation of glucose

transport and oxidation; glycogen,

lipid, and protein synthesis; and

modulation of gene expression.

Insulin Signaling Pathways

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Types of Glucose

Transporters

13

Insulin & Carbohydrate Metabolism

1) Insulin facilitates entry of glucose into muscle, adipose

and several other tissues

mainly by enhancing translocation of hexose transporters (GLUT4) from

the cytoplasmic vesicles to plasma membrane for efficient uptake of

glucose.

When blood levels of insulin decrease and insulin receptors are no

longer occupied, the glucose transporters are recycled back into

cytoplasm.

N.B: There are some tissues that do not require insulin for efficient uptake

of glucose; important examples are brain and the lens. This is because

these cells don't use GLUT4 for importing glucose, but rather, another

transporter that is not insulin-dependent.

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insulin on GLUT 4.swf




15

2) Insulin has several effects

in liver which stimulate

glycogen synthesis

It activates hexokinase, which

phosphorylates glucose, trapping it

within the cell. Coincidently, it acts to

inhibit activity of glucose-6-

phosphatase.

It activates glycogen synthase

responsible for glycogen synthesis.

Decreased activity in any of these steps could be responsible for

insulin resistance

http://content.nejm.org/content/vol335/issue18/images/large/04f1.jpeg

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Definitions of Insulin Resistance (IRS)

• A decrease in the sensitivity of tissues such as liver,

skeletal muscle and adipose tissue to action of insulin.

• A state in which a given concentration of insulin produces

a less-than-expected biological effect

17

The first progression

towards type-II diabetes

is hyperinsulinemia and

impaired glucose

tolerance (IGT), with

increases in post-prandial

glucose concentrations.

Most patients stay at this

level for a considerable

time with excess insulin

produced just matching

the blood glucose levels.

However, in time b- cells

begin to fail and are

unable to produce

sufficient insulin to

stabilize the raised blood

glucose, type-II diabetes

is developed.

Studies lean toward existence of both insulin

resistance and insulin deficiency in most NIDDM

patients, because a moderate degree of insulin

resistance is not sufficient to cause NIDDM.

From Insulin Resistance to Type-II Diabetes

18

Depends on the type and stage of the IRS state:

• Metabolic syndrome (syndrome X): clustering of

atherosclerotic cardiovascular disease risk factors including

obesity, IRS, low HDL, and systemic proinflammatory state.

• Obesity

• Type 2 diabetes mellitus: Chronic or acute.

• Impaired glucose tolerance

• History of hypertension

• Symptoms of coronary artery disease or microvascular

angina

• Symptoms of other macrovascular disease e.g. peripheral

vascular disease

• Polycystic Ovary Disease (PCOD): Patients present with

infertility associated with anovulation; menstrual irregularity.

Symptoms due to excess androgen.

Clinical Presentation of Insulin Resistance

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Hereditary: includes mutations of insulin receptor, glucose transporter, and

signaling proteins.

Acquired: includes physical inactivity, diet, medications, hyperglycemia

(glucose toxicity), increased free fatty acids, and aging process.

The underlying causes of insulin-resistant states can be categorized as follows:

Prereceptor

Abnormal insulin (mutations)

Anti-insulin antibodies

Receptor

Decreased number of receptors, mainly failure to activate tyrosine kinase

Reduced binding of insulin

Insulin receptor mutations

Insulin receptor–blocking antibodies

Postreceptor

Defective signal transduction

Combinations of defects are common. Obesity is associated mainly with

postreceptor abnormality and also decreased number of insulin receptors.

“Obesity is the most common cause of insulin resistance”

Causes of Insulin Resistance

20

Adipocyte is no longer regarded as a

passive depot for storing excess

energy in the form of TG, but as a

cell that actively regulates pathways

responsible for energy balance.

Obesity alone does

not always lead to IRS

Obesity & NIDDM

Adipocyte modulates energy balance

through secretion of peptide hormones and

other signaling molecules e.g. leptin is

secreted by TG-rich adipocytes, travels

through the circulation, crosses blood–brain

barrier, and reaches hypothalamus, where it

modulates a host of neuroendocrine and

autonomic nervous system activities,

resulting in decreased food intake and

increased energy expenditure.

Resistin, tumor necrosis factor,

adiponectin, free fatty acids are other

factors released by adipocytes, act in

peripheral tissues to influence sensitivity to

insulin and other cellular and metabolic

processes.

21

References:

• Clinical Biochemistry: An illustrated colour text, A. Gaw et al., Churchill

Livingstone.

• Clinical Chemistry, W.J. Marshall, Mosby.

• Clinical Chemistry: Interpretation and Techniques, A. Kaplan & L.L. Szabo, Lea

& Febiger, Philadelphia.

• Fundamentals of Clinical Chemistry, N.W. Tietz, W.B., Saunders Company,

Philadelphia, London, Tokyo….

• Clinical Biochemistry, A.F. Smith, G.J. Beckett, S.W. Walker & P.W. H Rae,

Blackwell Science Ltd, London…

• Interpretation of Diagnostic Tests, I. Wallach, Little, brown & Company, Boston,

London…..

• Practical Clinical Biochemistry, H. Varley, A.H. Gowenlock & M. Bell, William

Heinemann Medical Books LTD, London

15 disorders of carbohydrate metabolism

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