The main monosaccharide.

hexoses are reducing

sugars.
Naturally occurring polysaccharides are long-chain
carbohydrates composed of glucose subunits(
Starch, found in plants, is a mixture of amylose (straight
chains) and amylopectin (branched chains).
Glycogen, found in animal tissue, is a highly branched
polysaccharide
The main function of glucose is as a major tissue energy
source. The brain is highly dependent upon the extracellular
glucose concentration for its energy supply; indeed,
hypoglycaemia is likely to impair cerebral function or even
lead to irreversible neuronal damage. This is because the
brain cannot:
 The brain

1-synthesize glucose,
. can not

2-store glucose in significant amounts,

Can not
3-metabolize substrates other than glucose and ketones
plasma ketone concentrations are usually very low
...‫في الحاالت الفسلجية الطبيعية يكون تركيز الكيتونات قليالً جدا ً وليست ذات اهمية كمصدر للطاقة‬
and ketones are of little importance as an energy source u
physiological conditions,
4-extract enough glucose from the extracellular fluid (ECF)
at low concentrations for its metabolic needs,
because entry into brain cells is not facilitated by insulin.

:‫الدماغ اليمكنه‬
.‫ تخليق الگلوكوز‬-١
.‫ خزن الگلوكوز‬-٢
.‫ ايض مواد اخرى غير الگلوكوز والكيتونات‬-٣
.‫ عندما تكون تراكيزه قليلة عند حاجته اليها وألن العملية غير مسرعة باالنسولني‬ECF ‫ استخالص كميات كافية من الگلوكوز من الـ‬-٤
 .
Normally the plasma glucose concentration remains between about (4
mmol/L and 10 mmol/L, despite the intermittent load entering the body
from the diet.

The maintenance of plasma glucose concentrations below about 10

mmol/L minimizes loss from the body as well as providing the optimal
supply to the tissues.

Renal tubular cells reabsorb almost all the glucose filtered by the
glomeruli, and urinary glucose concentration is normally too low to be
‫تركيز الگلوكوز في االدرار يكون قليالً جدا ً عند قياسه بالفحوصات املعروفة بسبب‬
detected by the usual tests, ‫اعادة‬.‫بالكاربوهيدرات‬ ‫امتصاصه من قبل خاليا النبيبات الكلوية حتى ولو بعد وجبة غنية‬

even after a carbohydrate meal. Significant glycosuria usually occurs

only if the plasma glucose concentration exceeds about 10 mmol/L – the
renal threshold
mmol/L 10 ‫ عندما تحصل زيادة للگلوكوز الى من حد العتبة‬Glycosuria ‫تحصل حالة البول املحمل بالگلوكوز‬
.Control of plasma glucose concentration
During normal metabolism, little . glucose is lost unchanged
from the body. Maintenance of plasma glucose concentrations
within the relatively narrow range of 4–10 mmol/L, despite the
widely varying input from the diet, depends on the balance
between the glucose entering cells from the ECF and that leaving
them into this compartment.

Hormones concerned with glucose homeostasis •

Insulin
I

Insulin is the most important hormone controlling plasma

glucose concentrations. A plasma glucose concentration of greater
than about 5 mmol/L acting via the glucose transporter 2 stimulates
insulin release from the pancreas b-cell. These cells produce
proinsulin, which consists of the 51-amino-acid polypeptide insulin
and a linking peptide (C-peptide). Splitting of the peptide bonds by
prohormone convertases releases via intermediates (mostly 32–33
split proinsulin) equimolar amounts of insulin and C-peptide into
the ECF Proprotein Convertase 1 = Prohormone Convertase 3
. • .
Insulin – structure

Insulin is a polypeptide
containing 2 chains of
amino acids linked by
disulfide bridges
 ‫موضع‬
‫اتصال‬
‫الهرمون‬

‫موضع اتصال الـ ‪ATP‬‬ ‫مستقبالت االنسولني توجد في كل خاليا الجسم تقريبا ً وهي عبارة‬
‫وانزيم ‪Tyrosin Kinase‬‬ ‫عن تراكيب رباعية الوحدات )‪ (Tetramer‬وتتكون من جزئي الفا‬
‫وجزئي بيتا تترابطان مع بعضهما بـ ‪.Disul de Bond‬‬
‫‪fi‬‬
 .
Insulin binds to specific cell surface receptors on muscle and adipose
tissue, thus enhancing the rate of glucose entry into these cells.
Insulin-induced activation of enzymes stimulates glucose
incorporation into glycogen (glycogenesis) in liver and muscle Insulin
also inhibits the production of glucose(gluconeogenesis) from fats and
amino acids, partly by inhibiting fat and protein breakdown (lipolysis
‫دخول الگلوكوز لخاليا الكبد ال يعتمد على االنسولني ولكن في حال حصول نقص‬
and proteolysis) .‫ بطريقة غير مباشرة‬infusion ‫الگلوكوز فيها فان االنسولني يساعد في دخولها‬
1- The transport of glucose into liver cells is insulin independent but,
by reducing the intracellular glucose concentration, insulin does
indirectly promote the passive diffusion of glucose into them.
2- Insulin also directly increases the transport of amino acids,
potassium and phosphate into cells, especially muscle; these processes
‫االنسولني يعمل على زيادة انتقال االحماض االمينية‬
are independent of glucose transport. ً ‫والبوتاسيوم واالفوسفات الى داخل الخاليا وخصوصا‬
.‫ وهذه العملية غير متعلقة بنقل الگلوكوز‬،‫العضلية‬
3- In the longer term, insulin regulates growth and development and
the expression of certain genes. ‫على املدى الطويل فإن االنسولني ينظم النمو والتطور وتكوين الجينات‬
Glucagon • .
Glucagon is a single-chain polypeptide synthesized
by the alpha-cells of the pancreatic islets.
Its secretion is stimulated by hypoglycaemia.
Glucagon enhances hepatic glycogenolysis (glycogen
breakdown) and gluconeogenesis
Somatostatin GH‫يثبط افراز هرموني االنسولني و‬

This peptide hormone is released from the D cells of

the pancreas and inhibits insulin and growth hormone
(release
pancreas
(insulin,
glucagone,
somatostatin)
. . ‫عند نقص تراكيز االنسولني فإن تأثير هذه الهرمونات‬
‫يظهر جليا ً حتى لو كانت معدالت افرازها قليلة‬
Other hormones
When plasma insulin concentrations are low, for
example during fasting, the hyperglycaemic actions of
hormones, such as growth hormone (GH), glucoco-
rticoids, adrenaline (epinephrine) and glucagon,
become apparent, even if there is no increase in
secretion rates. ‫هرمونات التنظيم املعاكس )لالنسولني( يمكن ان تزداد في حاالت‬

Secretion of these so-called[counter regulatory

hormones] may increase during stress and in patients
acromegaly Cushing’s syndrome or in with
phaeochromocytoma (adrenaline and noradrenaline and
thus oppose the normal action of insulin.
a small vascular tumour of the adrenal medulla, causing
irregular secretion of adrenalin and noradrenaline leading to
attacks of raised blood pressure, palpitations, and headache.
The liver
.
The liver is the most important organ maintaining a
constant glucose supply for other tissues, including the
brain. It is also of importance in controlling the postprandial
plasma glucose concentration.
Portal venous blood leaving the absorptive area of the
intestinal wall reaches the liver first, and consequently
the hepatic cells are in a key position to buffer the Hyper-
glycaemic effect of a high-carbohydrate meal
The entry of glucose into liver and cerebral cells is not
directly affected by insulin, but depends on the ‫دخول الگلوكوز لخاليا الكبد‬
‫والدماغ ال يعتمد مباشرة‬

extracellular glucose concentration. ‫على االنسولني )ال يحتاج‬

‫لالنسولني( ولكنه يعتمد على‬
‫تراكيز الگلوكوز في الدم‬
The conversion of glucose to glucose-6-phosphate (G6P),
the first step in glucose metabolism in all cells, is catalysed in
the liver by the enzyme glucokinase, which has a low affinity
for glucose compared with that of hexokinase, which is found
in most other tissues. ‫تحسس الگلوكوكاينيز للگلوكوز‬
‫اقل من تحسس الهكسوكاينيز له‬
.
 Glucokinase activity is induced . by insulin. Therefore, hepatic
cells extract proportionally less glucose during fasting, when
concentrations in portal venous plasma are low, than after
carbohydrate ingestion. ‫للگلوكوز‬ ‫ ولذلك يقل سحب خاليا الكبد‬،Glucose ‫ بارتفاع تركيز الـ‬glucokinase ‫تُحفز فعالية الـ‬
‫ على‬، (ً‫ قليال‬Portal Veins ‫عند حصول نقص في تركيزه في الدم )عندما يكون تركيزه في الـ‬
.‫العكس من الحال بعد تناول وجبة كاربوهيدرات‬
This helps to maintain a fasting supply of glucose to
vulnerable tissues such as the brain.
.‫ االنسجة)املعتمدة عليه بشدة ( مثل الدماغ‬Glucose‫وهذا يساعد في تجهيز ال‬
The liver cells can store some of the excess glucose as
glycogen. The rate of glycogen synthesis (glycogenesis)
from G6P may be increased by insulin secreted by
the b-cells of the pancreas in response to systemic
hyperglycaemia.
The liver can convert some of the excess glucose to fatty
acids, which are ultimately transported as triglyceride in very
low-density lipoprotein (VLDL)
and stored in adipose tissue.
 ‫مختصر مهم وواضح‬
‫جدا ً أليض الـ‪Glucose‬‬
 .
Under normal aerobic conditions, the liver can synthesize glucose by
gluconeogenesis using the metabolic products from other tissues, such
as glycerol lactate or the carbon chains resulting from deamination of
certain amino acids (mainly alanine) .
.Phosphate ‫ ُيزيل الـ‬، Glucokinase ‫معاكس للـ‬
The liver contains the enzyme glucose-6-phosphatase, which, by
hydrolysing G6P derived from either glycogenolysis or
gluconeogenesis, releases glucose and helps to maintain extracellular
fasting concentrations.
Hepatic glycogenolysis is stimulated by the hormone glucagon,
secreted by the alpha-cells of the pancreas in response to a fall in the
plasma glucose concentration, and by catecholamines such as
adrenaline or noradrenaline.

any of a class of aromatic

amines which includes a
number of neurotransmitters
such as adrenaline and
dopamine
 .
During fasting, the liver converts fatty acids, released from adipose
tissue as a consequence of low insulin activity, to ketones. The
carbon chains of some amino acids may also be converted to ketones
.
Ketones can be used by other tissues, including the brain, as an
energy source when plasma glucose concentrations are low

‫القشرة الكظرية هي العضو الوحيد )مع الكبد( القادر على الـ‬

• Other organs .Glucose ‫ الى‬Glucose-6-P ‫ وتحويل‬gluconeogenesis

The renal cortex is the only other tissue capable of

gluconeogenesis, and of converting G6P to glucose. The
gluconeogenic capacity of the kidney is particularly important in
hydrogen ion homeostasis and during prolonged fasting.
Other tissues, such as muscle, can store glycogen but,
because they do not contain glucose-6-phosphatase, they cannot
release glucose from cells and so can only use it locally; this
glycogen plays no part in maintaining the plasma glucose
concentration
Systemic effects of glucose intake
. ‫ الناتجة من الوجبات الغذائية من‬hyperglycaemia‫يغير الكبد استجابته للـ‬
‫ عما هو الحال في‬Glucose‫خالل استخالص )استقطاب( كميات اكبر من ال‬
.‫حالة الصيام‬
The liver modifies the potential hyperglycaemic effect of a high-
carbohydrate meal by extracting relatively more glucose than in the
fasting state from the portal plasma. ‫ يتجاوز الكبد وهذه الزيادة‬Glucose‫بعض الـ‬
.Beta Cells ‫تحفز انتاج االنسولني من‬
However, some glucose does pass through the liver and the rise in the
systemic concentration stimulates the b-cells of the pancreas to secrete
insulin.
Insulin may further enhance hepatic and muscle glycogenesis.
More importantly, entry of glucose into adipose tissue and muscle
cells, unlike that into liver and brain, is stimulated by insulin and,
under physiological conditions, the plasma glucose concentration falls to
near fasting levels.
Conversion of intracellular glucose to G6P in adipose and muscle cells
is catalysed by the enzyme hexokinase, which, because its affinity for
glucose is greater than that of hepatic glucokinase, ensures that glucose
enters the metabolic pathways in these tissues at lower extracellular
concentrations than those in the liver.‫يدخلعكس‬ ‫حساسية )ألفة( الهكسوكاينيز للگلوكوز اعلى من حساسية الگلوكوكاينيز ولذلك‬
‫( على‬ECF)‫الگلوكوز للخاليا العضلية والدهنية حتى لو كانت تراكيزه قليلة في الـ‬
The relatively high insulin activity after a meal also inhibits the .‫الحال مع الكبد‬
breakdown of triglyceride (lipolysis) and protein (proteolysis). If there is
relative or absolute insulin deficiency, as in diabetes mellitus
 . muscle and adipose tissue
these actions are impaired. Both
store the excess post-prandial glucose, but the mode of
storage and the function of the two types of cell are very
different. Glycogen T.G.

Ketosis
Adipose tissue and the liver
Adipose tissue triglyceride is the most important long term energy store
in the body. Greatly increased use of fat stores, for example during
prolonged fasting, is associated with ketosis.
Adipose tissue cells, acting in conjunction with the liver, convert
excess glucose to triglyceride and store it in this form rather than as
glycogen.
The components are both derived from glucose, fatty acids from the
glucose entering hepatic cells and glycerol from that entering adipose
tissue cells the liver, triglycerides are formed from glycerol- 3-phosphate
(from triose phosphate or glyceraldehyde- 3-phosphate) and fatty acids
[from acetyl coenzyme A (CoA)].
 The triglycerides are transported
incorporated in VLDL, where they are hydrolysed by
. to adipose tissue cells
lipoprotein lipase.(‫االنسولني‬
FA ‫ حيث تدخل ال‬lipoprotein lipase‫ وتحلل على اعتاب خاليا النسيج الدهني بـ‬VLDL ‫ في الكبد وتنقل على‬TG ‫تنتج ال‬
‫)من أصل كبدي(للخلية الدهنية ويعاد ربطها مع الگليسرول الناتج من تحلل الگلوكوز )الذي دخل للخلية الدهنية بتأثير‬

The released fatty acids (of hepatic origin) are re-esterified

with in these cells with glycerol-3-phosphate, derived from
glucose, which has entered this tissue under the influence of
insulin.
The resultant triglyceride is stored and is far more energy
dense than glycogen.
During fasting, when exogenous glucose is unavailable and
the plasma insulin concentration is therefore low, endogenous
triglycerides are reconverted to free non-esterified fatty acids
(NEFAs) and glycerol by lipolysis .‫عن بعضهما‬.Hypoglycemia ‫ بشكل منفصل‬Glycerol‫ و ال‬FA‫ تنقل ال‬Lipolysis‫بعد الـ‬
‫الى الكبد النتاج الطاقة منهما في حالة ال‬

Both are transported to the liver in plasma, the NEFA being

protein bound, predominantly to albumin.
Glycerol enters the hepatic gluconeogenic pathway at the
triose phosphate stage; the glucose synthesized can be released
from these cells, thus minimizing the fall in glucose
concentrations.
 .
Most tissues, other than the brain, can oxidize fatty acids to acetyl CoA,
which can then be used in the TCA cycle as an energy source.
‫ النتاج الطاقة‬TCA Cycle ‫ والذي يستخدم بعدها في‬Acetyl-CoA ‫ الى‬FA‫معظم االنسجة )ما عدا الدماغ( يمكنها اكسدة ال‬

When the rate of synthesis exceeds its use, the hepatic cells produce
acetoacetic acid by enzymatic condensation of two molecules of acetyl CoA;
acetoacetic acid can be reduced to b-hydroxybutyric acid and decarboxylated
to acetone. ‫) فان الخاليا الكبدية‬FA‫ عن الحد الطبيعي )في حال اكسدة ال‬Acetyl-CoA ‫عند زيادة معدل انتاج ال‬
.Acetoacetic Acid ‫ الى‬Acetyle-CoA ‫تكثف )انزيميا ً( كل جزيىتني من‬
These ketones can be used as an energy source by brain and other tissues at a
time when glucose is in relatively short supply. Ketosis occurs when fat stores
are the main energy source and may result from fasting or from reduced
nutrient absorption, for example due to vomiting.
‫ مما يؤدي الى زيادة‬+H ‫ ساعة يتم االعتماد على الكيتونات وعندها ينتج تركيز عالي من الـ‬١٢ ‫في حالة الصيام الطويل ألكثر من‬
‫ على معالجتها وبالتالي سسوف تستهلك البيكاربونات ويقل تركيزها‬Buffering Mechanisms‫الحموضة بما يفوق قدرة االل‬
Mild ketosis may occur after as little as 12 h of fasting. After short fasts,
metabolic acidosis is not usually detectable, but, after longer periods, more
hydrogen ions may be produced than can be dealt with by homeostatic
buffering mechanisms, depleting the plasma bicarbonate concentration,
which therefore falls .
The plasma glucose concentration is maintained principally by hepatic
gluconeogenesis, but during prolonged starvation, such as that in anorexia
nervosa or during childhood, ketotic hypoglycaemia may occur.
 . acidosis
‫تخزن العضالت الگلوكوز الداخل‬
‫لها بتأثير االنسولني على شكل‬
Lactate production and lactic ‫گاليكوجني وال يمكن تحويله الى‬
‫گلوكوز بسبب عدم امتالكها‬
‫العضالت املحززة‬
G-6Phosphatase ‫لالنزيم‬
Striated muscle and liver ‫ بفعل‬G-6-P ‫اي ان الگلوكوز يتحول فقط الى‬
Glycolysis ‫االپنفرين )االدرينالني( ويكمل عملية ال‬
Under the influence of insulin ,glucose enters muscle
post prandially and is stored as glycogen. This glycogen
cannot be reconverted to glucose because of the absence
of G-6-phosphatase and can supply local needs.
Quantitatively ,muscle glycogen stores are second only
to those in the liver.
During muscular activity glycogenolysis is stimulated
by adrenaline (epinephrine) and the resultant G-6-P is
metabolized by glycolysis and the TCA cycle to supply
energy .The rate of glycolysis may exceed the
availability of oxygen needed in the TCA cycle and
glycolysis products may then accumulate .
 .
• The over all reaction for anaerobic glycolysis is:
• Glucose →2 Lactate +2H+.
The lactate is transported in the blood to the liver
where it can be used for gluconeogenesis providing
further glucose for the muscle .During gluconeogenesis ,
hydrogen ions are re-used. Under aerobic condition ,the
liver consumes much more lactate than it produces The
physiological accumulation of lactic acid during
muscular contraction is a temporary phenomenon and
rapidly disappears at rest, when slowing of glycolysis
allows aerobic processes to ‘catch up’.
 .

Cori cycle
Pathological lactic acidosis
.
Lactic acid, produced by anaerobic glycolysis, may either
be oxidized to CO2 and water in the TCA cycle or be
reconverted to glucose by gluconeogenesis in the liver. Both
the TCA cycle and gluconeogenesis need oxygen; anaerobic
glycolysis is a non-oxygen-requiring pathway. Pathological
accumulation of lactate may occur because:
1-production is increased by an increased rate of anaerobic
glycolysis,
2-use is decreased by impairment of the TCA cycle or
impairment of gluconeogenesis.
Tissue hypoxia due to the poor tissue perfusion of the
‘shock’ syndrome is usually the most common cause of lactic
acidosis. Hypoxia increases plasma lactate concentrations
because:
1-the TCA cycle cannot function anaerobically and oxidation
of pyruvate and lactate to CO2 and water is impaired.
 .
2-hepatic and renal gluconeogenesis from lactate cannot
occur anaerobically,
3- anaerobic glycolysis is stimulated because the falling
adenosine triphosphate (ATP) levels cannot be
regenerated by the TCA cycle under anaerobic conditions.
‫ الى‬+H ‫ وال‬Lactate ‫ يؤدي الى تحويل الكبد من عضو يستهلك ال‬Anaerobic Glycolysis ‫ و زيادة ال‬Gluconeogenesis ‫التزامن بني نقصان ال‬
.Lactic Acid ‫عضو منتج لل‬
The combination of impaired gluconeogenesis and
increased anaerobic glycolysis converts the liver from an
organ that consumes lactate and H to one that generates
large amounts of lactic acid.
Severe hypoxia, for example following a cardiac
arrest, causes marked lactic acidosis.
If diabetic ketoacidosis is associated with significant
volume depletion, this hypoxic syndrome may aggravate
the acidosis.
HYPERGLYCAEMIA AND DIABETES MELLITUS
Hyperglycaemia may be due to: .
1- intravenous infusion of glucose-containing fluids,
2--severe stress (usually a transient effect) such as trauma, myocardial infarction or
cerebrovascular accidents,
3-diabetes mellitus or impaired glucose regulation
Diabetes mellitus •
Diabetes mellitus is caused by an absolute or relative insulin deficiency. It has been
defined by the World Health Organization (WHO), on the basis of laboratory findings,
as a
1- fasting venous plasma glucose concentration of ≥ 7.0 mmol/L or more (on more
than one occasion or once in the presence of diabetes symptoms)
2- or a random venous plasma glucose concentration of ≥ 11.1 mmol/L or more.
Sometimes an oral glucose tolerance test (OGTT) may be required to establish the
diagnosis in equivocal cases diabetes mellitus can be diagnosed if the :
1- venous plasma glucose concentration is 7.0 mmol/L or more (fasting) and/or 11.1
mmol/L or more 2 h after the oral ingestion of the equivalent of 75 g of anhydrous
glucose. Diabetes mellitus can be classified into the following categories.
• Type 1 diabetes mellitus .
Previously called insulin-dependent diabetes mellitus, this is the term used to
describe the condition in patients for whom insulin therapy is essential because
they are prone to develop ketoacidosis. It usually presents during childhood or
adolescence.
1- Most of these cases are due to immune-mediated processes and may be
associated with other autoimmune disorders such as Addison’s disease, vitiligo
and Hashimoto’s thyroiditis.
2- It has been suggested that many cases follow a viral infection that has
damaged the b-cells of the pancreatic islets. Individuals most at risk are those
with human leucocyte antigen (HLA) types DR3 and DR4 of the major
histocompatibility complex.
3- Autoantibodies to islet cells, insulin, tyrosine phosphatases IA-2 and IA-
2b and glutamic decarboxylase (GAD) are found in about 90 per cent of cases.
There is a form of type 1 diabetes called idiopathic diabetes mellitus that is
not autoimmune mediated but is strongly inherited and more common in black
and Asian people.
The insulin requirement of affected people can fluctuate widely and the cause is
unknown.
4- There is also LADA (latent autoimmune diabetes of adults), sometimes
called slow-onset type 1 diabetes.
Type 2 diabetes mellitus • .
Previously called non-insulin-dependent diabetes
mellitus, this is the most common variety worldwide (about 90
per cent of all diabetes mellitus cases).

Patients are much less likely to develop ketoacidosis than

those with type 1 diabetes, although insulin may some times
be needed.

Onset is most usual during adult life; there is a familial

tendency and an association with obesity.

There is a spectrum of disorders ranging from mainly insulin

resistance with relative insulin deficiency to a
predominantly secretory defect with insulin resistance.
 .
Other specific types of diabetes mellitus
A variety of inherited disorders may be responsible for the
syndrome, either by reducing insulin secretion or by causing relative
insulin deficiency because of resistance to its action or of insulin
receptor defects, despite high plasma insulin concentrations
1-Genetic defects of b-cell function
2-Genetic defects of insulin action
3-Insulin deficiency due to pancreatic disease
4-. Endocrinopathies
5-Drugs.
6-Infections
7-Rare forms of autoimmune-mediated diabetes
Gestational diabetes mellitus
.
In the UK, about 4–5 per cent of pregnancies are complicated by gestational diabetes
mellitus (GDM). It is associated with
1- increased fetal abnormalities,
2-high birth weight,
3-cardiac defects and polyhydramnios. ‫كثرة السائل الوالدي‬
4-birth complications,
5-maternal hypertension and the need for caesarean section may occur.

If maternal diet/lifestyle factors fail to restore glucose levels,

insulin is usually required to try to reduce the risk of these complications.

Women at high risk for GDM include those who have had :

1- GDM before, have previously given birth to a high-birth weight baby, are obese,
2-have a family history of diabetes mellitus
3-and/or are from high-risk ethnic groups, for example black or South Asian.

These women should be screened at the earliest opportunity and, if normal, retested at
about 24–28 weeks, as glucose tolerance progressively deteriorates throughout pregnancy.

In some units 50 g oral glucose is used and the blood glucose is sampled at 1 h – plasma
glucose of more than or equal to 7.8 mmol/L being diagnostic.
 .
If fasting venous plasma glucose is 7.0 mmol/L or more and/or the
random measurement gives a concentration of 11.1 mmol/L or more.
the woman has GDM. In equivocal cases, an OGTT is indicated. Six
weeks post partum, the woman should be reclassified with a repeat OGTT

Impaired glucose tolerance

The WHO definition of impaired glucose tolerance (IGT) is a fasting venous

plasma glucose concentration of less than 7.0 mmol/L and a plasma glucose
concentration between 7.8 mmol/L and 11.1 mmol/L 2 h after an OGTT.

Some patients with IGT develop diabetes mellitus later and may require an
annual OGTT to monitor for this.

However, because of the increased risk of vascular complications, secondary

causes of IGT should be sought, dietary advice given, if necessary, and the
patient followed up.

In pregnancy IGT is treated as GDM because of the risks to the fetus.

 .
Impaired fasting glucose •
Impaired fasting glucose (IFG), like IGT, refers to a metabolic stage
intermediate between normal glucose homeostasis and diabetes mellitus.
The definition is that the fasting venous plasma glucose is 6.1 mmol/L or
more but less than 7.0 mmol/L, and less than 7.8 mmol/L 2 h after an OGTT.

Impaired Fasting Glucose Level (IGF)6.1 - less than 7 mmol/L

Subjects at risk of developing.diabetes mellitus
1- A strong family history of diabetes mellitus may suggest that
an individual is at risk of developing diabetes mellitus
(particularly type 2),
2-a family history of GDM, IGT or IFG.
3-Those with predisposing HLA types and autoimmune disease
may be susceptible to developing type 1 diabetes.
4- Type 2 diabetes is more common in certain racial groups,
such as Afro- Caribbeans, South Asians.
5-One of the reasons why type 2 diabetes is on the increase
tendency to obesity and central adiposity in urbanized and more
sedentary populations consuming high-calorie diets.
6- phenotype (Barker–Hales) hypothesis proposes that
nutritional deficiency in fetal and early infancy associated with
low birth weight increases the risk of developing type 2 diabetes
and insulin resistance.
Insulin resistance syndrome or metabolic syndrome
.
It has been recognized that certain coronary heart disease risk factors occur together.
There is an aggregation of lipid and non-lipid risk factors of metabolic origin.
A particular cluster is known as the metabolic syndrome, syndrome X or Reaven’s
syndrome and is closely linked to insulin resistance. One definition is the presence of
three or more of the following features:

Abdominal obesity (waist circumference):

– male more than 102 cm (40 in),
– female more than 88 cm (35 in).
Fasting plasma triglycerides more than 1.7 mmol/L.
Fasting plasma high-density lipoprotein (HDL)
cholesterol:
– male less than 1.0 mmol/L,
– female less than 1.3 mmol/L,
Blood pressure more than or equal to 130/85 mmHg.
Fasting blood glucose more than 5.5 mmol/L.
------------------------------------------------------------
Plasma levels of insulin would be expected to be raised, that is, hyperinsulinaemia.
Other associated features may include polycystic ovary syndrome, fatty liver, raised fi-
brinogen and plasminogen activator inhibitor 1 concentrations, renal sodium retention,
hyperuricaemia and dense low-density lipoprotein (LDL) particles ,
 .
Metabolic features of diabetes mellitus
Patients with type 1 diabetes tend to be diagnosed
before the age of 40 years, are usually lean and have
experienced weight loss at the time of presentation.
They may present with diabetic ketoacidosis.
Conversely, patients with type 2 diabetes often
present later, usually after the age of 40 years, and
are often overweight or obese.
The presentation can be insidious and they may
have had diabetes years before diagnosis.
Hyperglycaemia
.
If plasma glucose concentration exceeds about 10 mmol/L, glycosuria
would be expected. High urinary glucose concentrations produce an osmotic
diuresis and therefore polyuria.
Cerebral cellular dehydration due to hyperosmolality, secondary to
hyperglycaemia, causes thirst (polydipsia). ‫كتأثير ثانوي‬ ‫ الناتجة‬،hyperosmolality ‫جفاف الخاليا الدماغية نتيجة لـ‬
.(‫ كثرة شرب ملاء‬، ‫ يسبب العطش )العطاش‬،Hyperglycaemia‫للـ‬
A prolonged osmotic diuresis may cause excessive urinary electrolyte loss.
These ‘classic’ symptoms are suggestive of diabetes mellitus.
Diabetic patients on insulin may show the following conditions. The ‘dawn’
phenomenon is the physiological response of the elevation of blood glucose
concentration in the early morning prior to breakfast due to nocturnal
spikes in GH concentration and a rise in plasma cortisol concentration that
‫ تعني زيادة الگلوكوز في الصباح الباكر نتيجة لزيادة تراكيز‬Dawn ‫ظاهرة الفجر‬
increase hepatic gluconeogenesis. .Gluconeogenesis ‫ والذين ينشطان عملية ال‬Cortisol ‫ و ال‬GH ‫ال‬
Conversely, in some diabetic patients nocturnal hypoglycaemia may
evoke a rebound counter-regulatory hyperglycaemia called the Somogyi
phenomenon. (‫ظاهرة سوموجي هي عبارة عن انخفاض ليلي )عملية تعديل لتركيز الگلوكوز‬
.‫ صباحا ً عند املرضى املصابني بالسكري‬٤-٢ ‫في تركيز الگلوكوز في الدم عند‬
Patient blood glucose checking at 02.00– 04.00 h, or continuous glucose
monitoring if available, may distinguish these conditions, as the Somogyi
phenomenon reveals hypoglycaemia. It is sometimes possible to ameliorate
these conditions by giving intermediate-acting insulin before bedtime.
ً ‫ صباحا‬٤-٢ ‫يجب متابعة تركيز الگلوكوز عند املريض في‬
.‫او بصورة مستمرة‬
‫إعطاء االنسولني قبل وقت النوم يمكن ان يفاقم الحالة‬
 .
Abnormalities in lipid metabolism •
A- These may be secondary to insulin deficiency. Lipolysis is
enhanced and plasma NEFA concentrations rise.
In the liver,
1-NEFAs are converted to acetyl CoA and ketones,
2- or are re-esterified to form endogenous triglycerides and
incorporated into VLDLs; the latter accumulate in plasma
because lipoprotein lipase, which is necessary for VLDL
catabolism, requires insulin for optimal activity.
B- High-density lipoprotein cholesterol concentration tends to be
low in type 2 diabetes.
C-If insulin deficiency is very severe, there may also be
chylomicronaemia.
E-The rate of cholesterol synthesis is also increased, with an
associated increase in plasma LDL concentrations.
Consequently, patients with diabetes may show high plasma
triglyceride, raised cholesterol and low HDL cholesterol
concentrations
 Caused by Sorbitol accumulation

}
 The polyol pathway
The polyol pathway comprises two enzymes: Aldose Reductase and Sorbitol Dehydrogenase.
Aldose reductase normally reduces aldehydes generated by reactive oxygen species to inactive alcohol.
When glucose concentration in a cell becomes too high, aldose reductase reduces that glucose to
sorbitol.
Where Aldose Reductase has a (High Km) thus a (Low a nity) for Glucose, so it gets activated by the
high glucose concentration.
Sorbitol dehydrogenase then oxidises sorbitol to fructose, so this mechanism is helpful for the cells that
depends on fructose as an energy source; Like Spermatocytes.
Some of the tissues does not have the (Sorbitol Dehydrogenase); Like retina, Nephrons and Nerves, so
the sorbitol will accumulate (buildup) in these tissues making them su er the damaging e ects of
sorbitol in cells, including osmotic damage.
High intracellular osmolality shifts water inside the cell (to maintain the gradient) which may leads the
cell to swell and su er the (Retinopathy, Nephropathy and Neuropathy Respectively).
ff
ffi
ff
ff
 .
Long-term effects of diabetes mellitus •
Vascular disease is a common complication of diabetes mellitus.
A-Macrovascular disease due to abnormalities of large vessels
may present as coronary artery, cerebrovascular or peripheral
vascular insufficiency.
The condition is probably related to alterations in lipid
metabolism and associated hypertension. The most common cause
of death is cardiovascular disease, including myocardial infarction.
B- Microvascular disease due to abnormalities of small blood
vessels particularly affects the retina
a-(diabetic retinopathy) and the kidney
b- (nephropathy); both may be related to inadequate glucose
control. Diabetes is one of the most common causes of patients
requiring renal dialysis.
 .
Microvascular disease of the kidney is associated with proteinuria.
Kidney disease is associated with several abnormalities, including
proteinuria and progressive renal failure.
Proteinuria ‫ في الكليتني يكون مترافقا ً مع الـ‬Microvascular Disease ‫الـ‬
The presence of small amounts of albumin in the urine
(microalbuminuria) is associated with an increased risk of developing
progressive renal disease, which may sometimes be prevented by more
stringent plasma glucose and blood pressure control.
The renal complications may be partly due to the increased glycation
of structural proteins in the arterial walls supplying the glomerular
basement membrane; similar vascular changes in the retina may
account for the high incidence of diabetic retinopathy. Glycation of
proteinin the lens may cause cataracts. renal complications ‫الـ‬
‫تجمع البروتني في العني يمكن ان يسبب اعتامها‬
‫قد تكون ناتجة )جزئيا ً( عن‬
 .
Infections are also more common in diabetic patients, for
example urinary tract or chest infections, cellulitis and candida.
C-Diabetic neuropathy can occur, which can be peripheral
symmetric sensory, peripheral painful, acute mononeuropathies
or autonomic.
It has been suggested that sorbitol is implicated in the
aetiology of diabetic neuropathy through the action of aldolase
reductase. .aldolase reductase ‫ من خالل تأثيره عبر‬diabetic neuropathy‫ يعد جزءاً من االسباب املرضية للـ‬Sorbitol‫يوجد تصور بأن ال‬
Erectile dysfunction is also relatively common and in some
cases may be partly neurologically mediated.
Diabetic ulcers, for example of the feet, can lead to
gangrene and amputation.
The ulcers can be ischaemic, neuropathic or infective. The
joints can also be affected, for example Charcot’s joints.
Other features of diabetes mellitus are skin disorders, such
as necrobiosis lipoidica, and abscesses.
Gollagen Degeneration ‫خراج‬
Principles of management of. diabetes mellitus •
The management of diabetes mellitus is considered briefly, although consulting a
specialist text is recommended if further information is required.
Insulin requirements vary in patients with type 1 diabetes. For example, the dose
may need to be increased during any illness or during pregnancy and reduced if there is
increased activity or meals are missed.

In patients with type 2 diabetes, plasma glucose concentrations may be controlled by

diet, associated with weight reduction, and increased physical activity, but insulin may
be required during periods of stress or pregnancy.
In this group insulin secretion can be stimulated by the sulphonylurea drugs, such as
gliclazide, glipizide, glibenclamide or glimepiride.

Biguanides, usually metformin, can also be used and are particularly useful in obese
patients.
Metformin decreases intestinal glucose absorption and hepatic gluconeogenesis as
well as increasing tissue insulin sensitivity.
Metformin can inhibit oxidative phosphorylation, which can, under certain
circumstances, lead to lactic acid accumulation.Acarbose delays post-prandial
absorption of glucose by inhibiting a-glucosidase.
 .
Other oral agents are the thiazolidinediones or glitazones’, for example
rosiglitazone and pioglitazone, which activate g-peroxisome proliferator-activated
receptors and which can reduce insulin resistanceby a number of metabolic
pathways, some of which involve increasing the transcription of nuclear proteins
that control free fatty acid and tissue glucose uptake.

Repaglinide is a meglitinide that increases insulin release from pancreatic b-

cells and enhances tissue insulin sensitivity.
The incretins are gastrointestinal hormones that increase insulin release from
the pancreas after eating, for example glucagon-like peptide (GLP-1) and gastric
inhibitory peptide (GIP).

They are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP- 4).

Incretin mimetics such as exenatide or liraglutide or DPP-4 inhibitors such as

sitagliptin, vildagliptin or saxagliptin are being used in type 2 diabetes mellitus..

It is now recognized that diabetes mellitus is not just a glucose disorder. It is

important also to optimize abnormal plasma lipids and correct hypertension,
particularly if there is microalbuminuria or proteinuria .
 Glucokinase Vs Hexokinase

Ser Category Glucokinase Hexokinase

1 Site Liver only liver cells and β-pancreatic cells All tissue cells
Low affinity: it acts only in the presence High affinity: it acts even in the presence of low
of high Glucose blood concentration blood Glucose concentration

2 Affinity to glucose High Km Low Km

High Vmax
High capacity
3 Substrate Glucose only
4 Effect of insulin Induces synthesis of Glucokinase
5 Effect of glucose-6- phosphate No effect
Acts in liver after meals. It removes
glucose coming in portal circulation,
6 Function converting it into glucose-6-phosphate
to be used to synthesize glycogen in a
process known as glycogenesis.
7
8
9
Low Vmax
Low capacity
Glucose, galactose D-fructose, 5-keto-D-fructose,
2-deoxy-D-glucose and D-mannose.
No effect
Allosterically inhibits Hexokinase
Phosphorylates glucose inside the body
cells. This makes glucose concentration more in
blood than inside the cells This leads to
continuous supply of glucose for the tissues even
in the presence of low blood glucose

Similarities Between Hexokinase and Glucokinase

1- Hexokinase and glucokinase are two types of enzymes involved in glycolysis.
2- They are isoenzymes, enzymes with different structure and the same function.
3- Both convert glucose into glucose 6-phosphate.
4- They are rate-limiting enzymes in the glycolysis.
5- These enzymes trap glucose inside the cell since G6P cannot freely diffuse out of the cell.
 Diabetes Mellitus Drugs

ً ‫مهم جدا‬
 .
Monitoring of diabetes mellitus
Glycosuria
Glycosuria can be defined as a concentration of urinary glucose
detectable using relatively insensitive, but specific, screening tests.
These tests often depend on the action of an enzyme, such as glucose
oxidase, incorporated into a diagnostic strip.
Usually, the proximal tubular cells reabsorb most of the glucose in the
glomerular filtrate.
Glycosuria, as defined above, occurs only when the plasma, and therefor
glomerular filtrate, concentrations exceed the tubular reabsorptive capacity.
This may be because the plasma and glomerular filtrate concentrations
are more than about 10 mmol/L, and therefore the normal tubular
reabsorptive capacity is significantly exceeded.
Very rarely, if the glomerular filtration rate is much reduced, there may be
no glycosuria despite plasma glucose concentrations more than 10 mmol/L.
A diagnosis of diabetes mellitus should never be made on the basis of
glycosuria.
 .
Blood glucose
Blood glucose concentrations may be measured using glucose testing
reagent strips. The colour change of the strip can be assessed visually or
by using a portable glucose meter and the reaction often involves an
enzyme determination of glucose, for example glucose oxidase.
Meters should ideally be over seen by laboratory staff expert in point
of care testing . Although the measurement of blood glucose
concentrations
involves the discomfort of several skin punctures, many motivated
patients are able to adjust their insulin dose more accurately based on
these results than on those obtained by testing their urine.
This method of testing is also useful in the detection of
hypoglycaemia.
For patients who do not like blood testing, urinary glucose
testing can be used, but of course cannot detect
hypoglycaemia and is dependent on the renal glucose
threshold.
 .
Glycated haemoglobin
Glycated haemoglobin (HbA1c) is formed by nonenzymatic
glycation of haemoglobin and is dependent on the mean plasma:
1-glucose concentrations 2- on the lifespan of the red cell; falsely low
values may be found in patients with haemolytic disease.
Measurement of blood HbA1c may:
1- not reveal potentially dangerous short-term swings
2- nor does HbA1c detect hypoglycaemic episodes and thus plasma
glucose estimations may also be useful.
This was expressed as a percentage of total blood haemoglobin
concentration and gives a retrospective assessment of the mean
plasma glucose concentration during the preceding 6–8 weeks.
The higher the glycated haemoglobin, the poorer the mean diabetic or
glycaemic control.
Glycated haemoglobin used to be expressed in percentage units but
now is expressed as mmol/mol
Fructosamine .
The measurement of plasma fructosamine concentrations
may be used to assess glucose control over a shorter
time course than that of HbA (about 2–4 weeks), but
1c

the assay has methodological limitations.

1- Fructosamine reflects glucose bound to plasma proteins,

predominantly albumin, which has a plasma half-life of about 20
days but is problematic in patients with hypoalbuminaemia, for
example due to severe proteinuria.

2- This assay may sometimes be useful in pregnancy and also

if haemoglobin variants, for example HbS or HbC, exist that
may interfere with certain HbA assays.
1c
Blood ketones • ,
Monitoring of blood ketones may have a place in the home management of
type 1 diabetes. A b-hydroxybutyrate below 0.60 mmol/L is normal, whereas
values between 0.60 mmol/L and 1.0 mmol/L may necessitate more insulin, and
concentrations greater than 1.0 mmol/L a warning to seek medical advice.

Urinary albumin determination and diabetic nephropathy

One of the earliest signs of diabetic renal dysfunction
is the development of small amounts of albumin in the urine, called
microalbuminuria.
An albumin concentration less than 30 mg/day or less than 20 μg/min is
defined as normoalbuminuria.

Microalbuminuria is defined as a urinary albumin excretion of 30–300

mg/day or 20–200 μg/min.

Untreated, this can progress to overt albuminuria or proteinuria (more

than 300 mg/day), impaired renal function and finally end-stage renal
failure.
 . overnight collection can be
A random urine sample or timed
useful to assess urinary albumin excretion, although the standard
test is the urinary albumin to creatinine ratio (ACR), which
avoids a timed urine collection

This should normally be less than 2.5 g/mol in males

and less than 3.5 g/mol in females.

An abnormal result should be confirmed in two out of three urine

samples in the absence of other causes of proteinuria .

Apart from being predictive of diabetic renal complications,

urinary albumin excretion is also associated with increased
vascular permeability and enhanced risk of cardiovascular
disease.
 .
Acute metabolic complications of diabetes
mellitus
Patients with diabetes mellitus may develop various metabolic complications that
require emergency treatment, including coma, and these include the following.
1-Hypoglycaemia
This is probably the most common cause of coma seen in diabetic patients.
Hypoglycaemia is most commonly caused by

1-accidental over administration of insulin or sulphonylureas or meglitinides.

Precipitating causes include too high a dose of insulin or hypoglycaemic drug;

2- conversely, the patient may have missed a meal or taken excessive exercise after
the usual dose of insulin or oral hypoglycaemic drugs.

Hypoglycaemia is particularly dangerous, and some patients lack awareness of this;

that is to say, they lose warning signs such as sweating, dizziness and headaches.

Driving is a major hazard under such circumstances. Patients should monitor their
own blood glucose closely, carry glucose preparations to abort severe hypoglycaemia
and avoid high-risk activities during which hypoglycaemic attacks could be dangerous.
 .
2-Diabetic ketoacidosis •
Diabetic ketoacidosis may be precipitated by
1- infection,
2-acute myocardial infarction
3-vomiting.
4-The patient who reasons ‘no food, therefore no insulin’ could
mistakenly with hold insulin.

In the absence of insulin, there is increased lipid and protein

breakdown, enhanced hepatic gluconeogenesis and impaired
glucose entry into cells.
The clinical consequences of diabetic ketoacidosis are due to:
hyperglycaemia causing plasma hyperosmolality, metabolic
acidosis, glycosuria.
Plasma glucose concentrations are usually in the
range 20–40 mmol/L, but may be considerably higher,
 . ketoacidosis has been
although euglycaemic diabetic
described when plasma glucose concentrations are only
slightly elevated.
Hyperglycaemia causes glycosuria and hence an
osmotic diuresis.
Water and electrolyte loss due to vomiting, which is
common in this syndrome, increases fluid depletion. There
may be haemoconcentration and reduction of the glomerular
filtration rate enough to cause uraemia due to renal
circulatory insufficiency.
The extracellular hyperosmolality causes a shift of water
out of the cellular compartment and severe cellular
dehydration occurs.
Loss of water from cerebral cells is probably the
reason for the confusion and coma. Thus there is both
cellular and extracellular volume depletion.
 .
The rate of lipolysis is increased because of decreased
insulin activity; more free fatty acids are produced than
can be metabolized by peripheral tissues.
The free fatty acids are either converted to:
1- ketones by the liver
2-or of less immediate clinical importance, incorporated
as endogenous triglycerides into VLDL, sometimes
causing severe hypertriglyceridaemia .
Hydrogen ions, produced with ketones other than
acetone, are buffered by plasma bicarbonate. However,
when their rate of production exceeds the rate of
bicarbonate generation, the plasma bicarbonate falls
Hydrogen ion secretion causes a fall in urinary pH.
The deep, sighing respiration (Kussmaul’s respiration
 .
and the odour of acetone on the breath are classic features of diabetic
ketoacidosis.
Plasma potassium concentrations may be raised, secondarily to
the metabolic acidosis, before treatment is started.
This is due to 1- failure of glucose entry into cells in the absence of
insulin
2- and because of the low glomerular filtration rate.

During treatment, plasma potassium concentrations may fall as

potassium reenters cells, sometimes causing severe hypokalaemia
unless potassium is prescribed.
Plasma sodium concentrations may be low (hyponatraemia) or
low-normal at presentation, partly because of the osmotic effect of
the high extracellular glucose concentration, which draws water
from the cells and dilutes the sodium.
In the presence of a very high plasma glucose concentration, a
normal or raised plasma sodium concentration is suggestive of signifi-
cant water depletion.
 .
If there is severe hyperlipidaemia, the possibility of
pseudohyponatraemia.
When insulin is given, gluconeogenesis is inhibited,
glucose enters cells and sodium-free water follows along
the osmotic gradient.
If plasma sodium concentrations rise rapidly, the patient
may remain confused or even comatose as long as the
plasma osmolality remains significantly raised, despite a
satisfactory fall in plasma glucose concentration.
This may also occur if isosmolar or stronger saline
solutions are given inappropriately.
Hyperphosphataemia followed by hypophosphat -
aemia as plasma phosphate concentrations parallel those of
potassium may persist for several days after recovery from
diabetic coma. Similarly, hypermagnesaemia can result,
partly because of the acidosis.
 Plasma and urinary amylase activities may be markedly
.
elevated and, even in the presence of abdominal
pain mimicking an ‘acute abdomen’, do not necessarily
indicate acute pancreatitis. In some patients the amylase is of
salivary rather than pancreatic origin.

plasma creatinine assays cross-react with ketones, resulting

in a spurious plasma creatinine elevation.

Sometimes severe Hypertriglyceridaemia and

chylomicronaemia result, due to reduced lipoprotein lipase
activity in the face of insulin deficiency.

3- Hyperosmolal non-ketotic coma

In diabetic ketoacidosis there is always plasma

hyperosmolality due to the hyperglycaemia, and many of the
symptoms, including those of confusion and coma, are related to it.
 .
However, the term ‘hyperosmolal’ coma or ‘pre-coma’ is usually
confined to a condition in which there is marked hyperglycaemia but no
detectable ketoacidosis.

The reason for these different presentations is not clear. It has been
suggested that insulin activity is sufficient to suppress lipolysis but
insufficient to suppress hepatic gluconeogenesis or to facilitate
glucose transport into cells.

Hyperosmolal non-ketotic (HONK) coma now may be referred to as

hyperosmolar hyperglycaemic state (HHS) and may be of sudden onset.
It is more common in older patients.
Plasma glucose concentrations may exceed 50 mmol/L.

The effects of glycosuria are as described above, but

hypernatraemia due to predominant water loss is more commonly
found than in ketoacidosis and aggravates the plasma
hyperosmolality.
 .
Cerebral cellular dehydration, which contributes to the coma,
may also cause hyperventilation, and a respiratory alkalosis,
although sometimes plasma lactic acid may rise, evoking a
metabolic acidosis and thus a mixed acid–base disturbance may
occur. There may also be an increased risk of thrombosis.

4-Lactic acidosis
Lactic acidosis can cause a high anion gap
metabolic acidosis and coma.
.
Other causes of coma in .patients with diabetes •
mellitus
In addition to the comas described above, a patient with
diabetes mellitus may present with other comas:
Cerebrovascular accidents are relatively common in
diabetic patients because of the increased incidence
of vascular disease.
Diabetic patients can, of course, have any other coma,
for example drug overdose.
Diabetic patients are also more at risk of diabetic
Nephropathy and renal failure and thus uraemic coma.

.
Initial investigation of a diabetic patient presenting in coma

A diabetic patient may be in coma due to hyperglycaemia,

hypoglycaemia or any of the causes shown in Tables .

After a thorough clinical assessment, proceed as follows:

Notify the laboratory that specimens are being taken and ensure that
they are delivered promptly. This minimizes delays.
.
Take blood immediately for estimation of:
– glucose,
– sodium and potassium,
– urea and creatinine,
– bicarbonate,
– arterial blood gases.
Do a drug screen for aspirin and paracetamol if concomitant drug
overdose suspected.
Determination of plasma lactate will help diagnose a
lactic acidosis Test a urine sample or blood for ketones.
 If severe hypoglycaemia . is suspected on clinical
grounds or because of the results obtained using
reagent strips, glucose should be given
immediately while waiting for the laboratory
results.
It is less dangerous to give glucose to a patient
with Hyperglycaemia than to give insulin to a
patient with hypoglycaemia.
The results of point-of-care testing must be
interpreted with caution.
Also look for precipitating causes such as acute
myocardial infarction or infection.
 .
Oral glucose tolerance test
Before starting this test, contact your laboratory: local details may vary.

Procedure
The patient should be resting and should not smoke during the test.
The patient fasts overnight (for at least 10 h but not more than 16 h). Water, but no
other beverage, is
allowed.
A venous sample is withdrawn for plasma glucose estimation. If the glucose
concentration is measured in whole blood, the results will be approximately 1.0
mmol/L lower.

A solution containing 75 g of anhydrous glucose in 300 mL of water is hyperosmolar,

and not only may cause nausea and occasionally vomiting and diarrhoea, but also,
‫واضافة‬،‫ عالي االوزموالرية‬، 75g ‫املحلول هو عبارة عن گلوكوز منزوع املاء‬
because of delayed absorption, ‫ لذلك‬،‫الى كونه يسبب الغثيان والتقيؤ واالسهال ويكون امتصاصه بطيئا‬
ً
.‫فانه ايضا يؤثر على نتائج الفحص‬
‫لذلك يعطى املحلول كگلوكوز وسكريات قليلة التعدد لتقليل مقدار‬
.‫االوزموالرية خالل فترة الزمنية املخصصة للفحص‬

may affect the results of the test. It is therefore more usual to give a solution of a
mixture of glucose and its oligosaccharides, because fewer molecules per unit
volume have less osmotic effect than the equivalent amount of monosaccharide; the
oligosaccharides are all hydrolysed at the brush border, and the glucos
immediately enters the cells.
 .
solution that contains the equivalent of 75 g of anhydrous
glucose is: 113 mL of Polycal made up to approximately 300 mL
with water. This solution should be drunk slowly over a few
minutes. Further blood is taken 2 h after the ingestion of glucose.

.
The following factors may affect the result of the test: Previous
diet No special restrictions are necessary if the patient has been on
a normal diet for 3–4 days.

However, if the test is performed after a period of carbohydrate

restriction, for example as part of a weight-reducing diet, this may
cause abnormal glucose tolerance, probably because metabolism is
adjusted to the ‘fasted state’ and so favours gluconeogenesis.
Time of day Most OGTTs are performed in the morning and
the reference values quoted are for this time of day. There is
evidence that tests performed in the afternoon yield higher plasma
glucose concentrations and that the accepted ‘reference
values’ may not be applicable. This may be due to a
circadian variation in islet cell responsiveness.
Drug Steroids, oral contraceptives and thiazide
diuretics may impair glucose tolerance.
HYPOGLYCAEMIA .
By definition, hypoglycaemia is present if the plasma
glucose concentration is less than 2.5 mmol/L in a specimen
collected into a tube containing an inhibitor of glycolysis,
for example fluoride oxalate.
Blood cells continue to metabolize glucose in vitro, and
low concentrations found in a specimen collected without
such an inhibitor can be dangerously misleading
(pseudohypoglycaemia).
Symptoms of hypoglycaemia may develop at higher
concentrations if there has been a rapid fall from a
previously raised value, when adrenaline secretion is
stimulated and may cause sweating, tachycardia and
agitation
 .
As discussed earlier, cerebral metabolism
depends on an adequate supply of glucose from
ECF, and the symptoms of hypoglycaemia may
resemble those of cerebral hypoxia
(neuroglycopenia).

Faintness, dizziness or lethargy may progress

rapidly to coma and, if untreated, permanent
cerebral damage or death may occur.
Hypoglycaemia is a disease manifestation
and not a diagnosis. There is no completely
satisfactory classification of its causes. However,
one useful approach is to divide hypoglycaemia into
(inappropriate) hyperinsulinaemia, (appropriate)
hypoinsulinaemia and reactive hypoglycaemia .
 .
Hypoinsulinaemic hypoglycaemia
Non-pancreatic tumours (non-islet cell tumours)
Although carcinomas (especially of the liver) and sarcomas have been reported to
cause hypoglycaemia,
Endocrine causes
Hypoglycaemia may occur in hypothyroidism, pituitary or adrenal insufficiency.
However, it is rarely the presenting manifestation of these conditions.
Impaired liver function
The functional reserve of the liver is so great that, despite its central role
in the maintenance of plasma glucose concentrations, hypoglycaemia is a
rare complication of liver disease. It may complicate very severe hepatitis,
hypoxic liver disease associated with congestive cardiac failure or liver
necrosis if the whole liver is affected. Plasma IGF-1 concentration may be
low.
Renal failure
can result in hypoglycaemia as the kidney, like the liver, is a
gluconeogenic organ.
 .
Hyperinsulinaemic hypoglycaemia
Insulin or other drugs are probably the most common causes. It is most
important to take a careful drug history. Unless the facts are deliberately
concealed by the patient, the offending drug should be easily identifiable.
Hypoglycaemia in a diabetic patient may be caused by accidental insulin
overdosage, by changing insulin requirements, or by failure to eat after insulin has been
given.

Self-administration for suicidal purposes or togain attention is not unknown, and

homicidal use is a remote possibility. Sulphonylureas or meglitinides may also induce
hypoglycaemia, especially in the elderly.

Hypoglycaemia due to exogenous insulin suppresses insulin and C-peptide

secretion. Measurement of plasma C-peptide concentrations may help to
differentiate exogenous insulin administration, when C-peptide secretion is
inhibited, from endogenous insulin secretion, when plasma C-peptide is raised,
whether it is from an insulinoma or following pancreatic stimulation by sulphonylurea
drugs. An insulinoma is usually a small, histologically benign primary tumour of the
islet cells of the pancreas
 .
It may present at any age. Multiple tumours may occur and may be part of
the syndrome of multiple endocrine neoplasia (MEN). As with other
functioning endocrine tumours, hormone secretion is inappropriate and usually
excessive.
C-peptide and proinsulin are released in parallel with insulin, and plasma
concentrations are therefore inappropriately high in the presence of
hypoglycaemia. Some insulinomas secrete just proinsulin.

Attacks of hypoglycaemia occur typically at night and before breakfast,

associated with hunger, and may be precipitated by strenuous exercise.

Personality or behavioural changes may be the first feature; some patients

present initially to psychiatrists. Insulin antibodies can form in response to
exogenous insulin, probably less so for human insulin than for animal types.

Sometimes insulin antibodies form despitethe patient never having been

exposed to exogenous insulin – autoimmune insulin syndrome (AIS). Insulin
receptor antibodies may cause hypoglycaemia,
although they sometimes lead to insulin resistance and hyperglycaemia
Reactive (functional) hypoglycaemia
.
Some people develop symptomatic hypoglycaemia between 2 and 4 h after a meal or
a glucose load. Loss of consciousness is very rare. Similar symptoms may follow a
gastrectomy or bariatric gastric banding, when rapid passage of glucose into the
intestine, and rapid absorption, may stimulate excessive insulin secretion (‘late dumping
syndrome’). Reactive hypoglycaemia is uncommon.

Alcohol-induced hypoglycaemia
Hypoglycaemia may develop between 2 and 10 h after the ingestion of large amounts
of alcohol.

It is found most often in undernourished subjects and chronic alcoholics but may
occur in young subjects when they first drink alcohol.

Hypoglycaemia is probably caused by the suppression of gluconeogenesis during

the metabolism of alcohol.
Differentiation of hypoglycaemia from alcoholic stupor may be impossible unless
the plasma glucose concentration is estimated.
It may be necessary to infuse glucose frequently during treatment, until glycogen
stores are repleted and plasma glucose concentrations are stable.