GLUCOSE METABOLISM AND DISORDERS OF

GLUCOSE METABOLISM: DIABETES MELLITUS

AND HYPOGLYCEMIA

BY
Opuene Emmanuel Oyeinmieyi
CLI/2017/111
OUTLINE
 Introduction
 Glucose metabolism
 Glucose homeostasis
 Hormones involved in glucose homeostasis
 Organs involved in glucose homeostasis
 Diabetes Mellitus and hyperglycemia
 Acute metabolic complications of Diabetes Mellitus
 Hypoglycemia
INTRODUCTION
• Glucose is a reducing sugar and is an essential metabolic substrate of
all mammalian cells. It is the end product of carbohydrate
metabolism.
• Most tissues and organs in the body need glucose constantly as an
important source of energy.
• Derangement in glucose metabolism causes a number of diseases
ranging from Diabetes Mellitus to hypoglycemia.
• Therefore, blood glucose concentrations need to be maintained
stringently within narrow limits. The brain is highly dependent upon
the extracellular glucose concentration for its energy supply.
GLUCOSE HOMEOSTASIS
• Glucose homeostasis is of utmost importance to our health due to the
central importance of glucose as a source of energy, especially because the
brain cannot synthesize nor store glucose in significant amounts. Therefore
hypoglycemia is likely to greatly impair cerebral function or even lead to
irreversible neuronal damage.
• Thus maintaining adequate levels in the blood is necessary for survival.
• Plasma glucose concentration normally ranges between 4mmol/L and
10mmol/L.
• Normal glucose homeostasis is primarily maintained by glucagon, cortisol,
epinephrine, growth hormone(which raises blood glucose levels) and
insulin(which lowers blood glucose).
Hormones involved in glucose homeostasis
Insulin
• Insulin is the most important hormone controlling plasma glucose
concentration. It is produced by the beta cells of the pancreatic islets of
Langerhans, and it is made up of 51 amino acids.
• Beta cells produce the prohormone proinsulin but this undergoes
cleavage before secretion to form insulin and C-peptide.
• Its secretion from the beta cells is stimulated by a raised plasma glucose
greater than 5mmol/L via GLUT 2 on these cells. Gut hormones also
called incretins (Glucagon like peptide 1 and Gastric inhibitory peptide)
stimulate insulin secretion.
• The transport of glucose into the liver and brain does not depend on
insulin but on extracellular glucose concentration.
Glucagon
• Glucagon is a 29 amino acid polypeptide synthesized by the alpha
cells of the pancreatic islets of Langerhans.
• Its secretion is stimulated by hypoglycemia, and it acts to increase
blood glucose levels.
• It enhances hepatic glycogenolysis (glycogen breakdown) and
gluconeogenesis.
Organs involved in glucose homeostasis
The Liver : most important organ maintaining a constant glucose supply
to the other tissues, including the brain.
Others include:
1. The renal cortex
2. Adipose tissue
3. Skeletal muscle
The Liver
• The liver is the most important organ maintaining a constant glucose
supply to the other tissues, including the brain.
• The conversion of glucose into Glucose-6-Phosphate is catalyzed in
the liver by glucokinase. Glucokinase activity is induced by insulin.
• Hepatic cells can store some of the excess glucose as glycogen. The
rate of glycogenesis may be increased by insulin in response to
hyperglycemia.
• The liver can also convert some of the excess glucose to fatty acids,
which are ultimately transported as triglycerides in VLDL and are
stored in adipose tissue.
• The liver can also synthesize glucose by gluconeogenesis using the metabolic
products from other tissues such as glycerol, lactate or alanine.

• It contains the enzyme glucose-6-phosphatase which hydrolyses G6P from

either glycogenolysis or gluconeogenesis and releases glucose and helps to
maintain extracellular fasting concentrations. In fasting, hepatic glycogen are
used up after 24hrs.

• During fasting, the liver converts fatty acids released from adipose tissue to
ketones. Ketones can be used by other tissues including the brain as an energy
source when plasma glucose concentration is low.
 The Renal Cortex
• It is the only other tissue capable of gluconeogenesis, and of converting Glucose-
6-Phosphate to glucose (glycogenolysis).

• The gluconeogenic capacity of the kidney is particularly important during

prolonged fasting.
 Adipose Tissue
• Adipose tissue cells acting in conjunction with the liver, converts excess glucose into
triglycerides and stores it in this form. In the liver, TAG is formed from glycerol-3-phosphate and
fatty acids.

• The triglycerides are then transported to adipose tissue cells incorporated in VLDL, where they
are hydrolyzed by lipoprotein lipase. The released fatty acids are re-esterified within the
adipocytes with glycerol-3-phosphate (derived from glucose which entered the adipose tissue
under the influence of insulin).

• The resultant triglyceride is then stored and yields more energy when used than glycogen.

• During fasting, the triglycerides are reconverted to fatty acids and glycerol by lipolysis. Glycerol
can then enter the hepatic gluconeogenic pathway, thus minimizing the fall in glucose
concentration.
• The fatty acids can be converted by most tissues (except the brain) to acetyl CoA,
which then enters the TCA cycle as an energy source.

• Ketosis occurs when fat cells are the main energy source and may result from
fasting or from reduced nutrient absorption.

• Mild ketosis may occur after as little as 12 hours of fasting.

 Skeletal Muscle
• Under the influence of insulin, glucose enters the muscles and is stored as
glycogen. However, this glycogen cannot be reconverted to glucose because of
the lack of glucose-6-phosphatase. Hence, can only serve local needs.

• During muscular activity, glycogenolysis is stimulated by adrenaline and the

resultant Glucose-6-Phosphate is metabolized by glycolysis and TCA cycle to
produce energy.

• When the rate of glycolysis exceeds the availability of oxygen, lactate is

produced.

• The lactate is transported in the blood to the liver where it can be used in
gluconeogenesis, providing more glucose for the muscle (Cori-cycle).
DIABETES MELLITUS AND
HYPERGLYCAEMIA
• Hyperglycemia is the elevation of blood glucose levels above
11.1mmol/L.
• It may be due to:
1. Intravenous infusion of glucose-containing fluids
2. Severe stress : This is usually a transient effect
3. Diabetes mellitus and impaired glucose absorption
DIABETES MELLITUS
• Diabetes Mellitus (DM) is a Systemic metabolic disorder
characterized by chronic hyperglycemia with disturbances in
carbohydrate, fat and protein metabolism due to a defect in insulin
secretion/action or both.
• It has been defined by WHO on the basis of laboratory findings, as the
fasting venous plasma glucose concentration of 7.0mmol/L or more
(on more than one occasion or once in the presence of diabetes
symptoms) or a random venous plasma glucose concentration of
11.1mmol/L or more.
Classification Of Diabetes Mellitus
• Type 1- Absolute Insulin Deficiency: It usually presents acutely in
younger people
• Auto-immune : It results from a cellular –mediated autoimmune destruction of
the beta cells of pancreas. Histological investigation shows Islet cell antibodies
(ICA), Antibodies to insulin, and other proteins that are sensitive markers of
risk of progression of diabetes.
• Idiopathic: more common among the black and Asian people. It shows strong
inheritance patterns

• Type 2- Insulin Resistance: It usually presents more chronically in the middle-

aged and elderly. 95% of patients belong in this group. The disease is due to
the decreased insulin response to hyperglycemia as well as insulin resistance.
• Both type 1 and type 2 are genetically heterogenous. There is a
familial incidence in type 1, although to a lesser extent than with type
2 DM. Furthermore, different environmental factors are involved in
both type 1 and 2 DM.

• For Type 1 there is considerable circumstantial evidence that viral

antigens (e.g. coxsackie B) may initiate the autoimmune process in
some genetically susceptible individuals. Proteins in cows’ milk have
also been implicated, as has vitamin D deficiency.
• Environmental factors are also important in type 2 DM . Many
patients with type 2 DM are obese, and various drugs, including
corticosteroids and other immunosuppressants, protease inhibitors,
thiazides in high doses and some ‘atypical’ antipsychotics and β-
adrenergic antagonists, are diabetogenic.
DM from other specific causes

• Genetic defects of beta cell function- MODY 1, 2 and 3

• Genetic defects in insulin action- type A insulin resistance
• Diseases of the exocrine pancreas- pancreatitis, cystic fibrosis,
pancreatectomy
• Endocrinopathies- acromegaly, Cushing’s syndrome
• Drug- or chemical-induced- thiazide diuretics
• Infections- septicemia, congenital rubella
• Uncommon forms of immune-mediated diabetes- anti-insulin receptor
antibodies
• Other genetic syndromes sometimes associated with diabetes- Down’s,
Klinefelter’s, Turner’s syndromes
Type 4- Gestational DM :
• It is diabetes or impaired glucose tolerance recognized during
pregnancy
• Women at high risk for GDM include those who have had GDM
before, have previously given birth to a high-birthweight baby, family
history of DM, and are of Black or South Asian races. They are at a risk
of developing type 2 DM later.
• O’Sullivan’s screening test: the test is administered at about 24-28
weeks. 50g oral glucose is used and the blood glucose is sampled at
1hour. Plasma glucose of more than or equal to 7.8mmol/L being
diagnostic.
Metabolic features of Diabetes Mellitus
• Hyperglycemia: This is a condition in which an excessive amount of
glucose circulates in the plasma i.e. plasma glucose concentration
>11.1mmol/L. Hyperglycemia is associated with the following:
1. Glycosuria
2. Polyuria: The high urinary glucose concentration produce an osmotic
diuresis and therefore polyuria. This is the passage of urine of >3L.
3. Polydipsia: there is cerebral cellular dehydration due to hyperosmolality
which causes thirst.
4. Also polyphagia, to compensate for the loss of protein and glucose
5. There is also excessive urinary electrolyte loss
• Abnormal lipid metabolism: This is secondary to insulin deficiency.
Lipolysis is enhanced and plasma NEFA rise. In the liver, NEFAs are
converted to acetyl-coA and ketones, or re-esterified to form
endogenous TAG and incorporated to VLDLs, which now accumulates
in the plasma because lipoprotein lipase which is necessary for VLDL
metabolism, requires insulin for optimal activity.

Loop
Long-term effects of diabetes mellitus
• Vascular disease: it is a common complication of diabetes mellitus. It
may be a microvascular disease or a macrovascular disease.
• Kimmelstiel-Wilson lesions: it is associated with long-standing DM and
affects microvasculature i.e. capillary blood vessels in glomerulus. It
may cause nephrotic syndrome.
• Infections: urinary tracts and chest infections, cellulitis, candida
• Erectile dysfunction
• Diabetic ulcers which may lead to gangrene and amputation.
Management of diabetes mellitus
• The aims of treatment are to alleviate symptoms and prevent the acute
metabolic complications of diabetes, and to prevent long-term
complications.
• The first of these objectives is usually attainable with dietary control
with or without oral hypoglycaemic agents in patients with type 2 DM
(at least initially: insulin is often required later in the course of the
condition),
• Treatment in Type 1 DM patient includes dietary and insulin. Insulin
requirements vary in patients with type 1 DM. The dose may be
increased during illness or pregnancy and reduced if there is increased
activity or meals are missed.
Management of diabetes mellitus
• In patients with type 2 DM, plasma glucose can be controlled by diet,
associated with weight reduction and increased physical activity.
Insulin secretion can be stimulated by the sulphonylurea drugs such
as glipizide or glimepiride. Other drugs include:
• Metformin: decreases intestinal glucose reabsorption and hepatic
gluconeogenesis. It increases tissue insulin sensitivity.
• Incretin mimetics and enhancers
Monitoring of diabetes mellitus
Treatment in diabetes is monitored clinically, by ensuring that the
patient’s symptoms are controlled, and by measurement of blood
glucose concentration and other objective indicators of glycaemic
control.
Blood glucose: the blood glucose concentration can be measured using
glucose testing reagent strips and the color change of the strip can be
assessed visually. It can also be measured by using a portable glucose
meter and the reaction involves an enzyme determination of glucose.
Their preprandial and post prandial glucose concentration should be
monitored.
Monitoring of diabetes mellitus
• Urine testing for glucose is now little used; it should not be used to
monitor type 1 diabetes because it is only semi-quantitative and is of
no value in the detection of hypoglycaemia.
• Urine glucose excretion also depends on the renal threshold for
glucose. if this is low glucose may be present in the urine at normal
blood glucose concentrations. Urine testing for glucose should be
used in type 2 diabetes only in patients unable or unwilling to do
blood tests.
 Monitoring of diabetes mellitus

• Glycated hemoglobin HbA1c : This is the best index of long-term control of blood glucose level. It is
formed by the non-enzymatic glycation of hemoglobin and is dependent on:
1. Mean plasma glucose concentrations
2. Lifespan of the red cells.
It is a non-enzymatic reaction in which glucose forms a Schiff base with the N-terminal of the beta
chain hemoglobin. Once attached, glucose is not removed from hemoglobin.
It was expressed as percentage of total blood hemoglobin concentration and gives a retrospective
assessment of the mean plasma glucose concentration during the preceding 6-8 weeks (42-56 days).
The higher the glycated hemoglobin, the poorer the mean diabetic control.
Glycated hemoglobin, which used to be expressed in percentage unit is now expressed in mmol/mol
by subtracting 2.15 from the percentage of glycated hemoglobin and then multiplying the answer by
10.929.
The normal level of glycated hemoglobin is about 4-7%
Monitoring of diabetes mellitus
• Fructosamine: These are compounds that result from the glycation of
plasma protein e.g. Albumin. The measurement of plasma
fructosamine concentration is used to assess glucose control for
shorter weeks (about 2-4 weeks). It reflects glucose bound to plasma
proteins and it is problematic in patients with hypoalbuminemia.
• Blood ketones: a beta-hydroxybutyrate below 0.60mmol/L is normal,
whereas values between 0.60mmol/L and 1.0mmol/L may necessitate
more insulin.
Acute metabolic complications of diabetes
mellitus
Patients with diabetes mellitus may develop various metabolic
complications like coma that require emergency treatment and these
include the following:
• Hypoglycemia: it is the most common cause of coma seen in patients
with diabetes. It is most commonly caused by accidental over
administration of insulin or sulphonylureas. Precipitating causes
include too high a dose of insulin or hypoglycemic drug or the
patients may have missed a meal or taken excessive exercise after the
usual dose of insulin.
• Diabetes ketoacidosis:
A patient might think if he or she doesn’t eat, then there is no need to
take insulin. In the absence of insulin, there is increased lipid and protein
breakdown, enhanced hepatic gluconeogenesis and impaired glucose
entry into the cells. The clinical consequences of diabetic ketoacidosis
are due to: hyperglycemia causing plasma hyperosmolality, metabolic
acidosis and glycosuria.
Hyperglycemia causes glycosuria and hence an osmotic diuresis. The
extracellular hyperosmolality causes a shift of water out of the cellular
compartment and severe dehydration occurs. Loss of water from the
cerebral cells causes this coma.
The classic features of diabetes ketoacidosis is the Kussmaul’s respiration
and acetone breath.
• Hyperosmolar Hyperglycemic State (HHS):
It is also called pre-coma. It is a condition in which there is marked
hyperglycemia but no detectable ketoacidosis. 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. Hence, there is an elevation in glucose to very high levels.
DIAGNOSIS
• Classical Symptoms of DM
• Fasting plasma glucose ≥7.0mmol/L (126mg/dl)
• Random Blood glucose of ≥ 11.1mmol/L (200mg/dl)
• HbA1c of >6.5%
• 2 hours plasma glucose ≥ 11.1mmol/L (200mg/dl) during Oral Glucose
Tolerance Test (OGTT)
Oral Glucose Tolerance Test (OGTT)
• It is indicated when the diagnosis of diabetes is in doubt.
• The patient is instructed to have a good carbohydrate diet for 3 days
prior to the test. The patient should not smoke during the test.
• The patient fasts overnight (At least 10h fasting, maximum of 16h fast)
• A blood sample is taken to measure the glucose levels at lets say, 8am
to denote ‘0’ hour sample
• Then a solution of 75g anhydrous glucose in 300ml of water is given to
the patient to drink slowly over a few minutes.
• Blood samples are taken after 2 hours.
• There is classical and modern OGTT.
HYPOGLYCEMIA
• Hypoglycemia, also known as low blood sugar is when blood sugar
decreases to below normal levels or less than 2.5mmnol/l
• Symptoms include clumsiness, dizziness, confusion, loss of
consciousness, seizures or death
• The most common cause of hypoglycemia is medications used to
treat DM e.g. insulin, sulfonylureas, biguanides.
• Whipple’s triad is defined as hypoglycemia, neuroglycopenic
symptoms and relief of these symptoms on raising the blood glucose.
• Hypoglycemia is not a diagnosis, but rather a disease manifestation.
Classification of Hypoglycemia
• There is no completely satisfactory classification of its causes.
However a useful approach is to divide hypoglycemia into:
• Appropriate hypoglycemia- hypoinsulinemia
• Inappropriate hypoglycemia: hyperinsulinemia
• Reactive hypoglycemia
Hypoinsulinemic hypoglycemia
• The causes of hypoinsulinemic hypoglycemia include:
1. Endocrine: glucocorticoid deficiency, adrenal insufficiency, severe
hypothyroidism, hypopituitarism
2. Organ failure: severe liver disease, end-stage renal disease
3. Some non-pancreatic islet cell tumors e.g. insulin-like growth factor
2-secreting tumors, leukemia, lymphomas, myeloma, widespread
metastases
4. The mechanism is not always clear, but may be sometimes due to
the secretion of IGF-2 or abnormal glycosylated big IGF-2.
Reactive Hypoglycemia
• It is also known as postprandial hypoglycemia or sugar crash.
• It describes episodes of symptomatic hypoglycemia occurring
between 2-4 hours after a high carbohydrate meal in diabetics. It can
also occur in non-diabetics or after gastrectomy.
• Symptoms include blurry vision, fatigue, dizziness, sweating,
headaches, flushing, nausea, vomiting.
Alcohol-induced hypoglycemia
• Hypoglycemia may develop between 2 and 10 hours after the
ingestion of large amounts of alcohol.
• It is found most often in undernourished people and chronic
alcoholics, but may also occur in young people when they take alcohol
for the first time.
• The hypoglycemia is probably caused by the suppression of
gluconeogenesis during the metabolism of alcohol.
Hyperinsulinemic Hypoglycemia
• Hypoglycemia of this type is usually caused by excessive insulin which
may be endogenous or injected.
• Hypoglycemia in a diabetic patient may be caused by accidental
insulin overdose, changing insulin requirements or failure to eat after
insulin has been given.
• Hypoglycemia due to exogenous insulin suppresses insulin and C-
peptide secretion. Measurement of plasma C-peptide concentration
can help to differentiate between exogenous and endogenous
hyperinsulinemia. In the former, C-peptide secretion is inhibited while
in the latter, it is raised.
Management of Hypoglycemia
• Mild cases can be managed with oral glucose-containing preparations
• Severe hypoglycemia should be treated with urgent intravenous
administration of 10-20mL of at least 10% glucose solution.
• Intramuscular Glucagon 1mg
References
• Clinical Biochemistry and metabolic medicine eighth edition by Martin
A crook.
• Researchgate.net