Diabetes Mellitus

• Diabetes mellitus (DM) is a clinical syndrome

characterized by persistent hyperglycemia
(increased blood glucose level) due to
absolute or relative deficiency of insulin or
resistance or both.
 Increased blood glucose (sugar) levels
occur either due to:
• No insulin is being produced
• Insulin production is insufficient
• The body is resistant to the effects of insulin
 Classification of Diabetes Mellitus
1. Type-1 Diabetes Mellitus: Type-1 diabetes is an
autoimmune disease characterized by progressive
destruction of islet beta cells, leading to absolute
insulin deficiency. It typically occurs in younger
people who cannot secrete insulin.
2. Type-2 Diabetes Mellitus: Type-2 diabetes is
caused by insulin resistance and beta cell
dysfunction, resulting in relative insulin deficiency.
Autoimmunity is not involved. It typically occurs in
older, often obese, people who retain capacity to
secrete insulin but who are resistant to its action.
• 3. Gestational Diabetes Mellitus
• 4. Other specific type (secondary cause):
a. Genetic defects of ß-cell function
(decrease islet cell activity)
b. Genetic defects of insulin action
(decrease insulin activity)
c. Pancreatic disease-
 Pancreatitis
 Cystic fibrosis
 Fibrocalcific pancreatic disease
 Carcinoma pancreas
d. Endocrine disease
 Acromegaly
 Cushing syndrome
 Pheochromocytoma
 Carcinoma pancreas
e. Drug induced
 Steroid
 Thiazide
f. Associated with genetic syndrome
 Down’s syndrome
 Klinfelter’s syndrome
 Turner’s syndrome
 Clinical features Of DM
1. Classical symptoms:
 Polyuria (frequent urination)
 Polydipsia (excessive thrist)
 Polyphagia (excessive hunger)
 Tiredness, fatigue, lethargy
 Loss of weight
2. Asymptomatic (diagnosed at check-up)
3. Complication
 Retinopathy
 Neuropathy
 Nephropathy
 Diabetic coma
 Infections
 Cardiovascular complication
 Pregnancy related diabetic foot (due to
neuropathy, ulceration)
 Investigations for DM

1. Urine R/E:
• Glucose
• Ketone bodies
• Protein
2. Blood sugar
Normal (mmol/L) DM (mmol/L) IGT (mmol/L)

Fasting <6.1 _>7 6.1 – 7

2 hrs post- <7.8 _>11.1 7.8 – 11.1
prandial
3. Glycated/ Glycosylated Hb (HbA1C):
Normally 4-6% of total Hb are glycosylated. In
poorly controlled diabetes mellitus, 9% of
total Hb may be glycosylated.
4. Other investigations according to
complications.
 Management
• Principals of management ‘3D’
1. Diet
2. Drugs
3. Dicipline
• 3 methods of treatment are available for diabetic
patient-
1. Diet and life style advice alone: Approximate 50% of
new cases of diabetes can be controlled adequately
by diet alone.
[Link] anti-diabetic drugs: 25% will need an oral anti-
diabetic medication.
3. Insulin: 25% will require insulin.
 Discipline for diabetic patient
Lifestyle:
 Regular exercise
 Walking
 Stop smoking
 Reducing alcohol
Patient education:
 How to take insulin
 Urine testing/blood sugar testing
 Care of foot
 Hypoglycaemic symptoms
 Advice for follow-up.
 Classification of Antidiabetic Drug

According to route of administration, they are of

two types-
A. Parenteral hypoglycaemic agents: Insulin
B. Oral hypoglycaemic agents:
1. Insulin secretagogues
a. Sulfonylureas
• 1st generation
- Acetohexamide
- Tolbutamide
- Tolazamide
- Chlorpropamide
• 2nd generation
- Gliclazide
- Glipizide
- Glibenclamide
- Gliburide
• 3rd generation
- Glimepiride
b. Meglitinides (amino-acid derivatives)
- Repaglinide
- Nateglinide
2. Insulin sensitizers:
a. Thiazolidinediones
- Pioglitazone
- Rosiglitazone
b. Biguanides
- Metformin
- Phenformin
- Buformin
c. α-glucosidase inhibitors
- Acarbose
- Miglitol
d. Incretin based drugs: (less commonly used)
- Exenatide
e. Dipeptidyl peptidase-4 (DPP-4) inhibitors:
- Linagliptin
- Vildagliptin
- Sitagliptin
- Saxagliptin
f. Na-glucose co-transporter inhibitors:
- Empagliflozin
- Dapagliflozin
- Canagliflozin
Most commonly used antidiabetic drug

A. Parenteral hypoglycaemic drug: Insulin

B. Oral hypoglycaemic drugs:
 Metformin
 Gliclazide, Glipizide, Glimepiride
 Linagliptin
 Vildagliptin, Sitagliptin
 Pioglitazone, Rosiglitazone
 Empagliflozin, Dapagliflozin
 Acarbose
 Repaglinide, Nateglinide
 Insulin
• Insulin is a polypeptide hormone
• Secreted from ß-cells of pancreas
• Insulin consists of 2 peptide chain:
A chain: contains 21 amino acids
B chain: contains 30 amino acids
• Two chains are linked by two-disulphide
bridges
• When disulphide bond breaks insulin becomes
inactive
 Insulin preparations according to
duration of action
1. Rapid-acting, with very fast onset
and short duration; Bolus insulin
2. Short-acting, with rapid onset
of action;
3. Intermediate-acting,
4. Long-acting, with slow onset Basal insulin
of action.
Types Onset of Peak activity Duration of Directions
action action
1. Rapid-acting Within 10-30 30-90 minutes 3-5 hours Usually taken
or ultra short minutes immediately before a
acting insulin meal to cover the
Insulin aspart blood glucose
Insulin glulisine elevation from eating
Insulin lispro
2. Short-acting Within ½-1 2-4 hours 6-8 hours Usually taken about
insulin hours 30 minutes before a
Soluble/regular meal to cover the
insulin blood glucose
elevation from eating
3. Intermediate acting Within 1-2 8-10 hours 20-24 hours Often combined
insulin hours with rapid or short
NPH (isophane) acting insulin
insulin
Lente insulin
(insulin zinc
suspension)
4. Long acting insulin Within 3-4 5-12 hours 24-36 hours Often combined
Insulin glargine hours with rapid or short
(only soluble acting insulin.
long acting They lower blood
insulin) glucose levels when
 Insulin detemir rapid acting insulin
Insulin degludec stops working.
Classification of insulin according to source

1. Bovine insulin: Obtained from cow. It differs from

human insulin by 3 amino acids and it is more
antigenic.
2. Porcine insulin: Obtained from pork. It differs from
human insulin by 1 amino acid and thus less
immunogenic.
3. Human insulin: This is made either by enzyme
modification of porcine insulin or by using recombinant
DNA to synthesize the proinsulin. This is done by
introducing the DNA into either E. coli or yeast.
 Routes of administration of insulin

 Subcutaneous injection: The standard mode

of insulin therapy is subcutaneous (S/C)
injection using conventional disposable
needles and syringes.
Site: Abdomen, buttock, anterior thigh, dorsal
arm. Absorption is more rapid from the
abdominal wall, followed by the arm, buttock
and thigh.
 Intramuscular or intravenous: In emergency
situation (e.g. diabetes ketoacidosis).
 Inhaled insulin: This is finely powered and
aerosolized human insulin and is readily
absorbed into the blood stream through
alveolar walls. It has rapid onset and peak
insulin levels (by 30 min) and peak effect (2-
2.5hours) and duration of action (6-8hours).
 Indications of insulin
 Type-I diabetes mellitus
 Type-II diabetes mellitus
 All diabetic complications:
 Diabetic coma
 Diabetic ketoacidosis
 Diabetic nephropathy
 Diabetic neuropathy
 Diabetic retinopathy
 Non-ketotic coma
• Diabetes in pregnancy/gestational diabetes
mellitus
• Peroperative or postoperative management
IDDM & NIDDM
• Diabetes mellitus with severe infections
• Diabetic patient with RTA
• Cyclic vomiting in children
• Management of hyperkalaemia (as insulin
drives K into cells)
 Absolute inndications of insulin
• Type-I diabetes mellitus
• All diabetic complications:
 Diabetic ketoacidosis
 Diabetic nephropathy
 Diabetic neuropathy
 Diabetic retinopathy
• Diabetes in pregnancy
• Management of hyperkalaemia
 Mechanism of action of insulin

• Insulin receptor present on the surface of its

target cell. The receptor is glycoprotein
complex consisting of two α and two ß
subunits linked by disulphide bridges.
 α subunits are entirely extracellular and carry the
insulin binding site.
 ß subunits are transmembrane proteins &
manifest tyrosine kinase activity
(autophosphorilation).
 Insulin binds with the α-subunits of its receptor

Autophosphorylation of the ß-subunit of the insulin receptor

Activation of tyrosine kinase activity of the intracellular portion

of the ß-subunit

Phosphorylation of some cytoplasmic enzymes and

dephosphorylation of others

Activation of some of these enzymes while inactivation of

others

Effects of insulin, including-

• Translocation of glucose transporters (especially
GLUT 4) to the cell membrane with a resultant
increase in glucose uptake;
• Increased glycogen synthase activity and
increased glycogen formation.
• Multiple effects on protein synthesis, lipolysis
and lipogenesis;
• Activation of transcription factors that enhance
DNA synthesis and cell growth and cell division.
Adverse effects/complications of insulin
therapy
1. Immediate:
 Hypoglycaemia (most common)
 Hypoglycaemic shock
 Insulin allergy
2. Delayed:
 Immediate insulin resistance
 Lipodystrophy (atrophy or hypertrophy) at
injection sites
 Insulin oedema
 Weight gain
 Management of hypoglycaemic shock in
insulin therapy
• Insulin induced hypoglycaemia/ Hypoglycaemic
shock: Hypoglycaemic reactions are the most
common complications of insulin therapy
(hypoglycaemic level in a normal and diabetic
person is 2 mmol/L & 4mmol/L respectively). They
may result from-
• A delay in taking a meal
• Inadequated carbohydrate consumed
• Unusual physical exertion
• A dose of insulin that is too large for immediate
needs.
Clinical features of hypoglycaemia: Rapid
development of hypoglycaemia in individuals
with intact hypoglycaemic awareness causes
signs of autonomic hyperactivity, both
sympathetic and parasympathetic.
 Signs of sympathetic hyperactivity:
 Palpitation
 Tremor
 Sweating
 Nervousness
Signs of parasympathetic hyperactivity:
 Nausea
 Hunger
Sudden unconsciousness
If untreated, patients develops convulsion and
coma and ultimately death.
 Treatment of hypoglycaemia: All the
manifestations of hypoglycaemia are relieved
by glucose administration.
1. Mild hypoglycaemia in a patient who is
conscious and able to swallow: Simple sugar
or glucose should be given, preferably in a
liquid form. Dextrose tablet, glucose gel,
honey, sweet or any sugar containing
beverage or food may be given.
2. In case of unconscious patient:
 The treatment of choice is to give 20-50 ml of 50%
glucose solution (50% DA) by intravenous infusion
over a period of 2-3 minutes.
 Inj. 1 mg glucagon either subcutaneously or
intramuscularly.
 If IV therapy or glucagon is not available, then
small amounts of honey or syrup can be inserted
by NG tube.
 After prolonged hypoglycaemia, cerebral oedema
may occur. If patient does not respond to i.v.
glucose within 30 minutes i.v. dexamethasone
should be given.
 Advances of insulin over the oral
anti-diabetic agents
• Rapid onset of action
• Can be used in pregnancy
• Can be given in hepatic and renal insufficiency
• Can be given in diabetic ketoacidosis
 Disadvances of insulin over the oral
anti-diabetic agents
• Regular monitoring of blood glucose is
necessary
• Risk of hypoglycaemia is more
• Risk of hypersensitivity is more
• Needs regular injection
Insulin Secretagogues: Sulphonylurease

Insulin secretagogues: They called so, because

they increase insulin release from the endocrine
pancreas.
a. Sulfonylureas
1st generation
- Tolbutamide
- Chlorpropamide
- Acetohexamide
- Tolazamide
2nd generation (mostly used)
- Gliclazide
- Glipizide
- Glibenclamide
- Gliburide
3rd generation
- Glimepiride
b. Meglitinides (amino-acid derivatives)
- Repaglinide
- Nateglinide
 Indications of sulfonylureas

• In combination with insulin in some type I &

type II DM patient (especially in insulin
resistant cases as sulfonylureas increase
insulin receptor synthesis).
• Type II DM in non-obese persons (in obese
persons metformin is used)
 Adverse effects of sulfonylureas
• Hypoglycaemia
• Weight gain
• GIT upset: Nausea, vomiting, flatulence,
diarrhoea and constipation
• Blood: Agranulocytosis, aplastic and
haemolytic anaemia, cholestatic jaundice
• Headache, paresthesia
• Generalized hypersensitivity reaction (rashes,
photosensitivity)
• Teratogenicity
 Contraindication of sulfonylureas

• Type I DM
• Pregnancy and lactation
• Significant renal and hepatic insufficiency
• In elderly patient especially with cardiac
impairment.
 Biguanides (Metformin)

• Metformin
• Phenformin
• Buformin
(Metformin is now only the biguanide is use,
and is a major agent in the management of
type II diabetes. Metformin is taken with or
after [Link] chief use is in the obese patient
with type II diabetes either alone or with
combination with a sulfonylurea.)
 Indications of Biguanides/Metformin

 Biguanide (metformin) is recommended as

first-line therapy for type-2 diabetes mellitus.
Because metformin is an insulin-sparing agent
and does not increase weight or provoke
hypoglycaemia, it offers obvious advantages
over insulin or sulfonylureas in treating
hyperglycaemia in such persons. Its chief use
is in the obese patients type-II diabetes either
alone or in combination with sulfonylureas.
 Along with insulin in type-II DM.
 In type-II DM with insulin secretagogues or
thiazolidinediones in whom oral monotherapy
is inadequate.
 Insulin resistance syndrome.
 Metformin is efficacious in preventing the new
onset of type-II DM in middle aged, obese
person with impaired glucose tolerance and
fasting hyperglycaemia.
 Polycystic ovarian syndrome.
 Mechanism of action of Biguanides
(Metformin)
 Reduce blood glucose by reduce hepatic
glucose production (mainly) and stimulate
glycolysis.
 Reduce intestinal glucose absorption.
 Increased conversion of lactate from glucose
by electrolytes.
 Increase peripheral glucose uptake.
 Reduction of plasma glucagon levels.
 Advantages of Metformin

• Metformin is an insulin-sparing agent

• It does not cause hypoglycaemia
• Does not require functioning-ß cells
• Does not cause weight gain
• It is the first-line drug for type-II DM irrespective
of body weight
• Can be used in obese type-I DM
• It also decreases the risk of macrovascular as well
as microvascular disease.
 Adverse effects of Metformin
 GI upset
 Anorexia
 Nausea
 Vomiting
 Abdominal discomfort
 Diarrhoea
 Metallic taste
 Lactic acidosis
 Heavy prolonged use can cause vit B12 deficiency
due to malabsorption. Decreased vit B12 absorption
in chronic use leads to megaloblastic anaemia.
 Contraindications of Metformin

• Renal impairment (creatinine > 1.5 mg or

GFR <60 ml)
• Hepatic impairment
• Heart failure
• Hypoxia e.g. acute MI
• Alcoholism
• Diabetic ketoacidosios