This document discusses diabetes mellitus (DM), including its symptoms, complications if left untreated, and types. It focuses on Type 1 and Type 2 DM. Type 1 is an autoimmune disorder where antibodies destroy insulin-producing beta cells. Type 2 is caused by insulin resistance or insufficient insulin production. The document also covers insulin, its structure and production, mechanism of action, types used to treat DM, and oral hypoglycemic agents including sulfonylureas like tolbutamide.

1. Dr. Anshu Chaudhary Dudhe

2. Diabetes mellitus (DM):
 It is a metabolic disorder characterized by
hyperglycaemia, glycosuria, hyperlipemia, negative
nitrogen balance ( Nitrogen balance = Nitrogen intake
– Nitrogen loss) and sometime Ketonemia. Diabetes
mellitus (DM), commonly known as diabetes is
characterized by high blood sugar levels over a
prolonged period. Symptoms of high blood sugar
include frequent urination, increased thirst, and
increased hunger.

3. If left untreated, diabetes can cause many complications. A wide
spread pathological change includes
 -Thickening of capillary basement membrane
 - Increase in vessel wall matrix and cellular proliferation
resulting in vascular complication (Lumen narrowing, early
atherosclerosis)
 -Sclerosis of Glomerular capillaries
 - Retinopathy (damage to the blood vessel of retina)
 - Neuropathy (a result of damage to the nerves outside of
the brain and spinal cord (peripheral nerves), often causes
weakness, numbness and pain, usually in hands and feet).
 - Peripheral vascular insufficiency
 - Polydipsia (increased thirst) and Polyurea (Increase
urinary output)

4.  Causes- Diabetes can be caused by
 too little insulin.
Resistant to insulin
or both.
In both cases sugar level will be high.

6. Types of Diabetes mellitus:
 Type-I Diabetes Mellitus (Insulin dependent
diabetes mellitus, IDDM, Juvenile onset diabetes
mellitus because it often begins in child hood):
 It is autoimmune disorder; Antibodies ( type 1A) that
destroy β-cells of islets of langerhans in pancreas are
detected in the blood. Insulin in blood may be low or
absent.
 Type –I diabetic patients are more prone to ketosis.
This type is less common and has a low degree of
genetic predisposition.

7.  Type-II Diabetes Mellitus: (Non Insulin dependent
diabetes mellitus, NIDDM, Maturity onset Diabetes
mellitus because it often begins in adults):
 The pancreas makes insulin, but it either doesn't
produce enough, or the insulin does not work properly.
Nine out of 10 people with diabetes have type-II. This
type occurs most often in people who are over 40 years
old but can occur even in childhood if there are risk
factors present.

8.  - No antibodies are detected in the blood. There is no
loss or moderate reduction in β-cell mass. Insulin in
circulation is low, normal or even high. It has high
degree of genetic predisposition.
 -Type-II diabetes may sometimes be controlled with a
combination of diet, weight management and exercise.
However, treatment also may include oral glucose-
lowering medications (taken by mouth) or insulin
injections .

9. Causes of Type-II Diabetes:
 a. Abnormality in gluco-receptor of β-cell so that they respond at
high glucose concentration.
 b. Insulin Resistance
 Insulin resistant means body doesn’t use insulin
properly. Normally body may produce enough insulin to
transport the glucose to the cells but unfortunately, the body
resists that insulin and glucose level increase in the blood
leading to the symptoms associated with type -II diabetes.
 c. Reduced sensitivity of peripheral tissues to insulin or
reduction in no. of insulin receptor or down regulation.
 d. Excessive secretion of hyperglycemic harmone (glucagon etc.)
 e. Overweight/Obesity: Lack of exercise and unhealthy meal can
lead to obesity. Being overweight makes insulin resistant and can
also lead to many other health conditions.

10. Mg/dl Fasting Post prandial
Normal 80-100 mg/dl 170-200 mg/dl
Prediabetic 101-125 mg/dl 140-200 mg/dl
Diabetic 126+ mg/dl 220-300 mg/dl

11. 5.2. INSULIN AND ITS PREPARATION
 Insulin was discovered in 1921by Banting & Best. It was
first prepared in pure crystalline form in 1926. The
chemical structure was detected by Sanger in 1956.
 Insulin is a two chain polypeptide (A & B) having total
51 amino acids and Molecular weight is about 6000.
The A chain contain 21 Amino acid and B chain
contain 30 amino acid. The A and B chains are held
together by two disulfide bond.

12. Structure of Insulin

13. Beta-cells ofpancreatic islets of langerhans
Preproinsulin( 110 Amino acid)
Proinsulin ( 86 Amino acid)
24 Amino acid
'C' Peptide or coonnecting peptide of
35 Amino acid split of by proteolysis in golgi
Apparatus
Insulin ( 51 Amino acid)
The C peptide is secreted in blood along with Insulin.

14. Mode of Action of Insulin:
 Insulin act on specific receptor located on cell
membrane of particularly all cell. Insulin receptor is
heterotetrameric glycoprotein consisting of 2α and 2β-
subunits linked together by disulfide bonds. The α-
subunit contains insulin binding site while β-subunit
have tyrosine kinase activity.
 Binding of insulin to α subunits induces aggregation
and internalization of the receptor along with the
bound insulin molecules. This activates tyrosine
kinase activity of the β subunits → pairs of β subunits
phosphorylate tyrosine residues

15.  tyrosine residues of Insulin Receptor Substrate proteins (IRS1
IRS2, etc). In turn, a cascade of phosphorylation and
dephosphorylation reactions is set into motion which amplifies
the signal and results in stimulation or inhibition of enzymes
involved in the rapid metabolic actions of insulin.
Certain second messengers like phosphatidyl inositol
trisphosphate (PIP3) which are generated through activation
of a specific PI3-kinase also mediate the action of insulin on
metabolic enzymes.
 Insulin stimulates glucose transport across cell membrane
by ATP dependent translocation of glucose transporter GLUT4
to the plasma membrane.

16. The second messenger PIP3 and certain tyrosine
phosphorylated guanine nucleotide exchange proteins play
crucial roles in the insulin sensitive translocation of GLUT4
from cytosol to the plasma membrane,Genes for a large
number of enzymes and carriers are regulated by insulin
through Ras/Raf and MAP-Kinase as well as through the
phosphorylation cascade
 The internalized receptor-insulin complex is either
degraded intracellularly or returned back to the surface
from where the insulin is released extracellularly. The
relative preponderance of these two processes differs
among different tissues: maximum degradation occurs in
liver, least in vascular endothelium

17.  T—Tyrosine residue; GLUT4—Insulin dependent glucose transporter; IRS—Insulin receptor substrate
proteins;
 PIP3—Phosphatidyl inositol trisphosphate; MAP kinase—Mitogen-activated protein kinase; T-PrK—Tyrosine
protein
 kinase; Ras—Regulator of cell division and differentiation

18. Action of Insulin producing
Hypoglycaemia
Liver Muscle Adipose Tissues
1. Increase Glucose
uptake and glycogen
synthesis
2. Inhibit
glycogenolysis &
glucose level.
3. Inhibit
gluconeogenesis from
protein, pyruvate, Fatty
acid & Glycerol.
1. Increase glucose
uptake and utilization.
2. Inhibit proteolysis
and release of amino
acids, pyruvate in to
blood which form
substrate for
gluconeogenesis.
1. Increase glucose
uptake & storage as fat
& glycogen.
2. Inhibit lipolysis &
release of free fatty acid
and glycerol which
form substrate for
gluconeogenesis in
liver.

19. TYPES OF INSULIN
 1. Human Insulin: It is a protein having the structure of harmone produced by
human pancreas. It is produced either by enzymatic modification and suitable
purification of insulin obtained from the pancreas of pig or by recombinant
DNA Technology.

 2. Isophan Insulin (NPH, Neutral protamine hagedron): It is a sterile
buffered suspension of insulin complexes with protamine sulphate or other
suitable protamine. It is an intermediate acting. It has pH between 6.9 to 7.5.

 3. Protamine Zinc Insulin (PZI): It is sterile buffered suspension of insulin
complexes with protamine and Zinc Chloride. It has pH between 6.9 to 7.5.

 4. Insulin Zinc Suspension (lente): It is prepared by mixing 3 volume of
insulin Zinc suspension (amorphous) and 7 volume of Insulin zinc suspension
(crystalline) in to sterile container having pH- 6.7 to 7.5.

20. Type Onset Peak Duration use
Rapid Acting Aspart
glulisine
Lipsro
10-15m 1-1.5h 3-5h Usually taken sc
route about
immediately
before or after a
meal
Short acting Regular
Novolin R
Regular
Humulin R
Velosulin
30-35m 2-3h 6-8 h Usually taken sc
route about 30
min before a meal
Intermediate NPH,
Insulin Zinc
Suspension
or lente
1-3h 5-8h 14-18h Used to control
blood sugar
overnight while
fasting and
between meals.
Combined with
rapid and Short
acting insulin ,
taken by Sc route.
Twice a day.

21. Type Onset Peak Duration Use
Long acting Detemir
glargine
1-2h
1-2h
8-10h
No peak
12-24h
22-24h
Used to control
blood sugar
overnight while
fasting and
between meals.
,taken by Sc
route once or
Twice a day at
the same time
every day
( before
breakfast or
before
bed).often
combined with
short acting or
rapid acting
insulin

22. Uses of Insulin
 Insulin is used with proper diet and exercise to control
high blood sugar in people with diabetes. It also
prevent kidney damage, blindness( Diabetic
Retinopathy), ketoacidosis and neuropathy.

23. CLASSIFICATION OF ORAL HYPOGLYCAEMIC
AGENTS
 Oral Hypoglycaemic agents: Oral hypoglycaemic drugs lower blood
glucose level and are effective orally. The chief drawback of insulin is it
must be given by injection.
 I. Enhance insulin secretion
 a. Sulphonyl ureas
 i. First generation: Tolbutamide,chloropropamide
 ii. Second generation: Glibenclamide, Gliclazide, Glipizide,
Glimepride
 b. Meglitidine/ Phenylalanine analogue(Glinides): Repaglinide,
Nateglinide
 c. Glucogon like peptide -1 (GLP-1) receptor agonist: Exenatide,
Liraglutide
 d. Dipeptidylpeptidase-4-Inhibitors: Alogliptin
 II. Overcome insulin resistance
 a. Biguanides: Metformin, Phenformin
 b. Thiazolidinediones: Rosiglitazone, Pioglitazone
 Miscellaneous antidiabetic drugs:
 a. α-Glucosidase inhibitors: Acarbose, Miglitol, Voglibose
 b. Sodium-glucose contransport-2 (SGLT-2) inhibitor: Dapagliflozin

24. 5.3. SULPHONYL UREAS
 The sulphonylureas were discovered as oral
hypoglycaemic accidently. In 1942 M. Janbon &
Colleague observed that some sulphonamides
prepared for antibacterial properties caused
hypoglycaemia in experimental animals. The general
formula of sulphonyl ureas:
R1 SO2NHCONHR2

25.  All have similar pharmacological profile. Sulphonyl urea lowers blood glucose
level in normal subject and in Type-II diabetics, but not in Type-I diabetics.
Sulphonyl ureas also may further increase insulin level by reducing hepatic
clearance of the hormone.
R1 SO2NHCONHR2
R1 R2
Tolbutamide CH3 C4H9
Chlropropamide Cl CH2CH2CH3

26. Second generation Sulphonyl ureas
N
N
H3C
O
N
H
S
O
O
NH
N
H
O
Glipizide
N
O
N
H
S
O
O
NH
N
H
O
CH3
H3C
H3C
O
Glimipride

28. Mode of Action
The sulfonylureas (SU) and meglitinide analogues (Megli) block the sulfonylurea receptor (SUR1) which
constitutes a subunit of the inwardly rectifying ATP-sensitive K+ channel (KATP) in the membrane of
pancreatic beta cells
The inward flow of K+ ions is thereby restricted, intracellular K+ concentration falls
the membrane is partially depolarized augmenting Ca2+ channel opening as well as release of
Ca2+ from intracellular stores
The Ca2+ ions promote fusion of insulin containing intracellular granules with the plasma membrane
and exocytotic release of insulin.
Incretins such as glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP)
act upon their own G-protein coupled receptors on the â cell membrane to activate adenylyl cyclase and
generate cAMP,which also promotes exocytosis of insulin. Exenatide (Exe) and liraglutide (Lira) are GLP1
receptor agonists—producethe same response as GLP1.

29. SAR of sulphonyl ureas
 1. The aromatic ring contains R1 preferable in para position for hypoglycemic action. The R1 group on
the aromatic ring influence the duration of action of the compound.R1 and R2 must be lipophilic .
 2. R1 group may be NH2, CH3, CH3CO, Br, Cl, I. Group like COOH, OH CH2OH or NO2 in the para
position of aromatic ring cause abolishment of activity eg: Tolbutamide.
 3. The substitution of the urea nitrogen atom must have definite size. It should impart lipophilicity to
the molecule. The open chain containing compounds are better than the cyclic compound N-methyl
substituent’s is inactive while N-ethyl substituent show low activity.
 4. Maximum activity results when R2 consist of 3 to 6 carbon but if the substituent contains more
than 12 carbon then there is abolishment of activity. eg: Talbutamide and Glipizide
 5. Replacement of urea moiety causes abolishment of activity. If urea is
replaced by thiourea oral hypoglycemic activity decreases.
R1 SO2NHCONHR2
N
N
H3C
O
N
H
S
O
O
NH
N
H
O

30. TOLBUTAMIDE
 Tolbutamide is 3-butyl-1-[(4-methylphenyl) sulphonyl]
urea. Tolbutamide bind to a specific Sulfonylurea
receptor located on the pancreatic β cell membrane
and provoke a brisk release of insulin. The rate of
insulin secretion at any glucose concentration is
increased and insulin release is provoked even at low-
glucose concentration rising production of severe and
unpredictable hypoglycaemia.
H3C SO2NHCONHC4H9

31.  Synthesis of Tolbutamide: It is prepared by reacting
toluene with chlorosulphonic acid and condensing the
product 4-methylbenzene-1-sulfonyl chloride with
butylurea.
H3C
toluene
ClSO3H
H3C SO2Cl
4-methylbenzene-1-sulfonyl chloride
NH2CONHCH2(CH2)2CH3
H3C SO2NHCONHC4H9
Tolbutamide

32.  Tolbutamide is a first-generation potassium channel
blocker, sulfonylurea oral hypoglycemic medication.
This drug may be used in the management of type-II
diabetes.
 Tolbutamide is used together with diet and exercise to
improve blood sugar control in adults with type
2 diabetes mellitus. Tolbutamide is not for
treating type 1 diabetes.
 Preparation: Tolbutamide Tablets
 Brand name: Oramide, Orinase, Rastinon 0.5 gm tab.

33. CHLORPROPAMIDE
 It is 1-(4-Chlorobenzenesulphonyl)-3-propylurea. It belongs to
the class of drugs known as sulfonylureas. It lowers blood
sugar by causing the release of body’s natural insulin.
Chlorpropamide is an oral anti-hyperglycemic agent used for the
treatment of non-insulin-dependent diabetes mellitus
(NIDDM). Chlorpropamide is used with a proper diet and
exerise program to control high blood sugar in people with type-
II diabetes. It may also be used with other diabetes medications.
Controlling high blood sugar helps prevent kidney damage,
blindness, nerve problems,.
 Preparation: Chlorpropamide tablets
 Brand name: Diabinese 100 mg, 250 mg
Cl SO2NHCONHC3H7

34. GLIPIZIDE
 Glipizide is indicated in the control of blood glucose
levels in addition to the control of diet for patients
with non insulin dependent diabetes mellitus (Type
II diabetes) and Glipizide is not used for type –I
diabetes.
 Preparation: Glipizide Tablets
 Brand name: Glucotrol, Glibenese, Minodiab 5 mg
tabs. Glynase, Glide, Minidiab 5 mg tab
N
N
H3C
O
N
H
S
O
O
NH
N
H
O

35. GLIMEPIRIDE
 It is a medication used to treat diabetes mellitus type-
II. It is less preferred than Metformin. Use is
recommended together with diet and exercise. It is
taken by mouth.
 Use in during pregnancy and breast feeding is not
recommended.
 Brand name: Amaryl, Glypride, Glimer 1, 2 mg tab.
N
O
N
H
S
O
O
NH
N
H
O
CH3
H3C
H3C
O

36. 5.4. BIGUANIDES
 Two biguanide antidiabetics, phenformin and
metformin were introduced in the 1950s. Because of
higher risk of lactic acidosis, phenformin has been
banned in India since 2003. The generic formula of
Biguanides is
 They differ markedly from sulphonyl ureas causes little
or no hypoglycaemia in non diabetic patient and do
not stimulate pancreatic β-cell. Examples of
Biguanides are Phenformin and Metformin
 Metformin is used used widely. It is given alone or in
combination with sulphonyl urea improves glycaemic
control.
HN C
R1
NH
H
N C
NH
H
N R2
CH2 CH2 NH C
NH
NH C NH2
NH
Phenformin
N C
NH
NH C NH2
NH
Metformin
H3C
H3C

37. Mode of action of Biguanide
 1. It suppresses hepatic gluconeogenesis and glucose
output from liver- Probably the major action.
 2. Enhance binding of insulin to its receptors and
stimulate insulin mediated glucose disposal.
 3. Interfere with mitochondrial respiratory chain
promote peripheral glucose utilization by enhancing
anaerobic glycolysis.
 4. Inhibit intestinal absorption of glucose,other
hexoses, amino acid and Vit. B12

39. Uses:
 1. Metformin may prevent cardiovascular and possibly
the cancer complication of diabetes.
 2. It is used in type-II diabetes.
 3. Metformin has a lower risk of hypoglycemia than
sulphonyl urea.

40. METFORMIN HYDROCHLORIDE
 Metformin Hydrochloride is 1, 1-dimethylbiguanide
hydrochloride. It is a white, crystalline powder;
hygroscopic, and freely soluble in water. It is store in
well closed container, protected from light and
moisture.
N C
NH
NH C NH2
NH
Metformin hydrochloride
H3C
H3C
HCl

41.  It is used for type-II diabetes, antihyperglycaemic,
weight loss promoting. Metformin has been also
improved ovulation and fertility in some infertile
women with polycystic ovary. Metformin causes Vit
B12 deficiency.
 Preparation: Metformin Tablets
 Brand name: Glucophage, Glyciphage, Orabet, 500 mg
tab

42. 5.5 THIAZOLIDINEDIONES
 Only thiozolidinedione , Pioglitazone is currently available
in india.Rosiglitazone is banned in india since 2010 due to
unacceptable increase in risk of MI, CHF, stroke and death.
 These drug lower insulin resistnace by acting as agonist for
PPARγ. These agents bind to nuclear peroxisome
proliferator activated receptor- gamma (PPARγ) , a nuclear
harmone receptor. Activation of PPARγ regulates
transcription of insulin responsive gene, resulting in
increased insulin sensitivity in adipose tissue, liver and
skeletal muscle .
 It can be used alone or combination of other antidiabetic
drug. pioglitazone is second or third line agent for type-2
diabetes.

43. Mode of Action

44. PIOGLITAZONE
 It is a medication used to treat diabetes mellitus type-II
which exhibits insulin resistance in combination with
Metformin, a sulfonylurea, or insulin. Use is recommended
together with exercise and diet. It is not recommended in
diabetes mellitus type-I. Use in not recommended
in pregnancy or breastfeeding.
 Preparation: Pioglitazone tablet
 Brand name: Actos, Diaglit, Glizone 15 mg and 30 mg tabs.
N N
CH3
CH2CH2O
H3CH2C
CH2
NH
S
O
O
Piogilitazone

45. ROSIGLITAZONE MALEATE
 Rosiglitazone is an antidiabetic drug used to treat
diabetes mellitus type-II which exhibits insulin
resistance in combination with Metformin, a
sulfonylurea, or insulin.
 Preparation: Rosiglitazone tablet
 Brand name: Avandia , Avandamet, Avandaryl, Roglin,
Rosicon 4 mg and 8 mg tab.
N N
CH3
CH2CH2O
CH2
NH
S
O
O
Rosiglitazone Maleate
COOH
COOH

46. 5.6. MEGLITINIDES or D-PHENYLALANINE ANALOGUES (KATP
channel blockers)
 Its first member is orally active hypoglycemic drugs was Repaglinide in 1997.
Meglitinides (glinides) make up a class of drugs used to treat diabetes type-II
 Mode of Action

48. REPAGLINIDE
 Repaglinide is an antidiabetic drug in the class of
medications known as meglitinides.
 It is an oral antihyperglycemic agent used for the
treatment of non-insulin-dependent diabetes mellitus
(NIDDM). Repaglinide is an oral medication used in
addition to diet and exercise for blood sugar control in
type-II diabetes mellitus.
H3CH2CO
HOOC CH2CONH C H
CH2CH(CH3)2
N

49. NATEGLINIDE
 It is used in type-II DM along with other antidiabetics,
to control postprandial rise in blood glucose. Ingested
10 minutes before meal, it limits postprandial
hyperglycemia in type-II glycemia there is little effect
on fasting blood sugar level
C
H
COOH
NH
OC
CH
CH3
CH3

50. α-GLUCOSIDASE INHIBITORS
 Diabetes may also controlled by use of and α-glucosidase
inhibitor such as acarbose or miglitol. α-Glucosidase
inhibitor reduce intestinal absorption of glucose from a
carbohydrates load like starch, dextrin and disaccharides.
They act by inhibiting intestinal α-glucosidase.
 α-glucosidase inhibitors do not stimulate insulin release
and therefore do not cause hypoglycaemia. α-Glucosidase
inhibitors are pills that treat type-II diabetes. There are two
medications in this group, or class, of drugs: Acarbose
(Precose) and Miglitol (Glyset). They help keep the amount
of glucose in your blood from going up too fast after you
eat.

51. ACRABOSE
 Acarbose belongs to a class of drugs called α-
glucosidase inhibitors. It works by slowing the action
of certain enzymes that break food down into sugars.
This slows down digestion of carbohydrates to keep
your blood sugar from rising very high after you eat.
Acarbose should be avoided in patients with chronic
intestinal disease, inflammatory bowel disease or with
hepatic impairment.
OH
OH
CH2OH
N
H
O
CH3
OH
OH
O
O
CH2OH
OH
OH
O
O
CH2OH
OH
OH
OH
OH

52.  Mechanism of action: Acarbose is a compexe
oligosaccharideds which reversibly inhibits enzymes
(α- glucosidase), the final enzyme needed to
digest carbohydrates. In the brush border of the small
intestines and slow down and decrease digestion and
absorption of polysaccharide and sucrose.

53. AG: alpha Glucosidase , AGI- Alpha Glucosidase
Inhibitors

54.  Acarbose is used with a proper diet and exercise
program to control high blood sugar in people with type
2 diabetes.

55. VOGLIBOSE
 It is an α-glucosidase inhibitor used for lowering post-
prandial blood glucose levels in people with diabetes
mellitus. Voglibose is used to reduce high post meal
glucose level in diabetes mellitus patients.
 It is used along with diet and exercise to improve
blood sugar control in adults with type 2 diabetes
HO
HO HO
OH
OH N
H
OH
OH