Page |1

ANTIDIABETICS
Diabetics mellitus often referred to simply as diabetes, is a syndrome characterized by
disordered metabolism and abnormally high blood sugar (hyperglycemia) resulting from low
levels of the hormone insulin with or without abnormal resistance to insulin’s effects. The
characteristic symptoms are excessive urine production (polyurea), excessive thirst and
increased fluid intake (polydipsia), blurred vision, unexplained weight loss and lethargy. These
symptoms are likely to be absent if the blood sugar is only mildly elevated.
The World Health Organization (WHO) recognizes three main forms of diabetes mellitus: type 1,
type 2 and gestational diabetes (occurring during pregnancy. While, ultimately, all forms are due
to the beta cells of the pancreas being unable to produce sufficient insulin to prevent
hyperglycemia, the causes are different.
Type 1 diabetes (IDDM) is usually due to autoimmune destruction of the pancreatic beta cells.
Type 2 diabetes (NIDDM) is characterized by insulin resistance in target tissues. This causes a
need for abnormally high amounts of insulin and diabetes develops when the beta cells cannot
meet this demand.
Gestational diabetes is similar to type 2 in that it involves insulin resistance; the hormones of
pregnancy can cause insulin resistance in women genetically predisposed to developing this
condition.
Anti-diabetic drugs that treat diabetes mellitus by lowering glucose levels in the blood.
With the exceptions of insulin, exenatide and pramlintide, all are administered orally and are thus
also called oral hypoglycemic agents or oral antihyperglycemic agents. There are different
classes of anti-diabetic drugs and their selection depends on the nature of the diabetes, age and
situation of the person, as well as other factors.
Normal sugar Level:

• Fasting: <6.1 mmol/L

• After 2 hrs of eating: <7-8mmol/L
• Within 3 hrs: 6.1 mmol/L
Point to be noted:
Diabetes Insipidus

Excessive thirst, Polyurea

No involvement of insulin, β-cell
 Page |2

2 types of Diabetes Insipidus

Central DI Nephrogenic DI
 
() Arginine vasopressin (ADH) Due to kidney or nephron dysfunction
 
Diuresis () Sensitivity of nephron to ADH

Diuresis

 Chemistry: Antidiabetic agents include insulin preparations, oral hypoglycemic agents and
peptide mimetics that can be used to improve glycemic control.
1. Insulin: It is an endocrine hormone secreted by the β cells of the pancreas. It is 51 amino acid
protein composed of two polypeptide chains; an A chain of 21 amino acids and a B chain of 30
amino acids. Two interchain disulfide bonds connect the A and B chains, and a third intrachain
disulfide bond is found between Cys6 and Cys11 of the A chain. Insulin is derived from an 86 amino
acid precursor known as Proinsulin.
✓ The 3 sulfide bonds here are: 1. (A7+B7), 2. (A20+B19), 3. (A6+B11).
✓ Proinsulin−Insulin= C peptide (35AA)

 List of amino acids:

Essential (9) Non-essential (13)

• Histidine • Alanine
• Leucine • Arginine
• Isoleucine • Asparagine
• Lysine • Aspartic acid
• Methionine • Cysteine
• Phenylalanine • Glutamic acid
• Threonine • Glutamine
• Tryptophan • Glycine
• Valine • Ornithine
• Proline
• Selenocysteine
• Serine
• Tyrosine

(a) Source: At one time, insulin was available as bovine insulin (which differs from human insulin
by 3 amino acids), and porcine insulin (which differs from human insulin only in the terminal
 Page |3

amino acid); however owing to concerns of the transmission of mad cow disease and the limited
use of these products, regular insulin is currently available only as recombinant human insulin.
i) Human insulins are prepared either by enzymatic conversion of the terminal amino acid
of porcine insulin (Novolin) or by means of recombinant DNA technology (Humulin)
ii) Five synthetic insulin analogues – lispro insulin (Humalog), insulin aspart (NovoLog),
insulin glulisine (Apidra), insulin glargine (Lantus) and insulin detemir (Levemir) are also
available.
 Page |4

(b) Categories: Preparations of insulin are divided into three categories according to their onset,
duration and intensity of action after subcutaneous (SC) administration: short-acting,
intermediate-acting and long-acting. Insulin solubility at the injection site depends on the
physical state, the zinc content, the nature of the buffer and the protein onset.
1. Short acting insulins include lispro insulin, insulin aspart, insulin glulisine and regular
insulin.
i) Lispro insulin differs from normal insulin in that the Lys29 and Pro28 , and residues
of the B chain are reversed. This structural alteration provides for a shorter onset
(15-30 min) and duration (3-4 hr) than that of regular insulin.
ii) Insulin aspart differs from normal insulin in that the Pro28 residue of the B chain
is replaced with Asp. This structural change reduces the tendency of insulin to self-
associate as hexamers and thus provides for a rapid onset and short duration,
similar to that described for lispro insulin.
iii) Insulin glulisine differs from normal insulin in two ways. Asp3 of the B chain is
replaced by lysine and Lys29 of the B chain is replaced by Glu. Similar to lispro
insulin and insulin aspart, insulin glusine has a rapid onset and a short duration.
All three of these synthetic insulins can be taken from 15 min before to 15 min
after the initiation of a meal. Compared to regular insulin, all three of these
synthetic analogues have a lower propensity (প্রবণতা) to cause hypoglycemia, thus
reducing the need for snacks between meals.
iv) Regular insulin (also called insulin injection or crystalline zinc insulin) is a soluble
insulin prepared at neutral pH. It can be mixed with most other insulins (with the
exceptions of glargine and detemir) and is the only type that can be given
intravenously.
2. Intermediate acting insulins include isophane insulin (neutral protamine hagedorn; NPH)
and combination products of lispro insulin and insulin aspart.
i) Isophane insulin (NPH) is a complex containing stoichiometric amounts of the
protamine, a protein found in certain types of fish and insulin in a phosphate
buffer. The presence of protamine, along with low concentrations of zinc,
enhances the aggregation of insulin into dimers and hexamers after subcutaneous
injections and prolongs its duration.
ii) Lispro and aspart insulin are available as combination products with their
respective protamine complexes, neutral protamine lispro (NPL) and neutral
protamine aspart (NPA). Each combination contains 30 U/mL of either lispro or
aspart insulin along with 70 U/mL of NPL or NPA, respectively.
3. Long-acting insulins include insulin glargine and insulin detemir.
i) Insulin glargine differs from normal insulin in that Gly replaces Asn21 residue of
the A chain and a basic Arg-Arg dipeptide replaces the Thr30 of the B chain. These
structural alterations cause a decreased solubility at physiological pH,
 Page |5

precipitation and delayed absorption after subcutaneous injection and an

increased duration of action.
ii) Insulin detemir differs from normal insulin in two ways. A 14-carbon fatty acid
(myristic acid) is covalently bound to Lys29 of the B chain and Thr30 of the B chain
is removed.
2. Oral Antidiabetic/Hypoglycemic Agent: They can be classified as
i) Sulfonylureas are acidic compounds and include both 1st & 2nd generation agents.
Second-generation agents have larger groups attached to the aromatic ring (i.e., larger R1
substituents).
a) First generation
E.g., Tolbutamide, Chlorpropamide, Tolazamide and acetohexamide etc.
M/A: Stimulate beta cells & release insulin.
b) Second generation
E.g., Glipizide, Glibenclamide, Gliclazide, Glimepiride etc.
M/A: Same but more potent than 1st generation and are more lipid soluble.
ii) Meglitinide analogues are acidic compounds.
E.g., Repaglinide, Nateglinide etc.
M/A: Increase tissue sensitivity to insulin.
iii) Biguanides are basic compound and is currently the only available agent in its chemical
class.
E.g., Metformin, Buformin etc. An additional agent, Phenformin was withdrawn from the
market in 1977 because of a high incidence of fatal lactic acidosis.
M/A: Increase tissue sensitivity to insulin.
iv) Thiazolidinediones: acidic compounds.
E.g., Rosiglitazone, Pioglitazone etc. A third agent Troglitazone was withdrawn from the
market because of rare but severe hepatic toxicity.
M/A: Increase tissue sensitivity to insulin.
v) α-glucosidase inhibitors are basic analogues of either monosaccharides or
polysaccharides.
E.g., Miglitol (monosaccharide) has better oral absorption than the α 1-4 linked Acarbose
(tetra saccharide).
M/A: Increase tissue sensitivity to insulin.
vi) DPP4 (Dipeptidyl peptidase 4) inhibitors
E.g., Vildagliptin, Sitagliptin etc.
 Page |6

M/A:
Eating

() Glucose level

Secretion of GLP 1 (Glucagon Like Peptide 1) & GIP (Gastric Inhibitory Polypeptide)
hormone is increased in intestine

Stimulate β-cell & repair impaired β-cell

Less secretion of glucagon ( Glucose)

These hormones are inhibited by DPP4; thus glucose level is increased.

These drugs inhibit the action of DPP4

Thus decrease the level of glucose

Hypoglycemic effect

 Structures of some oral hypoglycemics:

 Page |7

 Synthesis of some 1st Generation Sulfonylureas:

(a) Synthesis of Tolbutamide:
 Page |8

Case history development of Tolbutamide:

Enhancing a side effect is a way to find a lead compound. The aim then would be to enhance the
desired side effect and to eliminate the major biological activity.

E.g., Sulfonamide ⎯⎯⎯→ Antibacterial Drug

Some sulfonamides could not be used clinically because they had convulsive side effects brought
on by hypoglycemia. This is an undesirable side effect for an antibacterial agent but ability of
lowering blood glucose levels would be useful in the treatment of diabetes. Therefor, structural
alterations were made to sulfonamides in order to eliminate antibacterial effect & to enhance
hypoglycemic activity that lead to the antidiabetic agent ‘Tolbutamide’

(b) Synthesis of Chlorpropamide:

“Removal of susceptible metabolic groups prolong the lifetime of the drug”

 Methyl groups on aromatic rings are often oxidized to carboxylic acids that was quickly
eliminated from the body.
E.g., Methyl group of tolbutamide replaced by a chlorine to give chlorpropamide which is much
longer lasting.
 Page |9

 Synthesis of 2nd Generation Sulfonylurea (Glipizide):

 Oral Hypoglycemic Agents at a glance:

 P a g e | 10

3. Peptide Mimetics include exenatide and pramlintide.

a) Exenatide is an incretin mimetic. Incretins are endogenous compounds such as
glucagon like peptide (GLP-1), that improve glycemic control. Exenatide is isolated
from the salivary gland venom of the lizard Heloderma suspectum (Gila monster).
b) Pramlintide is an amylinomimetic agent (i.e., a synthetic analogue of human
amylin). Amylin is a naturally occurring 37 amino acid neuroendocrine peptide
that is secreted by pancreatic β cells in response to food intake. Pramlintide
contains Proline in place of Ala25, Ser28 and Ser29 normally present in amylin.
This decreases the viscosity, instability and aggregation that occur if amylin is
placed into solution.

Postprandial effect of Pramlintide:

() Rate of gastric emptying

Inhibit glucose secretion by α cells

Loss of appetite

() Hepatic glucose output

Lecture of JEWEL MALLICK sir, Assistant Professor, Dept of Pharmacy, BGCTUB

Rewrite: CHINMOY BARUA, 28th Batch, B.Pharm (Hons.), BGCTUB