DIABETES AND ORAL

HYPOGLYCEMIC DRUG
By: Shreeharsh Sharma, Shubham Porte, Shivani Rathour,
Sneha Kesharwani, Soumya Jaiswal
Diabetes melitus:-
Diabetes is a metabolic disorder characterized by high level of sugars
in blood .

Causes:-
Deficiency of insulin which is secreted by B cells of pancreas .

Symptoms:-
◦ Polyuria (frequent urination) o Increased fatigue
◦ Polydipsia (increased thirst) o Slow healing sores
◦ Polyphagia (increased hunger) o Weight loss
 Types Of Diabetes
Mellitus

Gestationa
Type 1 Type 2 l DM
Other

Neonatal DM MODY
 Types of diabetes melitus:

1.) Type 1Diabetes Melitus (IDDM):-

Also known as “Insulin dependent diabetes melitus” or “juvenile diabetes”.

T1D manifest due to autoimmune damage of the B-cells which then leads to the
suppression or cessation of Insulin production.
T1D developed the condition before the age of 40.

It is less common.

Treatment by only Insulin.

2.) Type 2 Diabetes melitus :-
◦ Also known as Non-insulin-dependent diabetes melitus (NIDDM) or
“Adult-onset diabetes”.
◦ It results from Insulin resistance, a condition in which cells fail to use
insulin properly, sometimes combined with an absolute insulin deficiency.
◦ Moderate reduction in B-cells.
◦ Type 2 is the most common form of diabetes . Over 90% cases are of type
2 diabetes.
◦ In the case of insulin resistance, the body is producing the insulin, but
insulin sensitivity is reduced and it does not do the job as well as it should
do .
◦ The glucose is not entering the bodys cell properly, causing two problems
◦ A build up of glucose in the blood .
◦ The cells are not getting the glucose they need for energy and growth.

Causes :-

◦ Abnormality in glucoreceptor of B-cells so they respond at higher

glucose level.
◦ Reduced sestivity of peripheral tissue to insulin receptors.
◦ Excess hyperglycemic hormones (glucagon ) release.
GESTATIONAL
DIABETES MELLITUS
Gestational diabetes only happens during
pregnancy. It means you have high blood sugar
levels, but those levels were normal before you
were pregnant. If you have it, you can still have a
healthy baby with help from your doctor and by
doing simple things to manage your blood sugar
also called blood glucose. After your baby is born,
gestational diabetes usually goes away.
Gestational diabetes makes you more likely to
develop type 2 diabetes, but it won’t definitely
happen.
CAUSES OF GESTATIONAL DM
During pregnancy, the placenta makes hormones that can lead to a buildup of glucose in
your blood. Usually, your pancreas can make enough insulin to handle that. If not, the blood
sugar levels will rise and can cause gestational diabetes.

Risk factors for gestational diabetes mellitus

Age:- Women older than age 25 are at increased risk.
Family or Personal History:- Your risk increases if you have prediabetesor if a close
family member has type 2 diabetes. You're also at greater
risk if you had gestational diabetes during a previous pregnancy.
Weight: -Being overweight before pregnancy increases your risk.
Race:- For reasons that aren't clear, women who are black, American, Indian or Asian are
more likely to develop gestational diabetes
 OTHER TYPES OF DM
Maturity onset diabetes of the young (MODY) :- MODY is a rare form of diabetes.
MODY is caused by a mutation in a single gene. If a parent has this gene mutation, any
child they have, has a 50 per cent chance of inheriting it from them. If a child does inherit
the mutation they will generally go on to develop MODY before they’re 25, whatever their
weight, lifestyle, ethnic group etc.

Neonatal diabetes:- is a disease that affects an infant and their body's ability to produce
or use insulin. NDM is a monogenic (controlled by a single gene) form of diabetes that
occurs in the first 6 months of life. Infants do not produce enough insulin, leading to an
increase in glucose accumulation. It is a rare disease.
DIAGNOSE TEST FOR DIABETES
MELLITUS
Tests for type 1 and type 2 diabetes

1. Glycated hemoglobin (A1C) test:

• This blood test, which doesn't require fasting.
• It measures the percentage of blood sugar attached to hemoglobin.
• An A1C level of 6.5 percent or higher on two separate tests indicates that you have
diabetes.
• An A1C between 5.7 and 6.4 percent indicates prediabetes (A condition in which
blood sugar is high but not high enough to be type 2 diabetes)
• Below 5.7 is considered normal.
Random blood sugar test:
A blood sample will be taken at a random time. Regardless
of when you last ate.
a random blood sugar level of 140 milligrams per
deciliter (mg/dL) — 7.8 millimeters per liter
(ml/L) — or higher suggests diabetes.

Fasting blood sugar test:

A blood sample will be taken after an overnight fast.
A fasting blood sugar level less than 100 mg/dL (5.6
ml/L) is normal.
A fasting blood sugar level from 100 to 125 mg/dL (5.6
to 6.9 ml/L) is considered prediabetes.
If it's 126 mg/dL (7 ml/L) or higher on two separate
tests, you have diabetes.
Oral glucose tolerance test: For this test, you
fast overnight, and the fasting blood sugar level is
measured. Then you drink a sugary liquid, and
blood sugar levels are tested after next two hours.
A blood sugar level less than 140 mg/dL (7.8
mmol/L) is normal.
A reading of more than 200 mg/dL (11.1
mmol/L) after two hours indicates diabetes.
 A reading between 140 and 199 mg/dL (7.8
ml/L and 11.0 ml/L) indicates prediabetes.
Oral hypoglycemic Drug

◦ These drugs lower blood glucose levels and are

effective orally. The chief draw back of insulin is
—it must be given by injection
◦ The first clinically acceptable sulfonylurea
tolbutamide wasi in 1957 others followed soon
after. In the 1970s many so called ‘second
generation’ sulfonylureas were developed which
are 20–100 times more potent
A.) Enhance Insulin secretion
Sulfonylureas (KATP Channel blockers) First generation:- Tolbutamid Second
generation:- Glibenclamide (Glyburide), Glipizide, Gliclazide, Glimepirid
Meglitinide/phenylalanine analoguesn: Repaglinide, Nateglinide
Glucagon-like peptide-1 (GLP-1) receptor Agonists (Injectable drugs) Exenatide,
Liraglutide
Dipeptidyl peptidase-4 (DPP-4) inhibitor Sitagliptin, Vildagliptin, Saxagliptin,
Alogliptin, Linagliptin

B.) Overcome Insulin resistance

Biguanide (AMPK activator) Metformin
Thiazolidinedione’s (PPARγ activator) Pioglitazone
C.) Miscellaneous antidiabetic drugs
Alfa-Glucosidase inhibitors Acarbose,
Miglitol, Voglibose
Amylin analogue Pramlintide

Sodium-glucose cotransport-2 (SGLT-2)

inhibitor Dapagliflozin
Dopamine-D2 receptor agonist
Bromocriptin
 Sulfonylureas :-
The sulfonylureas were developed following the chance observation that a
Sulfonamides (used to treat typhoid) caused hypoglycemia.
It lower the Glucose level in Blood ( In type II diabetes)
All first generation compounds have been discontinued except tolbutamide
Being more potent and clinically superior, only the second generation SUs are
employed now
Mechanism of action
Mechanism of action

The principal action of sulfonylureas is on β cells, stimulating insulin secretion and
Thus reducing blood glucose.

High-affinity receptors for sulfonylureas are present on the KATP channels in β-cell
plasma membranes, and the binding of various  sulfonylureas parallels their potency in
stimulating insulin release.

These drugs reduce the permeability of K+ by competitively blocking sulfonyly urea 
receptors present on ATP sensitive K+ (KATP) channels.

The inhibition of K+ channels causes opening of voltage gated Ca2+ channels, which
Leads to increased influx of Ca2+ and thus stimulate insulin secretion from β cells of
Pancreas.

Reduced blood glucose level. They also suppress glucagon level which indirectly
contributes to their hypoglycemic Effects.
Pharmacokinetics :- 
◦ Sulfonylureas are well absorbed after oral administration,
◦ Most reach peak Plasma concentrations within 2-4 hours
◦ All bind strongly to plasma (90-98%). Plasma protein bindings are less for
first Generation drugs than the second generation
◦ Most sulfonylureas (or their active metabolites) are excreted in the urine, so
their Action is increased in the elderly and in patients with renal disease.
◦  Most sulfonylureas cross the placenta and enter breast milk; as a result, use of
Sulfonylureas is contraindicated in pregnancy and in breast feeding when diet
and, if Necessary, insulin is used.
 Meglitinide / D-phenylalanine analogues
(KATP Channel blockers)

These are KATP channel blockers with a quick And short lasting insulinemic action.

Repaglinide :-

It is designed to normalise meal-Time glucose excursions

It acts in an analogous manner by binding
To SUR → closure of ATP dependent K+Channels→ depolarisation → insulin release
Repaglinide is quickly absorbed and rapidly Metabolized ,Because of short Lasting
action it may have a lower risk of serious Hypoglycaemia
Nateglinide :-

It is a D-phenylalanine derivative, Which principally stimulates the 1st phase

insulin Secretion by closing β cell KATP channels
Resulting In faster onset and shorter lasting hypoglycaemia Than repaglinide
Glucagon-like peptide-1(GLP-1) receptor agonist

 GLP-1 receptor act like GPC Receptors

 GLP-1 receptors are present on alpha and beta cells ,intestinal mucosal cells
etc.
 Drugs of this class induces insulin release from pancreatic beta cells, only at
high blood glucose concentration.
 These drugs are used for type-2 diabetes.
 These drugs inhibit glucagon release from alpha cells
 These drugs slows gastric emptying and suppresses appetite by activating
specific GLP-1 receptors.
 Mechanism of action
The sulfonylureas and meglitinide analogues, block the sulfonylurea receptor which block
movement of potassium ion(k+)from pancreatic beta cells and the membrane is partially
depolarized.
Then voltage gated Ca2+ channel opens and Ca2+ influxoccur. The Ca²+ ions promote fusion of
insulin containing intracellular granules with the plasma membrane and exocytosis of insulin occur.
Incretins( group of metabolic hormones that decrease blood glucose level)such as (GLP1) and
glucose-dependent insulin atropic polypeptide (GIP)act upon their own GPC receptors on the Beta
cell membrane to activate adenylyl cyclase and generate cAMP,which also promotes exocytosis of
insulin.
Exenatide and liraglutideare GLP1 receptor agonists produce the same response as GLP1.
The incretins GLP1 and GIP are rapidly inactivated by the capillary endothelial enzyme
dipeptidyl peptidase-4 (DPP-4). Their action isinhibitedby DPP-4 inhibitors sitagliptin and
vildagliptin .
Drugs
Dulaglutide, taken by injection weekly
Exenatide, taken by injection twice daily
Semaglutide (Ozempic), taken by injection weekly
Semaglutide (Rybelsus), taken by mouth once daily
Liraglutide, taken by injection daily

Dipeptidyl peptidase-4(DPP-4)inhibitor
DPP-4 enzymes are present in capillary endothelial cells.

These enzymes inactivate GLP-1 so the insulin secretion decreases.

DPP-4 inhibitors are used to inhibit enzymes action.

These drugs indirectly help in increasing insulin release.

Mechanism Of Action
Drugs
1.) Sitagliptin-
It is competitive and selective DPP-4 inhibitor.
It is well absorbed orally.
Dose reduction is needed in case of renal impairment but not in liver disease.
Side effects-nausea, loose stools, headache, rashes, edema.

2.) Vildaglipin-
Longer duration of action.
Dose reduction, in case of severe liver and kidney disease.

3.) Saxagliptin-
It is orally absorbed and can be administered with or without food.
Dose reduction, in case of severe renal failure but not in liver disease.
Biguanide(AMPK activator)
Two biguanide antidiabetics-phenformin and metformin were used but
because of high risk of lactic acidosis, phenformin was withdrawn and has
been banned.
Metformin-It does not stimulate pancreatic ß cells. Metformin is reported to
improve lipid profile as well in type 2 diabetics.
 Mechanism of action

Biguanides do not cause insulin release, but presence of insulin is essential for their
action. Metformin activate AMP-activated protein kinase in liver and-

Causes-
1. Suppresses hepatic gluconeogenesis(generation of glucose)and glucose output
from liver.
2. Enhances insulin-mediated glucose uptake and disposal in skeletal muscle and
fat. Insulin resistance exhibited by type-2 diabetics is thus overcome.
3. It also retards intestinal absorption of glucose, other hexoses, amino acids and
Vit B12.
Adverse effects-

Abdominal pain, anorexia, nausea,

mild diarrhoea and tiredness
Metformin does not cause
hypoglycaemia except in overdose.
 THIAZOLIDINEDIONE (PPAR-GAMMA AGONIST)
PIOGLITAZONE

◦ These are insulin sensitizers, which do not promote insulin secretion

from beta cells but increases the insulin receptor sensitivity which on
binding with insulin shows rapid action.

◦ These drugs have higher duration of action

◦ Selective agonists for the nuclear receptor - peroxisome proliferator-

activated receptor (PPAR gamma )

◦ it mainly acts in fat cells

◦ Pioglitazone enhances the
transcription of several insulin
responsive genes and it also reverse
insulin resistance by enhancing
GLUT4 expression (regulation of
insulin stimulated glucose uptake)
and translocation

◦ It regulate adipocytes production ,

secretion of fatty acids and glucose
metabolism.

◦ The magnitude of blood glucose

reduction is less than SUs and
metformin. Improved glycaemic
control results in lowering of
circulating HbA1c in type 2 DM
patients.
Adverse effects - are plasma volume expands , oedema, weight gain, headache, myalgia
and mild anaemia

Contraindication - in liver disease (as causes fatal hepatotoxicity) and in CHF

Metabolized - by both CYP2C8 and CYP3A4

Interaction -  greater fluid retention, weight gain and precipitation of CHF after
combined use of Pioglitazones with insulin

 oral contraceptives levels are decreased with combined administrations.

 Pioglitazone should not be used during pregnancy.

Alpha Glucosidase inhibitors

Acarbose
◦ It is a complex enzymes which hydrolyses oligosaccharide to monosaccharides

◦ It reversibly inhibits alpha -glucosidases, which helps in the metabolism of carbohydrate

◦ It mainly act by slows down and decreases the digestion and absorption of polysaccharides
(starch, etc.) and sucrose.

◦ long-term acarbose treatment in prediabetes patient reduces occurrence of type 2 DM as

well as hypertension and cardiac disease
o Acarbose is a mild anti hyperglycaemic and use with other agents may result in
hypoglycaemic

Dosage - Acarbose 50- 100 mg TDS

(ter die sumendum ) is taken at the beginning of each major meal.

Adverse effect - uncomfortable i.e. symptoms. Hepatic transaminases may rise, but liver
damage is rare

Miglitol & Voglibose

It has a smaller molecule than acarbose and it is a stronger inhibitor of sucrase

Pharmacokinetics – acarbose is absorbed poorly and have their effect in the intestinal
lumen
Amylin mimetics – Amylin is neuroendocrine hormone peptide hormone co-
secreted with insulin from beta cells. Inhibits glucagon secretion

Pramilintide – modified amylin peptide which is agonist to amylin receptor

Dosage- 15-60 micro gram before meals

Adverse effect – nausea , diarrhoea , headache

Sodium-glucose co-transport-2 (SGLT-2) Inhibitor

Glucose filtered at the glomerulus is reabsorbed in the proximal tubules, major

transporter which accomplishes this is SGLT-2, whose inhibition induces glycosuria
and lowers blood glucose in type 2 DM

Dapagliflozin , Canagliflozin

These SGLT-2 inhibitors are approved for use in type 2 DM patients

Contraindication - in patients with renal insufficiency predispose urinary

Adverse effect - genital infections, electrolyte imbalance, ketoacidosis and

increased urinary frequency
Bile acid sequestrant
Colesevelam

It is a bile acid binding resin which lowers cholesterol as well as glucose levels
in blood. It is approved as add-on drug in type 2 DM patients

Mode of action – mainly act on enterohepatic circulation which reduces FXR

(farsinoid x receptor) – which , mainly act on regulation of glucose and lipid
homeostasis
DRUG FOR DIABETIC NEROPATHY
Epalrestat

Sorbitol is a minor metabolite of glucose generated by the enzyme aldose

reductase. In diabetics, excess sorbitol is produced and gets deposited in nerves
and other tissues. This is involved in the pathogenesis of diabetic neuropathy

Epalrestat is an aldose reductase inhibitor developed in Japan which has been

found to delay progression of diabetic neuropathy.

Nausea, vomiting and elevation of liver enzymes are the adverse effects.