This document discusses insulin and antidiabetic drugs. It defines diabetes mellitus and describes the different types. It then classifies and describes the mechanisms and uses of various oral antidiabetic drugs including insulin secretagogues, insulin sensitizers, alpha-glucosidase inhibitors, and DPP-4 inhibitors. It also discusses the mechanisms and uses of synthetic analogs of amylin and GLP-1. Finally, it covers the types and mechanisms of insulin and its effects in the liver, muscle, and adipose tissue.

1. HORMONES & RELATED DRUGS 2:
INSULIN AND ANTIDIABETICS
Dr. Mohd Aizuddin Mohd Lazaldin
Ph.D. in Pharmacology (UiTM)
Faculty of Dentistry, AIMST University
BDS Year 2 2021-2022

2. Learning Outcomes:
 List the antidiabetic drugs
 Describe the mechanism of action, adverse effects and specific
therapeutic uses and drug interactions of oral antidiabetic
drugs
 Explain the mechanism of action of insulin
 List various preparations of insulin, and adverse effects of
insulin
 Describe insulin regimens used in Type 1 diabetes mellitus
 Describe modes of administration of insulin including newer
methods of administration
• Recognize newer antidiabetic drugs

3. Diabetes Melitus (DM)
WHO:
• Diabetes is a chronic disease that occurs either when the pancreas does not produce
enough insulin or when the body cannot effectively use the insulin it produces.
• Insulin is a hormone that regulates blood sugar. Hyperglycemia, or raised blood
sugar, is a common effect of uncontrolled diabetes and over time leads to serious
damage to many of the body's systems, especially the nerves and blood vessels.
Types of DM:
1. Type 1:
• (previously known as insulin-dependent, juvenile or childhood-onset) is
characterized by deficient insulin production and requires daily administration of
insulin
• Symptoms include excessive excretion of urine (polyuria), thirst (polydipsia),
constant hunger, weight loss, vision changes, and fatigue.
2. Type 2:
• (formerly called non-insulin-dependent, or adult-onset) results from the body’s
ineffective use of insulin.
• More than 95% of people with diabetes have type 2 diabetes.
• This type of diabetes is largely the result of excess body weight and physical
inactivity.

4. Certain disorders and drugs can affect the way the body uses insulin and can lead to type 2
diabetes
Gestational diabetes:
• Gestational diabetes is hyperglycemia with blood glucose values above normal but below those
diagnostic of diabetes.
• Gestational diabetes occurs during pregnancy.
• Women with gestational diabetes are at an increased risk of complications during pregnancy and at
delivery.
• These women and possibly their children are also at increased risk of type 2 diabetes in the future.
Impaired glucose tolerance and impaired fasting glycaemia:
• Intermediate conditions in the transition between normality and diabetes.
• People with IGT or IFG are at high risk of progressing to type 2 diabetes, although this is not inevitable
Obesity
• Obesity is the chief risk factor for developing type 2 diabetes, and 80 to 90% of people with this
disorder are overweight or obese.
• Because obesity causes insulin resistance, obese people need very large amounts of insulin to
maintain normal blood glucose levels.
Abuse and abnormal secretion of drug/hormone:
• High levels of corticosteroids (most commonly due to use of corticosteroid drugs or Cushing syndrome)
• Diabetes also may occur in people with excess production of growth hormone (acromegaly) and in
people with certain hormone-secreting tumors. Severe or recurring pancreatitis and other disorders
that directly damage the pancreas can lead to diabetes.

5. Classification of Drugs used in DM: Oral AntidiabeticAgents
1. Insulin secretagogues
I. Sulfonylureas:
• Glyburide
(Glibenclamide)
• Glipizide
• Glimepiride
II. Meglitinide:
• Repaglinide
• Nateglinide
2. Insulin sensitizers
I. Biguanides:
• Metformin
• Buformin
II. Thiazolidinediones:
• Pioglitazone
3. α glucosidase inhibitors
I. Acarbose
II. miglitol
4. Inhibitor of dipeptidyl peptidase-4
(DPP-4)
I. Sitagliptin
II. Saxagliptin
III. Linagliptin
IV. Alogliptin

6. Classification of Drugs used in DM: ParenteralAntidiabeticAgents
1. Synthetic analog of amylin:
• Pramlintide
2. Synthetic analog of glucagon like polypeptide-1 (GLP-1)
• Exenatide
3. Insulin
Four principal types of injected insulin are available:
(1) rapid-acting [very fast onset and short duration]
(2) short-acting [rapid onset of action]
(3) Intermediate acting and
(4) long-acting [slow onset of action]

7. OralAntidiabetic Drugs: Insulin secretagogues (Sulfonylureas)
• More potent & commonly prescribed
• Less drug interactions & adverse effects
• Cautious in elderly and with CV diseases
(hypoglycemia)
• Glyburide: Long acting, used once daily .
• Glipizide: shortest acting (half life: 2- 4 hours)
 Produces less hypoglycemia,: safe in elderly
• Glimepiride: long acting, once daily
MOA:
• Major effects – acts by binding to Sulfonylurea
receptors of beta-cells and close the ATP
sensitive K+ channels.
• Beta cells are depolarized with influx of Ca2+
through voltage sensitive Ca2+ channels &
insulin released.
• Long-term administration of sulfonylureas to type
2 diabetics reduces serum glucagon levels,
which may contribute to the hypoglycemic effect
of the drugs.

8. ADME:
• All are orally well absorbed
• Should be given 30 minutes prior to meal
• Highly plasma protein bound (90-99%)
• Metabolized in liver and are excreted in urine
Drug Interactions:
• Warfarin & sulfonamides – induce hypoglycemia
• By inhibiting sulfonylureas metabolism
• Displaces from plasma protein binding.
Therapeutic Uses:
• Type 2 DM: To control hyperglycemia
• Used in patients who are unable to control blood glucose with diet &
exercises.
• Sulfonylureas require functional beta cells (Hence not useful in type
I DM).
Adverse effects: Hypoglycemia (common), Weight gain

9. • Very fast onset of action, rapidly reaches peak (one hour) & have very
short plasma half life.
• Used to control postprandial hyperglycemia in type 2 DM and administered
before each meal
• Common AE - hypoglycemia
• Nateglinide - Restores immediate release of insulin in response to high
glucose
OralAntidiabetic Drugs: Insulin secretagogues (Meglitinide)

10. Insulin Sensitizers: Biguanides (Metformin)
• Reduce the hepatic gluconeogenesis (it specifically reduces hepatic gluconeogenesis
without increasing insulin secretion, inducing weight gain or posing a risk of
hypoglycaemia)
• Enhance glucose uptake & utilization by skeletal muscles
• Slows absorption of glucose from GIT
• Euglycemic drug:
 Do not induce hypoglycemia
 Restore the blood sugar to normal or non-diabetic levels
Uses:
• first line drug in type 2 DM
• Prevents onset of type 2 DM in high risk people (middle age with obesity, impaired glucose
tolerance & fasting hyperglycemia)
• Type 2 DM with obesity
• Begins with low dose & gradually increase dose
• Polycystic Ovary Syndrome (PCOS)
- lowers serum androgens, restores normal menstrual cycles and induce ovulation
ADR:
• GI effects – Anorexia, Nausea, Vomiting, abdominal discomfort, Diarrhea, metallic taste
• observed in the beginning but are transient
• Lactic acidosis – due to decrease in lactate uptake.
• Worsened in patients with renal & hepatic impairment, hypoxia (CV diseases) & alcoholism.
Hence contraindicated in these patients

11. Insulin Sensitizers: Thiazolidinediones (Pioglitazone)
MOA:
• Binds and activate Peroxisome proliferator activated receptor –gamma (PPAR-γ),
nuclear receptors.
• Which regulate the genes involved with glucose and lipid metabolism in muscle,
adipose tissue and liver.
• Increase glucose transporter expression, uptake & utilization
• Inhibits hepatic glucose output
• Euglycemics - hypoglycemia is very rare.
• Used in type2 DM - used as monotherapy / with others.
Adverse effects
• Fluid retention – peripheral edema, Weight gain
• Macular edema (rare).
• Increase risk for fractures in women (decrease osteoblast formation)
• ↓TGs levels, but ↑HDL & LDL
• Hepatotoxicity (Troglitazone –withdrawn from market, produce fatal Hepatotoxicity )
• Pioglitazone – Increase OCPs metabolism
• Advice pts for additional contraceptive measures.
• Induces ovulation in anovulatory women – increase the risk of pregnancy

12. α glucosidase inhibitors: (Acarbose & Miglitol)
MOA
• Competitively inhibit α-glucosidases (maltase, sucrase, glycoamylase),
• Inhibits conversion of starch, oligosaccharides & disaccharides into
monosaccharides.
• Decrease digestion & absorption of carbohydrates
• Decrease postprandial hyperglycemia
• Reduce insulin requirement (insulin sparing effect)
• Hypoglycemia- very rare
Uses:
• Type 2 DM as monotherapy or with others (additive)
• Administered just before the ingestion of first portion of each meal
ADR:
• GI effects – Flatulence (buildup of gas in the digestive system that can
lead to abdominal discomfort), diarrhea, abdominal pain.
• All transient - Due to fermentation of undigested carbohydrate and release
of gas

13. Inhibitor of dipeptidyl peptidase-4 (DPP-4): Sitagliptin
• Responsible for inactivation of incretin hormones
• Prolongs action of incretin hormones (GLP-1)
• Which increases insulin secretion in response to meals & inhibits
secretion of glucagon
• Used alone or with other Optimal Oral Hypoglycaemic Agents (OHA) in
type-2 DM
ADR:
I. Nasopharyngitis
II. Headache
I. Allergic reactions

14. Synthetic Analog of Amylin: Pramlintide
• Synthetic analog of amylin
• Acts by inhibiting postprandial glucagon release, delays gastric
emptying & anorectic effects
• Used in type 1 & 2 DM to control postprandial hyperglycemia.
Administered SC prior to meal.
• ADR: hypoglycemia, nausea, vomiting
• Analog of glucagon-like-polypeptide 1 (GLP)
• Mechanisms ; Increase glucose mediated insulin release.
• Slow down gastric emptying, decrease food intake & postprandial
glucagon secretion
• Used in type 2 DM patients to improve postprandial glycemic control, who
fail to control blood glucose with sulfonylureas and/or metformin.
Administered by SC injection
ADR: Induce nausea & anorexia – weight loss
Synthetic analog of glucagon like polypeptide-1 (GLP-1): Exenatide

15. Insulin
• Insulin produce anabolic effects on Glucose, proteins and fats
• Insulin promotes cellular potassium uptake
Liver
• Inhibits glycogenolysis and gluconeogenesis
• Enhance glucose uptake & synthesis of glycogen
Muscle
• Enhance glucose uptake and glycogen synthesis
 Decrease the blood glucose
• Decreases breakdown & enhances synthesis of proteins
Adipose tissue: Enhance lipogenesis & glucose uptake
• Deficiency of insulin leads to
• Decreased glucose uptake by tissues & tissues uses fats and muscle proteins
as energy source.

16. Ultra-rapid onset and Very Short Acting:
Insulin lispro, Insulin aspart, Insulin glulisine
• Very rapid onset (5-15 minutes) & short duration of action (3 to 5 hours)
• Hence administered just before meal (5-15 minutes) to control postprandial hyperglycemia
Rapid onset - Short acting –
Regular / Crystalline Zinc insulin
• Useful in controlling postprandial hyperglycemia.
• Used intravenously in diabetic ketoacidosis
• Rapid acting (30 minutes) & short acting (5-8hours). administered 30-45 minutes prior to
meal
Intermediate Onset & duration of Action
Isophane / NPH [Neutral Protamine Hagedorn] insulin
• Mixed with protamine, slow onset of action (2-5 hours) and prolong effect (4-12 hours).
• Used to maintain basal insulin level to control blood glucose between meals
• Usually mixed with short / ultra-short acting insulin and administered 2 -4 times a day.
Slow Onset & Long Acting insulins
Insulin glargine & Insulin Detemir
• Slow onset of action (1 to 3 hours) but produces effects continuously for prolong
period (11- 24 hrs).
• Maintain low basal insulin level throughout the day - Prevents hyperglycemia between
the meals.
• Administered once or twice a day
• Do not mix with other insulin preparations in same syringe - reduces efficiency.

17. General – Onset of Action, Duration Action, Peak Effect

19. Insulin Therapy
• Insulins are administered by subcutaneous route
• Subcutaneous insulin therapy –
I. Long or intermediate acting insulins (maintain the basal insulin level)
II. Ultra-rapid and short acting insulins (control postprandial hyperglycemia)
Indications of insulin
 Type-1 DM
 Type 2 DM: who fail to control blood glucose with OHAs and during
stress
 Type-2 Diabetes Mellitus with complications:
I. Diabetic neuropathy
II. Diabetic nephropathy
III. Diabetic retinopathy
 Diabetic ketoacidosis
 Hyperosmolar Hyperglycemic Syndrome
 Gestational DM
 Patient going on surgery (during and after)

20. Insulin regimens

21. ADR of Insulin
1. Hypoglycemia:
• frequent and serious AE
May be due to – Delay in food intake after insulin inj, poor carbohydrate meal,
unusual physical exertion and high dose of insulin
• Signs & symptoms - sweating, anxiety, palpitation, tremor (sympathetic
over activity)
Dizziness, visual disturbances, weakness,
• Severe fall in blood glucose (< 40 mg/dl) lead to mental confusion,
seizures and coma
2. Local reactions: erythema
3. Immunological reactions; Insulin allergy –very rare
◦ Anaphylaxis – may be due to non-insulin proteins,
◦ Insulin resistance - Rare
4. Lipodystropy
Hypertrophy – Common,
◦ Due to repeated injection at same site
◦ Can be avoided by changing the site or liposuction
5. Weight gain, edema and hypokalemia

22. Treatment of Hypoglycemia
• Mild – Oral glucose sol, dextrose tabs, sugar containing
beverages/food
• Severe – 50% glucose IV, 20-50ml in 2-3 minutes
• Glucagon Inj 1mg, SC / IM
• If glucose infusion and glucagon in not available,
administer honey/syrup – buccal pouch
• Contact – Emergency Medical Services

23. Recommended reading
• Katzung Bertram G. (2018) Basic & Clinical pharmacology, (14th Edition), Mcgraw
Hill.
• Whalen,K., Finkel, R. (2019 )Lippincott Illustrated Reviews: Pharmacology (7th
Edition), Wolters Kluwer.
• Rang HP, (2020)Dale’s Pharmacology, (9th Edition), Elsevier,.
• Brunton. L.L., Hilal-Dandan. R., Knollmann. B.C., (2018) Goodman & Gilman's:
The Pharmacological Basis of Therapeutics, (13th Edition), Mcgraw Hill.
• Tripati, K.D. (2016) Essentials of Pharmacology for Dentistry, (3rd edition) Jaypee
Brothers.
• Tripati, K.D. (2019) Essentials of Medical Pharmacology, (8th Edition) Jaypee
Brothers.
• Rang, H.P., M.M and Ritter, J.M.(1999) Pharmacology (4th Edition), Churchill
Livingstone.
• Katjung B.G. (2000) Basic and Clinical Pharmacology, (8th Edition), Appleton and
Lange.
• Page, C.P., Curtis, M.J., Sutter, M.C., Walker, M.J.A and Hoffman, B.B. (2002)
Integrated Pharmacology. (2nd Edition), Mosby.
• Seymour.R, John G. Meechan and Yates. M., Pharmacology and Dental
Therapeutics (3rd edition) Oxford publication.