Antidiabetic Agents

Joy C. Fontanilla, MD, FACE, FPCP, FPCDE, FPSEM

Medical Pharmacology I
San Beda College of Medicine

Normal physiology of glucose

homeostasis
Gut

Carbohydrate

Incretins
(GLP-1,
GIP, etc.)

Pancreas
Blood
Glucose

Adipose
tissue

Beta cells-INSULIN, amylin

Alpha cells- glucagon
Liver

Insulin Inhibition of
hepatic glucose
production

Muscle

Insulinstimulated
glucose uptake

InsulinInhibition of
lipolysis

 In normal physiology, glucose is absorbed

from the gut into the bloodstream. The
increase in blood glucose stimulates release
of insulin from the pancreas and this is
followed by an increase in insulindependent glucose uptake into liver,
adipose tissue and muscle. Concomitantly,
excess glucose is stored in liver (and
muscle) as glycogen and insulin inhibits
breakdown of triglycerides into fatty acids
(lipolysis) in adipose tissue.

Insulin is the key

Cell

Glucose

Case 1: Im throwing up all the

time
A 14 y.o. female was in good health until
about 3 weeks ago, when she suddenly
developed severe polyuria, polydipsia &
polyphagia. She has lost 20 pounds (going
from 110 to 90).
For the past few days she has been nauseated
& vomiting & has become very weak.

Case 1: Im throwing up all the

time
Physical exam reveals a pale, lethargic
adolescent female breathing rapidly; blood
pressure is 102/76, pulse 110, RR 32. Her skin
is dry. Her breath had a fruity smell.

Case 1: Im throwing up all the

time

Lab data:
Serum Na+: 130 mEq/L (normal: 135-145)
K+: 5.1 mEq/L (normal: 3.5-5.1)
Serum glucose: 479 mg/dL
Serum Cl: 104 mEq/L
Arterial pH: 7.0 (normal: 7.35-7.45)
Arterial pO2: 92 mm Hg (normal: 80-105)
Urine & serum ketones: ++++

Case 1
What is your diagnosis?

A) Starvation ketosis

B) Diabetic ketoacidosis

C) Hyperosmolar nonketotic state

D) Food poisoning

Effects of Insulin Deficiency (& Glucagon

Excess)

Case 1
What type of diabetes mellitus does she most
likely have?

A) Type 1 diabetes mellitus

B) Type 2 diabetes mellitus

C) Maturity-onset diabetes in the young

D) Drug-induced beta cell failure

Classification of Diabetes Mellitus

(DM)
Type 2
Type 1
~90% of cases
~10 % cases
Non-insulin dependent
(NIDDM)
Insulin-dependent
(IDDM)
(Maturity - onset)
(Juvenile - onset)
Usually hyperinsulinemic in
initial stages; insulin
Immune-mediated
resistance (IR), relative
destruction of pancreas
insulin deficiency
Little or no extractable
Not usually prone to
insulin in pancreas
acidosis, ketosis
Prone to acidosis, ketosis
Usually undernourished Usually obese

Antidiabetic Agents
Insulin & insulin
analogue
preparations

Oral hypoglycemic
agents (OHAs)
Others

Structure of human insulin & proinsulin

Overview of Insulin Action

INSULIN
Fatty acids

Glucose

Amino acids

Triglycerides

Glycogen

Protein

Adipose tissue

Liver

Muscle

Fatty acids
Stimulated by insulin
Increased by feeding

Inhibited by insulin
Increased by fasting & in diabetes

Insulin Secretion
Insulin is released from pancreatic beta
cells at:
a) a low basal rate and
b) in response to variety of stimuli esp.
glucose
Other stimulants of insulin secretion:
Other sugars (mannose)
Certain amino acids (leucine, arginine)
Vagal activity
Incretins (GLP-1; glucose-dependent)

Normal Daily Plasma Insulin

Profile
U/mL
100

80
60
40
20
0600

0800

1200

1800

2400

Time of day
B=breakfast; L=lunch; D=dinner

Polonsky KS et al. N Engl J Med. 1988;318:1231-1239

0600

Insulin Degradation
Insulin degraded by insulinase;
removed from circulation by:
Liver (60% endogenous insulin; 3040% exogenous insulin)
Kidney (35-40% endogenous insulin;
60% exogenous insulin)

Half-life of circulating insulin is 35 minutes.

Case 1
What type of insulin would you give her?

A) Ultralente insulin

B) Insulin glargine

C) Regular insulin

D) NPH insulin

Insulin Preparations
Insulin
Human, Porcine, Bovine
Examples: Neutral Protamine
Hagedorn (NPH), Regular, Lente,
Ultralente
Mixture of different types of
insulin: 70% NPH + 30% Regular

Insulin analogues

Insulin analogues
Ultra-rapid-acting
Very rapid onset & short
duration of action
E.g., Lispro, Aspart

Long-acting
Slow onset & long
duration of action
E.g., Glargine, Detemir

Question:
Intermediate-acting insulin that is protaminated to
have an onset of action of 1-2 hours, peak action at
5-7 hours and duration of action of 13-18 hours
when injected subcutaneously:

A. Isophane insulin suspension (NPH)

B. Insulin glargine

C. Regular insulin

D. Insulin Lispro

E. Insulin Aspart

Properties of insulin preparations

Action*

Type

Preparation

Appearance

Ultra-shortacting

Aspart
Glulisine

(hours)

Onset

Peak

Duration

Clear

0.25

0.67-1

3-5

Lispro

Clear

0.25

0.5-1.5

2-5

Short-acting

Regular
soluble
(crystalline)

Clear

0.5-0.7

1.5-4

5-8

Intermediateacting

NPH
(isophane)

Cloudy

1-2

6-12

18-24

Long-acting

Detemir

Clear

6-8

20-22

Glargine

Clear

2-5

5-24

18-24

*Subcutaneous administration

Action Profiles of Insulin Preparations

Aspart, glulisine, lispro 46 hours
Regular 68 hours
Plasma Insulin Levels

NPH 1220 hours

Detemir 2022 hours

Glargine 24 hours

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Hours

Ultra-rapid acting insulin

Aspart
Analogue of human insulin in which the amino
acid proline at position 28 of the B chain in the
insulin molecule has been substituted with
aspartic acid.

Lispro
Insulin analogue in which proline at B28 has been
interchanged with lysine at position B29.

Case 1
How would you administer it to her?

A) Via inhalation

B) Via continuous intravenous infusion

C) Via subcutaneous route

D) Via oral route

E) Via IV push every 4-6 hours

Human Insulin
21 amino acids

A-chain
B-chain

30 amino acids

Monomers

Dimers

Zn++
Zn++

Hexamers

Self-aggregation
in solution

When injected subcutaneously, insulin lispro quickly

dissociates into monomers & is thus absorbed very rapidly.

The hexameric
formulation of
human insulin takes
2 to 3x longer to
dissociate &
become absorbed
when injected SQ.

Short-acting Insulin
Regular insulin
Soluble crystalline zinc*
insulin
Less costly than lispro or
aspart
Instantly converted to
monomeric form when
given intravenously.

*Zn is added to improve stability & shelf life

Intermediate-acting Insulin
NPH
Onset of action is delayed by combining
appropriate amounts of insulin and protamine so
that neither is present in an uncomplexed form
(isophane)

Long-acting Insulin
Detemir
Glargine
Peakless (i.e., having broad plasma
concentration plateau) ultra-long-acting insulin
analogue

Insulin Delivery Systems

Portable pen injectors
Continuous
subcutaneous insulin
infusion devices
Inhaled insulin
(withdrawn from the
market because of lack
of financial viability)

Case 1
She was subsequently discharged on NPH 12 units at bedtime
and insulin lispro 5 units immediately before breakfast, lunch
and dinner. She then noted that she would feel faint and get
palpitations, cold sweats, tremors, hunger pangs before
bedtime. Her blood sugar levels during these episodes were
noted to be low. What should she do?

A) Reduce her a.m. insulin lispro dose.

B) Reduce her nighttime NPH insulin dose.

C) Reduce her insulin lispro dose at noon.

D) Reduce her p.m. insulin lispro dose.

Common
multidose
insulin
regimens

Complications of Insulin Therapy

Hypoglycemia
Skin reactions
Lipodystrophy

Immunologic:
Allergy
Insulin resistance

Weight gain

Case 2: Im peeing all the time

46 y.o. male with complaints of

Incessant thirst
Polyphagia
Polyuria
5-lb weight loss over the last 2
months
His wife also notes the presence of
ants on the urinal.

Case 2: Im peeing all the time

PMHx: unremarkable
Family Hx: Mother & brother
have high blood sugar
P.E.: obese male; BP: 130/90
Neck & axilla exam shows
acanthosis nigricans

Acanthosis nigricans

Case 2: Im peeing all the time

Labs: Random blood sugar: 209 mg/dL (after
having just eaten a candy bar); HbA1c 8.5%
Serum electrolytes, SGPT, Crea and anion gap
were normal.
Urinalysis: +++glycosuria

Case 2
Whats your diagnosis?

A) Type 1 diabetes mellitus

B) Type 2 diabetes mellitus

C) Impaired glucose tolerance

D) Normoglycemia

Pathogenesis of Type 2 DM
Resistance to the action of insulin in
peripheral tissues (muscle, fat, liver)
Defective insulin secretion
Increased hepatic glucose production

The Pathophysiology of Type 2 Diabetes Includes Three

Main Defects
Islet

Insulin deficiency

Pancreas

Excess
glucagon
Diminished
insulin

Alpha cell
produces
excess
glucagon

Beta cell
produces
less insulin
Diminished
insulin

Hyperglycemia

Muscle and fat

Liver
Excess glucose output

Insulin resistance
(decreased glucose uptake)

Adapted from Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:14271483; Buchanan TA Clin
Ther 2003;25(suppl B):B32B46; Powers AC. In: Harrisons Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:21522180;
Rhodes CJ Science 2005;307:380384.

Oral Hypoglycemic Agents (OHAs)

Insulin secretagogues
Sulfonylureas (e.g. glibenclamide)
Meglitinides (e.g., repaglinide)

Biguanides (e.g., metformin)

Thiazolidinediones (e.g., pioglitazone)
Alpha-glucosidase inhibitors (e.g., acarbose)
DPP-IV inhibitors (e.g., sitagliptin)

Sites of Action of OHAs vs T2 DM

Dietary
carbohydrate
Alphaglucosidase
inhibitors

Sulfonylureas
Meglitinides

DPP4
inhibitors
Insulin deficiency

Pancreas

Excess
glucagon

Islet

Alpha cell
produces
excess
glucagon

Beta cell
produces
less insulin
Diminished
insulin

Diminished
insulin

Hyperglycemia
Liver
Excess glucose output

Muscle and fat

Metformin
TZDs

Insulin resistance
(decreased glucose uptake)

Adapted from Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:14271483; Buchanan TA Clin
Ther 2003;25(suppl B):B32B46; Powers AC. In: Harrisons Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:21522180;
Rhodes CJ Science 2005;307:380384.

Case 2
Despite lifestyle modifications such as diet and
exercise, his fasting blood sugar remains quite
elevated. Which of the following oral medications
would you choose to treat him and would most likely
not result in weight gain?

A) Glibenclamide

B) Metformin

C) Repaglinide

D) Rosiglitazone

E) Exenatide

Question:
Hypoglycemia is most likely to result from
which of the following agents?

A. Metformin

B. Rosiglitazone

C. Acarbose

D. Glibenclamide

Insulin Secretagogues: Sulfonylureas

First Generation
Chlorpropamide
Tolbutamide
Tolazamide
Acetohexamide

Second Generation
Glipizide
Glibenclamide
/Glyburide
Gliclazide
Glimepiride

Sulfonylureas:
Mechanism of Action
Stimulate insulin
release from
pancreatic beta cells
Administered OD or
BID depending on
formulation

Sulfonylureas: Mechanism of Action

Sulfonylureas

CA++

SUR1

K+
GLUT2
Glucose

K pump

Ca channel

ATP
Metabolism

Insulin

Beta Cell

 In the resting cell with normal (low)ATP levels, K

diffuses down its concentration gradient through
ATP-gated K channels, maintaining intracellular
potential at a fully polarized, negative level. Insulin
release is minimal. If glucose concentration rises,
ATP production increases, K channels close, and
depolarization of the cell results. Voltage-gated Ca
chanels open in response to depolarization,
allowing more Ca to enter the cell. Increased
intracellular Ca results in increased insulin
secretion. Insulin secretagogues close ATPdependent K channel, thereby depolarizing the
membrane and causing increased insulin release
by the same mechanism.

Sulfonylureas: Characteristics
Generic Name

Daily Dose
Range (g)

Duration
of action
(h)

Metabolism

0.5-3.0

6-12

By liver to inactive
product

Up to 60

By liver to less active

metabolites; excreted
by kidney intact

First Generation
Tolbutamide

Chlorpropamide 0.10-0.5

2nd Generation
Glipizide

5.0-40 (mg)

10-24

Glyburide/

2.5-20 (mg)

10-24

Glibenclamide

Gliclazide

40-320 (mg) 10-24

Glimepiride

1-8 (mg)

12-24

By liver to inert
products; renal
excretion

Sulfonylureas:
Side effects
Hypoglycemia - all agents but especially chlorpropamide

a. more likely in hepatic or renal insufficiency

b. drug interactions with bishydroyxycoumarin,

phenylbutazone, sulfonamides, alcohol, salicylates
Weight gain
Hyponatremia - antidiuretic action of chlorpropamide (SIADH)
Disulfiram-like reaction (esp. chlorpropamide)

Sulfonylurea-induced skin reactions

Erythema multiforme

Insulin secretagogues:
Meglitinides
Repaglinide, nateglinide
Stimulate insulin release by
closing ATP-dependent K+
channels in pancreatic beta
cells
Short half-life: ~ 1h
Usually administered TID
before meals; reduces mostly
postprandial blood sugars
Less incidence of
hypoglycemia compared to
SUs

Biguanides:
Metformin
Euglycemic rather than
hypoglycemic agent (does not
cause hypoglycemia with
monotherapy)
Does not cause weight gain
Half-life 1.5-3h
Not metabolized
Excreted by kidneys as active
compound

Metformin:
Mechanism of Action
Insulin sensitizer via:
Reduced hepatic glucose
production (esp.
gluconeogenesis)
Increased peripheral uptake
of glucose
Activates AMP-activated
protein kinase (AMPK) - liver
enzyme with important role in
insulin signaling, whole body
energy balance, and
metabolism of glucose and fats

Metformin: Uses
First-line T2DM
therapy (ADA, EASD)
Also used to treat
polycystic ovary
syndrome

Question:
Metformin is contraindicated in patients with renal
insufficiency because:

A. It increases the risk for ketoacidosis.

B. It increases the risk for lactic acidosis.

C. It causes fluid retention and congestive heart

failure.

D. It causes fulminant liver failure.

Metformin:
Adverse and other reactions
Gastrointestinal:
anorexia, nausea,
vomiting, abdominal
discomfort, diarrhea
(often transient)
Lactic acidosis
Does not cause wt.
gain (may induce minor
wt. loss)

Metformin:
Contraindications

Renal disease
Alcoholism
Liver disease
Conditions predisposing to anoxia (e.g.,
cardiopulmonary dysfunction)

Question:
Oral antidiabetic agent most likely to cause
edema and weight gain:

A. Metformin

B. Rosiglitazone

C. Acarbose

D. Insulin

E. Repaglinide

Thiazolidinediones (TZDs): Pioglitazone

Euglycemic agents
Insulin sensitizers via:
Increased glucose uptake in muscle & adipose tissue
Restraint of hepatic gluconeogenesis

Bind to & modulate a family of nuclear transcription

factors termed peroxisome proliferator-activated
receptors (PPAR-gamma)
PPAR gamma agonists

Thiazolidinediones: Pioglitazone
Metabolized via CYP450
Other effects:
Reduce visceral fat mass, increase
subcutaneous fat
Slight drop in triglycerides, increase in HDL,
increase (rosiglitazone) or decrease
(pioglitazone) in LDL

Thiazolidinediones:
Adverse reactions

Hepatotoxicity (troglitazone)
Edema (Fluid retention), CHF
Increased MI risk? (rosiglitazone)
Hypoglycemia in combination
with insulin, sulfonylureas
Weight gain
Dilutional anemia
Bone loss
Bladder CA? (pioglitazone)

Question:
Mechanism of action of acarbose:

A. Increase insulin secretion

B. Decrease hepatic glucose output

C. Delay carbohydrate absorption

D. Improve peripheral glucose uptake into

muscle and adipose tissue

Alpha-glucosidase Inhibitors (AGIs)

Acarbose
Voglibose
(Miglitol)

Acarbose, Voglibose (AGIs): Mechanism

of action
Complex starches, oligo- &
disaccharides must be broken
down into monosaccharides prior
to intestinal abosrption,
facilitated by digestive enzymes
(e.g., -glucosidase, -amylase)
AGIs competitively inhibit
intestinal -glucosidases &
thereby delay absorption of
ingested carbohydrates
Lower postprandial glycemic
excursions
Does not cause weight gain

Alpha-glucosidase Inhibitors: Effect on

The -Glucosidase
Inhibitors:
Postprandial
Glucose
MONOTHERAPY

Effect on Postprandial Glucose

Normal absorption of CHO

Without Acarbose
Acarbose blocks proximal
absorption
With Acarbose

Plasma Glucose
(mg/dL)

Duodenum
140

Jejunum

Ileum

Meal

Placebo
Acarbose

*
120
100

80

30 0
* P <.05

60
120
Time (min)

180

240

Dimitria dis, et al. Metabolism. 1982;31:841-843.

1999, Me dic al Age Publishing, Division of Snyder H ealthcare Communications Worldwide, Stamford, Connectic ut. All rights reserve d.

Alpha-glucosidase Inhibitors:
Adverse effects
Gastrointestinal: flatulence,
diarrhea, abdominal pain
Hepatic enzyme elevation
Contraindicated in bowel
disease, renal disease
Hypoglycemia unlikely with
monotherapy but may occur
with concurrent sulfonylurea,
insulin, other hypoglycemic
agents

Picture of flatulence
deodorizer

Glucagon
Pharmacologic effects
Hyperglycemic
factor
Mobilizes hepatic
glycogen stores
Inotropic,
chronotropic effects
on heart
Intestinal smooth
muscle relaxation

Glucagon
Clinical Uses
Treatment of severe
hypoglycemia
Endocrine dx (test for
pancreatic beta cell
reserve)
Treatment of betablocker poisoning
Bowel radiology

Incretin Mimetics
Incretin Enhancers
New antihyperglycemic agents

INCRETIN
INtestinal

Se CRET
ion
Of
INsulin

The Incretin Effect

Beta-Cell Response to Oral vs. IV Glucose
Crossover of Healthy Subjects (n = 6)
Oral Glucose
Intravenous (IV) Glucose

Plasma Glucose (mg/dL)

C-peptide (nmol/L)
2.0

*
200

Incretin Effect

1.5

1.0

100

0.5

0.0

0
0

60

120

180

60

Time (min)
Mean (SE); *P0.05
Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498

120

180

Incretins
The GI tract is an endocrine organ.
Incretins are gut hormones that
enhance insulin secretion in response
to food ingestion (glucose-dependent)
Incretin effect: Ingested food causes a
more potent release of insulin than
intravenous glucose.
In type 2 DM, incretin effect greatly
reduced or absent.
Incretin GLP-1-secreted by L cells of
ileum and colon

Multiple Sites of Action of GLP-1:

Controls Glucose Appearance
CNS:
Promotes satiety and
reduction of appetite

Liver:
Reduces hepatic glucose
output by inhibiting
glucagon release

Alpha cell:
Inhibits glucagon
secretion
Flint A, et al. J Clin Invest. 1998;101:515-520.
Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.
Nauck MA, et al. Diabetologia. 1996;1546-1553.
Drucker DJ. Diabetes. 1998;47:159-169.

Beta cell:
Stimulates glucosedependent insulin
secretion

Stomach:
Slows gastric
emptying

Treat DM with lizard spit

Exenatide member of
a new class of diabetes
drug derived from a
poisonous Gila
monster, a poisonous
lizard that lives in the
Southwest and in
Mexico

Incretin Mimetic (GLP-1 Agonist): Exenatide,

Liraglutide

Exenatide- the first

FDA-approved incretin
mimetic
Binds to glucagon-like
peptide 1 (GLP-1)
receptor

Exenatide:
GLP-1 agonist action
Stimulates insulin secretion in
glucose-dependent fashion
Restores first-phase insulin
response (1st 10 min after food
ingestion) lost early in type 2
diabetes
Suppresses inappropriately
elevated glucagon secretion
decreased hepatic glucose output
and insulin demand
Slows gastric emptying
Reduces appetite/food intake
May promote beta cell health/
survival

Exenatide
Disadvantage: injected
(BID-exenatide, ODliraglutide), nausea,
vomiting, diarrhea,
pancreatitis?
Advantages:
Lack of hypoglycemia
with monotherapy;
May produce substantial
and sustained weight
loss.

The Therapeutic Potential

of GLP-1 Is Limited by its Rapid Inactivation
Rapid inactivation (DPP-IV),
Short elimination half-life (~1-2 min)

GLP-1 must be administered

continuously (infusion)

Inconvenient for treating a chronic

disease like type 2 diabetes

Drucker DJ, et al. Diabetes Care. 2003;26:2929-2940.

DISCUSSION
Despite its favourable biological actions, the therapeutic potential of
GLP-1 is limited primarily by its rapid degradation by the ubiquitous
enzyme dipeptidyl peptidase-IV (DPP-IV).
The rapid inactivation of GLP-1, in addition to its rapid renal
clearance, contributes to a short half-life of less than two minutes.
Thus, sustaining plasma concentrations of GLP-1 long enough to
produce a therapeutic effect requires continuous administration.
As is typical of other peptides, GLP-1 requires administration by
injection.

DPP-IV inhibitors: Sitagliptin, Vildagliptin,

Saxagliptin, Linagliptin
Inhibit DPP-IV-mediated degradation of GLP-1
Do not cause weight gain or loss; weight
neutral
Given orally

Amylin Analog
Pramlintide

Pramlintide:
Mechanism of Action
Mimics the effects of amylin (which
is secreted with insulin by pancreatic
beta cells in response to food intake)
Slows gastric emptying (reduced rate
of glucose absorption)
Suppresses glucagon secretion
decreased hepatic glucose output
and insulin demand
Reduces food intake

Pramlintide
Disadvantages:

Hypoglycemia
Injected
Nausea
May delay absorption
of other medications

Case 2
Despite lifestyle modifications such as diet and exercise, his
fasting blood sugar remains quite elevated. Which of the
following medications would you choose to treat him with?

A) Glibenclamide

B) Metformin

C) Repaglinide

D) Rosiglitazone

E) Acarbose

F) Sitagliptin

G) Exenatide
5) In this particular patient, list the advantages and disadvantages
of your drug of choice.
6) Which medication would be appropriate to use in combination
with your drug of choice? Why?