Endocrine Pancreas: Pharmacology

Endocrine 1 Module
Dr. Mary L. Thomas, Ph.D.
Visiting Professor, Dept. of Biochemistry, Pharmacology,
Physiology
mthomas@rossu.edu
 For help with Endocrine Pharmacology

I’ll be in Knoxville through July 26, and available by email after that.

I am happy to meet with you to go over any difficulties and answer

questions . The most reliable way to be sure that I will be available to talk
with you is to arrange an appointment by email: mthomas@rossu.edu.
This can be arranged on short notice – I will try to check my email
frequently.

For all my lectures, there are practice questions with explicated answers
posted in Canvas.
Reading List and Supplementary Materials

• Access Medicine supplemental reading

– Chapter 41, Pancreatic Hormones and Antidiabetic Drugs. In:
Basic & Clinical Pharmacology, 14e, by Bertram Katzung.
http://accessmedicine.mhmedical.com/content.aspx?bookid=224
9&sectionid=175222393

• Review Dr. Wright’s lecture “Endocrine Pancreas: Physiology”

(this module)

• Practice Questions in Canvas

Pharmacology of the endocrine pancreas is essentially
management of diabetes mellitus

Type 1 and type 2 diabetes mellitus (DM) present quite different

pharmacological challenges.

1) Type 1 DM (hypoinsulinemia due to pancreatic b-cell destruction)

requires replacement therapy, but unlike Addison’s Disease or thyroid
replacement (in which replacement therapy is relatively
straightforward), it is a significant challenge to titrate the replacement
dose and timing appropriately to coordinate with dietary intake and
metabolic needs

2) Treatment of type 2 DM (loss of target tissue responsiveness to

insulin) requires enhancing target tissue responsiveness to insulin
and taking other steps to prevent hyperglycemia
Type 1 Diabetes Mellitus Drugs: Drug Classes and Drugs to know

(note: all insulin preparations are either native insulin or very similar analogs that
have nearly identical actions at insulin receptors)

Short-acting insulins Long-acting insulin

insulin lispro insulin regular insulin NPH insulin glargine

Type 2 Diabetes Mellitus Drugs: Drug Classes and Drugs to know
Biguanides Sulfonylureas Thiazolidinediones
metformin glimepiride rosiglitazone
glyburide

Alpha-glucosidase Incretin mimetics Gliflozins *

inhibitors (SGLT2 inhibitors)
acarbose exenatide canagliflozin
liraglutide

*Gliflozins (canagliflozin) will soon be

added to the drug list, and we think you
should hear about them briefly at this
time, but they will NOT be tested this
semester.
 Learning Objectives
Type 1 Diabetes Mellitus

Type I Diabetes Mellitus (type 1 DM): Severe insulin deficiency

• Apply a basic knowledge of the chemical nature of insulin and the physiology of
glucose and energy metabolism to develop an understanding of the challenges
involved in treating type 1 DM

• Be able to describe the general principles underlying the concept, formulations,

and use short-acting and and long-acting insulin preparations; be able to
associate these categories and how they are used with the drug names on the
drug list

• Be able to explain the concept of “tight control” of blood glucose levels and the
associated risks
 Learning Objectives
Type 2 Diabetes Mellitus
Type 2 Diabetes Mellitus (type 2 DM): Insulin resistance and insufficiency

• For each of the drug categories on the drug list, apply a basic knowledge of the
underlying pathophysiological changes that lead to the development of type 2
DM to explain
• the rationale/mechanism of action
• the primary sites of action
• route of administration
• possible adverse effects

• Be able to associate the drugs on the drug list with the appropriate class of
drug
Type I Diabetes Mellitus:
Insulin Therapy
Major concept in the management of type 1 DM:

Good management requires teamwork between the patient and a group of

health care experts including a nurse educator, a dietician/nutritionist, and the
physician as well as other possible team members depending on the patient’s
situation.

The goal of this team is to coordinate diet, lifestyle, and insulin to maintain
normoglycemia for the maximum possible amount of the time in order to slow
the progression of disease complications and functional physiological losses.

The major risk in maintaining “tight control” is that there is very little room
for error, and thus there is a high risk of developing hypoglycemia.

Hypoglycemia can quickly disable a person to the point that they need
outside help in order to prevent developing severe disability, losing
consciousness, and even dying.
 SIGNS & SYMPTOMS OF HYPOGLYCEMIA

Hypoglycemia
is a serious
and potentially
fatal situation.

From Dr. Wright’s lecture “Endocrine

Pancreas Physiology”
 FACTORS REGULATING INSULIN RELEASE
FROM PANCREATIC BETA CELLS
 PSNA Other It’s not a trivial
GI hormones Hormones challenge to
+/- provide exogenous
+ + insulin in a
Amino regimen to
Acids  SNA
+ - optimally mimic
PANCREAS Epi the combined
effects of
+ endogenous
 Glucose physiological
regulators of
insulin secretion
Insulin
 PANCREATIC b CELLS
INSULIN
Additional challenges
• 51 amino acid polypeptide
are posed by the
• Proinsulin – 84 amino acids chemical nature of
• C-terminal cleaved (C peptide) + insulin insulin

Unless chemically altered in some

• Insulin
way, insulin is not going to last
– Circulates unbound long once it enters the circulation
– Short half-life (~ 6 minutes)
In type 1 DM, insulin must be
administered parenterally *
(usually SC, but also IM or IV)
*one preparation of inhaled short-
acting insulin is now available – not on
drug list
 Treatment Goal in DM:
Maintain appropriate glucose levels as continuously as possible

Oversimplified strategy:

Use long-acting insulin to maintain baseline insulin to support

ongoing metabolic needs

Administer short-acting insulin prior to meals to guard against

postprandial hyperglycemia

Balance the above to prevent hypoglycemic episodes between

meals and overnight

How do we achieve this with a peptide hormone?

 A few basics of insulin preparations

In the past, insulin was obtained from animal sources: cows and pigs

Recombinant DNA (rDNA) technology has made it possible to synthesize insulin

with the human amino acid sequence
rDNA also permits synthesis of modifications of human insulin which can be
designed to alter the pharmacokinetics
Units (you do not need to know the details)

One unit of insulin was originally defined as:

The amount required to reduce the blood glucose concentration in a

fasting rabbit to 45 mg/dL.

Insulin is now supplied in solution or suspension of 100 units/ml,

which is ~3.6 mg insulin/ml. This is termed U-100. Some preparations
are also available as U-300 or U-500 (300 or 500 units/ml, respectively)
Pharmacokinetic aspects of subcutaneous insulin injection
Insulin replacement therapy in type 1 diabetes is via subcutaneous
insulin whether administered via a pump, a pen, or an injection

3 Major time-related characteristics are relevant for the

pharmacokinetics of insulin:
Onset of action
Attainment of peak levels
Duration of action

All of these are going to be determined by the interaction between

1) How quickly the insulin is absorbed from the subcutaneous
depot
and
2) The rate of metabolism of the insulin preparation
Insulin lispro (rapid acting) is an insulin analog

• Amino acid sequence modification of human insulin that does not affect
biological activity at the insulin receptor, but does prevent self-
aggregation

• The onset of action (absorption from the sc depot site) is more rapid and
the duration of action is short, making it useful for administration just
prior to a meal

• Binding to insulin receptors and circulating half-life are identical to

regular insulin

• May be categorized as “ultra-short acting” – these time-related labels

aren’t carved in stone

• Short (rapid) -acting insulins are used in current insulin pumps

It is easier to control dose and time with modified preparations that don’t
aggregate, but they have much shorter duration of action after administration
Regular insulin (short-acting)

• natural human insulin sequence

• zinc-insulin crystals dissolved in a clear liquid

• molecules associate as hexamers in neutral pH aqueous solution

• after sc injection, the crystals dissociate from hexamers to monomers or

dimers, which can enter the circulation

• delay in absorption requires lag time (~45’) between administration and

meal

• the duration of action of a given dose will depend primarily upon how long
the insulin continues to be released from the injection site

• IV administration for diabetic ketoacidosis or perioperative management of

patients who require insulin
Inhaled Insulin

A preparation of regular insulin attached to a crystallized carrier, which

provides a large surface area for adsorption of the protein hormone.
Delivered by a single-use device about the size of a referee whistle.

Approved for pre-meal administration in adults who use injected basal

insulin. Peak levels are reached in ~15’ with maximum effect by 1 hr and
levels return to baseline by 3 hrs. This is all slightly more rapid than with
injected lispro.

Cough is the main adverse effect

Contraindicated in smokers and patients with chronic lung diseases,

asthma, etc.
Long-acting insulin preparations

Modifications have also been made to insulin preparations to decrease the rate of
release from subcutaneous depots, thus permitting a single injection to supply
longer-lasting “background coverage” (basal insulin)

NPH insulin (neutral protamine Hagedorn insulin; insulin isophane): an intermediate-

acting combination of crystalline zinc insulin and protamine; after subcutaneous (sc)
injection, protamine is enzymatically digested by proteolytic enzymes to release
insulin that can then be absorbed into the circulation. (You do not need to know the
chemical details, just the concept).

Insulin glargine has sequence modifications that result in it being soluble at pH 4 (as
it is packaged) and aggregating when it is injected to pH neutral in vivo sc sites, thus
leading to slow release into the circulation. Provides a dependably sustained release
from depot injections.
 Insulin Preparations
(based on a depot, sc injection)
Preparation Onset of Peak Duration of action
action
Rapid-acting
Insulin lispro < 15 min 30-60 min 2-4 hrs
Short-acting
Insulin regular ~30 min 2-3 hours 3-6 hrs

Intermediate-acting
Insulin NPH 2-4 hrs 4-12 hrs 12-18 hrs
(Insulin isophane)
Long-acting
Insulin glargine 1-2 hrs No peak 20-24 hrs

Data from American Diabetes Association (note: these are general values only – you will find slight variations from different sources)
(http://www.diabetes.org/living-with-diabetes/treatment-and-care/medication/insulin/insulin-basics.html
Time to peak and duration of action for different types of insulin

Legend:
• Extent and duration of action of
various types of insulin as
indicated by the glucose infusion
rates (mg/kg/min) required to
maintain a constant glucose
concentration

• The durations of action shown are

typical of an average dose of 0.2-
0.3 U/kg

• The durations of regular and NPH

insulin increase considerably
when dosage is increased
Different insulin treatment regimens
• Injection vs. pump
 Several regimens for regulating blood glucose in type 1 diabetes mellitus

(lispro)
• Insulin pump maintains
a steady background
release of insulin

• The patient calculates

B – breakfast and triggers the bolus
L – lunch release, based on the
S – supper planned meal.
HS – hora somni (bedtime)
It is important to note that insulin regimens may have to be
adjusted in response to illness, changes in exercise/activity
and alcohol consumption.

We won’t go into detail at this point, but keep it in mind.

Alcohol can be particularly confusing, because while it may

provide carbohydrate, it can ultimately decrease hepatic
gluconeogenesis. Also the sugar content of possible mixers
plays into the equation.
Bottom line, what do you need to know about specific
insulin preparations?

1) Be able to explain why insulin preparations need to be

modified to meet the therapeutic needs of a patient with
type 1 diabetes; be able to relate this to the insulin
preparations on the drug list

2) Be able to explain in general terms why a person may need

to take more than one type of insulin every day, and what
criteria need to be considered to design an insulin
administration regimen.
 Type 2 Diabetes Mellitus Pharmacotherapy

3 Principle abnormalities in Type 2 Diabetes Mellitus (type 2 DM)

1. Insulin resistance in peripheral tissues, especially muscle and fat,

but also liver

2. Defective insulin secretion

3. Increased hepatic glucose production.

Lead to
Hyperglycemia

Pharmacotherapy of type 2 DM addresses these issues either directly or indirectly.

Type 2 Diabetes Mellitus Drugs: Drug Classes and Drugs to know
Biguanides Sulfonylureas Thiazolidinediones
metformin glimepiride rosiglitazone
glyburide

Alpha-glucosidase Incretin mimetics Gliflozins *

inhibitors (SGLT2 inhibitors)
acarbose exenatide canagliflozin
liraglutide

*Gliflozins (canagliflozin) will soon be

added to the drug list, and we think you
should hear about them briefly at this
time, but they will NOT be tested this
semester.
Categories of Drugs for Type 2 DM Pharmacotherapy

1. Act on liver, muscle, and/or adipose tissue to decrease glucose levels

(biguanides; thiazolidinediones)

2. Act via the sulfonylurea receptor to increase insulin secretion

(sulfonylureas)

3. Act via incretin receptors to increase insulin secretion (exenatide,

liraglutide)

4. Slow intestinal carbohydrate absorption (acarbose)

5. Inhibit renal glucose reabsorption (gliflozins)*

* Not on drug list

 Biguanides
(“Insulin sensitizers”)
Metformin – usually the first drug used when
pharmacotherapy is initiated for type 2 DM

Major mechanism of action involves activation of AMP-

activated protein kinase (AMPK)
↓ hepatic gluconeogenesis
↓ hepatic glycogenolysis

Good profile of side effects:

• Rarely cause hypoglycemia or increased body weight;
decreases serum triglyceride levels
 Sulfonylureas: glimepiride and glyburide
(Insulin releasers – orally active) Sulfonylurea

SUR1
Mechanism of action:
Bind to and inactivate the SUR1
(sulfonylurea receptor) subunit of
the ATP-sensitive K+ channel on
beta cells, analogous to the
response in the fed state, leading
to release of insulin

Note that sulfonylureas will increase

insulin release regardless of glucose
levels. Thus there is a risk of (review Dr. Wright’s
hypoglycemia. lecture: “Endocrine
Pancreas: Physiology”)
 Thiazolidinediones
(“Insulin sensitizers” – decrease insulin resistence)

Rosiglitazone

Mechanism of action: selective agonist of PPARg

– Heterodimerizes with RXR receptor

– Activation of insulin-responsive genes that regulate

carbohydrate and lipid metabolism

– Primary site of action is fat, but also muscle and liver

 Incretin Mimetics
(GLP-1 receptor agonists - insulin releasers)
Insulin release is glucose-dependent, thus hypoglycemia is not a
common adverse effect.

Exenatide:
• Glucagon-like peptide (GLP-1) analog – “incretin”
• “Glucose-dependent” insulin secretion
– Suppresses glucagon secretion
– Slows gastric emptying
– Decreases appetite
– Peptide – must be injected

• Can be used as monotherapy with diet and exercise or in combination with

other drugs in type-2 DM
Liraglutide - GLP-1 receptor agonist
GLP-1 analog designed for slow release into the blood
 longer biological half-life
 Same pharmacological activity as exenatide
 can be administered (by injection) once per day or once per week.

To create the extended action of liraglutide, a fatty acid molecule

was attached to the 7-37 amino acid sequence of GLP-1, which
causes the molecules to both self-associate and bind to albumin in
the subcutaneous tissues where it is injected as well as in the blood.
Active GLP-1 is released from albumin at a consistent slow rate. In
addition, albumin also protects the GLP-1 peptide from
bioinactivation, reducing renal elimination compared to the parent
compound.
 a-glucosidase inhibitors
(decrease glucose absorption)

Acarbose
Mechanism of action:
Inhibits breakdown of starch and oligosaccharides to
monosaccharides by inhibiting a-glucosidase

– Slows absorption of carbohydrates

– Blunts postprandial rise in plasma glucose

• Not used much in the U.S. due to GI side effects and relatively small
effect on glucose levels
 Gliflozins –
sodium-glucose cotransporter-2 (SGLT2) Inhibitors
(not on the drug list and will NOT be examined this semester)

Canagliflozin –increases renal excretion of glucose by preventing

tubular reabsorption
• Decreased serum glucose
• Increased incidence of urinary tract infections
• Increased incidence of leg and foot amputations
Algorithm for treatment of
Type 2 Diabetes Mellitus
 Summary

1) Treatment of Type 1 diabetes mellitus

• Replacement therapy
• Trying to maintain a balance between “tight control” of
blood glucose and excessive risk of hypoglycemia

2) Treatment of Type 2 diabetes primarily aims to increase

target tissue responsiveness to insulin and/or increase
insulin release.