Diabetes M1 Mech Aug8

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Diabetes
Home Study Project

Glucose Metabolism
Eli Lilly and Company
Diabetes Home Study Project

Copyright 2008 Eli Lilly and Company, with respect to proprietary product- and
market-specific information.
Copyright 2008 Whole Systems, with respect to all instructional design and
formats.
All rights reserved. Printed in the U.S.A.
No part of this work may be reproduced or transmitted in any form or by any
means, electronic or mechanical, including photocopying and recording, or by
any information storage and retrieval system without permission in writing from
the publisher.
Glucose Metabolism
Contents
Introduction
Instructions
The Patient Care Process
Lesson 1: What is the pancreas? 1
Lesson 2: How is blood glucose controlled? 11
Lesson 3: What is the role of incretin hormones in the
regulation of blood glucose? 23
Bibliography 37
Glossary 39


Glucose Metabolism
Introduction
Glucose is the primary fuel used by every cell in the body. The brain is completely
dependent on a steady supply of glucose for energy. For this reason, the body has a
system of intricate metabolic controls for keeping the level of glucose in the blood within a
tight range at all times. Understanding the metabolism of glucose is fundamental to
understanding diabetes, a disease that involves derangements in carbohydrate as well as
protein and fat metabolism.
This module, the first in the Eli Lilly Diabetes Home Study Project, lays the foundation for
your understanding of diabetes by providing a detailed review of glucose metabolism.
The module consists of two lessons. Lesson 1 describes the pancreas, an organ that
plays a vital role in glucose metabolism, as well as in digestion. Lesson 2 describes the
metabolic control of blood glucose through insulin, glucagon, and other hormones
produced and secreted by the pancreas.
This module also includes a section called the Patient Care Process. This describes the
iterative care cycle that doctors and other healthcare professionals (HCPs) follow to
diagnose, treat, and manage patients. The Patient Care Process is instructional
information that you may want to refer to from time to time as you read through the Lilly
Diabetes Home Study Project.

Instructions
The information in this module has been divided into discrete, logical lessons. Each lesson is
introduced by a focus question, which appears as the lessons title. The focus questions outline
the major concerns of the module. When you are able to answer all of the focus questions
readily and completely, you will have mastered the content of the program.
Within each lesson, learning objectives describe the main terms, relationships, concepts, or skills
taught in the lesson. Learning objectives also define the areas that will be tested in the final
exam. Reading through the learning objectives before you begin to study the text will help you
focus on the central issues of the lesson. By reviewing the objectives after studying the text, you
will be able to assess your command of the material.
Mastery check questions at the end of each learning objective topic actively involve you in the
learning process and ensure that you fully comprehend the material in one topic before you
begin another. After reading each topic, respond in writing to all questions; correct answers are
provided. When you are able to answer all of these questions with reasonable speed and
accuracy, you will know that you have mastered the information presented in the topic.
Following is a summary of these and other instructional tools used to aid in the learning and
retention of information presented within the text.

Learning objectives describe the main terms, relationships, concepts, or skills taught in the lesson
identify what you will be expected to demonstrate
Critical Information!
boxes

indicate information that will form the foundation of your knowledge; represent
the highest, or primary, level of importance
you will be tested on the information in these boxes
marked by the star symbol
Italicized text throughout the module, important points are emphasized using italicized text;
represents the secondary level of importance
Flash Forward boxes indicate specific information that will be important in later modules
Important to Know boxes highlight key information that may be helpful in discussions with healthcare
professionals
Flash Back boxes recall information learned earlier in the program that is important to the content
being discussed in a particular module
Nice to Know boxes add specific information that is relevant to the content (but not critically
important) in order to provide a broader perspective
Perspectives boxes provide supplemental information to help place key content points in a
meaningful context
Graphics illustrate information presented in the text
Animations reinforce the content being presented
Patient cases describe clinical situations to help illustrate the concepts in the text
Mastery check questions
and answers
actively involve learners in the learning process and ensure that they fully
comprehend the material in one topic before beginning another
Interactive exercises e-learning exercises that reinforce the module content
Lesson summaries review the fundamental content presented in each lesson
Glossary defines new or important terms; these terms appear in bold type when they are
discussed in the text
Glucose Metabolism
The Patient Care Process

The Patient Care Process describes the cyclical process that doctors and other healthcare
professionals (HCPs) follow to diagnose, treat, and manage patients (see the figure
below). This cycle applies to all patients new patients making their first visit to the
doctor, as well as patients who are being treated for diabetes. The Patient Care Process
provides a framework for understanding what matters to HCPs at each step in the
process. The HCP Perspective is in the middle, because it is the basis for understanding
differences in how each individual applies the Patient Care Process.

The Patient Care Process.
The Patient Care Process depicts the crucial decision points for the doctor as he or she
makes ongoing treatment decisions. It helps identify the points where information about
how a drug works as well as evidence regarding its efficacy, safety, and clinical impact
will be most useful and influential. A brief definition of each step follows.
Patient Presentation The patient must describe some symptoms (e.g., burning in the
chest), while others can be observed by the doctor (e.g., a rash or swelling). As a result,
this step may be very straightforward, or it can be very challenging.
Hypotheses As soon as experienced doctors observe or hear about a symptom, they
start to form hypotheses that are then tested and refined through the subsequent steps of
the Patient Care Process. These hypotheses are formed using a combination of
qualitative and quantitative data from the doctors personal experience, interaction with
peers, clinical studies, journal publications, and/or guidelines established by a local or
national organization.
History and Physical Examination After hypotheses are formed, the doctor begins to
test and refine them. At this point, most of the data being gathered is qualitative. If the
doctor has formed multiple hypotheses, he or she uses this step to rule out as many
hypotheses as possible (a differential diagnosis) before conducting more quantitative
tests. This step may involve asking more in-depth questions about the patients family
history, previous experience, and symptoms; in addition, affected body systems are
identified and, wherever possible, physically examined.
By the time the history and physical examination step is complete, the doctor may have
validated a single hypothesis and have a sufficiently high level of certainty to make a
diagnosis and select therapy without performing additional tests. Or, the doctor may
decide that the level of certainty is not high enough and that quantitative tests must be
performed.
Diagnostic Tests The primary purpose of ordering tests is to gather quantitative,
standardized evidence that will help rule out, confirm, or validate a hypothesis. Doctors
typically order tests based on accepted guidelines regarding which tests should be
ordered given a particular set of symptoms. If several hypotheses are still valid after the
history and physical examination step, multiple tests may be ordered to rule out some of
the suspected conditions and suggest others.
Interpret Results Test results give the doctor quantitative data on which to base the
diagnosis. Accepted values, abnormal values, abnormal findings, or findings that outline
the stages of disease progression all provide evidence to raise the doctors level of
certainty in making a diagnostic decision. Often test results are inconclusive or unhelpful;
in this case, the doctor may return to the history and physical examination step or make a
diagnosis based on his or her clinical experience or on the advice of other doctors.
Diagnosis When the doctors level of certainty is high enough, based on his or her
clinical experience, patient information, test results, and peer advice, he or she makes a
diagnosis. The level of certainty required will vary depending on the specialty, the
particular doctor, and the patients condition.
Therapeutic Intervention Therapy selection may be a qualitative or quantitative
decision, depending on the disease, the doctors level of certainty, and the doctors
diagnostic style. For some conditions, protocols and other types of guidelines have been
developed to suggest the best treatment approaches. Some therapy choices are made
based on these protocols or guidelines, but the physician often makes a choice based on
his or her judgment, the patient type, and patient values.
Evaluate Outcomes Once a therapy selection is made, the criteria for evaluating its
success should be delineated. These criteria include factors such as length of time to get
the desired response, degree of impact on the symptom, presence and severity of side
effects, the patients quality of life, comparative expense, and patient compliance, as well
as the products safety.
As you read through the program, you will notice the Patient Care Process graphic
sometimes appears in the left-hand margin. This is a signal that the corresponding text
describes an important step in the doctors decision-making process. These sections will
provide important information for understanding how a doctor makes decisions regarding
the diagnosis and treatment of a patient with diabetes.

Glucose Metabolism 1
Lesson 1
What is the pancreas?
Objectives
Describe the overall function and anatomy of the pancreas
Describe the role of the exocrine pancreas
Describe the role of the endocrine pancreas
Describe the role of the four cell types of the endocrine pancreas and the hormones
they secrete

Overall Function and Anatomy of the Pancreas
The pancreas is an elongated, yellowish organ 12 to 15 cm (5 to 6 in) in length. It is
located at the back of the abdomen, extending horizontally between the stomach
and duodenum. The pancreas is both an exocrine and an endocrine gland. The
exocrine pancreas is responsible for secreting enzymes into the intestinal tract that
are important for digestion. The endocrine pancreas, on the other hand, secretes
hormones such as insulin and glucagon into the bloodstream. These two
hormones play major roles in regulating blood glucose levels. Any irregularities in
the endocrine function of the pancreas may lead to illness, the most common of
which is diabetes.

CR I T I C A L I N F O R MA T I O N !
Diabetes
Diabetes mellitus is a metabolic disorder involving the endocrine pancreas.
Diabetes affects carbohydrate, lipid, and protein metabolism, and results from a
decrease in insulin production and/or a decrease in the ability of target organs to
respond to insulin. Click here to view an animation on the pathogenesis of type 1
and type 2 diabetes.

Terminology
Exocrine glands secrete
their products into the
bloodstream via a duct,
whereas endocrine glands
are ductless and secrete
their products directly into
the bloodstream.
1

2 Diabetes Home Study Project
Figure 1-1 shows the anatomy of the pancreas. The pancreas consists of four
regions: the head, neck, body, and tail, with the tail end lying close to the spleen on
the left side of the abdomen.

Figure 1-1. Anatomy of the pancreas.
Click on the icon to reinforce what you have learned about the anatomy of the
pancreas.
Q1. The exocrine pancreas is responsible for secreting ______________ that are important for
digestion. The endocrine pancreas is responsible for secreting______________.
A. enzymes; hormones
B. hormones; enzymes
C. insulin; enzymes
D. glucagon; enzymes
A1. A
Q2. Diabetes is a metabolic disorder involving the ________________ pancreas.
A. exocrine
B. endocrine
A2. B
Role of the Exocrine Pancreas
The pancreas is composed of cells that are specialized for its endocrine and
exocrine functions. The exocrine portion of the pancreas produces and releases
enzymes into the intestinal tract, where they play major roles in digestion.
Acinar Cells
The bulk of the pancreas is made up of exocrine tissue. The majority of this tissue
consists of acini, grape-like clusters of cells called acinar cells, which secrete
enzyme-containing
2
digestive juices into the duodenum. After being produced in the
acinar cells, pancreatic enzymes are transported, along with other pancreatic
exocrine secretions such as water, through ducts into the duodenum.

Acinar Cells of the Exocrine Pancreas
The majority of the exocrine tissue of the pancreas consists of acinar cells, which
secrete enzyme-containing digestive juices into the duodenum.

Q1. Acinar cells secrete enzyme-containing digestive juices into the:
A. pancreas.
B. duodenum.
C. liver.
D. bloodstream.
A1. B
Role of the Endocrine Pancreas
The endocrine pancreas produces hormones, the chemical messengers of the
endocrine system. The main pancreatic hormones are insulin and glucagon, which
are critically important in regulating the bodys metabolic processes, in particular the
storage and utilization of glucose. These hormones are secreted directly into the
bloodstream.
Chemical Structure of Hormones
A number of organs, such as the pituitary gland, the thyroid gland, the adrenal
glands, the testes, and the ovaries, produce hormones. Hormones released by the
various endocrine glands differ not only in their actions, but also in their chemical
structures.

Based on their chemical structures, hormones can be divided into three groups:
peptide, steroid, and amine hormones.
Peptide Hormones
Peptides are proteins, which means they are composed of amino acids linked
together. Insulin and glucagon are examples of peptide hormones.
Steroid Hormones
Steroid hormones are synthesized from cholesterol (a lipid), mainly by the ovaries,
testes, and adrenal glands. Examples of steroid hormones include androgens (e.g.,
testosterone) and estrogens (e.g., estradiol), which are sex hormones secreted by
the testes and ovaries, respectively, as well as corticosteroids, which are secreted
by the adrenal glands.
3

Amine Hormones
Amine hormones are derived from amino acids.
4
The hormones in this group
include epinephrine and norepinephrine, both produced in the adrenal glands, and
the thyroid hormones produced in and secreted by the thyroid gland.

Pancreatic Hormones
The main pancreatic hormones are insulin and glucagon, which are critically
important in regulating the bodys metabolic processes, in particular the storage
and utilization of glucose.

Click on the icon to reinforce what you have learned about the endocrine pancreas
and hormone groups.
Hormone Site of Action
Hormones are chemical messengers that are secreted by one tissue and travel to
another to elicit a response. Sometimes hormones also act locally, either within the
hormone-producing cell itself, or upon nearby or adjacent cells.
Hormones can be classified according to how they elicit a response on the target
tissue. In simple terms, hormones can stimulate receptors on the cell membrane of
the target cell, or they can enter the cell and stimulate receptors located inside the
cell. In general, amine and peptide hormones bind to and activate cell membrane
receptors, whereas steroid hormones travel to the interior of target cells.
4

Q1. True / False Pancreatic hormones are involved in regulating the bodys metabolic processes.
A1. true
Role of the Four Cell Types of the Endocrine Pancreas
and the Hormones They Secrete
The endocrine pancreas consists of small clusters of cells scattered throughout the
pancreas. These clusters are like islands of endocrine cells spread among the
exocrine cells. They are called islets of Langerhans, in honor of the scientist who
first described them (see Figure 1-2).

Figure 1-2. Islets of Langerhans and surrounding acini.
Islets produce several endocrine hormones, all of which are peptide hormones, and
secrete them directly into the bloodstream. The rapid uptake of these hormones into
the bloodstream is aided by the rich blood supply of the islets. The blood flow to the
islets has been found to be disproportionately large (10% to 20% of the pancreatic
blood flow) for the 1% to 2% of pancreatic volume.
5
The pancreatic islets produce
and secrete two main hormones involved in controlling blood glucose levels: insulin
and glucagon.
The endocrine pancreas contains more than one million islets. Each islet contains
about 2,500 spheroidal cells grouped as four distinct types of cells. The four types
of islet cells are called beta (), alpha (), delta (), and pancreatic polypeptide (PP)
cells. Each cell type produces and secretes a different hormone.
Click on the icon to reinforce what you have learned about the four cell types of the
endocrine pancreas.

Beta Cells ( Cells)
Beta cells ( cells) are the most abundant islet cell type and comprise between
60% and 80% of all islet cells. They produce and secrete insulin and another
hormone known as amylin.
5

Insulin, a peptide hormone, is secreted in response to increased blood glucose and
amino acids following ingestion of a meal. The primary action of insulin is to
stimulate glucose uptake and metabolism by peripheral tissues. Thus, insulin
increases the disappearance or clearance of glucose from the bloodstream.
Insulin helps control blood glucose levels in three ways: 1) signals the cells of
insulin-sensitive peripheral tissues, primarily skeletal muscle, to increase their
uptake of glucose; 2) acts on the liver to promote glycogenesis (the storage of
glucose in the form of glycogen); and 3) inhibits glucagon secretion, thus indirectly
signaling the liver to stop producing glucose via glycogenolysis (the enzymatic
breakdown of glycogen into glucose) and gluconeogenesis (the synthesis of
glucose from noncarbohydrate precursors). Insulin is therefore considered to be an
anabolic hormone.
3

Insulin
Insulin is a small peptide hormone composed of 51 amino acids (the building
blocks of proteins). Insulin is produced by the pancreatic cells and is the
hormone primarily responsible for controlling glucose metabolism.

Amylin is a peptide hormone co-secreted with insulin by pancreatic cells in
response to the intake of glucose and amino acids. Amylin works with insulin to help
coordinate the rate of glucose appearance and disappearance in the circulation,
thereby preventing an abnormal rise in glucose concentrations.
Alpha Cells ( Cells)
Alpha cells ( cells) secrete glucagon and constitute 15% to 20% of the total
number of islet cells.
5
Glucagon, which is also a peptide hormone, plays a major
role in sustaining blood glucose levels within a normal range during fasting
conditions by stimulating glucose production by the liver. Between meals, when
blood glucose levels fall below the normal range, glucagon secretion increases,
resulting in hepatic glucose production and return of blood glucose levels to the
normal range. During and immediately following a meal, when blood glucose levels
are high, glucagon secretion is suppressed. Suppression of glucagon secretion,
coupled with postprandial (following a meal) insulin secretion, results in a near-total
suppression of hepatic glucose output via the liver.
3

In type 2 diabetes, there is inadequate suppression of postprandial (following a
meal) glucagon secretion, which results in inappropriately elevated hepatic glucose
production. This condition contributes to postprandial (following a meal)
hyperglycemia in diabetes.

Delta Cells ( Cells)
Delta cells ( cells) produce and secrete somatostatin and comprise between 5%
and 10% of all islet cells.
5
Somatostatin is a peptide hormone secreted from the
pancreas and the hypothalamus that inhibits the release of growth hormone
(somatotropin), insulin, glucagon, and gastrin. While the effect of somatostatin on
insulin and glucagon is well described, its role in metabolic regulation is still unclear.
Pancreatic Polypeptide Cells (PP Cells)
PP cells produce and secrete pancreatic polypeptide hormone. While the exact
physiologic function of pancreatic polypeptide hormone is unknown, it may affect
gastrointestinal function by regulating food absorption from the gut. Pancreatic
polypeptide hormone may help regulate the release of pancreatic digestive enzymes
and thus contribute through a more indirect role in metabolic regulation.
Table 1-1 provides a summary of the hormones secreted by each of the four types
of pancreatic islet cells and their functions.

Hormones Secreted by the Pancreatic Islet Cells
Cell Type Hormones Secreted and Their Functions
Beta cells
( cells)

Insulin
promotes glucose and nutrient utilization and storage
promotes glucose uptake by cells
suppresses postprandial (following a meal) glucagon secretion
promotes protein and fat synthesis
Amylin
suppresses postprandial (following a meal) glucagon secretion
regulates gastric emptying
helps to regulate food intake and body weight
Alpha cells
( cells)
Glucagon
stimulates the breakdown of stored liver glycogen (glycogenolysis)
promotes hepatic gluconeogenesis (glucose production by the liver)
Delta cells
( cells)
Somatostatin
inhibits release of growth hormone (somatotropin), insulin, glucagon, and
gastrin
role in metabolic regulation unclear
Pancreatic
polypeptide
cells (PP cells)
Pancreatic polypeptide hormone
may help regulate release of pancreatic digestive enzymes
Table 1-1.
Click on the icon to learn about Brenda, a patient with type 1 diabetes.

CA S E S T U D Y
Brenda, a Patient with Type 1 Diabetes Since Childhood

Brenda is a 31-year-old female who was diagnosed with
type 1 diabetes when she was just 8 years old. Since
that time, she has been taking insulin injections every
day.
Because Brenda was so young when she was first
diagnosed with diabetes, at first she didnt quite
understand what it meant. Dr. Collins, her pediatrician,
explained to her that diabetes meant there was too
much sugar, or glucose, in her blood because a small
organ called the pancreas wasnt working any more. He
told her that within the pancreas, there are cells, which
make insulin. Insulin is a hormone that keeps the level
of sugar, or glucose, in the blood from going too high.
Insulin allows glucose in the food we eat to be converted
into energy for use right away, or stored for later use.
Dr. Collins said that in people like her with type 1
diabetes, the cells are destroyed, so no more insulin is
available. For this reason, she would need to take
insulin for the rest of her life, since it was necessary for
her to live.

Click on the icon to learn about Dave, a patient with type 2 diabetes.

CA S E S T U D Y
Dave, a Patient at Risk for Type 2 Diabetes

Dave is a 45-year-old male who is at risk for type 2
diabetes. The reason Dave is at risk is that he is
African-American, overweight, hardly ever engages in
any type of physical activity, is middle aged, and has a
family history of diabetes. Over the past several years,
his physician Dr. Naipaul has advised Dave to lose
weight in order to reduce his risk of diabetes. Dave
would agree, but then would just continue his old ways,
eating too much fast food and sitting down to watch TV
all the time.
Dave knows he needs to change his lifestyle, but he
figures hes been lucky this long, so he keeps
procrastinating. Lately, however, hes been a little
nervous because its almost time for his annual physical
examination, and hes been having some strange
symptoms that he knows he must tell Dr. Naipaul about.

Q1. Match the following cell types with the appropriate description:
______ alpha cells
______ beta cells
______ delta cells
______ pancreatic polypeptide cells
A. secrete insulin and amylin
B. secrete somatostatin
C. secrete glucagon
D. help regulate release of pancreatic digestive
enzymes
A1. C; A; B; D
Q2. True / False Insulin is a steroid hormone.
A2. false; insulin is a small peptide hormone composed of 51 amino acids
Lesson Summary
The pancreas is an elongated, yellowish organ 12 to 15 cm (5 to 6 in) in length. It is
located at the back of the abdomen, extending horizontally between the stomach
and duodenum. The pancreas is both an exocrine and an endocrine gland. The
exocrine pancreas is responsible for secreting enzymes into the intestinal tract that
are important for digestion. The endocrine pancreas, on the other hand, secretes
hormones such as insulin and glucagon into the bloodstream.
Diabetes mellitus is a metabolic disorder involving the endocrine pancreas.
Diabetes affects carbohydrate, lipid, and protein metabolism, and results from a
decrease in insulin production and/or a decrease in the ability of target organs to
respond to insulin.
The pancreas is composed of cells that are specialized for its endocrine and
exocrine functions. The exocrine portion of the pancreas produces and releases
enzymes into the intestinal tract, where they play major roles in digestion. The bulk
of the pancreas is made up of exocrine tissue. The majority of this tissue consists of
acini, grape-like clusters of cells called acinar cells, which secrete enzyme-
containing digestive juices into the duodenum. The endocrine pancreas produces
hormones, the chemical messengers of the endocrine system. The main pancreatic
hormones are insulin and glucagon, which are critically important in regulating the
bodys metabolic processes, in particular the storage and utilization of glucose.
Based on their chemical structures, hormones can be divided into three groups:
peptide, steroid, and amino acid-derived hormones. Hormones are chemical
messengers that are secreted by one tissue and travel to another to elicit a
response. Hormones can be classified according to how they elicit a response of
the target tissue. In simple terms, hormones can stimulate receptors on the cell
membrane of the target cell, or they can enter the cell and stimulate receptors
located inside the cell.
The endocrine pancreas consists of small clusters of cells scattered throughout the
pancreas. These clusters are called islets of Langerhans. Islets produce several
endocrine hormones, all of which are peptide hormones, and secrete them directly
into the bloodstream. The four types of islet cells are called beta (), alpha (), delta
(), and pancreatic polypeptide (PP) cells.
cells are the most abundant islet cell type and comprise between 60% and 80% of
all islet cells. They produce and secrete insulin and another hormone known as
amylin. Insulin is a small peptide hormone composed of 51 amino acids (the
building blocks of proteins). Insulin is produced by the pancreatic cells and is the
hormone primarily responsible for controlling glucose metabolism.
Amylin is a peptide hormone co-secreted with insulin by pancreatic cells in
response to the intake of glucose and amino acids. Amylin works with insulin to help
coordinate the rate of glucose appearance and disappearance in the circulation,
thereby preventing an abnormal rise in glucose concentrations.
cells secrete glucagon and constitute 15% to 20% of the total number of islet cells.
Glucagon, which is also a peptide hormone, plays a major role in sustaining blood
glucose within a normal range during fasting conditions by stimulating glucose
production by the liver.
PP cells produce and secrete pancreatic polypeptide, which may help regulate the
release of pancreatic digestive enzymes and thus contribute through a more indirect
role in metabolic regulation.

Lesson 2
How is blood glucose controlled?
Objectives
Describe how the endocrine system delivers hormones to maintain homeostasis
Describe general metabolism
Describe carbohydrate metabolism and storage
Explain how insulin and glucagon help to maintain glucose homeostasis
Describe the regulation of blood glucose
Describe normal glucose metabolism

As discussed in Lesson 1, insulin and glucagon play key roles in regulating glucose
metabolism. Youll learn more about these important hormones in this lesson.
The Endocrine System and Maintenance of Homeostasis
Together with the nervous system, the endocrine system directs metabolic activities
and helps to maintain homeostasis. Homeostasis is defined as the metabolic
reactions that continuously occur to maintain a state of internal balance. Like the
nervous system, the endocrine system uses chemical messengers to carry out its
activities. Both the nervous and endocrine systems use signaling to get their
messages across.
While the nervous system is built for speed, using rapid nerve impulses to stimulate
muscles and other body parts into action, the endocrine system is slightly slower to
act because it relies on the bloodstream to deliver hormones to their target cells.
Hormone Mode of Action
Endocrine hormones are released from their sites of synthesis in the endocrine
glands, and then they travel through the bloodstream and act on distant target cells.
As noted above, hormones carry out their actions by binding to specific receptors on
the surface of, or inside, their target cells. This binding to the receptor generates
intracellular signals that trigger a physiological action in the target cell.

Effects of Hormones
Hormones have widespread effects throughout the body, including the following:
Controlling and regulating homeostasis
Regulating metabolism
Regulating cellular proliferation and differentiation
Regulating growth and body maturation
Affecting reproductive function
Regulating blood pressure
2

Maintaining the water, electrolyte, and nutrient balance of the blood
2

Affecting behavior.

Click on the icon to reinforce what you have learned about the endocrine system
and maintenance of homeostasis.
Q1. The __________ system is slower to act than the __________ system.
A. nervous; endocrine
B. endocrine; nervous
A1. B
Q2. Which of the following is not one of the widespread effects of endocrine hormones?
A. controlling and regulating homeostasis
B. regulating metabolism
C. regulating cellular proliferation and differentiation
D. regulating growth and body maturation
E. transmitting nerve impulses
F. affecting reproductive function
G. regulating blood pressure
H. maintaining water, electrolyte, and nutrient balance of the blood
I. affecting behavior
A2. E

General Metabolism
The term metabolism refers to all the chemical and energy transformations that
occur in the cells of the body. Metabolic reactions are of two main types: anabolic
and catabolic.
Anabolism
Anabolism is the general term for the building up of tissue or storage of energy.
Fats, proteins, and carbohydrates can be stored as larger, more complex molecules,
and the energy later released. Formation of these large molecules from smaller,
simpler molecules requires the input of energy and is called anabolism. The energy
to drive anabolism is derived from ATP. Insulin is an anabolic hormone because it
promotes energy storage and utilization.
Catabolism
The bodys cells require energy to function. This energy is derived from nutrients
ingested in food namely, carbohydrates, proteins, and fats. Catabolism, or
degradation, is the process by which nutrients are broken down to salvage their
components or to generate energy, or both. It can be thought of as the opposite of
anabolism. During catabolism, the breakdown of complex molecules into simpler
structures results in the release of energy. One of the most basic metabolic
processes is the catabolism of glucose into carbon dioxide and water, which
produces energy for a variety of uses. Energy liberated during catabolism can also
be temporarily stored in a chemical compound called adenosine triphosphate
(ATP), a molecule that releases energy as it breaks down. The breakdown of ATP
provides cells with a readily available source of energy. An example of a catabolic
hormone is glucagon. Glucagon stimulates the breakdown of stored glycogen into
glucose, which is then used as energy.

Anabolism vs. Catabolism
While anabolism refers to the building up of tissue or storage of energy,
catabolism is the process by which nutrients are broken down to salvage their
components or to generate energy, or both.

Click on the icon to reinforce what you have learned about general metabolism.
Q1. Formation of large molecules from smaller, simpler molecules requires the input of energy
and is called:
A. metabolism.
B. catabolism.
C. anabolism.
A1. C

Carbohydrate Metabolism and Storage
Dietary carbohydrates, such as complex starch molecules, are catabolized into
individual sugar units, such as fructose (fruit sugar) and glucose (blood sugar, the
bodys main source of fuel).
If there is insufficient glucose present to support the energy needs of the cells, fats
are used as the primary source of energy. The body can also use proteins as a
source of energy, but only when carbohydrates and fats are relatively unavailable,
such as during severe starvation.
In the presence of adequate glucose and insulin, such as after eating a meal, liver
and muscle cells convert glucose to a complex carbohydrate known as glycogen,
the primary storage form of glucose. This anabolic process is known as
glycogenesis. As the blood glucose approaches the lower normal range, such as
during overnight fasting, glycogen is available to be catabolized back into glucose in
a process called glycogenolysis. The liver also manufactures new molecules of
glucose from fatty acids and amino acids in a process called gluconeogenesis.
Thus, not all blood glucose comes directly from ingested carbohydrates. Some
glucose is synthesized from other sources.

Glycogen
Glycogen is the primary storage form of glucose.

Click on the icon to reinforce what you have learned about carbohydrate metabolism
and storage.
Q1. What is the bodys main source of fuel?
A. glucose
B. fructose
C. protein
D. fat
A1. A
Q2. In the presence of adequate glucose and insulin, liver and muscle cells convert excess
glucose to a complex carbohydrate known as ___________________.
A. glycogen
B. lipids
C. catabolites
D. metabolites
A2. A

Q3. True / False Glycogen is the primary storage form of glucose.
A3. true
How Insulin and Glucagon Help to Maintain Glucose
Homeostasis
Insulin is made up of two separate chains of amino acids chemically joined together.
The A chain contains 21 amino acids, while the B chain contains 30 amino acids.
As blood glucose levels rise following the intake of nutrients in food, insulin levels
increase in response. Not only does insulin promote the uptake of glucose into
target cells where it is either used for energy or stored as glycogen, it also inhibits
glycogenolysis or the breakdown of glycogen into glucose.
The half-life of a molecule of insulin is only about 5 minutes, so the cell must
continuously secrete at least a small amount of insulin, even during starvation; about
80% of insulin is degraded by the liver and kidneys.
Glucagon is secreted by the pancreatic cells. Glucagon acts in an opposite
manner to insulin. Whereas insulin stimulates formation of glycogen from glucose in
the liver and muscle, glucagon stimulates the breakdown of glycogen, resulting in an
increase in blood glucose.

Insulin and Glucagon
Together, insulin and glucagon help to maintain glucose homeostasis. While
insulin promotes the uptake of glucose from the blood into target cells and inhibits
glycogenolysis, glucagon stimulates glycogenolysis, thereby raising blood glucose
levels.

Click on the icon to reinforce what you have learned about how insulin and glucagon
help to maintain glucose homeostasis.
Q1. Insulin is made up of _____ separate chains of amino acids chemically joined together.
A. 2
B. 12
C. 25
D. 30
A1. A

Q2. The half-life of insulin is about _____ minutes, and about _____ of secreted insulin is
degraded by the liver and kidneys.
A. 3; 70%
B. 5; 80%
C. 6; 85%
D. 8; 90%
A2. B
Q3. The cells of the pancreas secrete:
A. insulin.
B. glycogen.
C. lipids.
D. glucagon.
A3. D
Q4. When the blood glucose rises, the pancreas releases ______________, which stimulates the
uptake of glucose by the cells to be either used or stored. When the blood glucose
decreases, the pancreas releases ______________, which stimulate(s) the release of
glucose from glycogen stores in the liver.
A. insulin; glucagon
B. glucagon; amino acids
C. insulin; fatty acids
D. glucagon; insulin
A4. A
Regulation of Blood Glucose
In humans, the normal fasting plasma glucose (FPG) is between 75 mg/dL to
100 mg/dL. After meals, the blood glucose level may normally increase to about
140 mg/dL. Insulin and glucagon, in addition to a variety of other hormones, work in
concert to maintain glucose in the euglycemic range. The increase in blood glucose
after a meal stimulates insulin secretion, which in turn, stimulates peripheral glucose
uptake into insulin-responsive tissues, such as fat, liver, and muscle, where the
glucose is either metabolized for energy or stored as glycogen.

Regulation of Insulin Secretion
Glucose is perhaps the most powerful stimulant of insulin release. When blood
glucose levels decrease below 80 mg/dL, insulin secretion decreases, but the
insulin level never goes to zero unless type 1 diabetes is present. The presence
of insulin is vitally important, even during prolonged starvation, because of
insulins effect on controlling fat metabolism.

Food consumption causes up to a 10-fold increase of insulin levels over the fasting
state. Insulin secretion following food intake occurs in two distinct phases (biphasic
insulin response). As shown in Figure 2-1, the first phase (acute insulin response)
develops rapidly, peaking between 3 and 5 minutes and lasting for 10 minutes. The
second phase (not shown) does not occur until after 10 minutes and continues to
increase slowly as long as the blood glucose level remains elevated.
14

Figure 2-1. Fasting plasma glucose (FPG) and the acute insulin response. Adapted from Brunzell, 1976
15

In patients with type 2 diabetes, there is a loss of the first-phase insulin response, as
shown in Figure 2-2.

Figure 2-2. Loss of first-phase insulin response in type 2 diabetes.
16
Adapted from DeFronzo, 2005
During fasting and exercise, insulin release is diminished but is never completely
absent. Glucose production during the fasting state is known as basal (low-level)
insulin secretion, and it maintains blood glucose at a relatively constant level within
the normal range.
14

Click on the icon to reinforce what you have learned about the regulation of blood
glucose.
Effects of Insulin
Liver
The liver receives higher insulin concentrations than any other organ. In the liver,
insulin has the following actions:
Converts glucose into glycogen
Inhibits glycogenolysis
Promotes the synthesis of fats and proteins, while inhibiting gluconeogenesis and
ketogenesis
Skeletal Muscle
Insulin promotes glucose entry into muscle cells by facilitating the transport of
glucose across cell membranes. The primary means by which glucose enters
muscle cells is via the help of glucose transport proteins (GLUTs). Insulin first
attaches to the insulin receptor on the outside of the muscle cell. The binding of
insulin to its membrane receptor causes a signaling cascade inside the cell that
directs glucose transport proteins to migrate to the surface of the cell, form a
channel, and allow glucose to enter the cell. Without insulin, glucose transporter
proteins stay inside the cell and do not allow glucose entry. Once inside the cells,
glucose is either used by the cells as a source of energy, or stored as glycogen.
Figure 2-3 illustrates the facilitated transport of glucose into an insulin-responsive
target cell.

Figure 2-3. Facilitated transport of glucose into insulin-responsive target cell.
Click on the icon to reinforce what you have learned about how glucose enters a
cell.
Adipose Tissue
In the presence of insulin, glucose and fatty acids are transported into adipose (fat)
tissue for storage as triglycerides (storage form of fats). When insulin levels are
low or decreased, the stored triglycerides are released from the fat as free fatty
acids and glycerol, both of which can then be used as energy sources.
Cell Growth
As an anabolic hormone, insulin enhances protein and amino acid storage in all
organs that are responsive to insulin. In most tissues, therefore, insulin promotes
protein synthesis and growth, while at the same time inhibiting protein breakdown.
Effects on Glucagon Secretion
Insulin acts on nearby pancreatic cells to inhibit glucagon secretion.
Summary
In summary, you can see that insulin and glucagon play integral roles in controlling
blood glucose levels. Generally, insulin promotes carbohydrate anabolism and
inhibits glycogen breakdown, whereas glucagon promotes the catabolism of
glycogen and tends to raise glucose levels. Clearly, the actions between insulin and
glucagon are finely balanced. Both hormones are vital in maintaining glucose levels
within the narrow normal range.
Q1. What is the most powerful stimulant of insulin release?
A. glucose
B. glucagon
C. fat
D. protein
A1. A
Q2. When blood glucose levels decrease below _____ mg/dL, insulin secretion decreases.
A. 60
B. 70
C. 80
D. 90
A2. C
Q3. The first phase (acute insulin response) peaks between ____________ minutes.
A. 1 and 2
B. 3 and 5
C. 6 and 8
D. 10 and 12
A3. B
Q4. True / False Insulin inhibits glycogenolysis.
A4. true
Q5. The primary means by which glucose enters muscle cells is via:
A. glucose transport proteins (GLUTs).
B. diffusion across cell membranes.
C. binding to insulin.
D. binding to insulin receptors.
A5. A
Q6. True / False In the presence of insulin, glucose and fatty acids are transported into adipose
(fat) tissue for storage as glycogen.
A6. false; glucose and fatty acids are stored in adipose tissue as triglycerides
Normal Glucose Metabolism
Glucose supplies the bulk of the energy needed for nearly all metabolic functions.
The body derives most of the glucose it needs from ingested carbohydrates through
the following process: after ingestion of a meal, digestive enzymes break down the
carbohydrates into glucose and other sugars. Glucose is absorbed from the
gastrointestinal tract and enters the bloodstream. This absorbed glucose increases
the blood glucose levels. Then, in response to the increase in blood glucose and
amino acid levels, the pancreas increases its secretion of insulin in an attempt to
keep the glucose level in the normal range. In the presence of insulin, glucose in the
blood enters target cells, thereby keeping the blood glucose level relatively constant.
Without insulin, glucose cannot enter most cells. However, once inside the cells,
glucose is used as a source of energy or is converted to other metabolic or storage
products. It is important to note that insulin is not required for glucose to get into
certain cells, such as the brain, and to a limited extent, the liver. On the other hand,
insulin is required for fat and muscle cells to transport glucose across their cell
membranes.
In healthy (i.e., non-diabetic) individuals, the body also has mechanisms to raise the
blood glucose level to keep it in the normal range. As the blood glucose approaches
the lower limits of normal, insulin secretion markedly decreases, which decreases
further transport of glucose into cells. In addition, several hormones that raise blood
glucose levels begin to be released, such as glucagon and cortisol and epinephrine
(from the adrenal gland). It is clear that the maintenance of glucose in the normal
range is a complex process, requiring insulin to keep the glucose from rising too high,
and other hormones (mentioned above) to keep the glucose from going too low.

Glucose Homeostasis
Maintenance of glucose homeostasis results from a complex interplay between
hormones that keep blood glucose from rising too high (insulin) and hormones
that keep blood glucose from going too low (glucagon, cortisol, and epinephrine).

Q1. True / False Insulin is required for glucose to get into all cells.
A1. false; while glucose cannot enter most cells without insulin, insulin is not required for glucose
to get into certain cells, such as the brain, and to a limited extent, the liver
Lesson Summary
Together with the nervous system, the endocrine system directs metabolic activities
and helps to maintain homeostasis. While the nervous system is built for speed,
using rapid nerve impulses to stimulate muscles and other body parts into action,
the endocrine system is slightly slower to act because it relies on the bloodstream to
deliver hormones to their target cells.

Endocrine hormones are released from their sites of synthesis in the endocrine
glands, and then they travel through the bloodstream and act on distant target cells.
Hormones have widespread effects throughout the body, including the following:
controlling and regulating homeostasis; regulating metabolism; regulating cellular
proliferation and differentiation; regulating growth and body maturation; affecting
reproductive function; regulating blood pressure; maintaining the water, electrolyte,
and nutrient balance of the blood; and affecting behavior.
The term metabolism refers to all the chemical and energy transformations that
occur in the cells of the body. Metabolic reactions are of two main types: anabolic
and catabolic. While anabolism refers to the building up of tissue or storage of
energy, catabolism is the process by which nutrients are broken down to salvage
their components or to generate energy, or both. Insulin is an anabolic hormone
because it promotes energy storage and utilization.
Dietary carbohydrates, such as complex starch molecules, are catabolized into
individual sugar units, such as fructose (fruit sugar) and glucose (blood sugar, the
bodys main source of fuel). In the presence of adequate glucose and insulin, such
as after eating a meal, the liver and muscle cells convert glucose to a complex
carbohydrate known as glycogen. Glycogen is the primary storage form of glucose.
Insulin is made up of two separate chains of amino acids chemically joined together.
As blood glucose levels rise following the intake of nutrients, insulin levels increase
in response. Not only does insulin promote the uptake of glucose into target cells
where it is either used for energy or stored as glycogen, it also inhibits
glycogenolysis or the breakdown of glycogen into glucose.
Glucagon is secreted by the pancreatic cells. Glucagon acts in an opposite
manner to insulin. Whereas insulin stimulates formation of glycogen from glucose in
the liver and muscle, glucagon stimulates the breakdown of glycogen, resulting in an
increase in blood glucose.
Together, insulin and glucagon help to maintain glucose homeostasis. While insulin
promotes the uptake of glucose from the blood into target cells and inhibits
glycogenolysis, glucagon stimulates glycogenolysis, thereby raising blood glucose
levels.
Glucose is perhaps the most powerful stimulant of insulin release. When blood
glucose levels decrease below 80 mg/dL, insulin secretion decreases, but the insulin
level never goes to zero unless type 1 diabetes is present. The presence of insulin
is vitally important, even during prolonged starvation, because of insulins effect on
controlling fat metabolism.
Insulin secretion following food intake occurs in two distinct phases (biphasic insulin
response). The first phase (acute insulin response) develops rapidly, peaking
between 3 and 5 minutes and lasting for 10 minutes. The second phase does not
occur until after 10 minutes and continues to increase slowly as long as the blood
glucose level remains elevated. In patients with type 2 diabetes, there is a loss of
the first-phase insulin response.
The liver receives higher insulin concentrations than any other organ. In the liver,
insulin has the following actions: converts glucose into glycogen; inhibits;
glycogenolysis; promotes the synthesis of fats and proteins, which inhibit
gluconeogenesis and ketogenesis.
Insulin promotes glucose entry into muscle cells by facilitating the transport of
glucose across cell membranes. In the presence of insulin, glucose and fatty acids
are transported into adipose (fat) tissue for storage as triglycerides (storage form of
fats). As an anabolic hormone, insulin enhances protein and amino acid storage in
all organs that are responsive to insulin. Insulin acts on nearby pancreatic cells to
inhibit glucagon secretion.
Glucose supplies the bulk of the energy needed for nearly all metabolic functions.
Without insulin, glucose cannot enter most cells. However, once inside the cells,
glucose is used as a source of energy or is converted to other metabolic or storage
products. It is important to note that insulin is not required for glucose to get into
certain cells, such as the brain, and to a limited extent, the liver. On the other hand,
insulin is required for fat and muscle cells to transport glucose across their cell
membranes.
In healthy (i.e., non-diabetic) individuals, the body also has mechanisms to raise the
blood glucose and keep it in the normal range. Maintenance of glucose
homeostasis results from a complex interplay between hormones that keep blood
glucose from rising too high (insulin) and hormones that keep blood glucose from
going too low (glucagon, cortisol, and epinephrine).


Lesson 3
What is the role of incretin hormones in the
regulation of blood glucose?
Objectives
Describe incretin hormones and the incretin effect
Describe GLP-1 and its gluco-regulatory effect
Describe GIP and its gluco-regulatory effect

Incretin Hormones and the Incretin Effect
In addition to the pancreatic hormones discussed in Lesson 1, incretin hormones
have recently generated great scientific interest because of their important gluco-
regulatory effects. The most well-characterized incretin hormones are glucagon-
like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). In
response to food intake, incretin hormones are released into the circulation from
certain types of cells located in the small intestine. These hormones elicit what is
termed the incretin effect. This effect was demonstrated when scientists observed
that glucose administered orally evoked a greater insulin release compared to
glucose administered intravenously. Thus, the difference in insulin response (the
magnitude of insulin release and timing of maximum insulin release) between oral
versus intravenous glucose administration is known as the incretin effect.
The incretin effect in control subjects (i.e., non-diabetic individuals) is illustrated in
Figure 3-1(a). This figure is taken from a study in which healthy individuals were
given glucose first by mouth, then by intravenous infusion, so that the glucose
concentrations in the bloodstream were similar. Plasma insulin concentrations were
measured throughout the experiment. Despite identical blood glucose
concentrations, plasma insulin levels peaked much earlier and were greater in
response to an oral (yellow line) versus intravenous (green line) dose of glucose.
6

Patients with type 2 diabetes were found to have an impaired incretin effect (see
Figure 3-1(b), compared with subjects without diabetes. As you can see in
Figure 3-1(b), while the incretin effect is still present in type 2 diabetes, it is
diminished. The markedly reduced early peak of insulin after oral glucose, along
with the smaller differences in insulin levels between oral and intravenous glucose
doses, illustrate the decreased incretin effect in patients with type 2 diabetes.
6

Figure 3-1 (a)

Figure 3-1 (b)

Figure 3-1. Insulin levels following oral versus intravenous glucose administration in control (i.e., non-diabetic) subjects (a) and insulin levels following
oral versus intravenous glucose administration in patients with type 2 diabetes (b). The mean plasma insulin levels are shown at various times
following the administration of glucose. Time 0 indicates time of glucose administration. Adapted from Nauck, 1986
Click on the icon to reinforce what you have learned about incretin hormones and
the incretin effect.

The Incretin Effect in Patients with Type 2 Diabetes
The incretin effect in patients with type 2 diabetes is diminished compared to
subjects without diabetes.
6

The next two sections will discuss GLP-1 and GIP and their gluco-regulatory effects.
Q1. Incretin hormones are secreted by:
A. alpha cells in the pancreas.
B. beta cells in the pancreas.
C. certain types of cells located within the small intestine.
D. hormone-producing cells within the liver.
A1. C
Q2. In patients with type 2 diabetes, the incretin effect is:
A. diminished.
B. augmented.
C. absent.
D. the same as in subjects without diabetes.
A2. A
GLP-1 and Its Gluco-Regulatory Effect
Glucagon-like peptide-1 (GLP-1) is a hormone secreted by L-cells in the intestine
(jejunum and ileum) in response to food intake. Because GLP-1 comes from the
gut and also has some actions that regulate glucose, it is called an incretin hormone.
GLP-1 binds to a specific receptor on the surface of pancreatic cells, in addition to
other tissues.
GLP-1 has been shown to exert its effects on multiple tissues that contribute to the
maintenance of glucose homeostasis. GLP-1 has been shown to stimulate the
biosynthesis of insulin and enhance insulin secretion in a glucose-dependent
manner, suppress postprandial (following a meal) secretion of glucagon, slow gastric
emptying, and promote satiety (fullness)
7
, leading to decreased food intake. In
addition, animal studies indicate that GLP-1 promotes the growth and differentiation
of cells to increase -cell mass. It is important to note that the latter finding has
been demonstrated only in animal models, and not in humans.
8

Important to Know
As its name might imply,
GLP-1 is like glucagon, but
ONLY in structure. The
function of GLP-1 is
significantly different from
that of glucagon. GLP-1
should not be confused
with glucagon because
they are entirely different
hormones.
GLP-1
GLP-1 exerts its effects on multiple tissues that maintain glucose homeostasis.
GLP-1 has been shown to have the following actions:
8

Stimulates the biosynthesis of insulin and enhances glucose-dependent insulin
secretion
Suppresses postprandial (following a meal) secretion of glucagon
Slows gastric emptying
Promotes satiety, leading to decreased food intake
Promotes growth and differentiation of cells to increase -cell mass (in animal
models)

GLP-1 has a very short half-life (60 to 90 seconds) due to its rapid metabolism by
the enzyme dipeptidyl-peptidase 4 (DPP-4). This enzyme cleaves the first two
amino acids away from GLP-1, thus inactivating it.
GLP-1 has been shown to stimulate insulin release from cells in a glucose-
dependent manner, which means that in the presence of elevated glucose levels,
GLP-1 stimulates insulin release. However, as the glucose level returns to normal
(euglycemia), this effect of GLP-1 is lessened and insulin secretion decreases.

Figure 3-2 provides a graphic summary of the mechanism of action of GLP-1.

Figure 3-2. Mechanism of action of GLP-1.
Click on the icon to reinforce what you have learned about the gluco-regulatory
effects of GLP-1 and GIP.
As illustrated in Figure 3-3, postprandial (following a meal) GLP-1 levels are
decreased, but not absent, in patients with type 2 diabetes (T2DM) and in those with
impaired glucose tolerance (IGT), compared with control subjects without diabetes
(normal glucose tolerance [NGT]). However, the role of decreased GLP-1 levels on
glycemic control in patients with type 2 diabetes is unclear.
9

Figure 3-3. Postprandial (following a meal) GLP-1 levels are decreased in subjects with impaired glucose
tolerance (IGT) and patients with type 2 diabetes (T2DM). The top line represents GLP-1 concentrations in
subjects with normal glucose tolerance (NGT). GLP-1 concentrations are statistically significantly reduced in
patients with type 2 diabetes compared to NGT subjects from t = 60 to 150 minutes. Adapted from Toft-Nielsen,
2001
9

The glucose-dependent actions of GLP-1 in patients with type 2 diabetes are
highlighted in Figure 3-4. This figure describes a study wherein GLP-1 infusion in
patients with type 2 diabetes decreased glucose concentrations while enhancing
insulin secretion and suppressing glucagon secretion. Both of these actions reflect
the glucose-dependent characteristics of GLP-1.
10

Figure 3-4. Glucose-dependent actions of GLP-1 in patients with type 2 diabetes. Adapted from Nauck, 1993
10

Figure 3-4 describes a 4-hour infusion of either placebo (PBO) or GLP-1, on different
occasions, in fasted patients with type 2 diabetes:
10

Plasma glucose concentrations (left panel): The placebo infusion had little effect
on the glucose concentration. In contrast, during infusion of GLP-1, the glucose
concentration decreased into the normal range.
Insulin concentrations (middle panel): While insulin concentrations did not
change during placebo infusion, in response to the GLP-1 infusion, the insulin
levels increased rapidly. Most importantly, the insulin concentrations decreased
as the glucose levels (left panel) approached normal. Data such as these
demonstrate the glucose-dependent insulin release in response to GLP-1.
Glucagon concentrations (right panel): GLP-1 infusion decreased glucagon
levels at first. However, as glucose approached the normal range, the glucagon
concentration increased, consistent with a glucose-dependent action of GLP-1.
This increase in glucagon in the face of decreasing glucose levels is an important
protective mechanism against hypoglycemia.
-Cell Effect of GLP-1
As noted earlier, GLP-1 has been reported to promote the growth and differentiation
of cells to increase -cell mass in animal models
8
, thus transforming non-insulin-
producing cells into insulin-secretory cells.
-Cell Effect of GLP-1
In healthy individuals, glucagon secretion is suppressed during meals to protect
against inappropriate elevation of blood glucose. When postprandial (following a
meal) glucose concentrations begin to increase in response to the meal, increases
in GLP-1 and insulin suppress glucagon secretion, which in turn reduces hepatic
glucose output. In contrast, in patients with type 2 diabetes, glucagon
concentrations are often inappropriately elevated and remain so during and after
meals, resulting in inappropriately increased hepatic glucose output at a time when
excess glucose is not needed. GLP-1 suppression of glucagon stops during
hypoglycemia when normal counterregulatory measures are needed to raise blood
glucose.
Effect of GLP-1 on Gastric Emptying
The rate of gastric emptying is a key determinant of the rate of nutrient absorption,
an important factor in postprandial (following a meal) blood excursions and
consequently, insulin secretion. Control of gastric emptying can help regulate
postprandial (following a meal) blood glucose concentrations. In healthy individuals,
GLP-1 helps regulate gastric emptying, facilitating timely delivery of nutrients into the
small intestine and thereby limiting postprandial (following a meal) glycemic
excursions.
Figure 3-5 illustrates the effect of a subcutaneous injection of GLP-1 in slowing
gastric emptying in patients with type 2 diabetes. As can be observed, exogenous
GLP-1 slows the rate of gastric emptying, which in turn slows the delivery and
absorption of nutrients and allows a more timely match with insulin secretion and
action.
11

Figure 3-5. Effect of a single subcutaneous dose of GLP-1 (1.5 nmol/kg body weight) on gastric emptying after
gastric instillation of a liquid meal in patients with type 2 diabetes. Adapted from Nauck, 1996
11

Data from this clinical study demonstrated that GLP-1 delayed gastric emptying by
30 to 45 minutes. In the placebo and GLP-1 studies, gastric emptying was near
complete at 150 and 180 minutes, respectively.
11

Effect of GLP-1 on Satiety
The central nervous system is a critical site for regulating food intake, satiety, and
body weight. A number of factors, including GLP-1, appear to be important
regulators of satiety, although the actual mechanisms by which these effects occur
are unclear. Stimulation of GLP-1 receptors in the brain in animal studies results in
decreased food intake. An example of a study that has implicated a role for GLP-1
in regulating food intake in humans is shown in Figure 3-6.
12

Figure 3-6. Effect of 6-week continuous GLP-1 infusion on sensations associated with appetite in patients with
type 2 diabetes. Symptom reporting by GLP-1-treated patients on a visual analog rating scale showed changes
at Week 1 sustained to Week 6. Adapted from Zander, 2002
12

Figure 3-6 shows that GLP-1 infusion increased satiety and sense of fullness.
Reductions in prospective food intake and perception of hunger were also
observed.
12

In the placebo (saline) group (data not shown), there were no changes from baseline
in appetite sensations.
12

The known effects and proposed sites of action of GLP-1 with respect to digestive
function and metabolism in humans are summarized in Figure 3-7.

Figure 3-7. Effects and proposed sites of action of GLP-1. Adapted from Habener, 2005
8

Q1. Which of the following is a physiologic action of GLP-1?
A. stimulates glucose-dependent insulin secretion
B. slows gastric emptying
C. promotes satiety, leading to decreased food intake
D. all of the above
A1. D
Q2. How does the effect of GLP-1 on insulin release change when blood glucose concentrations
approach normal?
A. the effect intensifies
B. the effect remains unchanged
C. the effect is lessened
A2. C
GIP and Its Gluco-Regulatory Effect
Glucose-dependent insulinotropic peptide (GIP) was initially described in 1971 as
gastric inhibitory peptide because of its capacity to slow gastric emptying.
However, GIP has been renamed glucose-dependent insulinotropic peptide to
reflect its insulin-releasing activity, an effect with which the incretin hormones are
most commonly identified. GIP is synthesized in the K-cells of the duodenum and
jejunum and is released in response to food in the gastrointestinal tract.

GIP is a potent incretin hormone that stimulates insulin secretion and regulates fat
metabolism, but does not inhibit glucagon secretion or gastric emptying. GIP
release is stimulated by the ingestion of a meal, and levels are normal or slightly
elevated in type 2 diabetes. Like GLP-1, GIP has been shown to stimulate the
glucose-dependent secretion of insulin and is rapidly inactivated by DPP-4.
13

However, GIP does not appear to have meaningful effects on glucagon secretion,
and its effects on feeding behavior have not been described.
13

Effects of GIP
Like GLP-1, GIP has been shown to enhance the glucose-dependent secretion of
insulin and is rapidly inactivated by DPP-4.
13
However, GIP does not appear to
have meaningful effects on glucagon secretion, and its effects on feeding
behavior have not been described.
13

Q1. GIP:
A. inhibits glucagon secretion and gastric emptying.
B. stimulates insulin secretion and regulates fat metabolism.
C. is synthesized by L-cells in the intestine.
D. levels are decreased in type 2 diabetes.
A1. B
Lesson Summary
The most well-characterized incretin hormones are glucagon-like peptide-1
(GLP-1) and glucose-dependent insulinotropic peptide (GIP). In response to food
intake, incretin hormones are released into the circulation from certain types of cells
located in the small intestine. These hormones elicit what is termed the incretin
effect. The difference in insulin response (the magnitude of insulin release and
timing of maximum insulin release) between oral versus intravenous glucose
administration is known as the incretin effect. The incretin effect is diminished in
patients with type 2 diabetes compared to subjects without diabetes.
GLP-1 is a hormone secreted by L-cells in the intestine (jejunum and ileum) in
response to food intake. GLP-1 exerts its effects on multiple tissues that contribute
to the maintenance of glucose homeostasis. GLP-1 has been shown to have the
following actions: stimulates the biosynthesis of insulin and enhances glucose-
dependent insulin secretion; suppresses postprandial (following a meal) secretion of
glucagon; slows gastric emptying; promotes satiety, leading to decreased food
intake; promotes growth and differentiation of cells to increase -cell mass (in
animal models).
GLP-1 has been shown to stimulate insulin release from cells in a glucose-
dependent manner, which means that in the presence of elevated glucose levels,
GLP-1 stimulates insulin release.

Postprandial (following a meal) GLP-1 levels are decreased, but not absent, in
patients with type 2 diabetes and those with impaired glucose tolerance (IGT),
compared with control subjects without diabetes (normal glucose tolerance [NGT]).
However, the role of decreased GLP-1 levels on glycemic control in patients with
type 2 diabetes is unclear.
In healthy individuals, glucagon secretion is suppressed during meals to protect
against inappropriate elevation of blood glucose. When postprandial (following a
meal) glucose concentrations begin to increase in response to the meal, increases
in GLP-1 and insulin suppress glucagon secretion, which in turn reduces hepatic
glucose output. In contrast, in patients with type 2 diabetes, glucagon
concentrations are often inappropriately elevated and remain so during and after
meals, resulting in inappropriately increased hepatic glucose output at a time when
excess glucose is not needed.
In healthy individuals, GLP-1 helps regulate gastric emptying, facilitating timely
delivery of nutrients into the small intestine and thereby limiting postprandial
(following a meal) glycemic excursions. A number of factors, including GLP-1,
appear to be important regulators of satiety, although the actual mechanisms by
which these effects occur are unclear.
GIP is a potent incretin hormone that stimulates insulin secretion and regulates fat
metabolism, but does not inhibit glucagon secretion or gastric emptying. GIP
release is simulated by the ingestion of a meal, and levels are normal or slightly
elevated in type 2 diabetes. Like GLP-1, GIP has been shown to enhance the
glucose-dependent secretion of insulin and is rapidly inactivated by DPP-4.
However, GIP does not appear to have meaningful effects on glucagon secretion,
and its effects on feeding behavior have not been described.

1 OToole MT, ed. Encyclopedia & Dictionary of Medicine, Nursing, & Allied Health.
7th ed. Philadelphia, Pa: Saunders; 2003.
2 Marieb EN, Hoehn K. Human Anatomy & Physiology. 7th ed. San Francisco,
Calif: Pearson Benjamin Cummings; 2007.
3 Champe PC, Harvey RA, Ferrier DA. Lippincotts Illustrated Reviews:
Biochemistry. 3rd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2005.
4 Marks D, Kravitz L. Hormones and Resistance Exercise. University of New Mexico
Web site. Available at: http://www.unm.edu/~lkravitz/Article%20folder/
growthhormone.html. Accessed October 22, 2007.
5 Bonner-Weir S, Smith FE. Islets of Langerhans: morphology and its implications.
In: Kahn CR, Weir GC, eds. Joslins Diabetes Mellitus. 13th ed. Media, Pa:
Williams & Wilkins; 1994;15-28.
6 Nauck M, Stckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2
(non-insulin-dependent) diabetes. Diabetologia. 1986;29:46-52.
7 Mosbys Medical Dictionary. 7th ed. St. Louis, Mo: Mosby Elsevier; 2006.
8 Habener JF, Kieffer TJ. Glucagon and glucagon-like peptides. In: Kahn CR,
King GL, Moses AC, Weir GC, Jacobson AM, Smith RJ, eds. Joslins Diabetes
Mellitus. 14th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2005;179-193.
9 Toft-Nielsen M, et al. Determinants of the impaired secretion of glucagon-like
peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001;86:3717-3723.
10 Nauck MA, Klein N, rskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of
fasting hyperglycaemia by exogenous glucagon-like peptide 1 (736 amide) in type
2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741-744.
11 Nauck MA, Wollschlger D, Werner J, Holst JJ, rskov C, Creutzfeldt W, Willms B.
Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [736 amide]) in patients
with NIDDM. Diabetologia. 1996;39:1546-1553.
12 Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-
like peptide 1 on glycaemic control, insulin sensitivity, and -cell function in type 2
diabetes: a parallel-group study. Lancet. 2002;359:824-830.
13 Baggio LL, Drucker DJ. Islet amyloid polypeptide/GLP-1/exendin. In: DeFronzo
RA, Ferrannini E, Keen H, Zimmet P, eds. International Textbook of Diabetes
Mellitus. 3rd ed. Chichester, West Sussex, England: John Wiley & Sons Ltd;
2005:191-223.
14 Utzschneider KM, Porte D, Kahn SE. Normal insulin secretion in humans. In:
DeFronzo RA, Ferrannini E, Keen H, Zimmet P, eds. International Textbook of
Diabetes Mellitus. 3rd ed. Chichester, West Sussex, England: John Wiley & Sons
Ltd; 2005:139-151.
15 Brunzell JD, Robertson RP, Lerner RL, Hazzard WR, Ensinck JW, Bierman EL,
Porte D Jr. Relationships between fasting plasma glucose levels and insulin
secretion during intravenous glucose tolerance tests. J Clin Endocrinol Metab.
1976;42:222-229.
Bibliography
16 DeFronzo RA, Mandarino L, Ferrannini E. Metabolic and molecular pathogenesis
of type 2 diabetes mellitus. In: DeFronzo RA, Ferrannini E, Keen H, Zimmet P,
eds. International Textbook of Diabetes Mellitus. 3rd ed. Chichester, West
Sussex, England: John Wiley & Sons Ltd; 2005:389-438.
17 National Diabetes Information Clearinghouse (NDIC) Web site. Diagnosis of
Diabetes. National Institute of Diabetes and Digestive and Kidney Diseases.
National Institutes of Health. January 2005. NIH Publication No. 054642.
Available at: http://diabetes.niddk.nih.gov/dm/pubs/diagnosis.
18 Stedmans Online Dictionary. Baltimore, Md: Lippincott Williams & Wilkins; 2000.
Available at: http://www.thomsonhc.com.
19 American Diabetes Association (ADA) Web site. Diabetes Dictionary. Available at:
http://www.diabetes.org/diabetesdictionary.jsp. Accessed December 6, 2007.

A1C
see HbA
1C

acini
secrete digestive juices into the duodenum (singular,
acinus)
adenosine triphosphate (ATP)
a high-energy molecule involved in metabolism,
especially in the storage of energy
adipose (fat) tissue
connective tissue that has been specialized to store fat
amine
an organic compound containing nitrogen
1

amino acids
a class of organic compounds containing the amino
(NH
2
) and the carboxyl (COOH) groups; they are the
building blocks of proteins
amylin
hormone produced by pancreatic cells that
complements the glucose-lowering effects of insulin;
amylin is co-secreted with insulin
anabolic
general term referring to building up of tissue or
storage of energy
anabolism
the process of converting simpler substances to more
complex compounds usually involving the use of energy
beta cell ( cell)
a pancreatic islet cell that secretes insulin
carbohydrate
a group of compounds that have the typical formula
C
n
(H
2
O)
n
; this group includes simple glucose, starch,
glycogen, and cellulose
catabolism
a metabolic process in which complex substances are
broken down by living cells into simple compounds
7

complex carbohydrate
a group of compounds usually containing molecules
such as sucrose and glucose
delta cell ( cell)
a pancreatic islet cell that secretes somatostatin
diabetes mellitus
a complex disorder of carbohydrate, fat, and protein
metabolism that is primarily a result of a deficiency or
complete lack of insulin secretion by the cells of the
pancreas or resistance to insulin
7

duodenum
the first or proximal portion of the small intestine
electrolyte
an element or compound that, when dissolved in water,
is able to conduct an electric current; proper quantities
of principal electrolytes and balance among them are
critical to normal metabolism and function
7

endocrine
pertaining to the internal hormonal secretions of a
ductless gland
enzyme
a protein that acts as a catalyst to induce chemical
changes in other substances without it being changed
or altered itself
euglycemia
blood glucose concentrations in the normal range
exocrine
a glandular secretion delivery outwardly via a duct
fasting plasma glucose (FPG)
the level of glucose in the blood after at least 8 hours of
fasting
17

gastrin
a hormone produced in the stomach that is a major
physiological regulator of gastric acid secretion
glucagon
a hormone secreted by pancreatic cells in response to
decreasing blood glucose levels; stimulates glucose
synthesis and release into the blood from the liver;
therefore, its actions are opposite to those of insulin
glucagon-like peptide-1 (GLP-1)
a 30-amino acid peptide hormone produced in and
released from intestinal L-cells; GLP-1 suppresses
postprandial (following a meal) glucagon secretion,
regulates the rate of gastric emptying, and enhances
insulin secretion; GLP-1 is rapidly inactivated by DPP-4
gluconeogenesis
the formation of glucose from noncarbohydrates, such
as protein or fat
18

Glossary
glucose
a monosaccharide sugar classified as a carbohydrate;
glucose is the end-product of carbohydrate metabolism
and is the chief source of energy for living organisms; its
utilization is controlled by insulin
glucose-dependent insulinotropic peptide (GIP)
a hormone synthesized in the K-cells of the duodenum
and jejunum, and released in response to food in the
gastrointestinal tract; like GLP-1, GIP has been shown
to enhance the glucose-dependent secretion of insulin
and is rapidly inactivated by DPP-4
glycogen
a complex carbohydrate found mostly in the liver and
skeletal muscle; it is the principal storage form of
glucose and can be quickly converted into glucose
glycogenesis
the formation of glycogen from glucose
glycogenolysis
the enzymatic breakdown of glycogen into molecules of
glucose
HbA
1C
abbreviation for glycosylated hemoglobin; a substance
in red blood cells to which glucose is linked;
concentrations are therefore increased in the blood of
patients with diabetes mellitus; can be used as a
retrospective index of glucose control over time in such
patients
18

homeostasis
the tendency toward stability in the normal physiological
state of an organism
hormone
a regulatory substance formed in one tissue and
secreted into the extracellular tissue; hormones are then
carried by the blood or lymph to target organs, where
they exert their effects
hyperglycemia
blood glucose concentration above the normal range
hypoglycemia
a less than normal amount of glucose in the blood,
usually caused by administration of too much insulin,
excessive secretion of insulin by the islet cells of the
pancreas, or dietary deficiency
7

ileum
the last portion of the small intestine that communicates
with the large intestine
impaired glucose tolerance (IGT)
a condition in which blood glucose levels are higher
than normal but not high enough for a diagnosis of
diabetes; IGT, also called pre-diabetes, is a glucose
level of 140 to 199 mg/dL 2 hours after the start of an
oral glucose tolerance test; most people with pre-
diabetes are at increased risk of developing type 2
diabetes
19

incretin effect
the greater release of insulin in response to oral
glucose, compared with glucose given intravenously
incretin hormone
a substance released by the gut in response to food;
incretins enhance glucose-dependent insulin secretion
insulin
a small peptide hormone composed of 51 amino acids
2

that is secreted by the pancreatic cells when blood
glucose levels rise; it stimulates glucose uptake into
cells from the blood, so its actions are opposite to those
of glucagon
jejunum
the portion of the small intestine that extends from the
duodenum to the ileum
lipid
one of a group of water insoluble compounds that
include fats, phospholipids, and steroids
metabolic
of or pertaining to the chemical and physical processes
continuously going on in living organisms and cells
pancreas
an elongated, grayish-pink, lobulated gland that lies
across the posterior abdominal wall behind the
stomach; secretes various substances, such as insulin,
glucagon, and digestive enzymes
1, 7

pancreatic islets
islands formed by clusters of endocrine cells scattered
throughout the exocrine tissue of the pancreas; also
known as the islets of Langerhans
pancreatic polypeptide hormone
hormone secreted by the pancreatic polypeptide cells of
the endocrine pancreas; its exact physiological function
is unknown, but it may affect gastrointestinal function by
regulating food absorption
peptides
compounds consisting of two or more amino acids
joined together in a chain; larger peptides (typically
>100 amino acids) are classified as proteins
postprandial
following a meal
plasma
the fluid portion of the blood in which the formed
elements (blood cells) are suspended
1

protein
the major macromolecular constituent of cells; proteins
consist of long chains of amino acids, linked together by
peptide bonds in a specific sequence
satiety
a state of being satisfied, as in the feeling of being full
after eating
7

somatostatin
a hormone released by the hypothalamus in the brain
and pancreas that inhibits the release of somatropin,
insulin, glucagon, and gastrin
steroid
any of numerous natural or synthetic compounds
containing a 17-carbon 4-ring system and including the
sterols and various hormones and glycosides
triglycerides
readily absorbable form of lipid

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