diabetes m1 mech aug8

FOR INTERNAL USE ONLY. NOT FOR USE IN PRODUCT DETAILING. TLD-0871.

Diabetes Home Study Project

Glucose Metabolism

Eli Lilly and Company

Diabetes Home Study Project FOR INTERNAL USE ONLY. NOT FOR USE IN PRODUCT DETAILING. TLD-0871.

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 FOR INTERNAL USE ONLY. NOT FOR USE IN PRODUCT DETAILING. TLD-0871.

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


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


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 FOR INTERNAL USE ONLY. NOT FOR USE IN PRODUCT DETAILING. TLD-0871.

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.

C R I T I C A L I N F O R M A 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 FOR INTERNAL USE ONLY. NOT FOR USE IN PRODUCT DETAILING. TLD-0871.

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-containing2 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.

C A 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.

C A 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 pressure2

Maintaining the water, electrolyte, and nutrient balance of the blood2 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, 197615

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, 20019


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, 199310

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 models8, 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, 199611


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, 200212

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, 20058

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 HbA1C

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 nitrogen1

amino acids a class of organic compounds containing the amino (NH2) 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 Cn(H2O)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 compounds7

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 insulin7

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 function7

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 fasting17

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 fat18

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

HbA1C 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 patients18

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 deficiency7

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 diabetes19

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 acids2 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 enzymes1, 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 suspended1

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 eating7

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

diabetes m1 mech aug8

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