Upper Gastrointestinal Function And Glycaemic Control In Diabetes Mellitus
Funder
National Health and Medical Research Council
Funding Amount
$780,872.00
Summary
There is now increasing recognition that the stomach and intestines, by regulating the absorption of nutrients into the body and by releasing hormones that enhance insulin secretion, play a central role in the control of blood glucose in diabetes mellitus. We seek to understand the nature and causes of disturbed gut function in diabetes, so that we can optimise dietary and drug strategies to prevent and treat this condition.
Upper Gastrointestinal Motility And Glycaemic Control In Diabetes Mellitus
Funder
National Health and Medical Research Council
Funding Amount
$543,301.00
Summary
The application of novel techniques to evaluate gastrointestinal motor function has established that the rate at which the stomach empties is abnormally slow in ~50% of people who have insulin-dependent (type 1) or non-insulin dependent (type 2) diabetes. Delayed stomach emptying, which was thought to be an infrequent complication of diabetes, may contribute to a number of problems including symptoms such as nausea and bloating, and poor control of blood glucose concentrations. The blood glucose ....The application of novel techniques to evaluate gastrointestinal motor function has established that the rate at which the stomach empties is abnormally slow in ~50% of people who have insulin-dependent (type 1) or non-insulin dependent (type 2) diabetes. Delayed stomach emptying, which was thought to be an infrequent complication of diabetes, may contribute to a number of problems including symptoms such as nausea and bloating, and poor control of blood glucose concentrations. The blood glucose level itself also has a reversible effect on both stomach contractions and symptoms; when the blood glucose is abnormally high, the rate at which the stomach empties is slower, and symptoms, such as fullness, are greater. The rate of stomach emptying and the absorption of sugar from the intestine have a major influence on the rise in the blood glucose level after a meal. This is important because in people with diabetes it is desirable to maintain blood glucose levels as close as possible to normal to minimise the risk of complications such as eye and nerve damage. Specific modifications in diet and recently developed drugs which have actions similar to that of the hormone, glucagon-like peptide-1, may improve blood glucose control in type 2 diabetes by slowing the rate of gastric emptying. People with cystic fibrosis frequently develop diabetes which is often difficult to manage; this may result from abnormally rapid gastric emptying and impaired release of hormones. If so, pancreatic enzyme replacement, in the form of tablets, should prove effective. Our group has conducted research in this area for about 24 years and have performed the most comprehensive studies to date resulting in international recognition. The studies proposed in the current application represent a logical development from our previous work and have important implications for the management of diabetes.Read moreRead less
Cooperative Motor Control Of The Pyloric Junction By Myogenic And Neuronal Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$271,527.00
Summary
The coordinated muscle movement in the junction between the stomach and small intestine is an essential mechanism for controlling the speed of gastric content moving into the intestine for further digestion. The muscle movement determines the gastric emptying at an optimal rate and prevents intestinal contents reflux to the stomach. Failure of this coordination is likely to be involved in a variety of clinical conditions including accelerated or delayed gastric emptying. Up to date, little infor ....The coordinated muscle movement in the junction between the stomach and small intestine is an essential mechanism for controlling the speed of gastric content moving into the intestine for further digestion. The muscle movement determines the gastric emptying at an optimal rate and prevents intestinal contents reflux to the stomach. Failure of this coordination is likely to be involved in a variety of clinical conditions including accelerated or delayed gastric emptying. Up to date, little information is available about the interaction between nerve, muscle and pacemaker cells during this coordinated movement. In this project, we will investigate how the nerve, muscle and pacemaker cells work together to control this coordinated movement. We will study this mechanism at both cellular and organ levels and try to establish the patterns of muscle movement and their coordination between the stomach and the small intestine. The interaction between the nerve and pacemaker cells will be characterised in these studies. Our work will provide structural evidence for this activity. It includes identification of the nerve pathways connecting between the small intestine and stomach and determination of whether the pacemaker cell network is an uniform continuous or a discontinuous or a transitional structure across the junction. These studies will reveal the correlation between pacemaker cell mediated activity and the density of these cells in each junctional region. We will also determine whether the difference in propagation activity across the junction is due to differences in the number of cells for signal conduction or electrical connections between the cells. This study will advance our knowledge for understanding how the nerve, muscle and pacemaker cells work in concert in this junction, which is an important step for further clinical investigation of related disease.Read moreRead less
Gastroduodenal Motility And Glycaemic Control In Diabetes Mellitus
Funder
National Health and Medical Research Council
Funding Amount
$393,750.00
Summary
The recent application of novel techniques to evaluate gastrointestinal motor function has established that the rate which the stomach empties food is abnormally slow in ~50% of people who have insulin-dependent (type 1) or non-insulin dependent (type 2) diabetes. Delayed stomach emptying was thought to be an infrequent complication in diabetes; much less common than damage to the eyes, kidneys or nerves. Abnormal stomach emptying may contribute to a number of problems in diabetes, including sym ....The recent application of novel techniques to evaluate gastrointestinal motor function has established that the rate which the stomach empties food is abnormally slow in ~50% of people who have insulin-dependent (type 1) or non-insulin dependent (type 2) diabetes. Delayed stomach emptying was thought to be an infrequent complication in diabetes; much less common than damage to the eyes, kidneys or nerves. Abnormal stomach emptying may contribute to a number of problems in diabetes, including symptoms such as nausea and bloating, and poor control of blood glucose concentrations. It is now recognised that the blood glucose level itself has a reversible effect on both stomach contractions and symptoms. For example, when the blood glucose is abnormally high (hyperglycaemia), the rate at which the stomach empties food into the intestine is slower and symptoms, such as fullness, are greater. The rate of stomach emptying and the absorption of glucose from the intestine affect the rise in the blood glucose level after a meal; this is an important issue because it is desirable to maintain blood glucose levels within the normal range to minimise the risk of both the development and progression of the complications of diabetes. In many people with diabetes eating a meal results in a substantial fall in blood pressure, which may cause fainting and falls. By slowing gastric emptying the magnitude of the fall in blood pressure is minimised. Our group has been the recipient of ongoing support from the NH and MRC for approximately 18 years to conduct research in this area. As a result we have performed the most comprehensive studies to date and developed new methods to evaluate stomach and intestinal function in people with diabetes, resulting in international recognition. The studies proposed in the current application represent a logical development from our previous work and have important implications for the management of diabetes.Read moreRead less
Mechanics Of Normal And Disordered Gastric Emptying Studied Using Simultaneous Ultrasound And High Resolution Manometry
Funder
National Health and Medical Research Council
Funding Amount
$145,626.00
Summary
Optimal digestion and absorption relies on the stomach breaking down food and delivering it to the small intestine at an optimal rate. Abnormalities in the processes controlling the stomach's processing of food may lead to malnutrition, gastrointestinal symptoms or unpredictable drug absorption, and are commonly seen in patients with diabetes mellitus, gastrointestinal reflux disease and nonulcer dyspepsia, or following stomach surgery. Currently our understanding of the way the stomach empties ....Optimal digestion and absorption relies on the stomach breaking down food and delivering it to the small intestine at an optimal rate. Abnormalities in the processes controlling the stomach's processing of food may lead to malnutrition, gastrointestinal symptoms or unpredictable drug absorption, and are commonly seen in patients with diabetes mellitus, gastrointestinal reflux disease and nonulcer dyspepsia, or following stomach surgery. Currently our understanding of the way the stomach empties food is incomplete, and there is little information as to the mechanisms by which diseases cause abnormal stomach emptying. Recent developments in recording methods mean that we can now simultaneously measure stomach contractions, the pressures these generate and flow from the stomach. This information is synchronised and displayed for analysis using computer techniques. In this project these novel methods will be used initially to examine the normal processes by which meals with a variety of compositions and consistencies empty from the stomach. This will provide information as to which aspects of the way the stomach functions are important for breaking down food into particles, and which aspects control the flow of food from the stomach into the intestine. The mechanisms by which the rate of emptying of the stomach is controlled by feedback signals caused by the presence of foodstuffs in the small intestine will be investigated by examining the effects of infusing nutrients into the intestine on the motions of the stomach wall, pressures within the stomach and the passage of stomach contents into the small intestine. The mechanism of action of drugs and diseases which slow stomach emptying will then be examined by measuring the movements, pressures and emptying of the stomach in subjects receiving the drug, or in patients with dibetes, and comparing this information with the processes observed during normal stomach emptying.Read moreRead less
Gastric Motility And Blood Glucose Control In Diabetes Mellitus
Funder
National Health and Medical Research Council
Funding Amount
$354,947.00
Summary
The recent application of novel techniques to evaluate gastrointestinal motor function has established that the rate of which the stomach empties food is slow in up to 50% of people who have insulin-dependent (type 1) or non-insulin dependent (type 2) diabetes. Delayed stomach emptying was thought to be an infrequent complication in diabetes; much less common than damage to the eyes, kidneys or nerves. It is now recognised that disordered stomach emptying may contribute to a number of problems i ....The recent application of novel techniques to evaluate gastrointestinal motor function has established that the rate of which the stomach empties food is slow in up to 50% of people who have insulin-dependent (type 1) or non-insulin dependent (type 2) diabetes. Delayed stomach emptying was thought to be an infrequent complication in diabetes; much less common than damage to the eyes, kidneys or nerves. It is now recognised that disordered stomach emptying may contribute to a number of problems in diabetes, e.g. symptoms such as nausea and bloating and poor control of blood glucose concentrations. In some people symptoms are disabling and affect quality of life adversely. The effects of stomach emptying on blood glucose control is likely to be important, as it is desirable to maintain blood glucose levels within the normal range to minimise the risk of both the development and progression of complications of diabetes. In many people with diabetes, particularly older people with type 2 diabetes, there is a fall in blood pressure after a meal which may result in fainting and falls. The magnitude of the fall in blood pressure is determined by the rate at which the stomach empties; faster emptying results in a greater fall in blood pressure. In the past both slow stomach emptying and symptoms were assumed to result from irreversible nerve damage, however it is now recognised that the blood glucose level itself has a reversible effect on both stomach contractions and symptoms. Our group has been the recipient of ongoing support from the NH and MRC for approximately 15 years to conduct research in this area. As a result we have performed the most comprehensive studies to date and developed new methods to evaluate stomach function in people with diabetes, resulting in international recognition. The studies proposed in this current application represent a logical development from our previous work and have important implications for the management of diabetes.Read moreRead less
Properties And Electro-Physiology Of The Intrinsic Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$419,214.00
Summary
The gut contains a very large number of nerve cells which fall into several functionally distinct groups. We have identified virtually all these functional groups in the guinea-pig small intestine and have begun an analysis of the ways the different groups communicate with each other. We have developed methods to identify the functions of any nerve cell from which we record and have also developed novel methods for specifically stimulating individual functional classes of nerve cells that contac ....The gut contains a very large number of nerve cells which fall into several functionally distinct groups. We have identified virtually all these functional groups in the guinea-pig small intestine and have begun an analysis of the ways the different groups communicate with each other. We have developed methods to identify the functions of any nerve cell from which we record and have also developed novel methods for specifically stimulating individual functional classes of nerve cells that contact them. The aim of the proposed research is to exploit these methods to identify the chemicals used by specifc types of nerve cell in transmission of information to other nerve cells during the normal behaviour of the intestine. We will record the behaviour of individual nerve cells in the gut wall while stimulating specific nerve pathways that contact them. We will then use drugs that block the activity of the chemicals of interest (small proteins called tachykinins, and certain amine compounds) to try and block the transmission of information between the nerve cells involved. Identification of the nature of the chemicals used at specific connections between different functional groups of nerve cells in the gut will allow the design of drugs for treatment of gastrointestinal disorders that will have minimal side effects. Further because the chemicals that are used for communication in the gut are also found in the brain, the results will provide evidence about the functions of these chemicals elsewhere in the nervous system.Read moreRead less
Intramuscular Interstitial Cells Of Cajal; Ion Channels And Their Modulation By Calcium Ions And Neurotransmitters.
Funder
National Health and Medical Research Council
Funding Amount
$523,261.00
Summary
Disorders of gut motility manifest themselves in several ways, as either patterns of hyperactivity or patterns of reduced activity. Under normal conditions gut motility reflects a balance between myogenic, neuronal and hormonal factors but as yet how this balance is normally achieved is not understood. This project will examine the properties of a class of cells, whose importance in both myogenic and neural control mechanisms has only been recognized over the last 10 years. The muscular wall of ....Disorders of gut motility manifest themselves in several ways, as either patterns of hyperactivity or patterns of reduced activity. Under normal conditions gut motility reflects a balance between myogenic, neuronal and hormonal factors but as yet how this balance is normally achieved is not understood. This project will examine the properties of a class of cells, whose importance in both myogenic and neural control mechanisms has only been recognized over the last 10 years. The muscular wall of the gut is made up of two distinct types of cells. One group, smooth muscle cells, contains contractile elements and the coordinated behavior of these cells leads to the contractions of the gut wall, so ensuring the controlled passage of gut contents along the gastrointestinal tract. The other group of cells, Interstitial cells of Cajal, lack contractile elements. One set of these cells have recently been found to be the pacemaker cells of the gut responsible for the initiation of myogenic activity. They generate pacemaker waves which ensure that the gut contracts rhythmically. Another set of these cells are densely innervated, they receive messages from the nervous system and translate these messages into signals which alter the activity of the gut. Thus these cells play a key role in the neural control of the gut. In many disease states, the numbers of interstitial cells of Cajal have been found to be reduced. However as yet we know very little about these cells. This project will, for the first time, examine the properties of the interstitial cells involved in neural control and will determine how they carry out these essential functions.Read moreRead less
Glucose is a critical fuel for living organisms and its presence in the gut triggers nerves that slow stomach emptying. However, little is known of how glucose is actually detected in the gut. We have established that sweet taste molecules of the tongue are also present in the gut, where they may detect glucose. This research will measure the expression and function of these molecules in the gut of humans and mice, and reveal key information on their potential as targets in health and disease.
Control Of Gastrointestinal Motility By Interstitial Cells And Neuronal Projections
Funder
National Health and Medical Research Council
Funding Amount
$845,540.00
Summary
The gastrointestinal tract moves contents along its length in an ordered manner, so allowing digestion and absorption of gut contents. These movements are controlled by the properties of the cells in the muscle layers which in part make up the wall of the gastrointestinal tract, by activity in the nerves that innervate the gut and by hormonal factors. Recently we have shown that a key part of the control system lies in a set of special cells, interstitial cells, that lie amongst the muscle cells ....The gastrointestinal tract moves contents along its length in an ordered manner, so allowing digestion and absorption of gut contents. These movements are controlled by the properties of the cells in the muscle layers which in part make up the wall of the gastrointestinal tract, by activity in the nerves that innervate the gut and by hormonal factors. Recently we have shown that a key part of the control system lies in a set of special cells, interstitial cells, that lie amongst the muscle cells. This project will determine how these cells exert their control. These cells generate large long lasting waves of voltage which flow to nearby muscle cells so causing them to contract. The first aim is to determine how the special cells generate the command signals and the second aim is to determine how the signals spread to the muscle cells. The subsequent section of the project will determine how the behavior of the cells in the gastrointestinal tract are controlled by nervous influences. Disorders of the intestine are frequent and these appear to involve disrupted muscle contraction either because the intrinsic control system is malfunctioning or because the nervous system is unable to exert its normal influence. This project will determine how the normal control system works, invariably when this has been done with other systems, disease states are easier to rectify.Read moreRead less