Incretin Odyssey: A Journey to Optimal Diabetes Care | Day 2
18 Apr 2024
Dr. Augusto LitonjuaFollowing a very successful opening day, the scientific symposium entitled “Incretin Odyssey: A Journey to Optimal Diabetes Care”, followed through with more educational discussion on the second day. This time the focus was a revisit of the glucose-dependent insulinotropic polypeptide (GIP) hormone, a molecule that has been at the core of research and scientific discussions on the development of type 2 diabetes mellitus (T2DM) treatment.
The 2nd day was well-attended with around 100 healthcare professionals (HCPs) present for the live discussion at The Westin Manila Hotel in Ortigas district, Mandaluyong. Several other healthcare professionals from Taiwan, Malaysia, Thailand, and Indonesia also joined the session via livestream. Formally opening the session was Mr. Tse Wang, ZP Therapeutics’ (ZPT) regional medical lead for diabetes and obesity. The illustrious and multi-awarded Dr. Augusto Litonjua, considered the Father of Philippine Endocrinology and Professor Emeritus at the University of the Philippines College of Medicine, was the session speaker, who talked about “Revisiting the GIP Hormone, Therapeutic Target in Diabetes and Obesity.”
Dr. Augusto Litonjua speaking before the attendees
Dr. Litonjua opened his talk with a discussion on the evolution of the knowledge on incretin physiology. He said that the glucagon-like peptide 1 (GLP-1) has been the more favored incretin over GIP for research and development because of several reasons; its lack of action on both the release of glucagon and the uptake of fatty acids into adipocytes as compared to GIP. The most clinically significant factor however was the much earlier discovery of the GLP-1 antagonist. While GIP has been regarded as the more potent incretin in healthy humans, the earlier development of the GLP-1 antagonist allowed more scientific research on it to proceed way ahead than that for GIP.1
The Dominant Incretin
Studies comparing the activity of GIP and GLP-1 have been a robust area of scientific research. Dr. Litonjua presented data showing both incretins mediating prandial and post prandial insulin secretion following oral and IV glycemic challenge. Glycemia was seen in both IV and oral glucose cohorts, but the insulin and incretin response were only noted in the oral glucose group – highlighting the so-called “incretin effect”. Additionally, it was clear that GIP levels correlate more with the degree and pattern of insulin release suggesting that it may be the primary mediator of this effect.2,3 Antagonist studies also show that GIP had a more significant effect on insulin-mediated glucose clearance. Furthermore, studies also show that infusion of GIP into healthy humans during the glycemic challenge markedly increased glucose-dependent insulin release and the rate of clearance of glucose.4,5 Dr. Litonjua also presented data that among the factors contributing to insulin release, GIP accounted for 44% of the process, almost double than the influence of GLP-1 which was at 22%, proving that GIP is the dominant endogenous incretin.6
Receptor activity6
GIP receptors are distributed all over the body mostly in the α and β cells of the Islet of Langerhans, the adipose tissues and the brain which mediates a multitude of biochemical processes.
Islet of Langerhans activity7
The direct effect of GIP on the β-cell of the Islet of Langerhans to stimulate insulin release is a widely understood concept. Dr. Litonjua, however, highlighted the effect of GIP on the α-cells which together with the uptake of amino acids stimulates glucagon release. Dr. Litonjua opined that the glucagon release by the α-cells within the Islet of Langerhans, stimulates the adjoining β-cells by paracrine effect, resulting in more insulin secretion.
Brain activity8-10
Data from preclinical studies suggest that GIP activity in the brain may play a role in weight regulation. GIP binding with its receptors on the brain’s appetite control centers help reduce caloric intake. Studies have shown that dysregulation of these appetite control centers results in excessive weight gain. However, Dr. Litonjua was quick to emphasize that the exact mechanism of GIP on weight loss is not yet well-understood.
GIP activity in body organs of healthy individuals
Adipose tissue activity11-25
Another significant difference between the incretins is their effect on lipid metabolism. GIP causes capillary recruitment and increased blood flow into adipose tissues. Improved adipose tissue perfusion increases lipoprotein lipase availability enhancing the breakdown of triglycerides and thereby facilitating absorption into adipocytes. GIP also inhibits outflow of free fatty acid from the adipocytes. This dual effect of the GIP fatty acid transport is also known as the “buffering effect”. This helps keep fats where they are physiologically beneficial and limits “spillover fat” from being deposited in ectopic sites where they can be harmful. Ectopic fat deposition from dysregulated lipid partitioning is characteristic of T2DM. Lipid buffering physiologically protects and maintains functionality of the liver, skeletal muscles, and pancreatic cells by improving glucose uptake and tolerance and insulin sensitivity through adipokines produced by GIP-enhanced adipose tissues. Doctor Litonjua added that GIP improves glucose transporter 4 (GLUT4) translocation which is the probable mechanism of enhanced insulin sensitivity.
As shared by Dr. Litonjua, clinical studies suggest GIP may have cardioprotective properties by improving endothelial function with a decrease of atherosclerosis and inflammation. It also regulates atherosclerotic plaque size and stability. A potential beneficial role of GIP signaling on variables associated with cardiometabolic outcomes like BMI, and HDL cholesterol, is also suggested by genetic association studies on incretins.26-30
Future combination31-32
With a better understanding of incretin physiology, the enormous therapeutic potential of combining the pharmacologic activity of GIP with GLP-1 treatment bids well for improving glycemic control. With a dual action on pancreatic cells by both incretins stimulating insulin secretion plus a paracrine stimulation from glucagon, may theoretically stabilize insulin levels. With enhanced adipose tissue metabolism that limits “spillover effect” keeping fats where they are physiologically beneficial coupled with improved insulin sensitivity and glucose uptake through the adipokines, we may soon see the drug that measures up to the complexity of metabolic syndrome. GIP has also been demonstrated to promote weight loss by acting on multiple sites on the central nervous system, ultimately promoting satiety without subsequent nausea.
Dr. Litonjua and and Prof. SP Chan during the open forum.
Open Forum and Panel Discussion
A dynamic panel discussion ensued from the lecture presentation between the participants and the speaker. Dr. Nemencio Nicodemus Jr, Consultant Endocrinologist, was the moderator for the discussion where Dr. Litonjua was joined by Professor Chan Siew Pheng at the University of Malaya in Kuala Lumpur, Malaysia. It was clarified that there may be slight differences in incretin physiology and GIP response between healthy individuals and those with T2DM and the full physiologic effect of incretins in patients with chronic illness has yet to be studied. Changing the understanding of its physiology will come with new scientific data that can modify clinical applications, like from being previously considered obesogenic, GIP is now thought to be anorexigenic. The potential combination with thiazolidinediones which has a similar effect on weight is not yet well-documented and needs to be approached with caution considering side effects. The role of GIP in fatty liver disease and on osteoporosis is very promising and is the subject of research. Triple peptide compound comprised of glucan, GIP and GLP-1 currently are directed at achieving weight loss to a degree that is similar to what is achieved with surgery but also warrants caution from side effects. The consensus from all attendees was clear that introduction and better understanding of newer molecules is driving the development and optimism in the field of diabetes.
The 2nd day was well-attended with around 100 healthcare professionals (HCPs) present for the live discussion at The Westin Manila Hotel in Ortigas district, Mandaluyong. Several other healthcare professionals from Taiwan, Malaysia, Thailand, and Indonesia also joined the session via livestream. Formally opening the session was Mr. Tse Wang, ZP Therapeutics’ (ZPT) regional medical lead for diabetes and obesity. The illustrious and multi-awarded Dr. Augusto Litonjua, considered the Father of Philippine Endocrinology and Professor Emeritus at the University of the Philippines College of Medicine, was the session speaker, who talked about “Revisiting the GIP Hormone, Therapeutic Target in Diabetes and Obesity.”
Dr. Augusto Litonjua speaking before the attendeesDr. Litonjua opened his talk with a discussion on the evolution of the knowledge on incretin physiology. He said that the glucagon-like peptide 1 (GLP-1) has been the more favored incretin over GIP for research and development because of several reasons; its lack of action on both the release of glucagon and the uptake of fatty acids into adipocytes as compared to GIP. The most clinically significant factor however was the much earlier discovery of the GLP-1 antagonist. While GIP has been regarded as the more potent incretin in healthy humans, the earlier development of the GLP-1 antagonist allowed more scientific research on it to proceed way ahead than that for GIP.1
The Dominant Incretin
Studies comparing the activity of GIP and GLP-1 have been a robust area of scientific research. Dr. Litonjua presented data showing both incretins mediating prandial and post prandial insulin secretion following oral and IV glycemic challenge. Glycemia was seen in both IV and oral glucose cohorts, but the insulin and incretin response were only noted in the oral glucose group – highlighting the so-called “incretin effect”. Additionally, it was clear that GIP levels correlate more with the degree and pattern of insulin release suggesting that it may be the primary mediator of this effect.2,3 Antagonist studies also show that GIP had a more significant effect on insulin-mediated glucose clearance. Furthermore, studies also show that infusion of GIP into healthy humans during the glycemic challenge markedly increased glucose-dependent insulin release and the rate of clearance of glucose.4,5 Dr. Litonjua also presented data that among the factors contributing to insulin release, GIP accounted for 44% of the process, almost double than the influence of GLP-1 which was at 22%, proving that GIP is the dominant endogenous incretin.6
Receptor activity6
GIP receptors are distributed all over the body mostly in the α and β cells of the Islet of Langerhans, the adipose tissues and the brain which mediates a multitude of biochemical processes.
Islet of Langerhans activity7
The direct effect of GIP on the β-cell of the Islet of Langerhans to stimulate insulin release is a widely understood concept. Dr. Litonjua, however, highlighted the effect of GIP on the α-cells which together with the uptake of amino acids stimulates glucagon release. Dr. Litonjua opined that the glucagon release by the α-cells within the Islet of Langerhans, stimulates the adjoining β-cells by paracrine effect, resulting in more insulin secretion.
Brain activity8-10
Data from preclinical studies suggest that GIP activity in the brain may play a role in weight regulation. GIP binding with its receptors on the brain’s appetite control centers help reduce caloric intake. Studies have shown that dysregulation of these appetite control centers results in excessive weight gain. However, Dr. Litonjua was quick to emphasize that the exact mechanism of GIP on weight loss is not yet well-understood.
GIP activity in body organs of healthy individualsAdipose tissue activity11-25
Another significant difference between the incretins is their effect on lipid metabolism. GIP causes capillary recruitment and increased blood flow into adipose tissues. Improved adipose tissue perfusion increases lipoprotein lipase availability enhancing the breakdown of triglycerides and thereby facilitating absorption into adipocytes. GIP also inhibits outflow of free fatty acid from the adipocytes. This dual effect of the GIP fatty acid transport is also known as the “buffering effect”. This helps keep fats where they are physiologically beneficial and limits “spillover fat” from being deposited in ectopic sites where they can be harmful. Ectopic fat deposition from dysregulated lipid partitioning is characteristic of T2DM. Lipid buffering physiologically protects and maintains functionality of the liver, skeletal muscles, and pancreatic cells by improving glucose uptake and tolerance and insulin sensitivity through adipokines produced by GIP-enhanced adipose tissues. Doctor Litonjua added that GIP improves glucose transporter 4 (GLUT4) translocation which is the probable mechanism of enhanced insulin sensitivity.
As shared by Dr. Litonjua, clinical studies suggest GIP may have cardioprotective properties by improving endothelial function with a decrease of atherosclerosis and inflammation. It also regulates atherosclerotic plaque size and stability. A potential beneficial role of GIP signaling on variables associated with cardiometabolic outcomes like BMI, and HDL cholesterol, is also suggested by genetic association studies on incretins.26-30
Future combination31-32
With a better understanding of incretin physiology, the enormous therapeutic potential of combining the pharmacologic activity of GIP with GLP-1 treatment bids well for improving glycemic control. With a dual action on pancreatic cells by both incretins stimulating insulin secretion plus a paracrine stimulation from glucagon, may theoretically stabilize insulin levels. With enhanced adipose tissue metabolism that limits “spillover effect” keeping fats where they are physiologically beneficial coupled with improved insulin sensitivity and glucose uptake through the adipokines, we may soon see the drug that measures up to the complexity of metabolic syndrome. GIP has also been demonstrated to promote weight loss by acting on multiple sites on the central nervous system, ultimately promoting satiety without subsequent nausea.
Dr. Litonjua and and Prof. SP Chan during the open forum.Open Forum and Panel Discussion
A dynamic panel discussion ensued from the lecture presentation between the participants and the speaker. Dr. Nemencio Nicodemus Jr, Consultant Endocrinologist, was the moderator for the discussion where Dr. Litonjua was joined by Professor Chan Siew Pheng at the University of Malaya in Kuala Lumpur, Malaysia. It was clarified that there may be slight differences in incretin physiology and GIP response between healthy individuals and those with T2DM and the full physiologic effect of incretins in patients with chronic illness has yet to be studied. Changing the understanding of its physiology will come with new scientific data that can modify clinical applications, like from being previously considered obesogenic, GIP is now thought to be anorexigenic. The potential combination with thiazolidinediones which has a similar effect on weight is not yet well-documented and needs to be approached with caution considering side effects. The role of GIP in fatty liver disease and on osteoporosis is very promising and is the subject of research. Triple peptide compound comprised of glucan, GIP and GLP-1 currently are directed at achieving weight loss to a degree that is similar to what is achieved with surgery but also warrants caution from side effects. The consensus from all attendees was clear that introduction and better understanding of newer molecules is driving the development and optimism in the field of diabetes.