DSI Newsletter: Diabetes and Intestinal Incretin Hormones

DSI Newsletters, Issue 48:
Diabetes and Intestinal Incretin Hormones

Incretins are gut hormones that elicit insulin secretion after glucose ingestion. The incretin effect describes the enhanced insulin response from orally introduced glucose compared to intravenous glucose. It comprises between 20% and 60% of the postprandial insulin secretion but is diminished in type 2 diabetes (T2D). Glucagon-like peptide-1 (GLP-1) is an important incretin. In vitro and animal experiments demonstrated that GLP-1 increases -cell mass by stimulating islet cell neogenesis. In vitro data also show the inhibition of apoptosis of islets by GLP-1. The improvement of -cell function can be indirectly observed from the increased insulin secretory capacity of humans receiving GLP-1. Furthermore, GLP-1 inhibits glucagon secretion and the risk of hypoglycaemia is extremely rare. It may represent an attractive therapeutic method for T2D due to its multiple effects. However, only 20% of the GLP-1 administered intravenously is estimated to reach circulation biologically intact. Therefore, exenatide and long-acting GLP-1 analogues, both of which are resistant to degradation and classified as incretin mimetics, are under study, as well as a compound that inhibits incretin degradation.
For those of us taking care of people with diabetes, it seems that we are always being challenged to do better. In recent years, studies have demonstrated the benefit of lower blood pressure; lower lipid levels, and — at the core of diabetes management — lower blood glucose levels.
Fortunately, we also have newer treatments to help us reach this goal. New classes of medications and insulin analogues have become available, allowing the restoration of near-normal insulin physiology and glucose homeostasis. We can now more precisely mimic natural insulin secretory patterns, and reduce both hepatic and peripheral insulin resistance.
Another step toward restoration of normal physiology is a treatment aimed at another component of the complex mechanism of insulin secretion and glucose metabolism. Incretin hormones — the so-called "gut hormones" — have been recognized as playing a role in the coordination of insulin action with the influx of dietary carbohydrate. People with type 2 diabetes have a dysfunction in the action of these hormones. We are now on the verge of being able to replace the action of these hormonal coordinators, restoring yet another of the mechanisms needed to approach optimal glucose control.
In this program, we will explore how these hormones work, both in the normal state and in people who have type 2 diabetes. For those of us who provide medical care for people with diabetes, it is an opportunity to see what will soon be another therapeutic approach to treating this complex disease.
To understand the new treatments that will restore incretin function, it is important to start with a review of the pathophysiology of type 2 diabetes. Despite our best efforts, type 2 diabetes remains a chronic progressive metabolic disease characterized by hyperglycemia due to insulin resistance and relative insulin deficiency leading to end-organ complications and decreased survival. It is now well accepted that diabetes is a global problem and can be considered the most important chronic disease epidemic of the new millennium. In the year 2000, 177 million people around the world were known to have diabetes and this number will increase to over 350 million by the year 2030. The combined impact of a dramatic increase in rates of obesity, an increasingly sedentary lifestyle, and aging of the population, particularly in developed countries, are all contributing to this major health crisis. It is now well-recognized that increased visceral adipose tissue plays a pivotal role in mediating the pathophysiologic events responsible for hyperglycemia and the other metabolic abnormalities that are associated with type 2 diabetes. Elevations in free fatty acids and changes in the concentration of adipokines appear to be responsible for mediating both insulin resistance and impaired insulin secretion. Of interest, adiponectin is unique in that high levels are associated with improved insulin sensitivity and improved beta-cell function. When visceral adipose tissue increases, adiponectin, unlike the other adipokines, decreases in concentration. The insulin resistance, characteristic of type 2 diabetes, is associated with increased hepatic glucose production and decreased insulin-mediated glucose transport at the muscle and adipose tissue. Impaired beta-cell function is also a prominent feature of the progressive nature of type 2 diabetes. And, the quantity of visceral fat mediates the characteristic insulin resistance associated with type 2 diabetes. Insulin secretion in response to a standardized fixed glucose stimulus, as can be achieved with a hyperglycemic glucose clamp, has characteristically 2 components. First-phase rapid insulin release occurs within the first 5 to 10 minutes. This is followed by a more prolonged sustained insulin release, referred to as second-phase insulin secretion. In the context of type 2 diabetes, this normal physiology is disturbed early in the development of this metabolic abnormality. A prominent feature of type 2 diabetes is the loss of first-phase insulin secretion. It is said that in type 2 diabetes, beta-cell function becomes essentially "blind" to the stimulatory effects of glucose on beta-cell insulin release. One of the important lessons learned from the United Kingdom Prospective Diabetes Study (UKPDS) is that type 2 diabetes is a progressive disease and despite the implementation of intensive therapy, A1C, which initially improved, continued to deteriorate over time. The use of Glyburide, chlorpropamide, metformin, and even insulin in the UKPDS was associated with a progressive deterioration in A1C over time. The progressive nature of type 2 diabetes is manifest by a failure of traditional monotherapy to achieve clinical practice guideline targets of an A1C of less than 7%. The number of patients achieving an A1C of less than 7% declined progressively in those treated with both metformin as well as those treated with sulfonylureas. It is important to note that after 3 years of therapy, approximately 50% of patients needed more than one oral antidiabetes agent. It would appear that the deterioration in diabetes control observed in the UKPDS is a consequence of progressive loss of beta-cell function over time. At the time of diagnosis, 50% of beta-cell function had already been compromised and as the study continued, there was a further progressive decline in beta-cell function. Remarkably, despite long-duration type 2 diabetes, it would appear that a substantial amount of beta-cell mass may still be present and the problem is that beta-cell function is dramatically impaired. As a result of the loss of beta-cell function, it is not surprising that over time, many patients with type 2 diabetes will need exogenous insulin therapy to control glucose. There have now been a number of prospective studies that clearly demonstrate that improving blood glucose control and lowering A1C levels significantly reduces the risk of developing both microvascular and macrovascular complications. The Diabetes Control and Complications Trial (DCCT) compared a program of intensive diabetes management with one of conventional therapy in people with type 1 diabetes over a 9- to 10-year period. As shown on this slide, those receiving conventional therapy maintained an average A1C of approximately 9%, whereas those on intensive therapy were able to maintain an A1C of close to 7%, which is the current ADA A1C target. It is now clear that this lack of early insulin secretion contributes to postprandial hyperglycemia, primarily because of a failure to achieve rapid and effective suppression of hepatic glucose production. A study conducted by Dr. David Kelley and colleagues showed that absorption of ingested glucose is exactly the same in diabetic and nondiabetic subjects. However, people with diabetes have increased endogenous glucose production in the fasting state and fail to suppress it adequately in response to an oral glucose load. This is associated with a combination of insulin resistance in the liver and a decrease in the early, first-phase insulin secretory response, resulting in increased postprandial glucose levels. It is now clear that there are multiple risk factors for the development of atherosclerosis leading to macrovascular complications in patients with diabetes and that some of these risk factors, such as hypertension; also contribute to the development of microvascular disease. This means that we need to take a global approach to the treatment of patients with diabetes and focus on multiple risk factor reduction. This includes not only treatment of hyperglycemia but also aggressive treatment of hypertension and the dyslipidemia commonly seen in our patients, as well as attention to obesity, physical inactivity, and smoking. This is the idea behind Pfizer’s Caduet: combination of Norvasc and Lipitor.
Incretins
Incretins are peptide hormones that are secreted by the enteroendocrine cells in the gastrointestinal tract. Their major effect is to modulate pancreatic islet secretions as part of the so-called enteroinsular axis, although they also have been demonstrated to have other effects on nutrient homeostasis. The 2 major incretins that affect glucose metabolism are glucagon-like peptide-1, or GLP-1, and glucose-dependent insulinotropic polypeptide, or GIP. The incretin effect was described more than 35 years ago and refers to the fact that there is a much greater insulin response to glucose when it is given orally than when the same amount is administered as an intravenous infusion. It was not until the 1980s that GLP-1 and GIP were identified and their physiologic roles could be studied. Of the 2 incretins, GLP-1 is the more important one, although GIP is responsible for about 20% to 30% of the incretin effect on pancreatic beta-cell function. GLP-1 is a 37-amino acid polypeptide that is produced in intestinal L-cells as a part of proglucagon. It is released rapidly in response to the ingestion of glucose or a mixed meal and has very potent effects on pancreatic beta cells to increase insulin secretion in a glucose-dependent manner. It also suppresses glucagon secretion and has a number of effects that regulate the absorption and metabolism of nutrients. It is also important to note that people with IGT or type 2 diabetes have lower plasma GLP-1 levels in response to stimulation compared with healthy controls. This may contribute to the impaired beta-cell function seen in these conditions. GLP-1 has a number of actions in humans that have now been well characterized. When one ingests a mixed meal, GLP-1 is secreted from the intestinal L-cells, which in turn stimulates glucose-dependent insulin secretion. This is the originally described incretin effect. In addition, GLP-1 suppresses glucagon secretion, slows gastric emptying, and there are now data showing that it results in increased satiety and reduction of food intake. Originally there were some suggestions that it may directly improve insulin sensitivity but this is not well established. Its major biologic effects appear to be due to enhanced glucose-mediated insulin secretion and suppression of glucagon. Studies have been conducted in animal models that indicate that in addition to its acute effects, there are more chronic effects on beta cells to increase replication and neogenesis of new beta cells and to inhibit apoptosis. These findings are very encouraging and suggest that GLP-1 may play a significant role in the preservation and even possibly restoration of beta-cell mass and function in humans, although studies have not been done yet to confirm this. Another important characteristic of GLP-1 is that its effects on insulin and glucagon secretion are dependent on glucose. If one infuses GLP-1 in people with type 2 diabetes, there is rapid increase in insulin and suppression of glucagon and a fall in glucose concentrations toward normal. However, as glucose levels fall into the normal or near-normal range, the effects on insulin and glucagon secretion are reversed, with insulin levels decreasing and glucagon increasing. Another effect of GLP-1 is to delay gastric emptying. When a subcutaneous injection of GLP-1 is followed by ingestion of a liquid meal, there is a 30-minute delay in gastric emptying, which continues to occur over a 2- to 3-hour period of time. The effect of this would be to delay the digestion and absorption of carbohydrates and thus decrease the postprandial rise in blood glucose levels. GLP-1 has also been demonstrated to result in increased satiety and decreased food intake. Some of this may be related to the delay in gastric emptying and afferent neural signals from the gastrointestinal tract to the central nervous system. However, there is also some evidence that GLP-1 may have direct effects on the central nervous system. To summarize the effects of GLP-1 on beta cells, the best documented direct effects in humans are to enhance glucose-dependent insulin secretion. Subacute effects have been demonstrated in incubated human islet cells demonstrating that GLP-1 has major effects on glucose metabolism in beta cells and also increases the synthesis of insulin. Longer-term chronic effects have been observed in animal studies. These include increased proliferation and neogenesis of beta cells, decreased beta-cell apoptosis, and increased expression of important glucose-sensing factors such as Glut-2 glucose transporters and glucokinase. There are currently 3 strategies to enhance incretin action in patients with type 2 diabetes: 1) create GLP-1 analogues resistant to degradation by DPP-IV, with resultant prolonged pharmacokinetics; 2) administer exenatide, a synthetic formulation of Exendin 4, a natural component of salivary secretion from the Gila monster lizard, which is resistant to DPP-IV degradation and is a potent GLP-1 agonist being developed by Amylin Pharmaceuticals; and 3) administer inhibitors of DPP-IV with the goal of inhibiting breakdown of endogenous GLP-1 secretion. GLP-1 analogues like exenatide (Synthetic Exendin-4) are incretin mimetic agents. We did the Synthetic Exendin-4 study with Amylin Pharmaceuticals and the only significant adverse effect of combining exenatide with metformin was an increase in mild to moderate nausea. This occurred more frequently early in the study and tended to disappear after 8 weeks of treatment. The incidence of severe nausea was low: 2% in placebo, 3% in the 5-mcg exenatide group, and 4% in the 10-mcg exenatide group. Withdrawal due to nausea was low, occurring in 1% in the 5-mcg exenatide group and 3% in the 10-mcg exenatide group. When used with metformin, exenatide treatment did not result in any increase in overall hypoglycemia, and no severe hypoglycemia was observed. In summary, increasing incretin action as a therapy for the management of type 2 diabetes appears to have a significant impact on diabetes control and may represent a paradigm shift in the management of this common metabolic disorder. In our quest to restore normal glucose homeostasis and physiologic insulin action, we are on the verge of taking another important step forward. The treatments to restore incretin function will allow us to address yet another component in the complex cascade of events that normally support proper glucose metabolism for people with type 2 diabetes.
In summary, the potentially beneficial actions of Synthetic Exendin-4 (Exenatide), a new incretin mimetic, which is a long acting GLP-1 analog drug administered sub-Q BIDincludes:

Amplification of insulin secretion (insulinotropic effect), glucose dependent action with a fixed dose. When the glucose is low, there is no increase in insulin secretion. So, you can skip a meal without risk of hypoglycemia.
Insulin on demand. All you need, when you need it! Plus, all you don’t need when you don’t need it! All dependent on glucose concentration.
Suppression of postprandial glucagon secretion (glucagonostatic effect) which is paradoxically elevated in DM (unchecked gluconeogenesis caused by paradoxically elevated glucagon).
Reduction in food intake by increasing satiety which creates weight loss.
Modulation of nutrient delivery by decreasing gastric emptying (may cause nausea and vomiting, especially in the beginning without gradually increasing the dose).
Some antidiabetic actions are mediated by binding to the GLP-1 receptor (glucagon-like peptide).
GLP-1 is a gut peptide secreted by the small bowel mucosa L-cells which potentiates insulin secretion, suppresses glucagon secretion, and has a central satiety effect to make weight loss.
Prevents some people from requiring insulin.
Works to lower glucose in all patients.
Is additive to all existing therapies.
Is likely to help patients reach their goal sugar despite failing other agents.
Helps return pancreatic beta cell function back to normal.

This was a summary of the pathophysiology of how incretin mimetics like Synthetic Exendin-4 can safely lower glucose levels with less chance of hypoglycemia than SU’s while creating weight loss. Hopefully it will enable patients to be more comfortable with considering using this new drug when it becomes available in the near future. Even though it is new, I have been lucky to be part of the research and development process and I have been comfortable using it with my patients for years.

Sincerely:

Joseph Saponaro, MD, DABIM, FACP, CPI, CCI, CCRI, CCRC, CCRP
Board Certified Internist, JPMC
Principal Investigator, DSI
Diplomat American Board of Internal Medicine
Fellow American College of Physicians
Certified Physician Investigator by the AAPP
Certified Clinical Investigator by the DIA
Certified Clinical Research Investigator by the ACRP
Certified Clinical Research Coordinator by the ACRP
Certified Clinical Research Professional by SoCRA
Member: The American College of Preventive Medicine

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