Changing the Course of Disease: Gastrointestinal Hormones and Tomorrow’s Treatment of Type 2 Diabetes

Gastrointestinal Hormones: Emerging Players in Metabolic Regulation

Current treatments for type 2 diabetes provide significant benefits in targeting insulin deficiency and insulin resistance; however, management of this multihormonal disease remains suboptimal. “Despite intensive therapy for type 2 diabetes, hypoglycemia, weight gain, and resulting metabolic syndrome frequently develop,” said Harold E. Lebovitz, MD, Professor of Medicine, State University of New York, Health Science Center at Brooklyn, Brooklyn, New York. According to Dr. Lebovitz, gastrointestinal (GI) hormones play a key role in the pathogenesis of type 2 diabetes, and are a potential target for future treatment.

Diabetes and GI Hormones
“Proper metabolism is the result of many organ systems and hormones working in harmony,” Dr. Lebovitz said. Type 2 diabetes involves not only insulin deficiency and insulin resistance, but also defects such as amyloid deposits in islet cells, glucose toxicity, and lipotoxicity, which lead to increased apoptosis and progressive decline in beta-cell function. Current therapies are effective in reducing glucose levels, but fail to preserve or stop the loss of beta-cell function. In addition, these therapies often result in significant hypoglycemia, weight gain, and metabolic syndrome. “Because of the multifactorial disease process in type 2 diabetes, treatment to replace insulin and address insulin resistance alone does not achieve optimal disease control. Indeed, emerging evidence suggests the importance of an additional therapeutic target: GI hormone regulation,” Dr. Lebovitz explained.

Nutrient homeostasis is a complex process consisting of two main events following meal ingestion: 1) shutting down fasting hepatic glucose production, and 2) taking up glucose and other nutrients incrementally into the skeletal muscles and insulin-sensitive tissues. While shutting down hepatic glucose production involves insulin secretion and glucagon suppression, taking up meal-derived glucose requires insulin and its modulating GI hormones. “Indeed, the GI tract plays a major role in all aspects of nutrient homeostasis,” Dr. Lebovitz noted. The GI system has the mechanism to recognize when sufficient food has been eaten and to send signals to the brain to stop eating, and when to secrete more insulin and less glucagon to control rising blood glucose. Two GI peptides—gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)—are secreted in response to food ingestion.

The Role of GIP and GLP-1
In persons with normal metabolic physiology, GIP and GLP-1 are secreted in response to food ingestion, and exert multiple effects. These peptides bind to pancreatic beta-cell receptors. Through a cyclic AMP-mediated mechanism, GIP and GLP-1 contribute to the amplification of glucose-stimulated insulin secretion and, through a mechanism that is not completely understood, they decrease glucagon secretion from the alpha cells. GLP-1 is a physiologically relevant incretin hormone, shown to stimulate glucose-dependent insulin secretion and also decrease glucagon secretion, delay gastric emptying, and decrease appetite. In animal studies, GLP-1 has demonstrated an ability to increase beta-cell neogenesis and proliferation and to decrease beta-cell apoptosis.

GI Hormone Abnormalities
Patients with type 2 diabetes develop not only impaired insulin secretion, insulin resistance, and beta-cell insufficiency, but also a reduced incretin effect. “While GIP secretion is normal or slightly decreased, its action is markedly diminished in those with type 2 diabetes. However, GLP-1 secretion is diminished but its action remains normal. As a result, the incretin effect is significantly deficient in type 2 diabetes,” Dr. Lebovitz explained (Table 1). “Recent evidence shows that GLP-1 elimination is comparable in obese persons who have type 2 diabetes to obese persons who are healthy, suggesting that the postprandial reduced incretin effect is the result of decreased GLP-1 secretion,” he noted.

In persons with type 2 diabetes, treatment with GLP-1 infusion has been shown to help normalize response to a mixed meal. “Importantly, the action of GLP-1 is glucose dependent. Thus, in those with high glucose levels, GLP-1 infusion results in a dramatic decrease in glucose levels—and a lesser effect in those with normal or less elevated glucose levels,” the speaker explained. In closing, Dr. Lebovitz emphasized the need for further study of GI hormone replacement in the management of type 2 diabetes, as this treatment approach appears to help restore deficient regulatory functions of the GI tract in nutrient homeostasis and metabolism (Drucker DJ. Diabetes Care 2003;26:2929. Toft-Nielsen et al. J Clin Endocrinol Metab 2001;26:3717. Zander et al. Lancet 2002;359:824).

GLP-1-Based Therapies: The Rationale for Clinical Use

Type 2 diabetes, a disease that continues to increase in incidence, involves a combination of metabolic defects, including a failure of pancreatic beta-cell secretory capacity to compensate for tissue insulin resistance. “Indeed, a progressive loss of beta-cell function may occur even with weight loss and with metformin, sulfonylurea, or insulin treatment,” said David M. Kendall, MD, Chief of Clinical Services and Medical Director, International Diabetes Center, Park Nicollet Clinic, Minneapolis, Minnesota. According to Dr. Kendall, gastrointestinal (GI) hormones play a key role in the pathogenesis of type 2 diabetes, and glucagon-like peptide-1 (GLP-1) and incretin mimetics have been shown to improve blood glucose control and assist in preservation of beta-cell mass. Dr. Kendall provided a brief overview of the role of GI hormones in regulating postprandial glucose metabolism and nutrient homeostasis.

Type 2 Diabetes: Treatment Challenges
Current therapies for type 2 diabetes target insulin deficiency or insulin resistance. Several barriers exist in the treatment of this challenging disease, including the presence of multiple defects and need for a multiple-drug treatment approach, the management of postprandial blood glucose, increased rates of hypoglycemia, treatment-related weight gain and metabolic syndrome, and drug tolerance. Despite the numerous treatments used to treat diabetes, popu-lation studies show no im-provement in glycemic control from 1990 to 2000 (Koro. Diabetes Care 2004;27:17). “These treatment challenges suggest that understanding the multihormonal nature of type 2 diabetes will be critical and underscore the need for new therapeutic options—to allow us to not only achieve, but also maintain adequate glycemic control,” Dr. Kendall explained.

The Role of GI Hormones
Normal glucose homeostasis involves not only insulin and glucose, but other hormones as well. The key components that likely lead to the development of type 2 diabetes include insulin resistance, deficient insulin secretion, and impaired GLP-1 secretion with elevated postprandial glucagons levels. One potential target for the treatment of diabetes is GLP-1 deficiency. This peptide is secreted from the intestinal wall in response to food ingestion, and is decreased in persons with type 2 diabetes.

When given as therapy, GLP-1 infusion has been shown to possess both acute and chronic effects on glucose homeostasis (Table 1). In animal and preclinical research, GLP-1 has been shown to stimulate glucose-dependent insulin secretion, to suppress postprandial glucagon secretion, to lower blood glucose, to delay gastric emptying, and to preserve beta-cell mass and function. In patients with type 2 diabetes, GLP-1 infusion resulted in an improvement in insulin secretion, lowering of blood glucose, and appropriate suppression of glucagon levels. “The data show the effect of GLP-1 and other gut hormones to be glucose dependent: the greater the level of hyperglycemia, the more significant the improvement in glucose levels,” Dr. Kendall explained. In one placebo-controlled study, patients with type 2 diabetes received GLP-1 infusion for 6 weeks (Zander. Lancet 2002;359:824). The results showed a substantial effect at 1 week, as well as progressive increase in C-peptide levels and decrease in postprandial glucose, fasting glucose, and hemoglobin A1C levels over the treatment period. In addition, Zander and colleagues also demonstrated that, with a substantial impact in controlling postprandial blood glucose and delaying gastric emptying, positive effects on satiety and body weight may also be achieved. Finally, animal studies have demonstrated the potentiation of insulin mRNA transcription and regeneration of islet cells with GLP-1 replacement therapy (Endocrinology 1999;140:4904. J Clin Invest 1997;99:2883. Abraham. Endocrinology 2002;143:3152).

In closing, Dr. Kendall stressed the importance of the potential role of GLP-1 and other GI peptides in the development and future treatment of type 2 diabetes (Table 2), with emerging evidence demonstrating a positive impact not only on glucose control, but potentially also on satiety, weight loss, and pancreatic beta-cell mass and function.

Clinical Effects of Therapies Targeting GLP-1-Related Pathways in Patients with Type 2 Diabetes

We are in the midst of an epidemic of type 2 diabetes. The lifetime risk for the development of type 2 diabetes for persons born in the year 2000 is estimated to be 33% in men, 39% in women, and 53% in Latino-Hispanic women. “It is hoped that current treatments, combined with the numerous potential antihyperglycemic therapies presently under study, will offer promise in meeting the challenge of the growing epidemic of diabetes,” said Lawrence Blonde, MD, FACP, FACE, Director of the Ochsner Diabetes Clinical Research Unit in the Section on Endocrinology, Diabetes, and Metabolic Diseases at the Ochsner Clinic Foundation in New Orleans. According to Dr. Blonde, glucagon-like peptide-1 (GLP-1)-related pathways represent one promising target for future therapy.

GLP-1-Related Therapies
The gastrointestinal hormone, GLP-1, is a 30-amino acid peptide that is secreted from intestinal mucosa after food ingestion. GLP-1 receptors exist in islet cells, the central nervous system, and other tissues. Actions of GLP-1 include glucose-dependent potentiation of insulin secretion and suppression of glucagon secretion, delay of gastric emptying, and an apparent enhancement of satiety. Postprandial GLP-1 concentrations are significantly reduced in patients with type 2 diabetes, suggesting a potential therapeutic role for GLP-1 administration. However, plasma GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase (DPP)-IV, making injection therapy unsuitable. “Potential methods to enhance GLP-1 receptor stimulation include GLP-1 infusion, oral DPP-IV inhibitors, and incretin mimetics, which include GLP-1 analogs and exenatide [synthetic exendin-4],” Dr. Blonde said (Table 1).

In studies of GLP-1 infusion in persons with type 2 diabetes, Nauck and colleagues showed enhanced postprandial insulin secretion and reduced fasting and postprandial glucose and glucagon levels (Nauck et al. Diabetologia 1993; 36:741). Zander and colleagues showed similar results, as well as improved A1C and weight loss over a treatment duration of 6 weeks (Zander. Lancet 2002).

LAF237, a DDP-IV inhibitor, can be administered orally and acts to prolong the activity of endogenous GLP-1. In one placebo-controlled study, 40 diet-treated persons with type 2 diabetes underwent 4 weeks of LAF237 therapy and experienced reductions in fasting and postprandial glucose and postprandial glucagon levels (Ahren et al. Diabetes 2003;52(Suppl 1): A15).

The GLP-1 analog, NN2211, is an acetylated analog that binds to albumin, is slowly absorbed after injection, and resists inactivation by DDP-IV. In one study, type 2 diabetes patients received a subcutaneous NN2211 injection at bedtime for 12 weeks, and showed reductions in glucose and A1C. Weight was maintained with a trend towards a decrease (Matthews et al. Diabetes 2002;51(Suppl 2): A84).

Exenatide (synthetic exendin-4 or AC2993) is an incretin mimetic agent currently under study. Exenatide is a 39-amino acid peptide structurally identical to the naturally occurring hormone exendin-4 found in the salivary gland of the gila monster.

Multiple Effects of Exenatide Therapy
Exenatide exerts GLP-1 receptor binding equivalent to that of GLP-1, is rapidly absorbed after subcutaneous injection, and is resistant to inactivation by DPP-IV. When administered after an overnight fast, exenatide therapy resulted in significantly increased fasting plasma insulin levels and decreased fasting plasma glucose levels compared with placebo (Kolterman et al. J Clin Endocrinol Metab 2003; 3082). In another study, exenatide therapy resulted in decreased postprandial plasma glucagon and glucose levels (Kolterman et al. J Clin Endocrinol Metab 2003; 3082).

Three phase 3, randomized, double-blind, placebo-controlled multicenter trials of exenatide involved patients with type 2 diabetes who had been treated with a minimum of 1500 mg of metformin, or a maximally effective dose of a sulfonylurea, or both. Patients continued their oral therapy and were randomized to receive placebo or subcutaneous exenatide. Initial reports of results indicate that the average reduction in A_1C across the phase 3 program in patients completing the studies on the highest dose of exenatide (10 micrograms twice daily) was approximately one percentage point. Additionally, approximately 40% of these patients achieved A_1C values of 7% or less. On average, subjects in the phase 3 program on the highest dose of exenatide also showed statistically significant reductions in body weight of approximately 2 kilograms. The most common adverse event was mild to moderate, transient nausea.

In closing, Dr. Blonde noted that “preliminary results of phase 3 clinical trials with exenatide are encouraging, showing improved glycemia. Moreover, those on the highest dose had clinically and statistically significant weight loss rather than the weight gain that often accompanies most other antihyperglycemic treatments for type 2 diabetes patients. Other GLP-1-related therapies are also under study, so that hopefully agents enhancing GLP-1 receptor stimulation will become viable new options in the treatment of patients with type 2 diabetes.”