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GLP-1 Agonists and Lifestyle Changes: A Recipe for Success

Andre McMahon, PharmD Candidate UF College of Pharmacy

Achieving glycemic control is a critical goal in the management of patients with type 2 diabetes mellitus (DM).

Hyperglycemia contributes to the progression of DM by adversely affecting both the body’s sensitivity to insulin and beta-cell function. Type 2 DM results from impaired insulin secretion. As beta-cell function continues to decline, the body progressively loses metabolic control and eventually leads to the need for insulin treatment. Thus, preserving the beta cells from declining in function plays a pivotal role in preventing type 2 DM and altering the course of the disease. Glucagon-like peptide-1 (GLP-1) analogs, which include exenatide (Byetta®), liraglutide (Victoza®) and exenatide extended-release (Bydureon®), have been made available with the purpose of stimulating insulin secretion with an incretin-mimetic mechanism. Coupling GLP-1 analogs with lifestyle modifications can lead to treatment success in type 2 DM through management and prevention of hyperglycemia and targeting beta-cell dysfunction.1

See more GLP-1 Agonist Resources.

Animal studies have shown that chronic hyperglycemia in the presence of decreased beta-cell mass markedly decrease the ability of the remaining beta-cells to respond to an additional glucose stimulus. This impaired insulin response, or glucotoxicity, is reversed by correction of the chronic hyperglycemia. Additionally, animal studies have demonstrated that chronic hyperglycemia results in decreased muscular sensitivity to insulin. Overweight/obesity, which is common in type 2 DM, may also contribute to beta-cell dysfunction and thus disease progression. Increased tissue levels of free fatty acids associated with overweight/obesity may accumulate over time in beta-cells resulting in a loss of glucose-stimulated insulin secretion, or lipotoxicity.2 Also, lipotoxicity is associated with a decrease in beta-cell mass through accelerated apoptosis.3 Glucotoxicity and lipotoxicity are thought to play central roles in the progression of type 2 DM. The insulin resistance induced by glucotoxicity and lipotoxicity leads to insulin production that is insufficient to prevent hyperglycemia leading to beta-cell failure.4

Preserving the beta-cells from decline in function and eventual failure is crucial in preventing type 2 DM and changing the natural history of the disease in subjects affected. Theoretically, the protection of beta-cells can be achieved in several ways. Lifestyle changes based upon a healthier diet and regular exercise can improve insulin sensitivity and attenuate the demand to beta-cells as well as ameliorate the milieu of islets through a better blood flow and a diminished load of toxic insults. In addition to lifestyle changes, protection of the beta-cells can also be exerted by the use of certain drugs such as GLP-1 analogs.4

GLP-1 is a part of a family of peptide hormones known as incretins. Incretins are secreted by the entero-endocrine cells of the gastrointestinal tract to stimulate glucose-dependent insulin secretion and beta-cell proliferation. The natural GLP-1 produced by our body is rapidly metabolized resulting in a short half-life (1-2 minutes). GLP-1 analogs have been manufactured to be more resistant against metabolism in the body and have been shown to be effective in the treatment of type 2 DM. Through their incretin effects, GLP-1 analogs have been shown to improve insulin secretion, decrease glucagon production, increase satiety, and help decrease food intake. Additionally, GLP-1 analogs are thought to prevent beta-cell apoptosis and possibly cause beta-cell regeneration and proliferation.5

In a study by Farilla et al., GLP-1 added to freshly isolated human islets preserved morphology and function and inhibited cell apoptosis. Thus they concluded that GLP-1 analogs prevent beta-cell apoptosis.6 According to several other studies, GLP-1 analogs may also increase regeneration and proliferation of beta-cells.7,8 Thus, these pleiotropic effects of GLP-1 analogs may improve glycemic control in type 2 DM patients in the short- and long-term. The addition of lifestyle modifications may allow two pathogenic features of type 2 DM to be overcome; decreased insulin sensitivity and beta-cell dysfunction thus leading to increased glycemic control.

References:
  1. Stolar MW. Defining and Achieving Treatment Success in Patients With Type 2 Diabetes Mellitus. Mayo Clin Proc. 2010 December; 85(12_Suppl): S50-S59.
  2. Unger RH. Review Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes. 1995 Aug; 44(8):863-70.
  3. Wajchenberg BL. Review beta-cell failure in diabetes and preservation by clinical treatment. Endocr Rev. 2007; 2892):187-218.
  4. Bonora E. Protection of pancreatic beta-cells: Is it feasible? Nutr metab Cardiovasc Dis. 2008 jan;18(1):74-83.
  5. Powers AC, DAlessio D. Chapter 43. Endocrine Pancreas and Pharmacotherapy of Diabetes Mellitus and Hypoglycemia. In: Chabner BA, Brunton LL, Knollman BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011. http://ww.accesspharmacy.com. Accessed September 5, 2012.
  6. Farilla L, Bulotta A, et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets.
  7. Perfetti R, Zhou, et al. Glucagon-Like Peptide 1 Induces Cell Proliferation and Pancreatic-Duodenum Homeobox-1 Expression and Increases Endocrine Cell Mass in the Pancreas of Old, Glucose-Intolerant Rats. Endocrinology. 2000. December 1; 14(12) 4600-4605.
  8. Yusta B, Baggio Ll, et al. GLP-1 receptor activation improves B cell function and survival following induction of endoplasmic reticulum stress. Cell Metab. 2006 Nov; 4(5): 391-406.

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