High fat diet and GLP-1 drugs induce pancreatic injury in mice☆
Introduction
A number of drugs marketed for treatment of type-2 diabetes are active in the glucagon-like-peptide-1 (GLP-1) receptor signaling pathway. These GLP-1 based drugs function as either GLP-1 receptor agonists, (i.e., FDA approved exenatide (EXE) and liraglutide, and drugs still undergoing critical trials: lixisenatide, and albiglutide) or dipeptidyl-peptidase-4 (DPP-4) inhibitors (i.e., FDA approved sitagliptin (SIT), vildagliptin, saxagliptin, and linagliptin). In homeostasis, GLP-1 binds the GLP-1 receptor initiating signaling that increases cyclic-AMP (cAMP) and up-regulates pathways, primarily phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt), resulting in increased production and cellular uptake of insulin thereby lowering blood glucose (Marathe et al., 2013, Perry and Greig, 2003). Under normal physiological conditions, GLP-1 is rapidly degraded by DPP-4. Therapeutically, DPP-4 inhibitors allow prolonged survival of GLP-1 and potentiate the effects of GLP-1 receptor signaling. The efficacy of DPP-4 inhibitors is slightly lower than GLP-1 agonists because DDP-4 inhibitors produce a relatively modest increase in postpradial levels of intact GLP-1 and have minimal effects on the rate of gastric emptying (Marathe et al., 2013).
Safety concerns surrounding several GLP-1 based drugs have surfaced repeatedly in postmarketing surveillance of these drugs in those with type-2 diabetes mellitus. Thirty cases of EXE-associated pancreatitis were reported to FDA's Adverse Event Reporting System in 2005–2006 (Ahmad and Swann, 2008). Eighty-eight cases of acute pancreatitis associated with SIT were also reported to the FDA in 2006–2009 (U.S. FDA, 2009). Published case reports and epidemiology studies have also suggested that treatment of type-2 diabetes with EXE and/or SIT was associated with acute pancreatitis (Anderson and Trujillo, 2010, Ayoub et al., 2010, Denker and Dimarco, 2006, Elashoff et al., 2011, Garg et al., 2010a, Garg et al., 2010b, Iyer et al., 2012, Singh et al., 2013, Tripathy et al., 2008). Recently a pathological, immunohistochemical, and morphometric study using human pancreatic sections demonstrated that treatment of type-2 diabetes with EXE or SIT markedly increases the gross pancreatic size with cellular proliferation and dysplasia (Butler et al., 2013). However, a body of preclinical and clinical data also exists that indicates no association of GLP-1 drugs with pancreatic injury (Dore et al., 2011, Garg et al., 2010a, Romley et al., 2012, Vrang et al., 2012).
High fat and high carbohydrate diets, not uncommon in many human populations, could be one contributor to increased susceptibility. Elevated blood triglyceride is usually recognized as a risk factor for clinical acute pancreatitis (Tsuang et al., 2009), as are hyperlipidemia (Cameron et al., 1972, Yadav and Pitchumoni, 2003) and obesity. A high fat diet can produce a degree of insulin resistance in animal models and can lead to fatty infiltration in the pancreas. With anti-diabetic drug treatment, C57BL/6 mice (Fernandes-Santos et al., 2009) and amylin-expressing transgenic rats (Matveyenko et al., 2009) both demonstrated fatty infiltration in the pancreas that was associated with morphological changes of pancreatitis. More recently it has been demonstrated that high fat diet (HFD) in mice models can lead to obesity, metabolic disturbances, and pancreatic inflammation (Dawson et al., 2013), and can also activate oncogenic Kras via Cox2, leading to pancreatic inflammation and fibrosis, and development of pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma (Philip et al., 2013).
The objectives of the present study in a mouse model were 1) to determine whether or not EXE and SIT induce acute pancreatitis; 2) to determine whether or not HFD affects the exocrine pancreas; 3) to detect HFD and GLP-1 influences on the pro-inflammatory cytokine profile; 4) to characterize pathological changes of exocrine pancreatic injury and to explore possible pathogenesis.
Section snippets
Animals
Male C57BL/6 mice 6 to 8 weeks of age were purchased from Harlan Laboratories (Fredrick, MD). Mice were housed individually in an environmentally controlled room (18 °C–21 °C, 40%–70% relative humidity) with a twelve-hour light/dark cycle. Mice were initially fed Certified Purina Rodent Chow #5002 (Ralston Purina Co., St. Louis, MO) providing 63% of calories through carbohydrates, 24% from protein, and 13% from fat. Per the experimental design, some mice were subsequently placed on a Teklad Custom
Results
At termination, body weight and blood glucose levels were significantly greater in mice on HFD compared to mice on STD regardless of drug treatment (Fig. 2). Mice on HFD also exhibited higher levels of specific pro-inflammatory cytokines (TNFα, IL-1β, and KC). Serum levels of IL-1β were also significantly influenced by SIT treatment in HFD mice (Fig. 2). However, the serum levels of IL-10, IL-12p70 and IFNγ were not significantly elevated by diet or drug treatment (data not shown).
Discussion
Acute pancreatitis is an inflammatory process of the exocrine pancreas secondary to pancreatic tissue injury and necrosis (Gukovskaya and Gukovsky, 2012, Kloppel and Maillet, 1998). Pancreatic inflammation and cell death are critical to the evolution of acute pancreatitis from pancreatic injury (Gukovsky et al., 1998). Several studies in animal models have shown that experimental acute pancreatitis begins within acinar cells and is initiated by intracellular zymogen activation attributed to
Conclusion
This study implicates the GLP-1 drugs, exenatide and sitagliptin, in pancreatic injury in a mouse model. Study of cytokine and histopathology data support independent exacerbation of pancreatic injury by GLP-1 drugs and by a high fat diet that could be either additive or synergistic when both variables are present. The present study implies that high fat diet, as a risk factor, can enhance the susceptibility to and/or the severity of inadvertent pharmacologic initiation of acute pancreatitis by
Conflict of interest statement
The authors have no conflicts of interest or financial disclosures.
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The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy.