A chemical found in bear bile reduced the incidence of Type 1 Diabetes (T1D) in mice bred to develop that disease, a study reported.
There is increasing evidence that stress mechanisms play a role in the demise of beta cells in T1D. Stress to the endoplasmic reticulum (ER) and its signaling networks have been particularly implicated in this process, wrote Gökhan S. Hotamisligil, MD, PhD, of the Harvard School of Public Health, and his co-authors.
In a series of experiments, the authors identified two defects in expression of unfolded protein response mediators in mice and humans with T1D, and they administered tauroursodeoxycholic acid (TUDCA) to the mice in the pre-diabetic stage. TUDCA is a "chemical chaperone" found in bear bile, an ingredient used in traditional Chinese medicine that has also been used to alleviate endoplasmic reticulum stress and symptoms in atherosclerosis and type 2 diabetes.
The result was "a marked reduction of diabetes incidence in the T1D mouse models," the authors wrote, November 13th in Science Translational Medicine.
In one experiment, TUDCA was administered to both non-obese diabetic (NOD) mice and RIP-LCMV-GP mice, a breed in which T1D is brought on by viral infection. Both NOD and RIP-LCMV-GP mice received 250 mg/kg of TUDCA twice daily in the phase before diabetes typically occurs in these breeds.
The treatment "resulted in a striking reduction in diabetes incidence in both the NOD (44 vs 11%) (P<0.05, Kaplan-Meier estimate) and RIP-LCMV-GP (100 versus 40%) (P<0.05, χ2 test) models," the researchers wrote. Further experiments revealed "a clear dose-dependent beneficial effect of this chaperone."
The reduction, they said, was accompanied by "a significant decrease in aggressive lymphocytic infiltration in the pancreas, improved survival and morphology of beta cells, reduced beta cell apoptosis, [and] preserved insulin secretion."
Histological analysis of pancreatic sections revealed less aggressive insulitis in TUDCA-treated mice compared with NOD mice treated with a control, the authors wrote.
Islets from mice receiving TUDCA also remained largely intact, they said, despite the presence of inflammatory cells in both the NOD and RIP-LCMV-GP models, indicating that "treatment with TUDCA could render the beta cells of diabetes-prone mice significantly more resistant to aggressive immune cell infiltration than those of untreated animals."
TUDCA appeared to restore expression of the two unfolded protein response (UPR) mediators -- ATF6 and XBP1 -- identified by the researchers. The UPR's role is to maintain homeostasis in the ER. The researchers identified defects in ATF6 and XBP1 in both strains of T1D mice and in the pancreatic tissue of T1D patients obtained from the Network for Pancreatic Organ Donors with Diabetes.
In their experiments, the researchers demonstrated increasing decline in ATF6 and XBP1 in the pancreatic islets of NOD mice as they neared the age of typical T1D onset.
Analysis of the human samples revealed that, as in animal models, "ATF6 and XBP1 branches of the UPR are downgraded in beta cells from subjects with diabetes, and thus that these pathways may be important for disease pathogenesis."
Evidence suggests that both acute and chronic stimulation of beta cells by such mechanisms as viral infection, environmental toxins, chronic inflammation and an excess of nutrients such as glucose, arginine or lipids, requires the ER to engage in continuous protein synthesis, folding, trafficking and secretion.
"When the folding capacity of the ER is exceeded, mis-folded or unfolded proteins accumulate in the ER lumen, triggering the unfolded protein response (UPR)," the authors said. But severe or prolonged ER stress can induce the UPR to "engage in apoptotic pathways," the authors said.
The results of these studies indicate that the UPR is modulated during diabetes progression in the beta cells of NOD mice and precedes the decline in beta cell number and function and the emergence of frank diabetes," the authors wrote. Additionally, TUDCA's effect was lost on mice with a deletion of ATF6.
There are currently no effective regimens to prevent T1D, though detection of circulating islet auto-antibodies can identify people at risk for developing it, the authors said. This capability, they said, emphasizes the need for safe and effective approaches to prevent or even delay the disease.
"Our data support the possibility that ER-modifying agents such as TUDCA might be used for this purpose in high-risk autoantibody-positive individuals and perhaps in recently diagnosed T1D patients," the authors wrote.
TUDCA has been approved for human use in liver disease, and has not been associated with any major side effects. Its administration in obese humans and rodent models of Type 2 diabetes suggests that it increases insulin sensitivity, the authors said, "suggesting that ER stress can be similarly ameliorated in both species."
The authors had no disclosures to make.
The study was supported by a grant from Juvenile Diabetes Research Foundation to Gökhan S. Hotamisligil. Diane Mathis was supported by a grant from NIH. Decio L. Eizirik was supported by grants from the European Union and the Fonds National de la Recherche Scientifique. Wenxian Fu was supported by Schuylar funds.
Science Translational MedicineSource Reference: Engin F, et al "Restoration of the unfolded protein response in pancreatic B cells protects mice against Type 1 Diabetes" Sci Transl Med 2013; 5(211):211ra156.