Alterations in the secretory response of non-obese diabetic (NOD) mice to muscarinic receptor stimulation.

Salivary gland secretion in non-obese diabetic (NOD) and BALB/c mice was evaluated following stimulation with the muscarinic receptor agonist pilocarpine. Both saliva flow rates and total protein were similar in BALB/c and prediabetic NOD mice. With diabetes onset in NOD mice, the saliva flow rate and protein concentration were dramatically reduced. The level of cyclic AMP (cAMP) generated 10 min following agonist injection was similar for the parotid gland of BALB/c and prediabetic and diabetic NOD mice but was reduced in diabetic NOD mice. In the submandibular gland both prediabetic and diabetic NOD mice showed a reduced potential for the generation of cAMP compared with BALB/c mice. The parotid gland from NOD mice had elevated levels of basal and muscarinic receptor agonist (carbachol)-stimulated concentrations of inositol phosphate intermediates in in vitro assays compared with BALB/c animals, while in the submandibular gland of NOD mice, basal and agonist-stimulated concentrations of inositol phosphate intermediates were reduced relative to BALB/c. An evaluation of muscarinic receptor density showed a reduction with diabetes onset for the parotid gland, while a similar level was observed in prediabetic NOD and BALB/c mice. The receptor density was decreased for both the prediabetic and diabetic NOD submandibular glands compared with BALB/c animals. Sera from diabetic NOD but not BALB/c mice immunoprecipitated radiolabeled muscarinic receptor, indicating the presence of autoantibody to the receptor in diabetic mice. Thus, the reduction of muscarinic agonist response in NOD mice may be due, in part, to a generalized reduction in signal transduction components most evident in the prediabetic and diabetic submandibular gland and to a less certain degree in the parotid gland from diabetic NOD mice as a consequence of autoantibodies directed against cell surface antigens.