Effects of cholinergic m-receptor agonists on insulin release in islets from obese and lean mice of different ages: the importance of bicarbonate.
OBJECTIVE
Decreased beta-cell function is often observed in older individuals and may predispose to the development of type 2 diabetes. We have studied the age-related effects of M-receptor agonism on insulin release in islets isolated from female ob/ ob and lean mice.


METHODS
Islets were challenged with 11.1 or 16.7 mmol/L glucose in media with HCO3/CO2 (KRBH) or without (KRH).


RESULTS
Acetylcholine (ACh) (10 micromol/L) increased glucose-induced insulin release in islets from 4- to 5-week-old ob/ob mice both in KRBH and KRH. In islets from 9- to 13-month-old ob/ob mice, 10 micromol/L ACh and 10 micromol/L carbachol enhanced insulin release in KRBH but not in KRH. ACh increased insulin release in islets from 4- to 5-week-old and 16-month-old lean mice incubated in KRH but not in islets from 24-month-old lean mice. The Na/H exchange inhibitor dimethylamiloride (100 micromol/L) did not affect insulin release stimulated by M-receptor agonists. Carbachol did not enhance glucose-induced insulin secretion in islets from 9- to 10-month-old ob/ob mice in the presence of low extracellular Na concentration. ACh stimulated cytoplasmic Ca mobilization in islets from 9- to 10-month-old mice also when bicarbonate was omitted. The results suggest that cholinergic signal transduction involving extracellular bicarbonate and Na is reduced with age in mouse pancreatic islets.


CONCLUSIONS
Chronic hyperglycemia may add to the age-related decrease in M-receptor-mediated insulin release by affecting the buffering capacity of the islets through mechanisms other than amiloride-sensitive proton exchange.
Persson-Sjögren
Solveig
S
Department of Integrative Medical Biology, Section for Histology and Cell Biology, Umeå University, Umeå, Sweden. Solveig.Persson-Sjogren@histocel.umu.se
Lindström
Per
P
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000367:Age Factors; D000584:Amiloride / Q000494:pharmacology; D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008820:Mice, Obese; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009765:Obesity / Q000378:metabolism*; D010084:Oxidation-Reduction; D012964:Sodium / Q000378:metabolism; D013851:Thinness / Q000378:metabolism*
D001639:Bicarbonates; D002712:Chlorides; D007328:Insulin; D018721:Muscarinic Agonists; D000643:Ammonium Chloride; D000584:Amiloride; D002217:Carbachol; D012964:Sodium; D005947:Glucose; D000109:Acetylcholine; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D002118:Calcium