Blockade of muscarinic transmission increases the frequency of diabetes after low-dose alloxan challenge in the mouse

Diabetologia. 1996 Apr;39(4):383-90. doi: 10.1007/BF00400669.

Abstract

The diabetogenic action of the beta-cell toxin, alloxan, is transient when administered to mice at a dosage of 50 mg/kg. We examined whether increased cholinergic activity is involved in the compensatory mechanisms. Therefore, following administration of alloxan, methylatropine (32 mumol/kg) was given intraperitoneally once daily for 5 consecutive days. Methyl atropine worsened the degree of hyperglycaemia during the first week after alloxan administration. Recovery from the diabetes mellitus was observed in a substantial number of animals given alloxan without methyl atropine, whereas the risk of developing manifest diabetes was markedly enhanced by methyl atropine. At 35 days after alloxan administration, 33% of the animals, which were given alloxan alone and were diabetic after 4 days, still had diabetes. In contrast, of the animals rendered diabetic by alloxan with concomitant atropinization, 92% remained diabetic throughout the study (p = 0.0145 vs alloxan alone). Glucose-stimulated insulin secretion and pancreatic insulin content were markedly reduced in animals with diabetes while being less reduced in alloxan-injected animals without diabetes. Moreover, in situ hybridization and immunocytochemistry revealed markedly decreased levels of insulin mRNA and number of insulin cells in alloxan-treated animals. With regard to insulin secretion, pancreatic insulin content, insulin mRNA and insulin cell number, the reduction was the same irrespective of whether methyl atropine had been given. Thus, 5 days of atropinization increases the incidence of diabetes following alloxan at 50 mg/kg in mice. We suggest that cholinergic activity protects insulin cells from glucotoxicity during the first week after alloxan administration and therefore, reduces the frequency of diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alloxan*
  • Animals
  • Atropine Derivatives / pharmacology*
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / epidemiology
  • Diabetes Mellitus, Experimental / physiopathology*
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Female
  • Incidence
  • Insulin / biosynthesis*
  • Insulin / blood
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans / pathology
  • Mice
  • Mice, Inbred Strains
  • Parasympatholytics / pharmacology*
  • RNA, Messenger / analysis
  • RNA, Messenger / biosynthesis

Substances

  • Atropine Derivatives
  • Blood Glucose
  • Insulin
  • Parasympatholytics
  • RNA, Messenger
  • Alloxan
  • methylatropine