title: Early insulin therapy prevents beta cell loss in a mouse model for permanent neonatal diabetes (Munich Ins2(C95S)).
abstract: OBJECTIVE
  Heterozygous male Munich Ins2(C95S) mutant mice, a model for permanent neonatal diabetes mellitus, demonstrate a progressive diabetic phenotype with severe loss of functional beta cell mass. The aim of this study was to investigate the influence of early insulin treatment on glucose homeostasis and beta cell destruction in male Munich Ins2(C95S) mutants.
  
  
  METHODS
  One group of male Ins2(C95S) mutants was treated with subcutaneous insulin pellets, as soon as blood glucose levels began to rise; placebo-treated mutants and wild-type mice served as controls. An additional group of mutant mice received a sodium-dependent glucose transporter 2 (SGLT2) inhibitor (AVE2268) via rodent chow.
  
  
  RESULTS
  Insulin treatment normalised blood glucose concentrations, improved oral glucose tolerance, preserved insulin sensitivity and inhibited oxidative stress of Munich Ins2(C95S) mutant mice. Pancreatic C-peptide content, as well as total beta cell and isolated beta cell volumes, of insulin-treated mutant mice were higher than those of placebo-treated mutants. In addition, alpha cell dysfunction and hyperplasia of non-beta cells were completely normalised in insulin-treated mutant mice. Treatment with the SGLT2 inhibitor lowered blood glucose, improved glucose tolerance and normalised insulin sensitivity as well as oxidative stress of Ins2(C95S) mutants. The abundance of the endoplasmic reticulum (ER) stress markers binding Ig protein (BiP) and phosphorylated eukaryotic translation initiation factor 2 alpha (P-eIF2α) was significantly increased in the islets of mutants, before onset of hyperglycaemia, vs wild-type mice.
  
  
  CONCLUSIONS
  We conclude that early insulin treatment protects Munich Ins2(C95S) mutant mice from insulin resistance, alpha cell hyperfunction, beta cell loss and hyperplasia of non-beta cells, some well-known features of human diabetes mellitus. Therefore, insulin treatment may be considered early for human patients harbouring INS mutations.
authors.affiliation: Institute of Veterinary Pathology, Ludwig-Maximilians-Universität München, Veterinärstr. 13, 80539 Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kautz
authors.forename: L
authors.initials: L
authors.lastname: van Bürck
authors.forename: M
authors.initials: M
authors.lastname: Schuster
authors.forename: E
authors.initials: E
authors.lastname: Wolf
authors.forename: R
authors.initials: R
authors.lastname: Wanke
authors.forename: N
authors.initials: N
authors.lastname: Herbach
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002096:C-Peptide / Q000737:chemistry; D003920:Diabetes Mellitus / Q000378:metabolism*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism / Q000627:therapeutic use*; D050417:Insulin-Secreting Cells / Q000166:cytology*; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D010179:Pancreas / Q000378:metabolism; D010641:Phenotype; D010919:Placebos; D051297:Sodium-Glucose Transporter 2 / Q000235:genetics
chemical_list: D002096:C-Peptide; D007328:Insulin; D010919:Placebos; C490299:Slc5a2 protein, mouse; D051297:Sodium-Glucose Transporter 2; D005947:Glucose
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