Novel leptin receptor mutation in NOD/LtJ mice suppresses type 1 diabetes progression: I. Pathophysiological analysis.
A spontaneous single-base mutation in the leptin receptor of type 1 diabetes-prone NOD/LtJ mice (designated as Lepr(db-5J)) produced a glycine640valine transversion in the extracellular domain. All mutant mice became obese and hyperinsulinemic at weaning, with 70-80% developing early-onset hyperglycemia. However, these obese diabetic mice continued to gain weight without insulin therapy. Spontaneous diabetes remission was observed in all obese females and a subset of obese males. Insulitis was largely limited to islet perimeters, with intraislet insulitis infrequently observed. In 17 obese males (age 39 weeks), we observed phenotypic heterogeneity, including full remission from hyperglycemia (24%), intermediate hyperglycemia with elevated body weight (41%), and severe hyperglycemia and weight loss (35%). The remitting normoglycemic and intermediate hyperglycemic phenotypes were associated with extensive beta-cell hyperplasia. Unlike the extensive intraislet insulitis present in diabetic lean NOD/Lt mice, the severe obese diabetic phenotype was associated with islet atrophy without extensive intraislet insulitis. These results indicated that the manipulation of the leptin/leptin receptor axis may provide a novel means of downregulating autoimmunity in type 1 diabetes and confirmed a role for leptin as a mediator in the development of this disease in NOD mice.
Lee
Chul-Ho
CH
The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609, USA. ehl@jax.org
Reifsnyder
Peter C
PC
Naggert
Jürgen K
JK
Wasserfall
Clive
C
Atkinson
Mark A
MA
Chen
Jing
J
Leiter
Edward H
EH
D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D007515:Islets of Langerhans / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D009765:Obesity; D010641:Phenotype; D017354:Point Mutation; D011956:Receptors, Cell Surface / Q000235:genetics*; D054411:Receptors, Leptin; D013997:Time Factors
D001786:Blood Glucose; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C515447:leptin receptor, mouse