Changes in islet capillary angioarchitecture coincide with impaired B-cellfunction but not with insulin resistance in male Otsuka-Long-Evans-Tokushima fatty rats: Dimorphism of the diabetic phenotype at an advanced age

The Otsuka-Long-Evans-Tokushima fatty (OLETF) rat is a genetic model of spo ntaneous development of non-insulin-dependent diabetes mellitus (NIDDM) est ablished as an inbred strain after 20 generations of selective breeding. Al though they are thought to be genetically homogeneous, they show a dimorphi sm regarding the diabetic phenotype at an advanced age, with one remaining obese and modestly diabetic while the other becomes lean and overtly diabet ic. To clarify the causes for this divergence, we examined the physical, bi ochemical, and histopathological features in rats at 50 weeks of age, inclu ding an analysis of islet angioarchitecture. Sixty-one of 85 male OLETF rat s lost weight, while the remainder remained obese. Mean nonfasting plasma g lucose in the lean group was 21.8 +/- 4.6 mmol/L, significantly higher vers us the obese group (10.5 +/- 1.4 mmol/L) and the age-matched control Long-E vans-Tokushima-Otsuka (LETO) group (7.1 +/- 0.6 mmol/L). Morphological stud ies of the pancreas from the lean group showed enlarged multilobulated fibr otic islets with a paucity of B cells, whereas islets from the obese group appeared slightly enlarged and showed a relative abundance of B cells. The fine capillaries that form a network in the islets were extremely sparse in the lean group, resulting in a defective glomerular-like configuration, wh ereas those from the obese group were dense, forming a nearly typical glome rular-like configuration. Increased plasma insulin responses to oral and in travenous (IV) glucose and IV glucagon loads were nearly absent in the lean group, while they were evident in the obese group, although to a lesser ex tent compared with the LETO group. Mean insulin secretory output from the p erfused pancreas in response to 11.1 mmol/L glucose in the lean group (3.5 +/- 2.2 pmol/20 min) was significantly lower versus the obese group (8.8 +/ - 6.5 pmol/20 min) and LETO group (22.0 +/- 10.8 pmol/20 min). Similarly, p ancreatic insulin content was significantly lower in the lean group (9.3 +/ - 6.1 mu g) versus the others (26.1 +/- 17.3 mu g for obese and 41.1 +/- 24 .8 mu g for LETO). In vivo insulin-stimulated glucose uptake measured by a euglycemic clamp technique was significantly higher in the lean group compa red with the obese group. These results demonstrate that the dimorphism reg arding the diabetic phenotype in male OLETF rats at 50 weeks of age was due to differences in the number of islet B cells, which could be the result o f a variation in the capacity for B-cell proliferation among male OLETF rat s. Copyright (C) 1999 by W.B. Saunders Company.