Intrinsic defects of islet beta-cells may be
important in the pathophysiology of both non-immune and immune-mediated
diabetes. We studied NOD and C57BL/10 inbred mice strains that share the
autoimmune diabetes-resistant H2k major histocompatibility complex (NODk and
B10k strains, respectively). Neither strain develops diabetes on chow diet. Male
NODk mice stressed with either beta-cell transgenic (Tg) expression of hen egg
lysozyme (HEL) protein or high fat (HF) diet develop non-immune diabetes,
whereas male B10k do not (90 days old, fed blood glucose- NODk 5.1 ± 0.2 vs 23.5
± 4.1 mmol/l, p<0.001, and B10k 7.1 ± 0.5 vs 8.6 ± 1.2 mmol/l, NonTg vs Tg,
respectively; NODk 7.3 ± 0.3 vs 16.2 ± 2.9 mmol/l, p<0.001, and B10k 7.8 ±
0.5 vs 8.2 ±0.4 mmol/l, chow vs HF, respectively). The ratio of proinsulin/c-peptide
at 90 days of age was dramatically and similarly increased in HEL Tg mice irrespective
of whether the mouse background was NODk or B10k (NODk 0.08 ± 0.01 vs 1.83 ±
0.33, B10k 0.07 ± 0.01 vs 3.97 ± 0.82, nonTg vs Tg, respectively, p<0.001
for both); whereas HF diet had no effect to increase the proinsulin/insulin
ratio (NODk 0.052 ± 0.011 vs 0.019 ± 0.003, B10k 0.067 ± 0.012 vs 0.045 ± 0.008,
chow vs HF, respectively). NODk HEL Tg mice had increased islet mRNA expression
of five endoplasmic reticulum (ER) stress markers (p58, BIP, CHOP, GPR94 and
FKBP11) compared to one (p58) in B10k HEL Tg mice. The results show an enormous
capacity for islet beta-cell compensation for severe defects in insulin
processing without induction of ER stress and preservation of glycemia in B10k
HEL Tg mice. The same insult does cause ER stress and diabetes in NODk mice. Diabetes
development in HF fed NODk mice, however, is not associated with an abnormality
of insulin processing.