We have recently shown that in addition to β-endorphin the opioid peptides Met- and Leu-enkephalin and their apparent precursors are localized in islet endocrine cells of the rat pancreas. To begin evaluating a possible role for these pancreatic opiates in the pathophysiology of genetic diabetes in rodents, immunoreactive β-endorphin and Met- and Leu-enkephalins were measuredin acetic acid extracts of pancreas and pituitary of C57BL/KsJ db/db mice and their lean littermates. Groups of animals were studied during three phases of development of the diabetic syndrome in the mutant mice: at 4 (hyperinsulinemic and prediabetic); 6, 9, and 12 (frankly obese and diabetic); and 30 (hypoinsulinemic) wk of age.

Elevations or decreases (P < .05) were found in db/db mice (vs. lean littermates) as follows: pituitary content of Met-enkephalin was twofold higher at all ages studied; pituitary free Leu-enkephalin was lower at 4 wk and reversed to higher at 6–30 wk; pancreatic β-endorphin was 30% lower at 4 wk and reversed to threefold higher at 6–12 wk; Met- and Leu-enkephalin-containing larger peptides were elevated at one or more points between 6 and 12 wk in both the pancreas and the pituitary. Thus, the onset of overt obesity between 4 and 6 wk of age was accompanied by a marked rise in both pancreatic β-endorphin and pituitary Leu-enkephalin; similar elevations in these parameters have been reported previously in C57BL/6J ob/ob mice at ∼12 wk of age.

Pancreatic Met-enkephalin content, although not significantly different from controls of any age group, was threefold higher in db/db mice at 30 wk as compared with that at 4 wk and increased with age in dbldb (r = .501, P < .01) but not in control (r = −.041) mice. This difference between correlations by genotype was statistically significant (F = 32.8, P < .001). Pancreatic Met-enkephalin was also negatively correlated with plasma insulin concentration (r = −.404, P < .01) in all animals studied. These correlations suggest a relationship between increasing pancreatic Met-enkephalin content and the declining ability of the dbldb pancreas to secrete insulin. Because the pancreatic content of Met-enkephalin-containing precursor peptides decreased with age in both dbldb and control mice, the rising free Met-enkephalin in the dbldb pancreas suggests an increasing rate of processing of precursor to free enkephalin between 4 and 30 wk of age.

We conclude that the content and processing of opioid peptides in the pancreas and pituitary are regulated abnormally in C57BL/KsJ db/db mice during development of the diabetic syndrome. The known ability of these peptide neurohormones to modulate the secretion of other pituitary and pancreatic hormones suggests the possibility that altered pancreatic free Met-enkephalin content or altered rates of enkephalinprecursor processing may be involved in the pathophysiology of the hyperinsulinemia that declines with age in these mice.

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