These studies of partial pancreatectomy assess pancreatic proinsulin messenger RNA (mRNA) levels as an index of in vivo insulin biosynthesis, and show relationships to glucose homeostasis. Rats were subjected to sham operation, 50% pancreatectomy (Px), or 90% Px, and were examined after 1, 3, or 14 wk. Proinsulin mRNA was measured by dot hybridization to complementary DNA. After 50% Px there was a nearly complete adaptation of proinsulin mRNA. After 90% Px a marked increase of proinsulin mRNA occurred, but it was insufficient and it was not maintained with time. The deficit in insulin production is related to development of hyperglycemia.Sham-operated controls showed no worsening of fasting or fed blood glucose or of intraperitoneal glucose tolerance within the period of observation. Total proinsulin mRNA and pancreatic insulin content rose in proportion to body weight. 50% PN produced no change from controls in body weight or blood glucose. The concentration of proinsulin mRNA in the 50% pancreatic remnant paralleled that of controls after 1 and 3 wk, but then increased after 14 wk, such that total proinsulin mRNA approached control levels. This adaptive response was reflected by changes in serum insulin, but not by pancreatic insulin content, which was only 30% of control after 14 wk. Intraperitoneal glucose tolerance was impaired mildly, and did not worsen with time after pancreatectomy.90% Px led to elevated fed blood glucose and reduced serum insulin after 3 wk, and fasting hyperglycemia was seen after 14 wk. Proinsulin mRNA concentration in the 10% pancreatic remnant showed an adaptive increase after 1 and 3 wk, such that total proinsulin mRNA reached 40% of control. After 14 wk, however, remnant proinsulin mRNA concentration was no longer increased; total proinsulin mRNA and pancreatic insulin content were severely reduced. Intraperitoneal glucose tolerance was impaired more dramatically than with the 50% Px animals, and worsened with time after operation.These observations indicate ability to increase proinsulin mRNA levels as an adaptation to pancreatectomy. Insufficiency of this adaptation is associated with the development of hyperglycemia, and the loss of this adaptation correlates with a worsening of glucose tolerance.
These studies of a rat model for non-insulin-dependent diabetes mellitus (NIDDM) were performed to determine whether hyperglycemia occurs when capacity to synthesize insulin is exceeded. The neonatal streptozocin (STZ)-treated rat has acute hyperglycemia with marked destruction of pancreatic beta-cells, followed by gradual regeneration to 50-70% normal beta-cell number. At age 4 wk, fed serum glucose concentration is only mildly elevated relative to controls. With age, the rats become progressively hyperglycemic, and by 12 wk they have marked impairment of glucose-stimulated insulin release. In these studies, dexamethasone (0.125 mg/kg/day for 4 days) was administered to control and to STZ-treated animals to produce insulin resistance. The relationship between insulin biosynthesis and serum glucose concentrations was assessed. In control rats, response to dexamethasone was similar at both 4 and 12 wk. Serum glucose levels and pancreatic insulin concentration remained unchanged. Both insulin biosynthetic rates (as measured by 3H-leucine incorporation into proinsulin) and proinsulin mRNA levels increased twofold. STZ-treated rats at age 4 wk demonstrated mild hyperglycemia. Dexamethasone injection resulted in an increase in insulin biosynthesis and proinsulin mRNA in these animals, while serum glucose did not increase. STZ-treated rats at 12 wk showed more profound hyperglycemia (serum glucose 315 +/- 38 mg/dl versus control, 187 +/- 12 mg/dl). A marked rise in serum glucose (to 519 +/- 42 mg/dl) was observed after 4 days of dexamethasone injection. Pancreatic insulin content became severely depleted relative to saline-injected, STZ-treated animals, and there was no response of levels of proinsulin mRNA.
C57BL/KsJ db/db mice develop hyperphagic obesity and nonketotic diabetes similar to non-insulin-dependent diabetes mellitus in humans. Initially the mice demonstrate an abundant beta-cell mass and hyperinsulinemia, which is followed by apparent beta-cell loss. As an index of insulin synthesis, this study assesses pancreatic proinsulin mRNA, measured by dot hybridization to cloned cDNA, during the development of diabetes in the mice. Changes in proinsulin mRNA from 5 to 13 wk of age are compared with serum insulin, pancreatic insulin content, and blood glucose. In control (+/db) mice, total proinsulin mRNA and pancreatic insulin content increased with age. Both changes were proportional to an increase in body weight. Obesity, hyperglycemia, and hyperinsulinemia were evident in diabetic (db/db) mice at 5 wk of age. Although pancreatic insulin content was comparable to that in the +/db controls at 5 wk, a fourfold relative elevation of proinsulin mRNA was observed. Despite an increase in body weight, proinsulin mRNA concentration and total proinsulin mRNA fell to levels similar to those of the control mice at 10 and 13 wk, associated with a loss of hyperinsulinemia, a mild decrease in pancreatic insulin content, and a marked increased in fasting blood glucose. A separate group of db/db mice was pair fed with the +/db controls from 4 to 13 wk. These diet-restricted diabetic mice were heavier than control mice and gained weight with age, but they weighed less than the unrestricted mice at all ages. Compared with the unrestricted db/db mice, a more modest fasting hyperglycemia was apparent, and a persistent hyperinsulinemia was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
The insulin resistance produced by the recessive db mutation has led to more severe diabetes in C57BL/KsJ mice relative to that in C57BL/6J mice, suggesting genetic differences between the two strains affecting insulin production or insulin action. To assess these parameters blood glucose, serum insulin, pancreatic insulin, and proinsulin mRNA were measured in both normal and diabetic (db/db) KsJ and 6J strains. The mice were compared at 5 weeks of age, prior to the development of insulin lack known to occur with age in KsJ db/db mice. As a further provocation to insulin production, another group of the normal and db/db mice were given dexamethasone for 4 days. In normal mice there were no strain differences in blood glucose, serum insulin, pancreatic insulin, or proinsulin mRNA. Dexamethasone, presumably by augmenting insulin resistance, induced increases in serum insulin and proinsulin mRNA to the same extent in KsJ and 6J mice. In db/db mice, while blood glucose, serum insulin, and proinsulin mRNA were considerably higher than in normal mice, there were no strain differences observed. After dexamethasone the db/db mice exhibited strain differences which included higher blood glucose and higher serum insulin levels in KsJ mice. These findings were compatible with greater insulin resistance in KsJ than in 6J db/db mice. While dexamethasone treatment increased serum insulin in KsJ db/db mice, there was no augmentation of proinsulin mRNA in either strain, suggesting a limit to the insulin synthesis. Analysis of serum insulin/glucose and proinsulin mRNA/glucose ratios demonstrated a dexamethasone-induced increase in serum insulin/glucose in normal and diabetic mice of both strains.(ABSTRACT TRUNCATED AT 250 WORDS)
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