Lisofylline, a novel anti-inflammatory agent, enhances glucose-stimulated insulin secretion in vivo and in vitro: studies in prediabetic and normal rats.
Previous studies from this laboratory have shown that the novel anti-inflammatory agent, lisofylline (LSF), improves oral glucose tolerance in streptozotocin (STZ) diabetic rats. Subsequent studies suggested that the improved glucose tolerance could be the result of enhanced beta-cell functioning. The possibility that LSF enhancement of insulin release in these animals is the result of direct effects of this agent on a residual population of functionally normal beta cells was further evaluated in these studies. In vivo studies: 6- to 8-week-old male rats were administered STZ (35 mg/kg body weight) intravenously. After 10 days, LSF administration (25 mg/kg body weight, twice daily) was initiated in the treated group (n = 11) for comparison with the vehicle-injected controls (n = 10). Body weight, food intake, and serum glucose and insulin levels were monitored weekly. Glucose and insulin responses to an oral glucose bolus were measured at 4 to 5 weeks as an index of LSF effects on impaired glucose tolerance. Glucose areas under curve (AUC) during the 2-hour tolerance tests in the LSF-treated rats (n = 11) were 23,390 +/- 253 versus 29,390 +/- 1,006 mg/dL x min (P <.0001) in the vehicle-injected rats (n = 10). Improved glucose tolerance was associated with increases in blood insulin levels in the LSF-treated rats, AUC (+LSF) = 6,564 +/- 66 versus 5,127 +/- 633 microU/mL x min in the vehicle-injected STZ-rats (not significant [NS]). These observations suggested that the improved glucose tolerance is the result of direct effects of LSF on glucose-induced release of insulin.


METHODS
the validity of this hypothesis was subsequently tested using isolated perfused pancreas preparations from normal rats. In this series of experiments, 12-week-old animals were used, and pancreases were perfused in situ using single-pass technique. Three levels of LSF were directly infused into individual pancreas preparations and included 20 (n = 5), 40 (n = 4), and 60 (n = 4) micromol/L. First (minutes 3 to 10) and second (minutes 13 to 35) phase glucose-stimulated (300 mg/dL) insulin response areas (AUC) for the 2 phases measured in the LSF-infused pancreases were compared with AUC in vehicle-infused pancreases (n = 4). At LSF concentrations of 20 and 40 micromol/L, total insulin released during the first phase of glucose stimulation was more than twice that of the controls (3,919 +/- 739 and 3,643 +/- 630 microU, respectively v 1,481 +/- 269 microU, P <.03). A total of 60 micromol/L LSF did not significantly enhance first phase glucose-induced insulin secretion. Second phase comparisons of total insulin released in the LSF-infused versus the controls showed differences of comparable magnitude (about 2-fold) with statistical significance (P <.03) observed at all 3 levels of LSF. These findings demonstrate that LSF enhances glucose-stimulated insulin release in vitro. Enhanced beta-cell functioning by LSF likely represents an important factor underlying improved glucose tolerance in vivo. In addition, the in vitro observations in normal rat pancreas indicate that the LSF effect is not limited to beta-cell dysfunction per se. These results support the conclusion that agents, such as LSF, may have therapeutic benefits in type 2 diabetes.
Striffler
John S
JS
Division of Endocrinology, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Nadler
Jerry L
JL
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood; D004435:Eating / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood* / Q000378:metabolism; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D010431:Pentoxifylline / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011236:Prediabetic State / Q000097:blood*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015430:Weight Gain / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001786:Blood Glucose; D007328:Insulin; D005947:Glucose; C025189:lisofylline; D010431:Pentoxifylline