Chronic hyperglycemia causes a near-total disappearance of glucose-induced insulin secretion. To determine if glucose potentiation of nonglucose secretagogues is impaired, insulin responses to 10 Ϫ 9 M glucagonlike peptide-1 (GLP-1) (7-37) were measured at 2.8, 8.3, and 16.7 mM glucose with the in vitro perfused pancreas in rats 4-6 wk after 90% pancreatectomy (Px) and sham-operated controls. In the controls, insulin output to GLP-1 was Ͼ 100-fold greater at 16.7 mM glucose versus 2.8 mM glucose. In contrast, the increase was less than threefold in Px, reaching an insulin response at 16.7 mM glucose that was 10 Ϯ 2% of the controls, well below the predicted 35-40% fractional ␤ -cell mass in these rats. Px and control rats then underwent a 40-h fast followed by pancreas perfusion using a protocol of 20 min at 16.7 mM glucose followed by 15 min at 16.7 mM glucose/ 10 Ϫ 9 M GLP-1. In control rats, fasting suppressed insulin release to high glucose (by 90%) and to GLP-1 (by 60%) without changing the pancreatic insulin content. In contrast, in Px the insulin response to GLP-1 tripled in association with a threefold increase of the insulin content, both now being twice normal when stratified for the fractional ␤ -cell mass. The mechanism of the increased pancreas insulin content was investigated by assessing islet glucose metabolism and proinsulin biosynthesis. In controls with fasting, both fell 30-50%. In Px, the degree of suppression with fasting was similar, but the attained levels both exceeded those of the controls because of higher baseline (nonfasted) values.In summary, chronic hyperglycemia is associated with a fasting-induced paradoxical increase in glucose-potentiated insulin secretion. In Px rats, the mechanism is an increase in the ␤ -cell insulin stores, which suggests a causative role for a lowered ␤ -cell insulin content in the im-

The chemokine monocyte chemoattractant protein-1 is a potent chemoattractant for monocytes. Monocyte chemoattractant protein-1 is produced by vascular endothelial cells during inflammatory diseases such as atherosclerosis. In this study, we examined the effects of a thiazolidinedione on monocyte chemoattractant protein-1 expression in human vascular endothelial cells. In human vascular endothelial cells, interleukin-1L L and tumor necrosis factor-K K induced endogenous monocyte chemoattractant protein-1 protein secretion, mRNA expression and promoter activity. The thiazolidinedione inhibited these effects. In summary, our results indicated that the suppression of the expression of monocyte chemoattractant protein-1 can be accomplished by thiazolidinedione treatment, raising the possibility that thiazolidinedione may be of therapeutic value in the treatment of diseases such as atherosclerosis.z 1999 Federation of European Biochemical Societies.

The cause of compensatory hyperinsulinemia in normoglycemic insulin-resistant states is unknown. Using spontaneously hypertensive rats (SHR), we tested the hypothesis that a lowered a8-cell set-point for glucose causes a hypersecretion of insulin at a normal glucose level. Islets isolated from normoglycemic hyperinsulinemic SHR were compared to age-matched (12 wk old) Wistar-Kyoto (WK) rats. The ED5. for glucose-induced insulin secretion was 6.6±1.0 mM glucose in SHR versus 9.6±0.5 mM glucose in WK (P < 0.02). Glucokinase enzymatic activity was increased 40%in SHR islets (P < 0.02) without any change in the glucokinase protein level by Western blot. The level of the p-cell glucose transporter (GLUT-2) was increased 75% in SHR islets (P < 0.036).In summary, the P-cell sensitivity for glucose was increased in these normoglycemic insulin resistant rats by an enhanced catalytic activity of glucokinase. We have identified a regulatory system for glucokinase in the p-cell which entails variable catalytic activity of the enzyme, is modulated in response to variations in whole-body insulin sensitivity, and is not dependent on sustained changes in the plasma glucose level. (J. Clin. Invest. 1994.94:399-404.)

Successful treatment for women with IL-8 elevations in cervical mucus decreased rates of premature birth or pPROM.

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