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Two experiments were carried out on ewes with ovarian autotransplants to estimate the ovarian uptake of glucose and production of lactate. The first was carried out in the luteal phase of the oestrous cycle. Samples of carotid arterial, ovarian venous and jugular venous blood were collected simultaneously for glucose analysis. The arterial concentration of glucose (58.0 +/- 5.0mg/dL; Mean+/-SEM) was significantly higher than the ovarian venous concentration (42.3+/-2.4 mg/dL; P<0.001). Next, a second more complete experiment was carried out in the luteal and follicular phases of the oestrous cycle. The oestrous cycle was synchronised and samples of carotid arterial, ovarian venous and jugular venous blood were collected simultaneously for glucose and lactate analysis. There were significant positive arterio-venous differences in the concentration of glucose in the luteal (5.6+/-1.2mg/dL, mean+/-SEM; P=0.001), early (3.1+/-0.82 mg/d; P=0.003) and late follicular (6.4+/-1.3mg/dL; P=0.001) phases of the oestrous cycle. There was a significant negative arterio-ovarian venous difference in the concentration of lactate in only the luteal phase (-2.2+/-0.96 mg/dL; P=0.043). The results show significant removal of glucose from the arterial circulation during its passage through the ovary in the luteal, early follicular and late follicular phases of the oestrous cycle. Furthermore, there was lactate production in the luteal phase but not in the follicular phase suggesting that in the luteal phase of the oestrous cycle, ovarian metabolism can be anaerobic., ((c) 2010. Published by Elsevier Inc.)

The abnormal insulin secretion found in human diabetics and animal models of diabetes has been attributed to the deleterious effects of chronic hyperglycemia and/or elevated circulating levels of nonesterified fatty acids (NEFAs). In this study, abnormal glucose-induced insulin secretion (GIIS) was generated by a 48-hour infusion of glucose and assessed by the isolated perfused pancreas technique. In these hyperglycemic animals, abnormal GIIS is accompanied by a decrease in plasma NEFAs, while plasma and, more importantly, islet triglycerides remain at levels comparable to those in the controls. It is concluded that the abnormal insulin secretion in this glucose infusion model was likely caused by 48 hours of hyperglycemia and not by changes in circulating or islet lipids.

Administration of the murine-selective beta3 adrenoceptor agonist CL-316,243 corrects obesity and elevated blood glucose in diabetic rodents. This antiobesity effect is attributed to an increase in the thermogenic activity of brown adipose tissue (BAT). The antidiabetic effect is unknown, but has been attributed to the decline in body weight and plasma free fatty acids (FFAs). This study using the euglycemic-hyperinsulinemic clamp method was performed in nonobese, nondiabetic Sprague-Dawley rats fed normal rodent chow to determine if the beta3 agonist could improve insulin sensitivity and/or responsiveness in the absence of weight loss or lowering of circulating FFAs. Subcutaneous miniosmotic pumps delivered either saline to control or 1 mg x kg(-1) x day(-1) of CL-316,243 for 10-12 days. Fed plasma glucose, insulin, and FFA levels were similar between the groups. Significant increases in food consumption, resting metabolic rates, and body core temperatures occurred, but only after 7 days of treatment. A 14% decrease in the respiratory quotient was also observed. Plasma glucose and insulin excursions in response to an oral glucose load (2 g/kg) on day 11 were unaltered. Cl-316,243 treatment resulted in a decrease in abdominal and epididymal white fat pad weights, while interscapular brown adipose tissue (IBAT) weight doubled. Basal and insulin-stimulated whole-body glucose disposal rates were increased, while hepatic glucose output was suppressed to a greater extent in the CL-316,243 animals after 10 days of uninterrupted treatment. Chronic treatment with CL-316,243 resulted in an increase in basal and insulin-stimulated [3H]2-deoxyglucose (2-DG) uptake by the retroperitoneal and epididymal white tissue and IBAT, but skeletal muscle 2-DG uptake under the same conditions was unaltered. These studies demonstrate that treatment with CL-316,243 improves basal and insulin-stimulated glucose disposal, and these effects occurred in the absence of a decrease in body weights and FFA concentrations. A particularly interesting observation was that the tissues responsible for this effect were white and brown adipose tissue, while skeletal muscle remained unaffected.

The long-term effects of continuous and pulsatile glucose stimulation of islets of Langerhans microdissected from Syrian hamsters were examined. In the presence of a continuous glucose stimulus insulin secretion peaked during the first 3 h of stimulation followed by a decrease. In the presence of 11.2 mM glucose a second smaller peak of insulin secretion was observed 14-16 h after the perifusion started. Irrespective of the glucose concentration, insulin secretion then steadily decreased and reached very low levels by the end of the 48-h perifusion. However, glucose stimulus provided in a pulsatile manner appeared to reduce this rate of decrease in insulin secretion. Thus, after 48 h, islets exposed to the pulsatile glucose stimulus showed greater insulin responsiveness to glucose than those exposed to a constant glucose stimulus.

To evaluate the long-held concept that acidic guanidines lack glycemic effects, guanidinoalkanoic acids and the biguanide metformin (positive control) were administered to KKAy mice, a model of noninsulin-dependent diabetes. Two acidic guanidines, 3-guanidinopropionic acid (3-GPA) and guanidinoacetic acid, decreased the plasma glucose level; other compounds were ineffective. 3-GPA was more potent than even metformin. Insulin suppression tests in KKAy mice indicated that improved insulin sensitivity was the mode of action for 3-GPA. Glycemic effects in KKAy mice resulted from increased glucose disposal whereas gluconeogenesis, hepatic glycogen content and intestinal glucose absorption were unchanged. 3-GPA's glycemic effect was corroborated in two other models of noninsulin-dependent diabetes. In ob/ob mice, the compound reduced hyperglycemia, polyuria, glycosuria and hyperinsulinemia. In insulin-resistant rhesus monkeys, it increased the disappearance of i.v. glucose. The glycemic action of 3-GPA required the presence of some circulating insulin as well as hyperglycemia because the compound was ineffective in normoglycemic mice, insulinopenic Chinese hamsters and streptozotocin-diabetic rats. These data indicate that acidic guanidine derivatives can ameliorate hyperglycemia in animal models of noninsulin-dependent diabetes. Because acidic derivatives uniquely lack the propensity of guanidine compounds for inducing lactic acidosis, our finding suggests a new approach for developing improved antidiabetes compounds from this chemical class.