Increase In Islet Blood Flow Research Articles

CART decreases islet blood flow, but has no effect on total pancreatic blood flow and glucose tolerance in anesthetized rats

Cocaine- and amphetamine-regulated transcript (CART) is a neurotransmitter and hormone, involved in the regulation of e.g. food intake, body weight, reward and addiction, and stress response. CART has also been found to affect insulin secretion and beta cell morphology, both in vivo and in vitro. Furthermore, CART affects regulation of the cardiovascular system and helps to modulate vascular tone. The present study evaluated the local effect of CART on the pancreatic and islet circulation and function. CART (25 μg/h) or saline, combinations of CART and endothelin-A receptor antagonist (BQ123; 100 μg/kg), and glucose (2 g/kg) were intravenously infused in Sprague Dawley rats followed by blood flow measurements using a microsphere technique. Separately, CART-infused animals underwent an intravenous glucose tolerance test (ivGTT). The direct effect of CART on insulin release was investigated using isolated islets from Sprague Dawley rats. CART reduced islet blood flow, without reduction in total pancreatic blood flow. The normal glucose-induced islet blood flow increase was diminished by CART, albeit still present. Simultaneously, CART had no effect on systemic-, intestinal- or renal blood flow. The endothelin-A receptor antagonist BQ123 together with CART had no pancreatic vascular effects. We found that CART has pronounced vascular constrictive actions restricted to the pancreatic islet circulation but had no effect on insulin release neither in vivo nor in vitro. The mechanisms behind the vascular effects are still unknown, but may reflect a direct action on pancreatic blood vessels.

Ghrelin in rat pancreatic islets decreases islet blood flow.

The peptide ghrelin is mainly produced in some of the epithelial cells in the stomach, but also, during starvation, by the ε-cells in the endocrine pancreas. Ghrelin, as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R1α), exerts a variety of metabolic functions including stimulation of appetite and weight gain. Its complete role is not yet fully understood, including whether it has any vascular functions. The present study evaluated if ghrelin affects pancreatic and islet blood flow. Ghrelin and the GHS-R1α receptor antagonist GHRP-6 were injected intravenously in rats followed by blood flow measurements using a microsphere technique. Ghrelin decreased, while GHRP-6 in fasted, but not fed, rats selectively increased islet blood flow fourfold. GHS-R1α was identified not only on glucagon-producing cells but also seemed to be present in the islet arterioles. GHRP-6 in fasted rats, only, also improved the peak insulin response to glucose in vivo, thereby substantially blunting the hyperglycemia. GHRP-6 doubled glucose-stimulated insulin release in vitro of both islets obtained from fed and fasted rats. Our results indicate a novel role for endogenous ghrelin acting directly or indirectly as a local vasoconstrictor in the islets during fasting, thereby restricting the insulin response to hyperglycemia. This is to the best of our knowledge the first report that shows this physiological mechanism to restrict insulin delivery from the islets by acting on the vasculature; a mode of action that can be envisaged to complement the previously well-described mechanisms of ghrelin acting directly on the islet endocrine cells.

Blood lipids affect rat islet blood flow regulation through β₃-adrenoceptors.

Pancreatic islet blood perfusion varies according to the needs for insulin secretion. We examined the effects of blood lipids on pancreatic islet blood flow in anesthetized rats. Acute administration of Intralipid to anesthetized rats increased both triglycerides and free fatty acids, associated with a simultaneous increase in total pancreatic and islet blood flow. A preceding abdominal vagotomy markedly potentiated this and led acutely to a 10-fold increase in islet blood flow associated with a similar increase in serum insulin concentrations. The islet blood flow and serum insulin response could be largely prevented by pretreatment with propranolol and the selective β₃-adrenergic inhibitor SR-59230A. The nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester prevented the blood flow increase but was less effective in reducing serum insulin. Increased islet blood flow after Intralipid administration was also seen in islet and whole pancreas transplanted rats, i.e., models with different degrees of chronic islet denervation, but the effect was not as pronounced. In isolated vascularly perfused single islets Intralipid dilated islet arterioles, but this was not affected by SR-59230A. Both the sympathetic and parasympathetic nervous system are important for the coordination of islet blood flow and insulin release during hyperlipidemia, with a previously unknown role for β₃-adrenoceptors.

Pancreatic Islet Vasculature Adapts to Insulin Resistance Through Dilation and Not Angiogenesis

Pancreatic islets adapt to insulin resistance through a complex set of changes, including β-cell hyperplasia and hypertrophy. To determine if islet vascularization changes in response to insulin resistance, we investigated three independent models of insulin resistance: ob/ob, GLUT4+/−, and mice with high-fat diet–induced obesity. Intravital blood vessel labeling and immunocytochemistry revealed a vascular plasticity in which islet vessel area was significantly increased, but intraislet vessel density was decreased as the result of insulin resistance. These vascular changes were independent of islet size and were only observed within the β-cell core but not in the islet periphery. Intraislet endothelial cell fenestration, proliferation, and islet angiogenic factor/receptor expression were unchanged in insulin-resistant compared with control mice, indicating that islet capillary expansion is mediated by dilation of preexisting vessels and not by angiogenesis. We propose that the islet capillary dilation is modulated by endothelial nitric oxide synthase via complementary signals derived from β-cells, parasympathetic nerves, and increased islet blood flow. These compensatory changes in islet vascularization may influence whether β-cells can adequately respond to insulin resistance and prevent the development of diabetes.

Short-term glucosamine infusion increases islet blood flow in anesthetized rats

Impaired glucose tolerance and type 2 diabetes in rodents are associated with increased islet blood flow. If this is important for modulation of the endocrine function is at present unknown. We evaluated if glucosamine infusion, which induces peripheral insulin resistance and glucose intolerance, could be used to acutely increase islet blood flow. We infused anaesthetized Sprague-Dawley rats for 2 h with glucosamine (6 mg/kg body weight), in some cases followed by glucose administration. The former induced a 2-fold increase in serum insulin concentrations while plasma glucose remained unchanged. In vitro an augmented insulin response to hyperglycemia and decreased insulin content in batch type islet incubations with glucosamine for 24 h were seen. After 2 h glucosamine exposure in vitro, insulin release was decreased. In vivo glucosamine infusion increased islet blood flow, without affecting other regional blood flow values. Glucose increased islet blood flow to the same extent in control and glucosamine-infused rats. When exposed to 10 mmol/L glucosamine arterioles of isolated perfused islets showed a 10% dilation of their vascular smooth muscle. Thus, application of this model leads to acute hyperinsulinemia in vivo but a decreased insulin release in vitro, which suggests that effects not located to β cells are responsible for the effects seen in vivo. An increased islet blood flow in previously healthy animals was also seen after glucose administration, which can be used to further dissect the importance of blood flow changes in islet function.

The α2-Adrenoceptor Antagonist Yohimbine Normalizes Increased Islet Blood Flow in GK Rats: A Model of Type 2 Diabetes

Overexpression of α2A-adrenoceptors contributes to type 2 diabetes in GK rats. We aimed to investigate if α2-adrenoceptor inhibition affected islet blood flow in these rats. Anesthetized GK and Wistar-F rats were given the α2-adrenoceptor inhibitor yohimbine (2.5 mg/kg BW) intravenously. The GK rats had higher blood glucose and serum insulin concentrations than WF rats. Yohimbine affected neither of these values in WF rats, but decreased blood glucose and increased serum insulin concentrations in GK rats. Total pancreatic and islet blood flows, measured with microspheres, were increased in GK when compared to WF rats. Yohimbine affected none of the blood flow values in WF rats, whereas islet blood flow in GK rats was reduced to values similar to those seen in WF rats. Overexpression of α2-adrenoceptors may contribute to the increased islet blood flow seen in GK rats, and may be eligible for pharmacologic intervention.

Two‐week treatment with the β3‐adrenoceptor antagonist SR59230A normalizes the increased pancreatic islet blood flow in type 2 diabetic GK rats

The Goto-Kakizaki (GK) rat, a type 2 diabetes model, has increased pancreatic islet and white adipose tissue (WAT) blood flow, and this can be normalized by acute administration of SR59230A, a β₃ -adrenoceptor antagonist. We now implanted osmotic pumps which allowed a constant release of saline or SR59230A (0.6 mg/kg × day) for 2 weeks. A decrease in islet blood flow was seen also after 2 weeks of continuous SR59230A treatment in the GK rat. However, no improvement in glucose tolerance was seen in the GK rats. Neither did SR59230A affect insulin secretion from isolated islets in vitro. WAT blood flow was not affected by the 2-week SR59230A treatment. Thus, the increased islet blood flow seen in the GK rat can be normalized for up to 2 weeks, which opens the possibilities for further studies on the long-term functional role on the islet blood flow increase in this type 2 diabetes model.

Angiotensin II type 1 receptor antagonists prevent glucose‐induced increases in islet blood flow in rats

Objective. Renin‐angiotensin system inhibitors are reported to be beneficial in delaying the onset of diabetes mellitus. Since islet blood hyperperfusion during hyperglycaemia may be detrimental to endothelium in pancreatic islets and eventually lead to β‐cell dysfunction, we studied acute and chronic effects of angiotensin II type 1 receptor blockers (ARB) on islet blood flow before and after glucose load. Material and methods. Islet blood flow was measured using the colour microsphere method in anaesthetized Sprague‐Dawley rats before and 3 min after glucose injection. Results. Olmesartan significantly reduced blood pressure, but did not affect islet blood flow 10 min after its injection. However, pretreatment with olmesartan blunted the glucose‐induced increase in islet blood flow (62 % of control). In rats treated with olmesartan or candesartan for 4 weeks, islet blood flow was not different from untreated control, whereas the glucose‐induced increase in islet blood flow was significantly suppressed in chronically ARB‐treated rats (olmesartan 59 % of control, candesartan 64 % of control, respectively). Acute or chronic treatment with ARB did not change insulin secretion before and in response to glucose load. Pancreatic or duodenal blood flow was not affected by ARB treatment, although acute olmesartan administration reduced pancreatic blood flow after glucose load. Conclusion. ARB appears to suppress the hyperglycaemia‐induced islet hyperperfusion, which may ameliorate haemodynamic stress in pancreatic islets.

Glucose-Induced Time-Dependent Potentiation of Insulin Release, but not Islet Blood Perfusion, in Anesthetized Rats

Background: Repeated administration of glucose in vivo leads to a time-dependent potentiation of insulin release. Glucose is also known to stimulate pancreatic islet blood flow, but whether this is associated with a time-dependent potentiation is unknown. We therefore repeatedly administered glucose to anesthetized rats and evaluated effects on insulin release and islet blood flow.Methods: Male Wistar-Furth rats, anesthetized with thiobutabarbital, were injected intravenously with 1 ml of saline or glucose at times 0, 30 and 60 min. The combinations used were saline + saline + saline (SSS), glucose + saline + saline (GSS), saline + saline + glucose (SSG) and glucose + glucose + glucose (GGG). Regional organ blood flow values were measured 3 min after the final injection with a microsphere technique, and at this time also serum insulin concentrations were determined with ELISA.Results: Serum insulin concentrations as well as total pancreatic, pancreatic islet and duodenal blood flow were higher in SSG and GGG-treated rats when compared to those given SSS and GSS. However, only insulin concentrations, not blood flow values, were higher in GGG rats when compared to SSG animals.Conclusions: Glucose-induced time-dependent potentiation of insulin release occurs in vivo in thiobutabarbital-anesthetized rats, but is not associated with a further increase in islet blood flow.

Duct ligation and pancreatic islet blood flow in rats: physiological growth of islets does not affect islet blood perfusion

The aim of this study was to evaluate islet blood-flow changes during stimulated growth of the islet organ without any associated functional impairment of islet function. A duct ligation encompassing the distal two-thirds of the pancreas was performed in adult, male Sprague-Dawley rats. Pancreatic islet blood flow was measured in duct-ligated and sham-operated rats 1, 2 or 4 weeks after surgery. In some animals studied 4 weeks after surgery, islet blood flow was also measured also during hyperglycaemic conditions. A marked atrophy of the exocrine pancreas was seen in all duct-ligated rats. Blood glucose and serum insulin concentrations were normal. An increased islet mass was only seen 4 weeks after surgery. No differences in islet blood perfusion were noted at any time point after duct ligation. In both sham-operated and duct-ligated rats islet blood flow was increased during hyperglycaemia; the response was, however, slightly more pronounced in the duct-ligated part of the gland. Normal, physiological islet growth does not cause any major changes in the islet blood perfusion or its regulation. This is in contrast to findings during increased functional demands on the islets or during deteriorated islet function, when increased islet blood flow is consistently seen.

Nateglinide, a non-sulfonylurea rapid insulin secretagogue, increases pancreatic islet blood flow in rats

We studied whether the rapid hypoglycemic action of nateglinide is associated with an increase in islet blood flow. Islet blood flow was measured using the two-colour microsphere method. Orally administered nateglinide with glucose acutely increased islet blood flow to levels greater than those after glucose alone or tolbutamide with glucose in conscious Sprague–Dawley rats (percent increase at 10 min after oral administration; nateglinide+glucose, 125±25%; glucose, 33±11%, p<0.001; tolbutamide+glucose, 42±23%, p<0.01). Nateglinide administered with non-metabolisable 3-O-methylglucose also increased islet blood flow (61±17%). The stimulated islet blood flow significantly correlated with serum insulin levels. NG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, completely inhibited the increase in islet blood flow induced by nateglinide with glucose. Intravenously administered nateglinide did not significantly affect the already increased islet blood flow in diabetic Otsuka Long–Evans Tokushima Fatty rats. Our results indicated that nateglinide acutely increased islet blood flow at least in part through a nitric oxide-dependent mechanism.

Lack of compensatory increase in islet blood flow and islet mass in GK rats following 60% partial pancreatectomy

The effects of a 60% partial pancreatectomy were studied in hyperglycemic GK (Goto-Kakizaki) rats. Partial pancreatectomy or a sham operation was performed on 12-week-old female Wistar rats, GK rats or hybrids between male GK rats and female Wistar rats. Measurements of pancreatic blood flow and islet blood flow were performed by a microsphere technique 2 weeks after surgery. Glucose tolerance was decreased in hybrid compared with Wistar rats, and in GK rats compared with both hybrid and Wistar rats before surgery. Partial pancreatectomy induced minor changes in glucose tolerance. Wistar rats had a decreased islet mass following partial pancreatectomy. Both hybrid and GK rats showed a significant decrease in relative islet volume, but only GK rats in total islet mass, compared with Wistar rats 2 weeks after surgery. Pancreatic blood flow and islet blood flow did not significantly differ between sham-operated Wistar, hybrid or GK rats. After partial pancreatectomy, islet blood flow in relation to islet mass increased 3-fold in Wistar rats and 2-fold in hybrid rats. In contrast, GK rats showed no increase in islet blood flow following partial pancreatectomy. It is concluded that compensatory mechanisms after partial pancreatectomy are operating less efficiently in hybrid and GK rats.

Unaltered oxygen tension in rat pancreatic islets despite dissociation of insulin release and islet blood flow.

The present study investigated the importance of a tightly regulated islet blood flow for an optimal oxygenation of the islet tissue during different demands for insulin release. Glucose and/or a non-specific nitric oxide synthase inhibitor (L-NNA) were infused intravenously in non-pretreated or vagotomized rats and the animals were subjected to measurements of islet blood flow, oxygen tension and serum insulin concentrations. Islet blood flow was measured using a non-radioactive microsphere technique, tissue oxygen tension was recorded with Clark microelectrodes and insulin concentrations were determined by enzyme-linked immunosorbent assay technique. Administration of L-NNA (0.3 mg kg(-1) min(-1)) for 10 min halved basal islet blood flow, but did not affect serum insulin concentrations. Glucose administration (10 mg kg(-1) min(-1)) induced a marked increase in islet blood flow, which could be prevented by vagotomy or L-NNA. The serum insulin concentrations increased in all glucose-infused animals. The islet tissue oxygen tension remained similar in all animals despite these interventions. Reasons other than oxygenation of the islet tissue must explain the normally existing tight regulation of islet blood flow.

Glucose-induced islet blood flow increase in rats: interaction between nervous and metabolic mediators.

This study investigated the mechanisms for glucose-induced islet blood flow increase in rats. The effects of adenosine, adenosine receptor antagonists, and vagotomy on islet blood flow were evaluated with a microsphere technique. Vagotomy prevented the islet blood flow increase expected 3, 10, and 20 min after injection of glucose, whereas theophylline (a nonspecific adenosine receptor antagonist) prevented the islet blood flow increase from occurring 10 and 20 min after glucose administration. Administration of selective adenosine receptor antagonists suggested that the response to theophylline was mediated by A1 receptors. Exogenous administration of adenosine did not affect islet blood flow, but local accumulation of adenosine, induced by the adenosine uptake inhibitor dipyridamole, caused a doubling of islet blood flow. In conclusion, the increased islet blood flow seen 3 min after induction of hyperglycemia is caused by the vagal nerve, whereas the increase in islet blood perfusion seen at 10 and 20 min after glucose administration is caused by both the vagal nerve and adenosine.

Unaltered pancreatic islet blood perfusion in islet amyloid polypeptide-deficient mice.

Several biological activities have been ascribed to islet amyloid polypeptide (IAPP). However, their physiological relevance remains unclear. Previous studies in rats with exogenous administration of IAPP suggest that the peptide may increase splanchnic vascular resistance and redistribute the blood flow within the pancreas to the islets. In this study, the use of IAPP-deficient mice allowed us to evaluate possible effects of the lack of IAPP on splanchnic blood perfusion and we could thereby circumvent the potentially pharmacological actions of exogenously administered IAPP. Regional splanchnic blood flow was measured after exogenous administration of IAPP and in IAPP-deficient mice. Blood flow values were determined using a non-radioactive microsphere technique in anesthetized animals. No differences in whole pancreatic blood flow or islet blood flow could be detected in IAPP-deficient mice when compared with control mice; neither did IAPP deficiency affect the glucose-induced increase in islet blood flow. Duodenal, ileal and colonic blood flows were similar in IAPP-deficient and control mice. Exogenous administration of IAPP selectively increased islet blood flow in wild-type control mice. The present findings in the IAPP-deficient mice suggest that the vascular effects seen in the islets after exogenous administration of IAPP to normal mice reflect pharmacological, rather than physiological effects of the peptide. We conclude that the lack of endogenous IAPP within the splanchnic vascular system does not alter the blood perfusion of pancreatic islets or other splanchnic organs.

Secretin and pancreatic islet blood flow in anesthetized rats: increased insulin secretion with no augmentation of blood perfusion.

Secretin is a stimulator of both endocrine and exocrine secretions of the pancreas, and we aimed to evaluate its effects on splanchnic blood flow in rats with a microsphere technique. Anesthetized rats were infused with secretin (0.5 or 2.0 micrograms/kg body weight/hr) for 10 minutes. Some animals were normoglycemic, whereas other received a glucose injection 3 minutes before blood flow measurements. Secretin did not affect serum insulin concentrations in normoglycemic animals but consistently led to higher insulin concentrations in the hyperglycemic rats. Total pancreatic blood flow was increased by the highest secretin dose in normoglycemic animals, whereas no effects were seen in the hyperglycemic rats. Administration of glucose caused a pronounced increase in islet and fractional islet blood flow in saline-infused animals. Secretin affected neither islet nor fractional blood flow in normoglycemic or hyperglycemic rats. Glucose administration increased duodenal blood flow in animals infused with saline and both duodenal and colonic blood flow in rats given the lowest dose of secretin. No effects on either colonic or duodenal blood perfusion were seen in animals infused with the highest dose of secretin. Secretin mainly affects blood flow to the whole pancreas and not that of the islets. Furthermore, glucose-induced insulin release can be achieved without a simultaneous increase in islet blood flow; that is these two events may be dissociated from one another.

Pancreatic islet blood flow in conscious rats during hyperglycemia and hypoglycemia

Anesthesia affects general hemodynamics and regulation of organ perfusion. We used colored microspheres to measure pancreatic islet blood flow in conscious rats at two time points, during either hyperglycemia or hypoglycemia. This method, using black and green microspheres, was validated by comparison with previous microsphere experiments and by lack of effect of a nonmetabolizable glucose analog, 3-O-methylglucose, on islet perfusion. Basal and glucose-stimulated islet blood flow levels were similar in pentobarbital sodium-anesthetized and conscious rats. However, the basal distribution of pancreatic blood flow was altered by anesthesia (fractional islet blood flow 5.8 +/- 0.4% in conscious rats, 7.9 +/- 0.8% in pentobarbital-anesthetized rats, P < 0.05). Insulin-induced hypoglycemia significantly increased whole pancreatic blood flow in conscious rats, whereas islet blood flow remained unchanged and fractional islet blood flow was decreased (5.8 +/- 0.5% in the basal state, 4.2 +/- 0.4% during hypoglycemia, P < 0.001). Methylatropine pretreatment significantly increased islet blood flow during hypoglycemia by 181%. This result suggests that prevention of hypoglycemia-induced increase in islet perfusion may be mediated, at least in part, by a cholinergic, vagal muscarinic mechanism.

Capillary blood pressure in the endocrine and exocrine parenchyma of rat pancreas transplants

Background. Transplantation of isolated organs or cells leads to a functional denervation of the organ, which may cause a hyperperfusion of blood. The current study evaluated to what extent blood perfusion and capillary blood pressures were affected in the transplanted rat pancreas. Methods. Inbred, male Wistar-Furth rats underwent transplantation with a syngeneic pancreaticoduodenal graft. Four weeks later, blood flow to the native and transplanted pancreases was measured with a microsphere technique. Capillary pressures were measured by direct micropuncture technique. Results. An increased islet blood flow was consistently observed in the transplanted pancreas as compared with the native organ, while whole pancreatic and duodenal blood flow was similar in the native and transplanted organs. The capillary pressure was twice as high in the exocrine pancreas (6-7 mm Hg) of both the native and transplanted glands when compared with that of the islets (approximately 3 mm Hg). There were no differences in the capillary pressures in either the islets or exocrine gland when native and transplanted pancreases were compared. Conclusions. We conclude that the transplanted whole pancreas retains a low islet capillary blood pressure after transplantation despite having a higher islet blood perfusion. (Surgery 2001;129:196-202.)

Intraportal glucose infusion and pancreatic islet blood flow in anesthetized rats.

The aim of the study was to evaluate whether a selective increase in portal vein blood glucose concentration can affect pancreatic islet blood flow. Anesthetized rats were infused (0.1 ml/min for 3 min) directly into the portal vein with saline, glucose, or 3-O-methylglucose. The infused dose of glucose (1 mg. kg body wt(-1). min(-1)) was chosen so that the systemic blood glucose concentration was unaffected. Intraportal infusion of D-glucose increased insulin release and islet blood flow; the osmotic control substance 3-O-methylglucose had no such effect. A bilateral vagotomy performed 20 min before the infusions potentiated the islet blood flow response and also induced an increase in whole pancreatic blood flow, whereas the insulin response was abolished. Administration of atropine to vagotomized animals did not change the blood flow responses to intraportal glucose infusions. When the vagotomy was combined with a denervation of the hepatic artery, there was no stimulation of islet blood flow or insulin release after intraportal glucose infusion. We conclude that a selective increase in portal vein blood glucose concentration may participate in the islet blood flow increase in response to hyperglycemia. This effect is probably mediated via periarterial nerves and not through the vagus nerve. Furthermore, this blood flow increase can be dissociated from changes in insulin release.

Islet Blood Flow in Multiple Low Dose Streptozotocin-Treated Wild-Type and Inducible Nitric Oxide Synthase-Deficient Mice.

The present study tested the hypothesis that changes in islet blood perfusion occur during the development of diabetes in the multiple low dose streptozotocin-treated mouse. Streptozotocin (40 mg/kg) or citrate buffer was given ip once daily for 5 consecutive days to wild-type and inducible nitric oxide synthase (iNOS)-deficient C57BL/6 x 129 SvEv hybrid mice. The blood flows were then determined by a microsphere technique. The islet blood perfusion was almost 2-fold higher in wild-type mice treated with streptozotocin than in those given vehicle. Whole pancreatic blood flow was also increased in the streptozotocin-treated wild-type mice. In iNOS-deficient mice, neither islet blood flow nor whole pancreatic blood flow was affected by repeated streptozotocin treatment. These combined findings suggest an increased islet blood perfusion in the prediabetic stage mediated by an iNOS-dependent mechanism. In combination with increased vasopermeability and expression of adhesion molecules on the islet endothelium, as previously described, this increased islet blood flow may be of crucial importance for the recruitment of inflammatory cells into the islets during the development of diabetes in this animal model. Indeed, an increased degree of insulitis was observed in wild-type mice compared with mice deficient in iNOS as well as a more rapid decrease in islet volume and an earlier debut of manifest diabetes. We also describe altered islet blood perfusion in the iNOS-deficient mice during basal conditions due to a compensatory increase in constitutive NOS activity.