Intragastric administration of allyl isothiocyanate increases carbohydrate oxidation via TRPV1 but not TRPA1 in mice

The transient receptor potential (TRP) channel family is composed of a wide variety of cation-permeable channels activated polymodally by various stimuli and is implicated in a variety of cellular functions. Recent investigations have revealed that activation of TRP channels is involved not only in nociception and thermosensation but also in thermoregulation and energy metabolism. We investigated the effect of intragastric administration of TRP channel agonists on changes in energy substrate utilization of mice. Intragastric administration of allyl isothiocyanate (AITC; a typical TRPA1 agonist) markedly increased carbohydrate oxidation but did not affect oxygen consumption. To examine whether TRP channels mediate this increase in carbohydrate oxidation, we used TRPA1 and TRPV1 knockout (KO) mice. Intragastric administration of AITC increased carbohydrate oxidation in TRPA1 KO mice but not in TRPV1 KO mice. Furthermore, AITC dose-dependently increased intracellular calcium ion concentration in cells expressing TRPV1. These findings suggest that AITC might activate TRPV1 and that AITC increased carbohydrate oxidation via TRPV1.     

Intragastric administration of AMG517, a TRPV1 antagonist,enhanced activity-dependent energy metabolism via capsaicin-sensitive sensory nerves in mice

ABSTRACT

Transient receptor potential vanilloid 1 (TRPV1), a nociceptive cation channel, is known to play roles in regulating the energy metabolism (EM) of the whole body. We previously reported that TRPV1 antagonists such as AMG517 enhanced EM in mice, however, these mechanisms remain unclear. The aim of this study was to explore the mechanisms underlying the enhancement of EM by AMG517, a selective TRPV1 antagonist, in mice. Respiratory gas analysis indicated that intragastric administration of AMG517 enhanced EM along with increasing locomotor activity in mice. Next, to clarify the possible involvement with afferent sensory nerves, including the vagus, we desensitized the capsaicin-sensitive sensory nerves of mice by systemic capsaicin treatment. In the desensitized mice, intragastric administration of AMG517 did not change EM and locomotor activity. Therefore, this study indicated that intragastric administration of AMG517 enhanced EM and increased locomotor activity via capsaicin-sensitive sensory nerves, including vagal afferents in mice.     

Pancreatic beta-cell lipoprotein lipase independently regulates islet glucose metabolism and normal insulin secretion

Lipid and glucose metabolism are adversely affected by diabetes, a disease characterized by pancreatic beta-cell dysfunction. To clarify the role of lipids in insulin secretion, we generated mice with beta-cell-specific overexpression (betaLPL-TG) or inactivation (betaLPL-KO) of lipoprotein lipase (LPL), a physiologic provider of fatty acids. LPL enzyme activity and triglyceride content were increased in betaLPL-TG islets; decreased LPL enzyme activity in betaLPL-KO islets did not affect islet triglyceride content. Surprisingly, both betaLPL-TG and betaLPL-KO mice were strikingly hyperglycemic during glucose tolerance testing. Impaired glucose tolerance in betaLPL-KO mice was present at one month of age, whereas betaLPL-TG mice did not develop defective glucose homeostasis until approximately five months of age. Glucose-simulated insulin secretion was impaired in islets isolated from both mouse models. Glucose oxidation, critical for ATP production and triggering of insulin secretion mediated by the ATP-sensitive potassium (KATP) channel, was decreased in betaLPL-TG islets but increased in betaLPL-KO islets. Islet ATP content was not decreased in either model. Insulin secretion was defective in both betaLPL-TG and betaLPL-KO islets under conditions causing calcium-dependent insulin secretion independent of the KATP channel. These results show that beta-cell-derived LPL has two physiologically relevant effects in islets, the inverse regulation of glucose metabolism and the independent mediation of insulin secretion through effects distal to membrane depolarization.     

Enhanced insulin secretion and sensitization in diabetic mice on chronic treatment with a transient receptor potential vanilloid 1 antagonist

AimsInhibition of transient receptor potential vanilloid 1 (TRPV1) suppresses calcitonin gene-related peptide (CGRP) secretion in pancreatic nerve fiber cells, thereby stimulating insulin secretion. We examined the effects of repeat administration of the TRPV1 antagonist N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamidte monohydrochloride (BCTC) to ob/ob mice, a model of type 2 diabetes with insulin resistance, on whole body glucose and lipid metabolism.Main methodsWe measured blood parameters, including levels of glucose, insulin, and triglycerides, and performed the oral glucose tolerance test (OGTT) after repeat administration of BCTC to ob/ob mice twice a day for four weeks.Key findingsWe found that BCTC treatment reduced fasting glucose, triglyceride, and insulin levels in the whole body. The effects were comparable to that of pioglitazone, a major insulin-sensitizing agent. Further, we found that administration of BCTC significantly increased plasma insulin secretion in the OGTT, which differed from the effect of pioglitazone treatment.SignificanceOur study is the first to show the anti-diabetic pharmacological effects of the TRPV1 signal inhibitor BCTC. These findings suggest that TRPV1 antagonists may represent a new class of drugs effective in treating type 2 diabetes mellitus because of their dual effects as insulin sensitizers and secretagogues.     

TRPA1 agonists--allyl isothiocyanate and cinnamaldehyde--induce adrenaline secretion

Thermosensitive transient receptor potential (TRP) channels, especially TRPV1 and TRPA1, are activated by the pungent compounds present in spices. TRPV1 activation by the intake of capsaicin, the irritant in hot pepper, induces adrenaline secretion and increases energy consumption. TRPV1 is mainly expressed in the sensory neurons and coexpressed with TRPA1 at a high frequency. However, the mechanism underlying adrenaline secretion by TRPA1 agonists such as allyl isothiocyanate (AITC) and cinnamaldehyde (CNA), the pungent ingredients in mustard and cinnamon, is not known. We examined whether AITC and CNA could induce adrenaline secretion in anesthetized rats. An intravenous injection of AITC or CNA (10 mg/kg) increased adrenaline secretion. These responses disappeared completely in capsaicin-treated rats with an impaired sensory nerve function. Moreover, pretreatment with cholinergic blockers (hexamethonium and atropine) attenuated the AITC- or CNA-induced adrenaline secretion. These results suggest that TRPA1 agonists activate the sensory nerves and induce adrenaline secretion via the central nervous system.     

Glucagon-like peptide-1 and islet lipolysis.

A role for glucagon-like peptide 1 (GLP-1) has been suggested in stimulating beta-cell lipolysis via elevation of cAMP and activation of protein kinase A, which in turn may activate hormone-sensitive lipase (HSL), thereby contributing to fatty acid generation (FFA) from intracellular triglyceride stores. FFAs may then be metabolized to a lipid signal, which is required for optimal glucose-stimulated insulin secretion. Since HSL is expressed in islet beta-cells, this effect could contribute to the stimulation of insulin secretion by GLP-1, provided that a lipid signal of importance for insulin secretion is generated. To examine this hypothesis, we have studied the acute effect of GLP-1 on isolated mouse islets from normal mice and from mice with high-fat diet induced insulin resistance. We found, however, that although GLP-1 (100 nM) markedly potentiated glucose-stimulated insulin secretion from islets of both feeding groups, the peptide was not able to stimulate islet palmitate oxidation or increase lipolysis measured as glycerol release. This indicates that a lipid signal does not contribute to the acute stimulation of insulin secretion by GLP-1. To test whether lipolysis might be involved in the islet effects of long-term GLP-1 action, mice from the two feeding groups were chronically treated with exendin-4, a peptide that lowers blood glucose by interacting with GLP-1 receptors, in order to stimulate insulin secretion, for 16 days before isolation of the islets. The insulinotropic effects of GLP-1 and forskolin were exaggerated in isolated islets from exendin-4 treated mice given a high-fat diet, with a augmented palmitate oxidation as well as islet lipolysis at high glucose levels in these islets. Exendin-4 treatment had less impact on mice fed a normal diet. From these results we conclude that while GLP-1 does not seem to induce beta-cell lipolysis acutely in mouse islets, the peptide affects beta-cell fat metabolism after long-term adaptation to GLP-1 receptor stimulation.     

TRPA1 Agonists—Allyl Isothiocyanate and Cinnamaldehyde—Induce Adrenaline Secretion

Thermosensitive transient receptor potential (TRP) channels, especially TRPV1 and TRPA1, are activated by the pungent compounds present in spices. TRPV1 activation by the intake of capsaicin, the irritant in hot pepper, induces adrenaline secretion and increases energy consumption. TRPV1 is mainly expressed in the sensory neurons and coexpressed with TRPA1 at a high frequency. However, the mechanism underlying adrenaline secretion by TRPA1 agonists such as allyl isothiocyanate (AITC) and cinnamaldehyde (CNA), the pungent ingredients in mustard and cinnamon, is not known. We examined whether AITC and CNA could induce adrenaline secretion in anesthetized rats. An intravenous injection of AITC or CNA (10 mg/kg) increased adrenaline secretion. These responses disappeared completely in capsaicin-treated rats with an impaired sensory nerve function. Moreover, pretreatment with cholinergic blockers (hexamethonium and atropine) attenuated the AITC- or CNA-induced adrenaline secretion. These results suggest that TRPA1 agonists activate the sensory nerves and induce adrenaline secretion via the central nervous system.     

An incretin-based tri-agonist promotes superior insulin secretion from murine pancreatic islets via PLC activation

Recently, a unimolecular tri-agonist with activity at glucagon-like peptide 1 receptor (GLP-1R), glucose dependent insulinotropic receptor, and the glucagon receptor was reported to improve glycemic control in mice. Here, we defined the underlying molecular mechanisms of enhanced insulin secretion in murine pancreatic islets for a specific tri-agonist. The tri-agonist induced an increase in insulin secretion from murine islets compared to the respective mono-agonists. GLP-1R mainly signals via activation of the Gα_s pathway, but inhibition of protein kinase A (H89) and exchange protein activation by cAMP (EPAC) (ESI-09) could not completely block insulin release induced by tri-agonist. Electrophysiological observations identified a strong increase of intracellular Ca²⁺ concentration and whole-cell currents induced by tri-agonist via transient receptor potential channels (TRPs). Although, EPAC activation mobilizes intracellular Ca²⁺ via TRPs, the TRPs blockers (La³⁺ and Ruthenium Red) had a larger inhibitory impact than ESI-09 on tri-agonist stimulatory effects. To test for other potential mechanisms, we blocked PLC activity (U73122) which reduced the superior effect of tri-agonist to induce insulin secretion, and partially inhibited the induced Ca²⁺ influx. This result suggests that the relative effect of tri-agonist on insulin secretion caused by GLP-1R agonism is mediated mainly via Gα_s signaling and partially by activation of PLC. Therefore, the large portion of the increased intracellular Ca²⁺ concentration and the enhanced whole-cell currents induced by tri-agonist might be attributable to TRP channel activation resulting from signaling through multiple G-proteins. Here, we suggest that broadened intracellular signaling may account for the superior in vivo effects observed with tri-agonism.     

Insulinotropic effect of the non-steroidal compound STX in pancreatic β-cells

The non-steroidal compound STX modulates the hypothalamic control of core body temperature and energy homeostasis. The aim of this work was to study the potential effects of STX on pancreatic β-cell function. 1-10 nM STX produced an increase in glucose-induced insulin secretion in isolated islets from male mice, whereas it had no effect in islets from female mice. This insulinotropic effect of STX was abolished by the anti-estrogen ICI 182,780. STX increased intracellular calcium entry in both whole islets and isolated β-cells, and closed the K(ATP) channel, suggesting a direct effect on β-cells. When intraperitoneal glucose tolerance test was performed, a single dose of 100 μg/kg body weight STX improved glucose sensitivity in males, yet it had a slight effect on females. In agreement with the effect on isolated islets, 100 μg/kg dose of STX enhanced the plasma insulin increase in response to a glucose load, while it did not in females. Long-term treatment (100 μg/kg, 6 days) of male mice with STX did not alter body weight, fasting glucose, glucose sensitivity or islet insulin content. Ovariectomized females were insensitive to STX (100 μg/kg), after either an acute administration or a 6-day treatment. This long-term treatment was also ineffective in a mouse model of mild diabetes. Therefore, STX appears to have a gender-specific effect on blood glucose homeostasis, which is only manifested after an acute administration. The insulinotropic effect of STX in pancreatic β-cells is mediated by the closure of the K(ATP) channel and the increase in intracellular calcium concentration. The in vivo improvement in glucose tolerance appears to be mostly due to the enhancement of insulin secretion from β-cells.     

Studies on the role of beta-cell metabolism in the insulinotropic effect of alpha-ketoisocaproic acid.

alpha-Ketoisocaproic acid has been shown to be a potent insulin secretagogue but the mechanism has not been elucidated. To define the role of beta-cell metabolism in the insulinotropic activity of alpha-ketoisocaproic acid the utilization of glucose and the oxidation of alpha-ketoisocaproic and isovaleric acid by incubated islets of obese hyperglycemic mice were measured. Glucose metabolism was never enhanced by alpha-ketoisocaproic acid. The same 14CO2 amounts were released from the non-secretagogue [1-14C]isovaleric acid (10 mM) or from alpha-keto[2-14C]isocaproic acid (5--20 mM). Pyruvate (20 mM) did not inhibit alpha-ketoisocaproic acid-induced insulin secretion in spite of reduction of decarboxylation of alpha-ketoisocaproic acid by more than 40%. The results indicate that stimulated insulin release in response to alpha-ketoisocaproic acid is not mediated by an indirect increase in glucose metabolism and further suggest that isovaleryl-CoA and following CoA-esters in alpha-ketoisocaproic acid degradation are not likely recognized as signals. The possibility, however, remains that enhanced intramitochondrial production of reducing equivalents elicits insulin secretion.     

Studies on the role of β-cell metabolism in the insulinotropic effect of α-ketoisocaproic acid

α-Ketoisocaproic acid has been shown to be apotent insulin secretagogue but the mechanism has not been elucidated. To define the role of β-cell metabolism in the insulinotropic activity of α-ketoisocaproic acid the utilization of glucose and the oxidation of α-ketoisocaproic and isovaleric acid by incubated islets of obese hyperglycemic mice were measured.Glucose metabolism was never enhanced by α-ketoisocaproic acid. The same ¹⁴CO₂ amounts were released from the non-secretagogue [1-¹⁴C]isovaleric acid (10 mM) or from α-keto [2-¹⁴C]isocaproic acid (5–20 mM). Pyruvate (20 mM) did not inhibit α-ketoisocaproic acid-induced insulin secretion in spite of reduction of decarboxylation of α-ketoisocaproic acid by more than 40%.The results indicate that stimulated insulin release in response to α-ketoisocaproic acid is not mediated by an indirect increase in glucose metabolism and further suggest that isovaleryl-CoA and following CoA-esters in α-ketoisocaproic acid degradation are not likely recognized as signals. The possibility, however, remains that enhanced intramitochondrial production of reducing equivalents elicits insulin secretion.     

Activation of TRPV4 channel in pancreatic INS-1E beta cells enhances glucose-stimulated insulin secretion via calcium-dependent mechanisms

Transient receptor potential channel vanilloid type 4 (TRPV4) is a Ca²⁺- and Mg²⁺-permeable cation channel that influences oxidative metabolism and insulin sensitivity. The role of TRPV4 in pancreatic beta cells is largely unknown. Here, we characterize the role of TRPV4 in controlling intracellular Ca²⁺ and insulin secretion in INS-1E beta cells. Osmotic, thermal or pharmacological activation of TRPV4 caused a rapid rise of intracellular Ca²⁺ and enhanced glucose-stimulated insulin secretion. In the presence of the TRPV channel blocker ruthenium red (RuR) or after suppression of TRPV4 protein production, TRPV4 activators failed to increase [Ca²⁺]_i and insulin secretion in INS-1E cells.     

The pentose cycle and insulin release in isolated mouse pancreatic islets during starvation.

When islets from mice were incubated with 16.7 mM-glucose, previous starvation for 48 h decreased the rate of insulin release by approx. 50% and glucose utilization was decreased by approx. 35%. The maximally extractable activity of glucose 6-phosphate dehydrogenase was diminished by 28% after starvation. The formation of 14CO2 from both [1-14C]glucose was, however, higher than the rate of oxidation of [6-14C]-glucose in islets from both fed and starved mice. The fraction of glucose utilized that was oxidized (specific 14CO2 yield) ranged from one-fifth to one-third and was higher in islets from starved mice with both [1-14C]glucose and [6-14C]glucose as substrate. The contribution of pentose-cycle oxidation to total glucose metabolism was small (3% in the fed state and 4% in the starved state). The absolute rates of glucose carbon metabolism via the pentose-cycle oxidation to total glucose metabolism was small (3% in the fed state and 4% in the starved state). The absolute rates of glucose carbon metabolism via the pentose cycle and the turnover of NADPH in this pathway were identical in islets from fed and starved animals. After incubation at 16.7 mM-glucose for 30 min the contents of glucose (6-phosphate and 6-phosphogluconate were both unchanged by starvation. It is concluded that there is no correlation between the decreased sensitivity of the insulin secretory mechanism during starvation and the metabolism of glucose via the pentose cycle, the islet content of glucose 6-phosphate or 6-phosphogluconate.     

ARA290 Improves Insulin Release and Glucose Tolerance in Type 2 Diabetic Goto-Kakizaki Rats

Effects of ARA290 on glucose homeostasis were studied in type 2 diabetic Goto-Kakizaki (GK) rats. In GK rats receiving ARA290 daily for up to 4 wks, plasma glucose concentrations were lower after 3 and 4 wks, and hemoglobin A_1c (Hb A_1c) was reduced by ~20% without changes in whole body and hepatic insulin sensitivity. Glucose-stimulated insulin secretion was increased in islets from ARA290-treated rats. Additionally, in response to glucose, carbachol and KCl, islet cytoplasmic free Ca²⁺ concentrations, [Ca²⁺]_i, were higher and the frequency of [Ca²⁺]_i oscillations enhanced compared with placebo. ARA290 also improved stimulus–secretion coupling for glucose in GK rat islets, as shown by an improved glucose oxidation rate, ATP production and acutely enhanced glucose-stimulated insulin secretion. ARA290 also exerted an effect distal to the ATP-sensitive potassium (K_ATP) channel on the insulin exocytotic pathway, since the insulin response was improved following islet depolarization by KCl when K_ATP channels were kept open by diazoxide. Finally, inhibition of protein kinase A completely abolished effects of ARA290 on insulin secretion. In conclusion, ARA290 improved glucose tolerance without affecting hematocrit in diabetic GK rats. This effect appears to be due to improved β-cell glucose metabolism and [Ca²⁺]_i handling, and thereby enhanced glucose-induced insulin release.     

Overexpression of Bcl-x(L) in beta-cells prevents cell death but impairs mitochondrial signal for insulin secretion

To study effects of Bcl-x(L) in the pancreatic beta-cell, two transgenic lines were produced using different forms of the rat insulin promoter. Bcl-x(L) expression in beta-cells was increased 2- to 3-fold in founder (Fd) 1 and over 10-fold in Fd 2 compared with littermate controls. After exposure to thapsigargin (10 microM for 48 h), losses of cell viability in islets of Fd 1 and Fd 2 Bcl-x(L) transgenic mice were significantly lower than in islets of wild-type mice. Unexpectedly, severe glucose intolerance was observed in Fd 2 but not Fd 1 Bcl-x(L) mice. Pancreatic insulin content and islet morphology were not different from control in either transgenic line. However, Fd 2 Bcl-x(L) islets had impaired insulin secretory and intracellular free Ca(2+) ([Ca(2+)](i)) responses to glucose and KCl. Furthermore, insulin and [Ca(2+)](i) responses to pyruvate methyl ester (PME) were similarly reduced as glucose in Fd 2 Bcl-x(L) islets. Consistent with a mitochondrial defect, glucose oxidation, but not glycolysis, was significantly lower in Fd 2 Bcl-x(L) islets than in wild-type islets. Glucose-, PME-, and alpha-ketoisocaproate-induced hyperpolarization of mitochondrial membrane potential, NAD(P)H, and ATP production were also significantly reduced in Fd 2 Bcl-x(L) islets. Thus, although Bcl-x(L) promotes beta-cell survival, high levels of expression of Bcl-x(L) result in reduced glucose-induced insulin secretion and hyperglycemia due to a defect in mitochondrial nutrient metabolism and signaling for insulin secretion.     

Enhanced glucose homeostasis in BHE/cdb rats with mutated ATP synthase

The BHE/cdb rat has a mutation in adenosine triphosphate (ATP) synthase that impairs insulin secretion. However, male BHE/cdb rats have normal circulating glucose and enhanced glucose tolerance. The aim of the current study was to identify mechanisms of enhanced glucose tolerance. The respiratory exchange ratio was increased, indicating increased oxidation of carbohydrate in BHE/cdb rats, consistent with increases in liver pyruvate dehydrogenase activity and muscle citrate synthase activity. Liver also exhibited diminished phosphoenol pyruvate carboxykinase content, which correlated with a decreased counter-regulatory response in the insulin tolerance test. Signaling via Akt or AMP-dependent kinase pathways in the liver could not account for lower blood glucose. We conclude that chronically low insulin secretion leads to adaption in glucose metabolism primarily in liver to maintain euglycemia.     

Decreased islet sensitivity to insulin in hamsters with dietary-induced insulin resistance

In the present study, we evaluated the autocrine modulatory effect of insulin on glucose metabolism and glucose-induced insulin secretion in islets isolated from hamsters with insulin resistance (IR) induced by administration of a sucrose-rich diet (SRD) during 5 weeks. We used an approach of two metabolic pathways (glucose oxidation and utilization) based on the measurement of 14CO2 and 3H2O production from D-[U-14C]-glucose and D-[5-(3)H]-glucose, respectively, in isolated islets incubated with 3.3 and 16.7 mM glucose alone, or with 5 or 15 mU/ml insulin, anti-insulin guinea-pig serum (1:500), 25 microM nifedipine, or 150 nM wortmannin. Insulin release was measured by radioimmunoassay in islets incubated with 3.3 or 16.7 mM glucose, with or without 75, 150, and 300 nM wortmannin. Results showed that the stimulatory effect of insulin upon 14CO2 and 3H2O production in control islets was not observed in SRD islets. Addition of anti-insulin serum, nifedipine or wortmannin to the medium with 16.7 mM glucose decreased 14CO2 and 3H2O production in control but not in SRD islets. Whereas wortmannin did not decrease insulin release induced by 16.7 mM glucose in SRD hamsters, it did in controls. We can conclude that the autocrine stimulatory effect of insulin upon glucose metabolism observed in normal islets is attenuated or even absent in islets from IR animals. Such decreased islet sensitivity to insulin did not prevent the compensatory secretion of insulin from maintaining glucose homeostasis, suggesting that, at least in this model, the islets can put forward alternative mechanisms to overcome such defect.     

Dual action of adiponectin on insulin secretion in insulin-resistant mice

Adiponectin is secreted by adipocytes and has been implicated as a mediator of insulin sensitivity. In this study, the acute effects of adiponectin on islets isolated from normal or diet-induced insulin resistant mice were examined. In normal islets, adiponectin (5 microg/ml) had no significant effect on insulin secretion. In contrast, in islets from mice rendered insulin resistant by high-fat feeding, adiponectin inhibited insulin secretion at 2.8 mM (P < 0.01) but augmented insulin secretion at 16.7 mM glucose (P < 0.05). The augmentation of glucose-stimulated insulin secretion by adiponectin was accompanied by increased glucose oxidation (P < 0.005), but without any significant effect on palmitate oxidation or the islet ATP/ADP ratio. Furthermore, RT-PCR revealed the expression of the adiponectin receptor AdipoR1 mRNA in mouse islets, however, with no difference in the degree of expression level between the two feeding groups. The results thus uncover a potential dual role for adiponectin to modify insulin secretion in insulin resistance.     

Effect of Dexamethasone on Insulin Secretion: Examination of Underlying Mechanisms

ObjectiveTo study the mechanism of increased insulin secretion in response to short-term administration of dexamethasone.MethodsMale Wistar rats were injected intraperitoneally with dexamethasone (dexamethasone; 200 mcg/kg body weight per day) or saline for 3 consecutive days. Insulin secretion in response to glucose, ionomycin, and KCl was quantified in islets isolated from the animals, and the amount of glucokinase was measured by Western blot.ResultsDexamethasone-treated animals had 1.18-fold higher fasting blood glucose concentration and 6.5-fold increase in fasting serum insulin concentration compared with findings from animals injected with saline. Compared with islets isolated from control rats, islets from dexamethasone-treated rats secreted more insulin at 60 minutes in response to 5.5 mM glucose (416.4 vs 115.6 fmoles/10 islets, P = .011) and in response to 16.6 mM glucose (985.5 vs 520.6 fmoles/10 islets, P = .014); no change in insulin secretion was observed at 10 minutes. Insulin secretion from islets of dexamethasone-treated rats and control rats was not differentially augmented in response to either ionomycin or potassium chloride. Glucokinase expression was not altered by treatment with dexamethasone.ConclusionsAugmentation of insulin secretion in response to glucose in the pancreatic islets from dexamethasone-treated rats is preserved in islets studied in vitro. The increase in glucose-stimulated insulin secretion appears to be mediated by steps upstream to β -cell membrane depolarization and the attended increase in intracellular calcium in the signaling pathway of insulin secretion. (Endocr Pract. 2010;16:763-769)