Early intervention with liraglutide improves glucose tolerance without affecting islet microcirculation in young Goto–Kakizaki rats

Wu, Lin; Olverling, Anna; Fransson, Liselotte; Ortsäter, Henrik; Kappe, Camilla; Gao, Xin; Sjöholm, Åke

doi:10.1016/j.regpep.2012.05.091

Cited by 12 publications

(15 citation statements)

References 30 publications

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“…However, we took care to avoid these side effects by slowly increasing the dosage until the final dose of liraglutide was reached and as indicated by the similar food intake in liraglutide-exposed mice as compared to mice treated with corticosterone or vehicle this dosing regime was successful. Liraglutide has previously been shown to efficaciously curb glucose intolerance and diabetes in both animal models [29] and in human T2DM patients [30]. However, its potential to counteract the diabetogenic effects of long-term steroid treatment has not previously been rigorously tested.…”

Section: Discussionmentioning

confidence: 99%

Liraglutide counteracts obesity and glucose intolerance in a mouse model of glucocorticoid-induced metabolic syndrome

Fransson

Santos

Wolbert

et al. 2014

Diabetol Metab Syndr

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BackgroundGlucocorticoid excess is commonly associated with diabetogenic effects, including insulin resistance and glucose intolerance. The effects of the long-term glucagon-like peptide 1 receptor agonist treatment on the metabolic syndrome-like conditions are not yet fully elucidated. Thus, we aimed to test whether long-term liraglutide treatment could be effective as a therapy to counteract the metabolic dysfunctions induced by chronic glucocorticoid exposure.MethodsMice were given corticosterone or vehicle via their drinking water for five consecutive weeks. In addition, mice were treated with once-daily injections of either PBS or liraglutide.ResultsLiraglutide treatment slowed progression towards obesity and ectopic fat deposition in liver that otherwise occurred in corticosterone-treated mice. The drug reduced the increment in serum insulin caused by corticosterone, but did not affect the reduction of insulin sensitivity. Furthermore, liraglutide improved glucose control in mice exposed to corticosterone as evident by a delay in the progression towards post-prandial hyperglycemia and enhanced glucose clearance during a glucose tolerance test. Glucose-stimulated C-peptide levels were higher in those mice that had received liraglutide and corticosterone compared to mice that had been treated with corticosterone alone, indicating a positive role of liraglutide for beta-cell function. Morphometric analysis revealed increased beta- and alpha-cell masses that were associated with more Ki67-positive islet cells in corticosterone-treated mice irrespective of whether they were co-treated with liraglutide or not. Liraglutide had no discernible effect on alpha-cell mass.ConclusionLiraglutide can be beneficial for subjects at risk of developing metabolic complications as a result of glucocorticoid excess.

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Section: Discussionmentioning

confidence: 99%

Liraglutide counteracts obesity and glucose intolerance in a mouse model of glucocorticoid-induced metabolic syndrome

Fransson

Santos

Wolbert

et al. 2014

Diabetol Metab Syndr

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“…The experiments were performed according to a protocol previously described in detail [10][11][12][13][14][15][16][17][18]. Non-fasting rats were anaesthetized with an intraperitoneal injection of thiobutabarbital sodium (120 mg/kg of body weight; Inactin TM , Research Biochemicals International), and placed on a heated operating table to maintain the body temperature.…”

Section: Blood Flow Measurementsmentioning

confidence: 99%

“…Both of these substances were dissolved in saline. These treatment conditions (time period and concentrations) were chosen based upon previous publications [4,7,[11][12][13][14][15][16][17][18]24] and recommendations from the drug provider. An advantage of this acute setting, over chronic treatment, is that non-specific changes due to alterations in, for example, body weight does not confound the outcome.…”

Section: Blood Flow Measurementsmentioning

confidence: 99%

“…The former type of illumination allowed us to count the microspheres, whereas the latter enabled localization of the microspheres from either the endocrine or exocrine parenchyma [10]. The number of microspheres in the islets and exocrine tissue was counted as previously described in detail [10][11][12][13][14][15][16][17][18]. The microsphere contents of the adrenal glands were used as a control to confirm an even distribution of the microspheres in the arterial circulation.…”

Section: Blood Flow Measurementsmentioning

confidence: 99%

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Acute regulation of pancreatic islet microcirculation and glycaemia by telmisartan and ramipril: discordant effects between normal and Type 2 diabetic rats

et al. 2013

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Diabetic patients are often treated with an ACEi (angiotensin-converting enzyme inhibitor) or angiotensin receptor antagonist against hypertension or albuminuria. These drugs also have a positive impact on glucose tolerance, but the mechanism for this remains elusive. Hypothesizing a positive non-additive effect, we studied whether the angiotensin receptor antagonist telmisartan or the ACEi ramipril acutely influence insulin secretion and glycaemia in vivo in healthy and Type 2 diabetic rats through effects on islet blood perfusion. Telmisartan and ramipril were injected intravenously into anaesthetized non-diabetic Wistar rats or Type 2 diabetic GK (Goto-Kakizaki) rats. In non-diabetic Wistar rats, neither whole PBF (pancreatic blood flow) nor IBF (islet blood flow) were significantly influenced by telmisartan and ramipril, alone or in combination. Renal blood flow was enhanced significantly by telmisartan and ramipril when used in combination, whereas ABF (adrenal blood flow) was not affected by any of the drugs. Telmisartan and ramipril both significantly increased serum insulin levels, but did not influence glycaemia. In Type 2 diabetic GK rats, both whole PBF and IBF were significantly decreased by telmisartan and ramipril, but only when used in combination. Renal blood flow was enhanced significantly by telmisartan and ramipril alone, but not when used in combination, whereas ABF was not affected by any of the drugs. Telmisartan and ramipril both significantly decreased serum insulin levels, and non-additively elevated blood glucose levels. In conclusion, the present study suggests that a local pancreatic RAS (renin-angiotensin system), sensitive to acute administration of telmisartan and ramipril, controls pancreatic IBF and insulin secretion and thereby has an impact on glucose tolerance. Our findings indicate unexpected significant differences in the effects of these agents on islet microcirculation, in vivo insulin secretion and glycaemia between healthy and Type 2 diabetic rats.

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“…The non-fasting blood glucose levels were monitored using a glucose kit and concentrations of liraglutide were determined with a GLP-1 ELISA kit. Since there is 97% sequence homology between liraglutide and native GLP-1, this ELISA fully cross-reacts with liraglutide (Wu et al 2012). The relative bioavailability (F) was calculated by comparing the subcutaneous Lrg-MVLs with Lrg-S according to the following equation:…”

Section: Experiments Designmentioning

confidence: 99%

Liraglutide-loaded multivesicular liposome as a sustained-delivery reduces blood glucose in SD rats with diabetes

et al. 2016

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Subcutaneous liraglutide-loaded multivesicular liposomes (Lrg-MVLs) were developed as a sustained drug-delivery system for treating diabetes and their properties were characterized. The Lrg-MVLs prepared using a two-step water-in-oil-in-water double emulsification process had a spherical appearance with a mean diameter of 6.69 mm and an encapsulation efficiency of 82.23 ± 4.78% without any initial burst release. Their pharmacodynamics (PD) and pharmacokinetics (PK) were also studied after a single subcutaneous administration to Sprague-Dawley (SD) rats with diabetes. The PD results demonstrated that Lrg-MVLs presented sustained glucose-lowering effects for nearly a week, while the pharmacokinetic parameters showed that the plasma liraglutide concentration of the designed preparation produced C max of 81.979 ± 12.140 pg/ml and an MRT 0-t of 88.224 ± 3.893 h. Furthermore, retention of Lrg-MVLs at the injection site was studied semiquantitatively by an in vivo imaging system, which can be used to evaluate the drug release from MVLs in vivo. In conclusion, MVLs are a promising carrier for liraglutide and Lrg-MVLs deserve further study for the treatment of diabetes.

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Early intervention with liraglutide improves glucose tolerance without affecting islet microcirculation in young Goto–Kakizaki rats

Cited by 12 publications

References 30 publications

Liraglutide counteracts obesity and glucose intolerance in a mouse model of glucocorticoid-induced metabolic syndrome

Liraglutide counteracts obesity and glucose intolerance in a mouse model of glucocorticoid-induced metabolic syndrome

Acute regulation of pancreatic islet microcirculation and glycaemia by telmisartan and ramipril: discordant effects between normal and Type 2 diabetic rats

Liraglutide-loaded multivesicular liposome as a sustained-delivery reduces blood glucose in SD rats with diabetes

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