Dual amylin and calcitonin receptor agonists (DACRAs) are known to induce a significant weight loss and improve glucose tolerance and glucose control in rats. However, it is unknown if DACRAs has an insulin sensitizing effect beyond that induced by weight loss and if DACRAs affect tissue specific glucose uptake. Additionally, clamp studies with DACRAs have not previously been performed in diabetic rats. Pre-diabetic ZDSD and diabetic ZDF rats were treated with the DACRA KBP-088 (1.5 nmol//kg, s.c.) for 12 days, and a hyperinsulinemic clamp was conducted on day 13, 24 h post-dosing. In ZDSD rats a hyperinsulinemic euglycemic clamp was carried out, while a hyperinsulinemic isoglycemic clamp was carried out in ZDF rats. In addition, specific glucose uptake was assessed during a hyperinsulinemic isoglycemic clamp in ZDF rats. In ZDSD rats, KBP-088 treatment resulted in a significant reduction in body weight and fasting blood glucose, and improved insulin sensitivity by increasing the glucose infusion rate (GIR) (vehicle: 8.6, KBP-088: 12 mg glucose/kg/min) . In ZDF rats, KBP-088 significantly reduced fasting blood glucose and improved insulin sensitivity (GIR, vehicle: 1.5, KBP-088: 16.5 mg glucose/kg/min) , independent on weight loss. In both studies, KBP-088 increased the rate of glucose clearance, likely be increasing glucose storage, but without altering the endogenous glucose production. Direct assessment of tissue specific glucose uptake showed, that KBP-088 significantly increased glucose uptake in both muscles and adipose tissues when compared to vehicle. In summary, KBP-088 significantly improved insulin sensitivity in both pre-diabetic and diabetic rats and markedly increased tissue specific glucose uptake. Importantly, KBP-088 has an insulin sensitizing effect independent of weight loss, highlighting DACRAs as promising agents for treatment of diabetes. Disclosure A.T.Larsen: Employee; Nordic Bioscience. N.Sonne: None. E.Bredtoft: None. M.A.Karsdal: Employee; Nordic Bioscience A/S, Nordic Bioscience A/S, Nordic Bioscience A/S. K.Henriksen: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S.
Dual amylin and calcitonin receptor agonists (DACRAs) are potential therapeutic candidates for treatment of obesity. Preclinical studies have shown favorable effects of DACRAs on appetite regulation contributing to a reduction in body weight. Interestingly, the DACRA-induced effects on weight loss are superior to the effects of a suppressed food intake, suggesting an effect on energy expenditure potentially by targeting the mitochondria. We investigated the effects of long-term treatment with a class of DACRAs, namely KBPs, on body weight, food intake and mitochondrial respiratory capacity (MRC) in Sprague-Dawley rats fed a high-fat diet and treated s.c. with KBPs for 8 weeks. Moreover, a pair-fed (PF) group was used to examine food intake-independent effects of KBPs on MRC. At study end, MRC was analyzed in perirenal (pAT) and inguinal (iAT) adipose tissue using high resolution respirometry. Expectedly, KBP treatment significantly reduced body weight compared to PF and vehicle. PF was successfully KBP-matched in terms of accumulated food intake and the food intake was significantly lower than that of vehicle-treated rats. Coupled and uncoupled MRC supported by complex I+II substrates and fatty acids were significantly greater in iAT and pAT after KBP treatment indicating effects on both carbohydrate and lipid metabolism. Additionally, an increased oligomycin-induced leak-respiration was found to be independent of food intake in iAT. Further analysis will shed light on whether these changes in MRC are a result of an increased mitochondrial content or of the respiratory capacity of each mitochondrion. In conclusion, treatment with KBPs in obese rats is associated with an increased MRC in pAT and iAT and elicits effects additional to those obtained by diet-induced weight loss. This highlights DACRAs’ potential as anti-obesity agents with possible benefits on energy expenditure as a contributing cause to the DACRA-induced weight loss. Disclosure E.A.Petersen: Employee; Nordic Bioscience A/S. I.Blom: None. S.A.Melander: None. M.A.Karsdal: Speaker's Bureau; Pfizer Inc. S.Larsen: None. K.Henriksen: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S. A.T.Larsen: Employee; Nordic Bioscience A/S. Funding Innovation Fund Denmark
Obesity and metabolic-related complications, especially insulin resistance, have been linked to cognitive dysfunction. Dual amylin and calcitonin receptor agonists (DACRAs) elicit beneficial effects on body weight, glucose control, and insulin action, making them novel candidates for treating obesity and related comorbidities. Whether DACRAs affect cognition has yet to be addressed. With these studies, we evaluated the effect of DACRA treatment on spatial learning and memory in rat models of metabolic syndrome. Spatial learning and spatial memory retention were evaluated by Morris Water Maze in ZDSD rats treated with KBP-336 (4.5 nmol/kg Q3D) for 7 months and ZSF1 rats treated with KBP-336 (4.5 nmol/kg Q3D) for 2 months. In the ZDSD study, rats performed 8 training trials with a hidden platform in a constant position and a 60 s probe without the platform. At the study end, rats performed a 60 s probe followed by 4 re-training trials and another probe. At study end of the ZSF1 study, rats performed 6 training trials with a hidden platform in a constant position followed by a 60 s probe without the platform. In both studies, KBP-336 treatment improved the overall metabolic status, including glucose control and insulin action. In ZDSD rats, KBP-336-treated rats spent more time and traveled longer distances in Whishaw's corridor than vehicle-treated rats during the probes at the study end. Together indicating a possible treatment improvement in spatial memory on KBP-336. In ZSF1 rats, KBP-336 treatment resulted in increased time spent in the platform quadrant and Whishaw's corridor, as well as increased distance, traveled in Whishaw's corridor during the probe. In both studies, the treatment did not affect the spatial learning evaluated as latency to reach the hidden platform during the training trials. Altogether, we found that the improved metabolic status obtained with KBP-336 treatment might have a beneficial effect on spatial memory in diabetic and obese rat models. Disclosure K.Mohamed: Employee; Nordic Bioscience. A.T.Larsen: Employee; Nordic Bioscience A/S. S.A.Melander: None. M.A.Karsdal: Speaker's Bureau; Pfizer Inc. K.Henriksen: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S. Funding Danish Research Foundation; Innovation Fund Denmark; European Union’s Horizon 2020 Research and Innovation Program (814244)
Long-acting dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for the treatment of type 2 diabetes and obesity due to their beneficial effects on both body weight, glucose control and insulin action. However, whether DACRAs affect hypertension, and diabetes-related cardiovascular complications remain unknown. In this study, the cardiovascular protective effect of the DACRA KBP-336 was evaluated in obese Zucker diabetic fatty-Spontaneously hypertensive heart failure F1 hybrid (ZSF1) rats. Obese ZSF1 rats were treated for 60 days with the KBP-336 (4.5 nmol/kg Q3D) and treatment efficacy on glucose control and blood pressure measured by tail cuff was evaluated. Furthermore, serum biomarkers of cardiovascular complications were evaluated. KBP-336 treatment significantly lowered fasting blood glucose levels compared to vehicle (P<0.001). This was also illustrated in the HbA1c levels at study end, where KBP-336 resulted in significantly (P<0.001) lower levels than vehicle. Importantly, KBP-336 significantly reduced both systolic (AUC levels reduced by 13.3%, P<0.001) and diastolic (AUC levels reduced by 17.0%, P<0.001) blood pressure compared to vehicle without affecting the heart rate. Notably, the beneficial effects on both glucose control and blood pressure were obtained independent of weight loss as KBP-336 only resulted in a small and transient weight reduction. Furthermore, serum levels of the marker of cardiovascular disease, rPRO-C6 (collagen type VI formation marker) were 6.4% lower in KBP-336 treated rats compared to vehicle, supporting improvement in cardiovascular parameters. In summary, we show for the first time that KBP-336 benefits blood pressure in a metabolic rat model suffering from hypertension. In addition, KBP-336 improved glucose control independent of weight loss. These data highlight KBP-336 as a promising candidate for treating obesity and related comorbidities including type 2 diabetes and hypertension. Disclosure S.A.Melander: None. A.T.Larsen: Employee; Nordic Bioscience A/S. K.Mohamed: Employee; Nordic Bioscience. M.A.Karsdal: Speaker's Bureau; Pfizer Inc. K.Henriksen: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S. Funding Danish Research Foundation; Innovation Fund Denmark; European Union’s Horizon 2020 Research and Innovation Program (814244)
Long-acting dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for treatment of type 2 diabetes (T2D) and obesity due to their beneficial effects on both body weight, glucose control and insulin action. Cagrilintide, which is currently in clinical trials, has shown promising effects on weight loss. In this study we compared a new long-acting DACRA (KBP) to cagrilintide in pre-clinical models of obesity and T2D. In vitro potencies were assessed using receptor assays. In vivo efficacies were investigated head-to-head in high fat diet (HFD) fed obese and T2D (ZDF) rat models. In vitro data showed that both peptides active both the amylin and the calcitonin receptor, with KBP being more potent on both receptors. This was further confirmed in vivo by assessment of acute effects on food intake and CTX suppression. KBP (1.5, 4.5 and 13.5 nmol/kg) and cagrilintide (10, 30 and 100 nmol/kg) induced a potent and dose-dependent weight loss in HFD rats, with the highest dose of KBP being superior to cagrilintide. In diabetic ZDF rats, DACRA treatment improved glucose control and preserved plasma insulin compared to vehicle. Interestingly, despite similar levels of plasma insulin, KBP treatment was superior to cagrilintide in improving glucose control. This was further reflected in the HbA1c levels at study end, where KBP treatment resulted in significantly lower levels compared to cagrilintide. In summary, both DACRAs induced weight loss and improved glucose tolerance, insulin action as well as glucose control. However, KBP treatment results in superior efficacy on both weight loss and glucose control. These findings highlight KBP as a promising once-weekly agent for treatment of obesity and T2D. Disclosure A.T.Larsen: Employee; Nordic Bioscience. N.Sonne: None. K.Mohamed: None. E.Bredtoft: None. F.Andersen: None. M.A.Karsdal: Employee; Nordic Bioscience A/S, Nordic Bioscience A/S, Nordic Bioscience A/S. K.Henriksen: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S.
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