KBP-042 improves bodyweight and glucose homeostasis with indices of increased insulin sensitivity irrespective of route of administration

Andreassen

et al. 2016

Obesity

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Objective: In this study, KBP-042, a dual amylin-and calcitonin-receptor agonist, was investigated as a treatment of obesity and insulin resistance in five different doses (0.625 mg/kg-10 mg/kg) compared with saline-treated and pair-fed controls. Methods: Rats with obesity received daily s.c. administrations for 56 days, and glucose tolerance was assessed after one acute injection, 3 weeks of treatment, and again after 7 weeks of treatment. To assess the effect on insulin sensitivity, rats received 5 mg/kg KBP-042 for 21 days before hyperinsulinemic-euglycemic clamp. Results: KBP-042 induced a sustained weight loss of up to 20% without any significant weight reduction in the pair-fed groups. Decreases in adipose tissues and lipid deposition in the liver were observed, while plasma adiponectin was increased and plasma leptin levels were decreased. Acute administration of KBP-042 led to impaired glucose tolerance and increased plasma lactate, while this diabetogenic effect was reversed by chronic treatment. Finally, assessment of insulin sensitivity using the hyperinsulinemiceuglycemic clamp showed that KBP-042 increased the glucose infusion rate. Conclusions: The study indicates that KBP-042 combines two highly relevant features, namely weight loss and insulin sensitivity, and is thus an excellent candidate for chronic treatment of obesity and insulin resistance.

Section: Discussionsupporting

confidence: 89%

The dual amylin‐ and calcitonin‐receptor agonist KBP‐042 increases insulin sensitivity and induces weight loss in rats with obesity

Andreassen

et al. 2016

Obesity

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“…High‐fat feeding resulted in a phenotype with significantly increased body weight (596 ± 12 vs. 545 ± 8 g, P < 0.05), hyperinsulinaemia (1.9 ± 0.1 vs. 0.9 ± 0.1 ng·mL −1 , P < 0.05), impaired glucose control without hyperglycaemia (OGTT tAUC 1343 ± 18.1 vs. 1259 ± 17.1, P < 0.05) and impaired insulin sensitivity (HOMA‐IR) (11.3 ± 0.3 vs. 4.3 ± 0.3, P < 0.05), compared with the lean age‐matched controls. Thus, the HFD rats resembled an obese and pre‐diabetic phenotype as expected from previous studies (Hjuler et al ., ; Gydesen et al ., ).…”

Section: Resultsmentioning

confidence: 99%

“…To investigate the anti‐obesity potential of KBP‐089 in vivo , we treated HFD rats for 8 weeks. Previously, DACRAs have been shown to induce hypophagia (Hjuler et al ., ; Gydesen et al ., ); therefore, a pair‐fed group to the highest concentration of KBP‐089 was included to explore the impact of food restriction on body weight. KBP‐089 was s.c. administered in three doses (0.625, 1.25 and 2.5 μg·kg −1 ) for 56 days.…”

Section: Resultsmentioning

confidence: 99%

“…In vivo studies of DACRAs have recently demonstrated a protection against diet‐induced weight gain, a reduction in overall adiposity, as well as adipocyte hypertrophy (Gydesen et al ., ). Furthermore, DACRAs have been shown to improve glucose homeostasis in the diabetic Zucker Diabetic Fatty ZDF‐Lepr fa /Crl (ZDF) rats, a phenomenon not observed with selective and less potent amylin receptor agonists (Mack et al ., , ; Andreassen et al ., ; Hjuler et al ., ), while alleviating obesity‐derived insulin resistance (Hjuler et al ., ). Hence, the DACRAs induce amylin receptor‐mediated responses in vivo – reduce food intake, results in weight reduction and suppression of glucagon levels (Roth et al ., ), and also have additional beneficial effects on fasting blood glucose and insulin sensitivity.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A novel dual amylin and calcitonin receptor agonist, KBP‐089, induces weight loss through a reduction in fat, but not lean mass, while improving food preference

Freving

et al. 2017

British J Pharmacology

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*These authors contributed equally to this work BACKGROUND AND PURPOSEObesity and associated co-morbidities, such as type 2 diabetes and non-alcoholic fatty liver disease, are major health challenges. Hence, there is an important need to develop weight loss therapies with the ability to reduce the co-morbidities. EXPERIMENTAL APPROACHThe effect of the dual amylin and calcitonin receptor agonist (DACRA), KBP-089, on body weight, glucose homeostasis and fatty acid accumulation in liver and muscle tissue and on food preference was investigated. Furthermore, we elucidated weightindependent effects of KBP-089 using a weight-matched group. KEY RESULTSRats fed a high-fat diet were treated, s.c., with KBP-089 0.625, 1.25, 2.5 μg·kg À1 or vehicle. KB-089 induced in a dose-dependent and sustained weight loss (~17% by 2.5 μg·kg À1 ). Moreover, KBP-089 reduced fat depot size and reduced lipid accumulation in muscle and liver. In Zucker Diabetic Fatty rats, KBP-089 improved glucose homeostasis through improved insulin action. To obtain a weight-matched group, significantly less food was offered (9% less than in the KBP-089 group). Weight matching led to improved glucose homeostasis by reducing plasma insulin; however, these effect were inferior compared to those of KBP-089. In the food preference test, rats fed a normal diet obtained 74% of their calories from chocolate. KBP-089 reduced total caloric intake and induced a relative increase in chow consumption while drastically reducing chocolate consumption compared with vehicle. CONCLUSIONS AND IMPLICATIONSThe novel DACRA, KBP-089, induces a sustained weight loss, leading to improved metabolic parameters including food preference, and these are beyond those observed simply by diet-induced weight loss. AbbreviationsDACRA, dual amylin and calcitonin receptor agonist; FPG, fasting plasma glucose; HbA1c, glycated haemoglobin; HFD, high-fat diet; HOMA-IR, homeostatic model assessment for insulin resistance; IVGTT, i.v IntroductionObesity and associated morbidities, such as diabetes, non-alcoholic fatty liver disease, cardiovascular disease and cancer, are among this century's greatest health challenges (Pi-Sunyer, 1999;Cohen et al., 2008;Aballay et al., 2013). The incidence is increasing and the treatment of obesity is in most cases limited to lifestyle interventions. However, when these fail, bariatric surgery and a few pharmacotherapies are available, although these are only used in cases of severe obesity (Fried et al., 2007). Furthermore, due to the potential complications of surgery, novel therapies with an improved efficacy in terms of weight loss and reduction of co-morbidities are of great interest (Batterham and Cummings, 2016).The most recently developed therapy for obesity is highdose liraglutide, which leads to sustained weight loss at least partially due to a reduction in appetite. Furthermore, liraglutide reduces hyperglycaemia, albeit it is still somewhat limited in terms of efficacy and has challenges on tolerability (Kanoski et al., 2012;Lean et al., 2014). Anot...

“…Weight loss has on multiple occasions been associated with beneficial effects on adipocytokines (14) and leptin metabolism -leptin sensitivity, which has previously been shown to be improved by DACRAs (5). Furthermore, weight loss and reduction in adipose cell size are involved in restoring plasma insulin concentration toward normal, concomitant with the return of normal tissue insulin sensitivity (13), and whether KBP-088 has a direct effect on adipocyte hypertrophy needs further investigations.…”

Section: Discussionmentioning

confidence: 98%

KBP-088, a novel DACRA with prolonged receptor activation, is superior to davalintide in terms of efficacy on body weight

Andreassen

American Journal of Physiology-Endocrinology and Metabolism

et al. 2016

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This study aims to elucidate the mechanism behind the potent weight loss induced by dual amylin and calcitonin receptor agonists (DACRA) through comparison of the novel DACRA KBP-088 with the amylinomimetic davalintide with regard to in vitro receptor pharmacology and in vivo efficacy on food intake and body weight. KBP-088 and davalintide were tested for their ability to activate the amylin and calcitonin receptors as function of dose and time. Two doses of KBP-088 (1.67 and 5.0 μg/kg) were compared with similar davalintide doses in high-fat diet (HFD)-fed rats receiving subcutaneous dosing once daily for 62 days. Glucose tolerance was assessed after 3 and 7 wk of treatment. KBP-088 demonstrated activation of amylin and calcitonin receptors and prolonged receptor activation compared with davalintide as well as a potent reduction of acute food intake. KBP-088 transiently reduced food intake and induced and notably sustained a significant ∼16% vehicle-corrected weight loss without significant weight loss in the calorie-restricted control groups. Additionally, KBP-088 reduced white adipose tissues and adipocyte hypertrophy. Finally, KBP-088 alleviated hyperinsulinemia and improved oral glucose tolerance even with significantly lower insulin levels after 3 and 7 wk of treatment. KBP-088 is a potent amylin and calcitonin receptor agonist with prolonged receptor activation compared with davalintide. Moreover, KBP-088 induced and sustained significant weight loss and reduced overall adiposity and adipocyte hypertrophy in HFD rats. Finally, KBP-088 improved oral glucose tolerance and alleviated hyperinsulinemia, underscoring the potential of KBP-088 as an antiobesity agent with benefits on glucose control.