Objective: The current set of studies describe the in vivo metabolic actions of the novel amylin-mimetic peptide davalintide (AC2307) in rodents and compares these effects with those of the native ...peptide. Research design and methods: The anti-obesity effects of davalintide were examined after intraperitoneal injection or sustained peripheral infusion through subcutaneously implanted osmotic pumps. The effect of davalintide on food intake after lesioning of the area postrema (AP) and neuronal activation as measured by c-Fos, were also investigated. Results: Similar to amylin, davalintide bound with high affinity to amylin, calcitonin and calcitonin gene-related peptide receptors. Acutely, davalintide displayed greater suppression of dark-cycle feeding and an extended duration of action compared with amylin (23 versus 6 h). Davalintide had no effect on locomotor activity or kaolin consumption at doses that decreased food intake. Davalintide-induced weight loss through infusion was dose dependent, durable up to 8 weeks, fat-specific and lean-sparing, and was associated with a shift in food preference away from high-fat (palatable) chow. Metabolic rate was maintained during active weight loss. Both davalintide and amylin failed to suppress food intake after lesioning of the AP and activated similar brain nuclei, with davalintide displaying an extended duration of c-Fos expression compared with amylin (8 versus 2 h). Conclusion: Davalintide displayed enhanced in vivo metabolic activity over amylin while retaining the beneficial properties possessed by the native molecule. In vitro receptor binding, c-Fos expression and AP lesion studies suggest that the metabolic actions of davalintide and amylin occur through activation of similar neuronal pathways.
Exenatide (exendin-4) is an incretin mimetic currently marketed as an antidiabetic agent for patients with type 2 diabetes. In preclinical models, a reduction in body weight has also been shown in ...low-fat-fed, leptin receptor-deficient rodents.
To more closely model the polygenic and environmental state of human obesity, we characterized the effect of exenatide on food intake and body weight in high-fat-fed, normal (those with an intact leptin signaling system) rodents. As glucagon-like peptide-1 receptor agonism has been found to elicit behaviors associated with visceral illness in rodents, we also examined the effect of peripheral exenatide on kaolin consumption and locomotor activity.
High-fat-fed C57BL/6 mice and Sprague-Dawley rats were treated with exenatide (3, 10 and 30 microg/kg/day) for 4 weeks via subcutaneously implanted osmotic pumps. Food intake and body weight were assessed weekly. At 4 weeks, body composition and plasma metabolic profiles were measured. Kaolin consumption and locomotor activity were measured in fasted Sprague-Dawley rats following a single intraperitoneal injection of exenatide (0.1-10 microg/kg). Exenatide treatment in mice and rats dose-dependently decreased food intake and body weight; significant reductions in body weight gain were observed throughout treatment at 10 and 30 microg/kg/day (P<0.05). Decreased body weight gain was associated with a significant decrease in fat mass (P<0.05) with sparing of lean tissue. Plasma cholesterol, triglycerides and insulin were also significantly reduced (P<0.05). Exenatide at 10 microg/kg significantly reduced food intake (P<0.05) but failed to induce kaolin intake. In general, locomotor activity was reduced at doses of exenatide that decreased food intake, although a slightly higher dose was required to produce significant changes in activity.
Systemic exenatide reduces body weight gain in normal, high-fat-fed rodents, a model that parallels human genetic variation and food consumption patterns, and may play a role in metabolic pathways mediating food intake.
Peptide YY (PYY) is a 36 amino-acid peptide secreted from ileal L cells following meals. The cleaved subpeptide PYY3-36 is biologically active and may constitute the majority of circulating PYY-like ...immunoreactivity. The peptide family that includes PYY, pancreatic peptide and neuropeptide Y is noted for its orexigenic effect following intracerebroventricular administration.
To investigate the effects of peripheral (intraperitoneal and chronic subcutaneous) infusions of PYY3-36 on food intake, body weight and glycemic indices.
Food intake was measured in normal mice and in several rodent models of obesity and type II diabetes. In marked contrast to the reported central orexigenic effects, in the present study, PYY3-36 acutely inhibited food intake by up to 45%, with an ED(50) of 12.5 microg/kg in fasted female NIH/Swiss mice. A 4-week infusion reduced weight gain in female ob/ob mice, without affecting the cumulative food intake. In diet-induced obese male mice, PYY3-36 infusion reduced cumulative food intake, weight gain and epididymal fat weight (as a fraction of carcass) with similar ED(50)'s (466, 297 and 201 microg/kg/day, respectively) and prevented a diet-induced increase in HbA1c. Infusion at 100 microg/kg/day for 8 weeks in male fa/fa rats reduced the weight gain (288+/-11 vs 326+/-12 g in saline-infused controls; P<0.05), similar to effects in a pair-fed group. In female ob/ob and db/db mice, there was no acute effect of PYY3-36 on plasma glucose concentrations. In male diabetic fatty Zucker rats, PYY3-36 infused for 4 weeks reduced HbA1c and fructosamine (ED(50)'s 30 and 44 microg/kg/day).
Peripheral PYY3-36 administration reduced the food intake, body weight gain and glycemic indices in diverse rodent models of metabolic disease of both sexes. These findings justify further exploration of the potential physiologic and therapeutic roles of PYY3-36.
Aims: Davalintide is a second‐generation amylinomimetic peptide possessing enhanced pharmacological properties over rat amylin to reduce food intake in preclinical models. The current experiments in ...rats describe additional glucoregulatory actions of davalintide consistent with amylin agonism, and explore the duration of action of these effects.
Methods: Subcutaneous (SC) injection of davalintide slowed gastric emptying with equal potency to amylin (ED50's = 2.3 and 4.1 µg/kg). This effect was maintained for 8 h with davalintide, but not amylin. Intraperitoneal injection of davalintide also reduced food intake with a potency similar to amylin (ED50's = 5.0 and 11.3 µg/kg). Consistent with amylin agonism, davalintide (10 µg/kg, SC) suppressed the plasma glucagon response over 90 min following an intravenous arginine bolus in anaesthetized rats. The elimination t1/2 of davalintide (200 µg/kg, SC) was 26 min, similar to the t1/2 of amylin, suggesting that pharmacokinetic‐independent mechanisms contribute to davalintide's enhanced duration of action. Binding kinetic studies using 125I davalintide revealed no appreciable dissociation from the amylin nucleus accumbens receptor after 7 h while 125I rat amylin did dissociate from this receptor (Koff = 0.013/min). Sustained SC infusion of davalintide (275 µg/kg/day) or amylin (300) decreased plasma glucose after an oral glucose challenge at 2 weeks (by 27 and 31%) and suppressed gastric emptying at 3 weeks (by 29 and 47%), demonstrating durable glucoregulatory actions of both peptides.
Conclusions: These data show glucoregulatory properties of davalintide consistent with amylin agonism and suggest that slowed receptor dissociation plays a role in davalintide's prolonged pharmacodynamic actions.
In rodents, weight reduction after peptide YY3-36 (PYY3-36) administration may be due largely to decreased food consumption. Effects on other processes affecting energy balance (energy expenditure, ...fuel partitioning, gut nutrient uptake) remain poorly understood. We examined whether s.c. infusion of 1 mg/(kg·d) PYY3-36 (for up to 7 d) increased metabolic rate, fat combustion, and/or fecal energy loss in obese mice fed a high-fat diet. PYY3-36 transiently reduced food intake (e.g., 25-43% lower at d 2 relative to pretreatment baseline) and decreased body weight (e.g., 9-10% reduction at d 2 vs. baseline) in 3 separate studies. Mass-specific metabolic rate in kJ/(kg·h) in PYY3-36-treated mice did not differ from controls. The dark cycle respiratory quotient (RQ) was transiently decreased. On d 2, it was 0.747 ± 0.008 compared with 0.786 ± 0.004 for controls (P < 0.001); light cycle RQ was reduced throughout the study in PYY3-36-treated mice (0.730 ± 0.006) compared with controls (0.750 ± 0.009; P < 0.001). Epididymal fat pad weight in PYY3-36-treated mice was approximately50% lower than in controls (P < 0.01). Fat pad lipolysis ex vivo was not stimulated by PYY3-36. PYY3-36 decreased basal gallbladder emptying in nonobese mice. Fecal energy loss was negligible (approximately2% of ingested energy) and did not differ between PYY3-36-treated mice and controls. Thus, negative energy balance after PYY3-36 administration in diet-induced obese mice results from reduced food intake with a relative maintenance of mass-specific energy expenditure. Fat loss and reduced RQ highlight the potential for PYY3-36 to drive increased mobilization of fat stores to help meet energy requirements in this model.
Aim
Glucose‐dependent insulinotropic peptide (GIP) is an incretin hormone that is released from intestinal K cells in response to nutrient ingestion. We aimed to investigate the therapeutic potential ...of the novel N‐ and C‐terminally modified GIP analogue AC163794.
Methods
AC163794 was synthesized by solid‐phase peptide synthesis. Design involved the substitution of the C‐terminus tail region of the dipeptidyl peptidase IV (DPP‐IV)‐resistant GIP analogue d‐Ala2GIP(1–42) with the unique nine amino acid tail region of exenatide. The functional activity and binding of AC163794 to the GIP receptor were evaluated in RIN‐m5F β‐cells. In vitro metabolic stability was tested in human plasma and kidney membrane preparations. Acute insulinotropic effects were investigated in isolated mouse islets and during an intravenous glucose tolerance test in normal and diabetic Zucker fatty diabetic (ZDF) rats. The biological actions of AC163794 were comprehensively assessed in normal, ob/ob and high‐fat‐fed streptozotocin (STZ)‐induced diabetic mice. Acute glucoregulatory effects of AC163794 were tested in diet‐induced obese mice treated subchronically with AC3174, the exendatide analogue Leu14 exenatide. Human GIP or d‐Ala2GIP(1–42) were used for comparison.
Results
AC163794 exhibited nanomolar functional GIP receptor potency in vitro similar to GIP and d‐Ala2GIP(1–42). AC163794 was metabolically more stable in vitro and displayed longer duration of insulinotropic action in vivo versus GIP and d‐Ala2GIP(1–42). In diabetic mice, AC163794 improved HbA1c through enhanced insulinotropic action, partial restoration of pancreatic insulin content and improved insulin sensitivity with no adverse effects on fat storage and metabolism. AC163794 provided additional baseline glucose‐lowering when injected to mice treated with AC3174.
Conclusions
These studies support the potential use of a novel GIP analogue AC163794 for the treatment of type 2 diabetes.
Exendin-4 is a 39 amino acid peptide isolated from the salivary secretions of the Gila monster (Heloderma suspectum). It shows 53% sequence similarity to glucagon-like peptide (GLP)-1. Unlike GLP-1, ...exendin-4 has a prolonged glucose-lowering action in vivo. We compared the potency and duration of glucose-lowering effects of exendin-4 and GLP-1 in hyperglycemic db/db and ob/ob mice. Whereas reductions in plasma glucose of up to 35% vanished within 1 h with most doses of GLP-1, the same doses of exendin-4 resulted in a similar glucose-lowering effect that persisted for >4 h. Exendin-4 was 5,530-fold more potent than GLP-1 in db/db mice (effective doses, 50% ED50s of 0.059 microg/kg +/-0.15 log and 329 microg/kg+/-0.22 log, respectively) and was 5,480-fold more potent in ob/ob mice (ED50s of 0.136 microg/kg+/-0.10 log and 744 microg/kg+/-0.21 log, respectively) when the percentage fall in plasma glucose at 1 h was used as the indicator response. Exendin-4 dose-dependently accelerated glucose lowering in diabetic rhesus monkeys by up to 37% with an ED50 of 0.25 microg/kg +/-0.09 log. In two experiments in which diabetic fatty Zucker rats were injected subcutaneously twice daily for 5-6 weeks with doses of exendin-4 up to 100 microg x rat(-1) x day(-1) (approximately 250 microg/kg), HbA1c was reduced relative to saline-injected control rats. Exendin-4 treatment was also associated in each of these experiments with weight loss and improved insulin sensitivity, as demonstrated by increases of up to 32 and 49%, respectively, in the glucose infusion rate (GIR) in the hyperinsulinemic euglycemic clamp. ED50s for weight loss and the increase in clamp GIR were 1.0 microg/kg+/-0.15 log and 2.4 microg/kg+/-0.41 log, respectively. In conclusion, acute and chronic administration of exendin-4 has demonstrated an antidiabetic effect in several animal models of type 2 diabetes.
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