Oral salmon calcitonin attenuates hyperglycaemia and preserves pancreatic beta‐cell area and function in Zucker diabetic fatty rats

Abstract

BACKGROUND AND PURPOSE Oral salmon calcitonin (sCT), a dual‐action amylin and calcitonin receptor agonist, improved glucose homeostasis in diet‐induced obese rats. Here, we have evaluated the anti‐diabetic efficacy of oral sCT using parameters of glycaemic control and beta‐cell morphology in male Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. EXPERIMENTAL APPROACH Male ZDF rats were treated with oral sCT (0.5, 1.0 or 2 mg·kg−1) or oral vehicle twice daily from age 8 to 18 weeks. Zucker lean rats served as control group. Fasting and non‐fasted blood glucose, glycosylated haemoglobin (HbA1c) and levels of pancreas and incretin hormones were determined. Oral glucose tolerance test and i.p. glucose tolerance test were compared, and beta‐cell area and function were evaluated. KEY RESULTS Oral sCT treatment dose‐dependently attenuated fasting and non‐fasted hyperglycaemia during the intervention period. At the end of the study period, oral sCT treatment by dose decreased diabetic hyperglycaemia by ∼9 mM and reduced HbA1c levels by 1.7%. Furthermore, a pronounced reduction in glucose excursions was dose‐dependently observed for oral sCT treatment during oral glucose tolerance test. In addition, oral sCT treatment sustained hyperinsulinaemia and attenuated hyperglucagonaemia and hypersecretion of total glucagon‐like peptide‐1 predominantly in the basal state. Lastly, oral sCT treatment dose‐dependently improved pancreatic beta‐cell function and beta‐cell area at study end. CONCLUSIONS AND IMPLICATIONS Oral sCT attenuated diabetic hyperglycaemia in male ZDF rats by improving postprandial glycaemic control, exerting an insulinotropic and glucagonostatic action in the basal state and by preserving pancreatic beta‐cell function and beta‐cell area.

Novel antidiabetic nutrients identified by in vivo screening for gastric secretion and emptying regulation in rats

“…The effect of two other classes of antidiabetic drugs i.e., amylin and GLP-1 analogs, rely, at least in part, on their gastric action. Amylin's or its synthetic analog pramlintide's antidiabetic effects act on three fronts: they inhibit glucagon secretion, they inhibit food intake, and they delay gastric emptying (2,11,27,37). Our data support this view, as amylin reduced postprandial hyperglycemia, independent of whether glucose was applied intraduodenally or intraperitoneally (Fig.…”

“…In agreement with its pharmacological role, amylin reduced postprandial hyperglycemia and plasma insulin concentration (Fig. 5, A and G) (11,27), whereas L-alanine had no significant effect (Fig. 5, B and H).…”

“…We did not observe a reduction of blood glucose concentrations within this modified IP GTT for candidate nutrients, whereas amylin had a significant effect as expected (Fig. 6, A-F) (11,27). To further delineate whether only the impact of candidate nutrients on gastric function or alternatively on the small intestine is relevant for the observed reduction in postprandial hyperglycemia, we administered glucose by an ID infusion catheter (Fig.…”

Amylin: Pharmacology, Physiology, and Clinical Potential

“…This enables the complex to access the higher pH environment in the upper small intestine intact and then dissociate enabling improved systemic absorption (reviewed in Karsdal et al, 2011). In DIO rats, oral gavage of this formulation reduced glucose and insulin area under the curve during an oral glucose tolerance test, and weight-lowering effects in various models have also been achieved (Feigh et al, 2011(Feigh et al, , 2012. These findings highlight the potential for oral delivery of amylin agonists rather than via multiple daily injections.…”

A novel oral dual amylin and calcitonin receptor agonist (KBP-042) exerts antiobesity and antidiabetic effects in rats

“…Recently, oral delivery of salmon calcitonin (sCT) demonstrated glucoregulatory efficacy by improved fasting and postprandial glycemic control, with a concomitant weight loss in diet-induced obese (DIO) rats (15,31). Importantly, oral sCT attenuated diabetic hyperglycemia and preserved pancreatic ␤-cell function and mass in Zucker diabetic fatty (ZDF) rats (14). Hence, novel oral peptides with these abilities could be promising interventions in type 2 diabetes.…”