Sustained linagliptin administration: superior glycemic control and less pancreatic injury in diabetic rats

• Published in: Pharmaceutical development and technology Vol. 29; no. 8; p. 874
• Main Authors: Zakaria, Esraa M, El-Gamal, Shrouk Fayrouz, Mahmoud, Samar Mortada, El-Nahas, Hanan M, El-Bassossy, Hany M
• Format: Journal Article
• Language: English
• Published: England 01.10.2024
• Subjects: Adiponectin; Administration, Oral; Animals; Blood Glucose - analysis; Blood Glucose - drug effects; Caspase 3 - metabolism; Delayed-Action Preparations; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Type 2 - drug therapy; Dipeptidyl-Peptidase IV Inhibitors - administration & dosage; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Glucose Tolerance Test; Glycemic Control - methods; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacology; Insulin; Linagliptin - administration & dosage; Linagliptin - pharmacology; Male; Pancreas - drug effects; Pancreas - metabolism; Pancreas - pathology; Rats; Rats, Sprague-Dawley; incretins; nano preparation; Linagliptin; type 2 diabetes; sustained release
• ISSN: 1097-9867
• DOI: 10.1080/10837450.2024.2407852

While linagliptin is the most potent dipeptidyl peptidase 4 inhibitor, its use is limited due to poor bioavailability and the potential risk of pancreatic injury. Here, we investigated whether the sustained weekly administration of linagliptin could provide better effect compared to frequent daily oral administration. Type 2 diabetes was induced by feeding rats a high fructose/fat/salt diet followed by STZ injection. Compared to the partial glycemic control achieved with daily oral linagliptin, a weekly subcutaneous injection containing about one-fourth of the oral dose produced superior glycemic control, as evidenced by the 4-week postprandial glucose follow-up and oral glucose tolerance test. This was confirmed by the significant increase in serum insulin in the case of the sustained linagliptin administration. Higher levels of the anti-inflammatory cytokine adiponectin and lower triglyceride levels were observed after sustained linagliptin administration compared with daily oral linagliptin. In addition, sustained linagliptin displayed a significant increase in β-cells' insulin immunoreactivity when compared with daily linagliptin. More reduction in collagen deposition and caspase-3 immunoreactivity in pancreatic tissue were observed in sustained linagliptin compared with oral linagliptin. In conclusion, sustained linagliptin administration provided superior glycemic control, which seems to be mediated by more reduction in pancreatic injury.