Insulin reverses major portal hypertension-related derangements in rats with liver cirrhosis and diabetes

Abstract

Liver cirrhosis is accompanied by increased intrahepatic resistance and angiogenesis-related portosystemic collaterals formation. Diabetic patients suffer from abnormal vasoresponsiveness and angiogenesis that can be ameliorated by glucose control. However, the relevant presentation is not clear in those with cirrhosis and diabetes, in whom insulin is the treatment of choice. Liver cirrhosis was induced in Sprague–Dawley rats with common bile duct ligation (BDL) and sham rats were used as controls. Streptozotocin 60 mg/kg (STZ, i.p., to induce diabetes) or vehicle was injected. The rats received BDL and STZ injections were injected with insulin or vehicle. On the 29th day after the procedure, the groups were surveyed for (1) systemic and portal hemodynamics; (2) mesenteric vascular density; (3) severity of portosystemic collaterals; (4) hepatic resistance using in situ liver perfusion; (5) histology survey of mesentery and liver; and (6) mesentery angiogenesis- and liver fibrogenesis-related protein expressions. Compared with the cirrhotic rats, the cirrhotic diabetic rats had lower body weight, cardiac output, superior mesenteric arterial (SMA) resistance and portal venous (PV) resistance, and higher SMA and PV flow, which were mostly reversed by insulin. The cirrhotic diabetic rats also had increased mesenteric vascular density, and enhanced pERK, pAkt, VEGF, VEGFR2 protein expressions that were reversed by insulin. Insulin decreased the degree of shunting in the diabetic cirrhotic rats. Hepatic perfusion pressure and severity of liver fibrosis were not significantly influenced by diabetes and insulin treatment in the cirrhotic rats. In conclusion, diabetes aggravated hemodynamic derangements, mesenteric angiogenesis and collaterals in the cirrhotic rats, which were mostly ameliorated by insulin. Further clinical investigations are warranted.

Fluid dynamics analyses of the intrahepatic portal vein tributaries using 7-T MRI

“…In humans, Doppler ultrasound has been the standard modality for this purpose; 10 yet it often yields incomplete or inaccurate hemodynamic data due to the limited size of acoustic windows, which can be compounded by overlying gas-filled bowels, 11 observer variability, 12 the difficulty of visualizing complex PV branches, 11 and the inability to measure three-dimensionally-variable flow using a 2D scanning technique. In small animals, flow meters, [13][14][15] lase specs, 16 and microspheres, 17,18 have been used to evaluate PV flow, but these modalities are too invasive to be used repeatedly, and the flow velocity data they provide is insufficiently detailed. Alternatively, several studies have used MRI to evaluate PV flow in humans and rodents, 19,20 concluding that MRI offers several advantages over the aforementioned modalities, including noninvasiveness, objectivity as opposed to examiner dependence, and a three-dimensional scanning area.…”

Selection and Warning of Evidence-Based Antidiabetic Medications for Patients With Chronic Liver Disease

“…However, insulin has been reported to decrease intrahepatic fat content in drug-naïve patients with T2D ( 90 ). It reversed major portal hypertension-related derangements in rats with diabetes and liver cirrhosis ( 91 ). Elkrief et al ( 92 ) reported that 62% of 348 patients with hepatitis C-related cirrhosis were on insulin therapy ( Table 1 ).…”