Insulin treatment improves liver histopathology and decreases expression of inflammatory and fibrogenic genes in a hyperglycemic, dyslipidemic hamster model of NAFLD

Abstract Background Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are highly prevalent comorbidities in patients with Type 2 diabetes. While many of these patients eventually will need treatment with insulin, little is known about the effects of insulin treatment on histopathological parameters and hepatic gene expression in diabetic patients with co-existing NAFLD and NASH. To investigate this further, we evaluated the effects of insulin treatment in NASH diet-fed hamsters with streptozotocin (STZ) -induced hyperglycemia. Methods Forty male Syrian hamsters were randomized into four groups (n = 10/group) receiving either a NASH-inducing (high fat, fructose and cholesterol) or control diet (CTRL) for four weeks, after which they were treated with STZ or sham-injected and from week five treated with either vehicle (CTRL, NASH, NASH-STZ) or human insulin (NASH-STZ-HI) for four weeks by continuous s.c. infusion via osmotic minipumps. Results NASH-STZ hamsters displayed pronounced hyperglycemia, dyslipidemia and more severe liver pathology compared to both CTRL and NASH groups. Insulin treatment attenuated dyslipidemia in NASH-STZ-HI hamsters and liver pathology was considerably improved compared to the NASH-STZ group, with prevention/reversal of hepatic steatosis, hepatic inflammation and stellate cell activation. In addition, expression of inflammatory and fibrotic genes was decreased compared to the NASH-STZ group. Conclusions These results suggest that hyperglycemia is important for development of inflammation and profibrotic processes in the liver, and that insulin administration has beneficial effects on liver pathology and expression of genes related to inflammation and fibrosis in a hyperglycemic, dyslipidemic hamster model of NAFLD.

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Empagliflozin Improves Metabolic and Hepatic Outcomes in a Non-Diabetic Obese Biopsy-Proven Mouse Model of Advanced NASH

International Journal of Molecular Sciences ◽

10.3390/ijms22126332 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6332

Author(s):

Nikolaos Perakakis ◽

Pavlina Chrysafi ◽

Michael Feigh ◽

Sanne Skovgard Veidal ◽

Christos S. Mantzoros

Keyword(s):

Mouse Model ◽

Cell Activation ◽

Stellate Cell ◽

Liver Steatosis ◽

Tolerance Test ◽

The Body ◽

Oral Glucose ◽

Alcoholic Fatty Liver ◽

Metabolic Outcomes ◽

Anti Inflammatory

Empagliflozin, an established treatment for type 2 diabetes (T2DM), has shown beneficial effects on liver steatosis and fibrosis in animals and in humans with T2DM, non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). However, little is known about the effects of empagliflozin on liver function in advanced NASH with liver fibrosis and without diabetes. This study aimed to assess the effects of empagliflozin on hepatic and metabolic outcomes in a diet-induced obese (DIO) and insulin-resistant but non-diabetic biopsy-confirmed mouse model of advanced NASH. Male C57BL/6JRj mice with a biopsy-confirmed steatosis and fibrosis on AMLN diet (high fat, fructose and cholesterol) for 36-weeks were randomized to receive for 12 weeks: (a) Empagliflozin (10 mg/kg/d p.o.), or (b) vehicle. Metabolic outcomes, liver pathology, markers of Kupffer and stellate cell activation and lipidomics were assessed at the treatment completion. Empagliflozin did not affect the body weight, body composition or insulin sensitivity (assessed by intraperitoneal insulin tolerance test), but significantly improved glucose homeostasis as assessed by oral glucose tolerance test in DIO-NASH mice. Empagliflozin improved modestly the NAFLD activity score compared with the vehicle, mainly by improving inflammation and without affecting steatosis, the fibrosis stage and markers of Kupffer and stellate cell activation. Empagliflozin reduced the hepatic concentrations of pro-inflammatory lactosylceramides and increased the concentrations of anti-inflammatory polyunsaturated triglycerides. Empagliflozin exerts beneficial metabolic and hepatic (mainly anti-inflammatory) effects in non-diabetic DIO-NASH mice and thus may be effective against NASH even in non-diabetic conditions.

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SGLT-2 Inhibitors: Are They a Promising Treatment Option in T2DM Patients with NAFLD?

Acta Medica (Hradec Kralove Czech Republic) ◽

10.14712/18059694.2018.15 ◽

2017 ◽

Vol 60 (4) ◽

pp. 167-170 ◽

Cited By ~ 2

Author(s):

Dimitrios Patoulias

Keyword(s):

Treatment Option ◽

Specific Treatment ◽

Liver Function Tests ◽

Diabetic Patients ◽

Efficacy And Safety ◽

Alcoholic Fatty Liver ◽

Beneficial Effects ◽

Co Morbidity ◽

Promising Treatment

Sodium glucose co-transporter type 2 inhibitors (SGLT-2 inhibitors) are a class of antidiabetics, recently approved for the treatment of patients with T2DM. They feature cardioprotective and renoprotective action, while they exert beneficial effects on metabolic parameters. Non-alcoholic fatty liver disease (NAFLD) is a frequent co-morbidity in diabetic patients. Its prevalence reaches up to 70%. Since there is no specific treatment approved for NAFLD, both experimental and clinical studies have been recently conducted highlighting the efficacy and safety of SGLT-2 inhibitors mainly in animal models and secondarily in patients with T2DM and NAFLD. This class of antidiabetics seems very attractive, improving both glycemic control and liver function tests, while inhibiting NAFLD progression. However, further investigation is required to establish them as a first-line treatment option in T2DM patients with NAFLD, after thorough assessment of their efficacy and safety in clinical practice.

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Pharmacological Macrophage Attenuation by Imatinib Reverts Hepatic Steatosis and Inflammation in Obese Mice

10.1101/241224 ◽

2017 ◽

Author(s):

Shefaa AlAsfoor ◽

Theresa V. Rohm ◽

Angela J. T. Bosch ◽

Thomas Dervos ◽

Diego Calabrese ◽

...

Keyword(s):

Hepatic Steatosis ◽

Immune Modulation ◽

Diabetic Patients ◽

Human Monocytes ◽

Obese Mice ◽

Alcoholic Fatty Liver ◽

Murine Macrophages ◽

Beneficial Effects

AbstractAimsNon-alcoholic fatty liver disease (NAFLD) has become one of the most common liver diseases worldwide. As macrophages play a key role in NAFLD, therapies targeting macrophages have been postulated. Indeed, strategies depleting macrophages or blocking monocyte recruitment into the liver improve NAFLD, however, are not feasible in clinical practice. Our goal was to assess whether attenuation of macrophages can be achieved by imatinib, an anti-leukemia drug with known anti-inflammatory and anti-diabetic properties, and how this impacts NAFLD.Materials and MethodsMurine macrophages were polarized in vitro to different activation states in the presence or absence of imatinib; mice on high fat diet orally treated with imatinib or vehicle; and human monocytes of diabetic patients and healthy controls treated with or without imatinib for translational application.ResultsImatinib specifically attenuated pro-inflammatory murine macrophages in vitro and in vivo. In livers of obese mice, imatinib caused Kupffer cells to adopt an attenuated phenotype via modulation of the TNFα-pathway. This immune-modulation resulted in markedly improved hepatic steatosis along with beneficial effects on liver function, lipids and systemic inflammation. The immune-dampening effect of imatinib also prevailed in human monocytes, indicating translational applicability.ConclusionsImmune-modulation of myeloid cells as exemplified by imatinib may be a novel therapeutic strategy in patients with NAFLD.

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Healing gone wrong: convergence of hemostatic pathways and liver fibrosis?

Clinical Science ◽

10.1042/cs20191102 ◽

2020 ◽

Vol 134 (16) ◽

pp. 2189-2201

Author(s):

Jessica P.E. Davis ◽

Stephen H. Caldwell

Keyword(s):

Wound Healing ◽

Liver Disease ◽

Hepatic Fibrosis ◽

Cell Activation ◽

Stellate Cell ◽

Factor Xa ◽

Clinical Trial Data ◽

Chronic Liver ◽

Healing Response ◽

Wound Healing Response

Abstract Fibrosis results from a disordered wound healing response within the liver with activated hepatic stellate cells laying down dense, collagen-rich extracellular matrix that eventually restricts liver hepatic synthetic function and causes increased sinusoidal resistance. The end result of progressive fibrosis, cirrhosis, is associated with significant morbidity and mortality as well as tremendous economic burden. Fibrosis can be conceptualized as an aberrant wound healing response analogous to a chronic ankle sprain that is driven by chronic liver injury commonly over decades. Two unique aspects of hepatic fibrosis – the chronic nature of insult required and the liver’s unique ability to regenerate – give an opportunity for pharmacologic intervention to stop or slow the pace of fibrosis in patients early in the course of their liver disease. Two potential biologic mechanisms link together hemostasis and fibrosis: focal parenchymal extinction and direct stellate cell activation by thrombin and Factor Xa. Available translational research further supports the role of thrombosis in fibrosis. In this review, we will summarize what is known about the convergence of hemostatic changes and hepatic fibrosis in chronic liver disease and present current preclinical and clinical data exploring the relationship between the two. We will also present clinical trial data that underscores the potential use of anticoagulant therapy as an antifibrotic factor in liver disease.

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The Effect of Insulin Treatment on the Balance between Tissue Plasminogen Activator and Plasminogen Activator Inhibitor-1 in Type 2 Diabetic Patients

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656359 ◽

1992 ◽

Vol 68 (03) ◽

pp. 253-256 ◽

Cited By ~ 23

Author(s):

Thomas Vukovich ◽

Sylvia Proidl ◽

Paul Knöbl ◽

Harald Teufelsbauer ◽

Christoph Schnack ◽

...

Keyword(s):

Plasminogen Activator ◽

Insulin Treatment ◽

Plasminogen Activator Inhibitor ◽

Diabetic Patients ◽

Plasminogen Activator Inhibitor 1 ◽

Type 2 Diabetic Patients ◽

Glycemic Regulation ◽

Type 2 Diabetic ◽

Pai 1

SummaryBeside hypercoagulation and hyperactivated platelets disturbances of the fibrinolytic system towards hypofibrinolysis have been reported to be associated with both glycemic and lipidemic derangement in diabetic patients. In the present prospective follow-up study the effect of 16 weeks insulin treatment and glycemic regulation on plasma levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1), the main regulators of fibrinolysis, was investigated in 19 type-2 diabetic patients with secondary failure to sulphonylureas. A similar glycemic regulation was obtained in a control group of 10 type 2 diabetic patients with sufficient metabolic response to strict dietary treatment and continuation of sulphonylurea treatment. Compared to 27 healthy subjects levels of tPA and PAI-1 were not significantly increased in type 2 diabetic patients before metabolic intervention. Although a hypofibrinolytic state due to an increase of PAI-1 levels was previously reported in obese hyperinsulinemic patients, no effect of insulin treatment on both tPA- and PAI-1 levels was observed in the present study including patients with only slightly increased body mass index (median 26.0 kg/m2). By correlation analysis PAI-1 levels were significantly related to serum cholesterol (R = 0.52) and glycemic control (glucose R = 0.41) in the whole group of diabetic patients at entry and in both subgroups after 16 weeks of treatment (insulin group: cholesterol R = 0.46, HbA1c R = 0.51; sulphonylurea group: cholesterol R = 0.59, HbA1c R = 0.58). In healthy subjects tPA and PAI-1 was correlated to serum insulin (R = 0.54, R = 0.56) and triglycerides (R = 0.46, R = 0.40). In conclusion, our results indicate that insulin treatment associated with metabolic improvement has no adverse effect to fibrinolysis in type 2 diabetic patients.

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