From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options

Abstract

The worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) is estimated to have reached 25% or more in adults. NAFLD is prevalent in obese individuals, but may also affect nonobese insulin-resistant individuals. NAFLD is associated with a 2-to 3-fold increased risk of developing type 2 diabetes (T2D), which may be higher in patients with more severe liver diseasefibrosis increases this risk. In NAFLD, not only the close association with obesity, but also the impairment of many metabolic pathways, including decreased hepatic insulin sensitivity and insulin secretion, increase the risk of developing T2D and related comorbidities. Conversely, patients with diabetes have a higher prevalence of steatohepatitis, liver fibrosis and end-stage liver disease. Genetics and mechanisms involving dysfunctional adipose tissue, lipotoxicity and glucotoxicity appear to play a role. In this review, we discuss the altered pathophysiological mechanisms that underlie the development of T2D in NAFLD and vice versa. Although there is no approved therapy for the treatment of NASH, we discuss pharmacological agents currently available to treat T2D that could potentially be useful for the management of NASH.

A diabetologist’s perspective of non‐alcoholic steatohepatitis (NASH): Knowledge gaps and future directions

“…One would expect that intensive lifestyle or pharmacological interventions (at least with pioglitazone as proven in five randomized controlled trials [RCTs]) see (Table ) would reduce the risk of cirrhosis in this population. Furthermore, worse micro‐ and macrovascular complications may occur in patients with NAFL or NASH . Diabetologists are becoming increasingly aware that NASH should be screened for in the same way as diabetic retinopathy or nephropathy.…”

“…The mechanisms remain poorly understood but include among others, genetic factors, insulin resistance, dysfunctional adipose tissue (lipotoxicity), chronic hyperglycemia (“glucose toxicity” or glucotoxicity), altered gut microbiome and many others. Recent in‐depth reviews have examined the many genetic and environmental factors at play. NASH may accelerate the progression of prediabetes to diabetes and make it more difficult to control.…”

“…NASH may accelerate the progression of prediabetes to diabetes and make it more difficult to control. On the other hand, diabetes itself appears to accelerate steatohepatitis and the progression of fibrosis to cirrhosis, although there are few controlled prospective studies to date. In a recent small head‐to‐head analysis more significant fibrosis progression was found in 18 months in patients with diabetes than in those without.…”

“…The links between diabetes and NAFLD are complex and bidirectional, with one worsening the other and vice-versa. 10 The mechanisms remain poorly understood but include among others, genetic factors, insulin resistance, dysfunctional adipose tissue (lipotoxicity), chronic hyperglycemia ("glucose toxicity" or glucotoxicity), altered gut microbiome and many others. Recent in-depth reviews [10][11][12][13][14] have examined the many genetic and environmental factors at play.…”

“…Furthermore, worse micro-and macrovascular complications may occur in patients with NAFL or NASH. 6,10 Diabetologists are becoming increasingly aware that NASH should be screened for in the same way as diabetic retinopathy or nephropathy.…”