Cover Story Current Issue

Non-alcoholic fatty liver disease (NAFLD) encompasses a set of pathologies associated with ectopic lipid accumulationin hepatocytes. NAFLD can progress to non-alcoholic steatohepatitis (NASH), an inflammatory condition which is increasing in prevalence in parallel with other diseases connected to lipid metabolism, such as type 2 diabetes and cardiovascular disease. NASH is characterized by hepatic necrosis, increased inflammatory signaling, immune cell infiltration, and the potential to progress to fibrosis, cirrhosis, hepatocellular carcinoma, and ultimately liver failure.

David Montefusco, Maryam Jamil, Melissa A. Maczis, William Schroeder, ... L. Ashley Cowart

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Current Issue

Increased glycolysis affects β-cell function and identity in aging and diabetes

Naoya Murao, Norihide Yokoi, Harumi Takahashi, Tomohide Hayami, ... Susumu Seino

Objective

Age is a risk factor for type 2 diabetes (T2D). We aimed to elucidate whether β-cell glucose metabolism is altered with aging and contributes to T2D.

Methods

We used senescence-accelerated mice (SAM), C57BL/6J (B6) mice, and ob/ob mice as aging models. As a diabetes model, we used db/db mice. The glucose responsiveness of insulin secretion and the [U-13C]-glucose metabolic flux were examined in isolated islets. We analyzed the expression of β-cell-specific genes in isolated islets and pancreatic sections as molecular signatures of β-cell identity. β cells defective in the malate-aspartate (MA) shuttle were previously generated from MIN6-K8 cells by the knockout of Got1, a component of the shuttle. We analyzed Got1 KO β cells as a model of increased glycolysis.

Results

We identified hyperresponsiveness to glucose and compromised cellular identity as dysfunctional phenotypes shared in common between aged and diabetic mouse β cells. We also observed a metabolic commonality between aged and diabetic β cells: hyperactive glycolysis through the increased expression of nicotinamide mononucleotide adenylyl transferase 2 (Nmnat2), a cytosolic nicotinamide adenine dinucleotide (NAD)-synthesizing enzyme. Got1 KO β cells showed increased glycolysis, β-cell dysfunction, and impaired cellular identity, phenocopying aging and diabetes. Using Got1 KO β cells, we show that attenuation of glycolysis or Nmnat2 activity can restore β-cell function and identity.

Conclusions

Our study demonstrates that hyperactive glycolysis is a metabolic signature of aged and diabetic β cells, which may underlie age-related β-cell dysfunction and loss of cellular identity. We suggest Nmnat2 suppression as an approach to counteract age-related T2D.

Increased glycolysis affects β-cell function and identity in aging and diabetes

Naoya Murao, Norihide Yokoi, Harumi Takahashi, Tomohide Hayami, ... Susumu Seino

Objective

Age is a risk factor for type 2 diabetes (T2D). We aimed to elucidate whether β-cell glucose metabolism is altered with aging and contributes to T2D.

Methods

We used senescence-accelerated mice (SAM), C57BL/6J (B6) mice, and ob/ob mice as aging models. As a diabetes model, we used db/db mice. The glucose responsiveness of insulin secretion and the [U-13C]-glucose metabolic flux were examined in isolated islets. We analyzed the expression of β-cell-specific genes in isolated islets and pancreatic sections as molecular signatures of β-cell identity. β cells defective in the malate-aspartate (MA) shuttle were previously generated from MIN6-K8 cells by the knockout of Got1, a component of the shuttle. We analyzed Got1 KO β cells as a model of increased glycolysis.

Results

We identified hyperresponsiveness to glucose and compromised cellular identity as dysfunctional phenotypes shared in common between aged and diabetic mouse β cells. We also observed a metabolic commonality between aged and diabetic β cells: hyperactive glycolysis through the increased expression of nicotinamide mononucleotide adenylyl transferase 2 (Nmnat2), a cytosolic nicotinamide adenine dinucleotide (NAD)-synthesizing enzyme. Got1 KO β cells showed increased glycolysis, β-cell dysfunction, and impaired cellular identity, phenocopying aging and diabetes. Using Got1 KO β cells, we show that attenuation of glycolysis or Nmnat2 activity can restore β-cell function and identity.

Conclusions

Our study demonstrates that hyperactive glycolysis is a metabolic signature of aged and diabetic β cells, which may underlie age-related β-cell dysfunction and loss of cellular identity. We suggest Nmnat2 suppression as an approach to counteract age-related T2D.

2021 impact factor: 8.568

The 60 Second Metabolist

In this section authors briefly report on their work recently published in Molecular Metabolism.

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