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

Abstract

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- 13 C]-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.

Sex differences in islet stress responses support female β cell resilience

“…S2A,B ; Supplementary file 2). While these data do not address the reasons for the sex-biased risk of T2D, and could reflect differences in medication [ [62] , [63] , [64] , [65] ], age [ 12 , 16 , [66] , [67] , [68] ], and body mass index [ 15 , 68 ], our data suggest biological sex influences β cell gene expression in T2D.

Figure 1 Sex differences in human islet transcriptomic and functional responses in type 2 diabetes.

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Biomarkers of aging

“…By examining β cell [Ca 2+ ] and electrical communication during aging in mouse and human islets, Westacott et al (2017) found that there was a decline in the coordination of [Ca 2+ ] dynamics, gap junction coupling, and insulin secretion dynamics with age, indicating an age-related decay in stimulus-secretion coupling in β cell. In addition, aged mouse islets show increased glycolysis and altered cytosolic NAD metabolism, affecting β cell function and identity, similar to that seen in diabetic islets (Murao et al, 2022). Metabolite profiling identified 1,5-AG, 5′-methylthioadenosine (5′-MTA), X-11315 as potential biomarkers of pancreatic aging and T2D in human serum, saliva, and urine samples (Mook-Kanamori et al, 2017;Pramodkumar et al, 2016;Wang et al, 2017e;Zhang et al, 2021c).…”

Pancreatic β-cell failure, clinical implications, and therapeutic strategies in type 2 diabetes

“…[38] Similarly, in the human pancreas, PDX1 expression is markedly downregulated with aging. [39] Remarkably, a single-cell RNA-seq analysis revealed that the number of bihormonal cells that simultaneously expressed both insulin and glucagon mRNA increased with age, and the presence of such transcriptionally noisy cells suggests a fate drift between α- and β-cells in the aging pancreas, resulting in a loss of β-cell identity and function. Likewise, these transcriptionally noisy cells associated with aging are also observed in pancreatic islet cells from cynomolgus monkeys.…”