Episodic β‐cell death and dedifferentiation during diet‐induced obesity and dysglycemia in male mice

Abstract

Loss of functional islet β-cell mass through cellular death or dedifferentiation is thought to lead to dysglycemia during the progression from obesity to type 2 diabetes. To assess these processes in a mouse model of obesity, we performed measures of circulating cell-free differentially methylated insulin II ( Ins2) DNA as a biomarker of β-cell death and aldehyde dehydrogenase 1 family member A3 (ALDH1A3) and forkhead box 01 (Foxo1) immunostaining as markers of β-cell dedifferentiation. Eight-week-old, C57BL/6J mice were fed a low-fat diet (LFD; 10% kcal from fat) or a high-fat diet (HFD; 60% kcal from fat) and were followed longitudinally for up to 13 wk to measure glycemic control and β-cell mass, death, and dedifferentiation. Compared with LFD controls, β-cell mass increased during the feeding period in HFD animals, and statistically greater β-cell death (unmethylated Ins2) was detectable at 2 and 6 wk after diet initiation. Those times correspond to periods when significant step increases in fasting glucose and glucose intolerance, respectively, were detected. ALDH1A3 and Foxo1 immunostaining of the pancreas revealed evidence of β-cell dedifferentiation by 13 wk when fed an HFD, but not in LFD controls. In conclusion, early episodic β-cell death may be a feature of cellular turnover correlated with changes in glycemia during β-cell mass accrual in obesity, whereas β-cell dedifferentiation may be a feature seen later in established disease.-Tersey, S. A., Levasseur, E. M., Syed, F., Farb, T. B., Orr, K. S., Nelson, J. B., Shaw, J. L., Bokvist, K., Mather, K. J., Mirmira, R. G. Episodic β-cell death and dedifferentiation during diet-induced obesity and dysglycemia in male mice.

VMAT2 Safeguards β-Cells Against Dopamine Cytotoxicity Under High-Fat Diet–Induced Stress

“…Our results confirmed that HFD triggered the dedifferentiation and adaptive proliferation of β-cells, as previously reported ( 24 , 28 , 29 ). In HFD-fed βVmat2KO islets, dedifferentiation and cell death in β-cells are accelerated compared with in controls, which seems to attribute to β-cell failure.…”

Circulating unmethylated CHTOP and INS DNA fragments provide evidence of possible islet cell death in youth with obesity and diabetes

“…Given that all individuals are either obese or overweight, it is possible that the unmethylated INS signal might be arising from adipocyte turnover; however, the elevations in unmethylated CHTOP-817, assuming that they are arising from the same cell type, likely point to an islet cell origin. In a prior study using high-fat diet feeding in mice, we observed that overweight/obese mice exhibit periodic increases in unmethylated INS DNA, and that these elevations correlated with increases in β cell death, as verified by immunostaining of pancreas sections from these animals [30]. These data suggest that the elevated unmethylated INS and CHTOP-817 signal in our cohort of overweight/obese youth might be arising from death of islet cells, recognizing that our assay cannot definitively conclude the specific islet cell type giving rise to this signal.…”

“…First, our studies in humans utilized cross-sectional cohorts, and we cannot comment on the occurrence or the timing of islet cell death following initial islet assault during the progression from obesity to T2D or from antibody-negative FDR to T1D. Given the short (~90 min) half-life of DNA in the circulation [15], if β cell death was episodic during disease progression in humans (as we observed previously in mice [30]), signals corresponding to cell death could be missed depending on the timing of sampling. Additional studies measuring differentially methylated INS and CHTOP from longitudinal cohorts are needed to resolve this issue.…”

Intravascular Follistatin gene delivery improves glycemic control in a mouse model of type 2 diabetes

“…4,45 As ALDH1A3 expression is inhibited by Foxo1 activity in β-cells, ALDH1A3 increases as Foxo1 expression is lost in diabetic mice. 4,8,46,47 Follistatin gene delivery did not reduce the ALDH1A3 expression in insulin-positive islet cells, suggesting that combination treatment with other strategies that target the key transcriptional programs in β-cells may offer scope to enhance long-term β-cell functionality further. Our studies do not rule out the possibility that the increased numbers of insulin-positive cells after treatment may also in-part result from increased proliferation and/or reduced apoptosis of β-cells.…”