The undoing and redoing of the diabetic β-cell

Abstract

A hallmark of type 2 diabetes (T2DM) is the reduction in functional β-cell mass, which is considered at least in part to result from an imbalance of β-cell renewal and apoptosis, with the latter being accelerated during metabolic stress. More recent studies, however, suggest that the loss of functional β-cell mass is not as much due to β-cell death but rather to de-differentiation of β-cells when these cells are exposed to metabolic stressors, opening the possibility to re-differentiate and restore functional β-cell mass by therapeutic intervention. In parallel, clinical observations suggest that temporary intensive insulin therapy in early diagnosed humans with T2DM, so as to “rest” endogenous β-cells, allows these patients to regain adequate insulin secretion and to maintain euglycemia for prolonged periods free of continued pharmacotherapy. Whether observations made in (mostly rodent) models of diabetes mellitus and in clinical trials are revealing identical mechanisms and therapeutic opportunities remains a tantalizing possibility. Our intention is for this review to serve as an overview of the field and commentary of this particularly exciting field of research.

Improvement of skeletal muscle insulin sensitivity by 1 week of SGLT2 inhibitor use

“…The duration of diabetes mellitus was negatively correlated with the degree of improvement in insulin sensitivity through SGLT2 inhibitor administration. Although the progressive loss of β-cell function is associated with glycemic deterioration ( 10 ), short-term intensive insulin therapy can ameliorate the disturbances in insulin sensitivity and preserve residual β-cell function in T2DM patients, particularly those with a short diabetes history ( 25 ). However, high-dose insulin requirements were independently associated with greater weight gain ( 26 ) when insulin therapy was initiated.…”

Sonodynamic therapy inhibits palmitate-induced beta cell dysfunction via PINK1/Parkin-dependent mitophagy

“…As human beings age, the regeneration capacity of islet beta cells is significantly reduced, and both the number and function of beta cells gradually deteriorate 34,35 . In particular, high concentrations of glucose and FFAs accelerate the loss and malfunction of beta cells, eventually leading to the failure of insulin secretion 14,15 . Thus, the progression of diabetes depends on the degree of beta cell failure.…”

“…Although these interventions can partially control blood glucose or temporarily improve insulin secretion, the incidence of cardiovascular events caused by T2DM has not decreased significantly 12,13 . The intrinsic cause might be the lack of a modality to directly protect beta cells, and current modalities cannot inhibit the functional decline of beta cells 14,15 .…”

Neuroligin-2-derived peptide-covered polyamidoamine-based (PAMAM) dendrimers enhance pancreatic β-cells' proliferation and functions

“…91 The combination of a low replication rate of the β-cells and the absence of a sufficient antioxidative response leads to cell death during diabetes. 92 Classical antioxidant therapy was tested in many clinical antidiabetic trials. 93 Unfortunately, direct antioxidative stress protection of β-cells and maintenance of β-cell mass were never achieved.…”