Reversing pancreatic β-cell dedifferentiation in the treatment of type 2 diabetes

Abstract

The maintenance of glucose homeostasis is fundamental for survival and health. Diabetes develops when glucose homeostasis fails. Type 2 diabetes (T2D) is characterized by insulin resistance and pancreatic β-cell failure. The failure of β-cells to compensate for insulin resistance results in hyperglycemia, which in turn drives altered lipid metabolism and β-cell failure. Thus, insulin secretion by pancreatic β-cells is a primary component of glucose homeostasis. Impaired β-cell function and reduced β-cell mass are found in diabetes. Both features stem from a failure to maintain β-cell identity, which causes β-cells to dedifferentiate into nonfunctional endocrine progenitor-like cells or to trans-differentiate into other endocrine cell types. In this regard, one of the key issues in achieving disease modification is how to reestablish β-cell identity. In this review, we focus on the causes and implications of β-cell failure, as well as its potential reversibility as a T2D treatment.

Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity.

“…6f) and PDX1 (Fig. 6g) were both downregulated at the mRNA level in human islets exposed to glucolipotoxicity, consistent with the previously reported de-differentiation phenotype pertinent to β-cell demise (75)(76)(77)(78). Yet, in the presence of 43 this de-differentiation was prevented (Fig.…”

Ethyl Acetate Fractions of Tectona Grandis Crude Extract Modulate Glucose Absorption and Uptake as Well as Antihyperglycemic Potential in Fructose–Streptozotocin-Induced Diabetic Rats

“…Persistent hyperglycaemia is a clinical manifestation of T2D. Reports have linked elevated blood glucose to insulin insufficiency, which could result from pancreatic β-cell mass reduction and peripheral tissues and cells’ inability to respond to insulin action [ 41 , 42 , 43 ]. It was observed in our study that untreated diabetic rats showed elevated blood glucose ( Figure 4 ) with low-serum insulin ( Table 2 ) and sullen pancreatic morphology ( Figure 6 ).…”

FoxO1 as a tissue-specific therapeutic target for type 2 diabetes

“…In contrast to AKT, phosphorylation of FoxO1 by inflammatory pathways like c-Jun N-terminal kinase (JNK) augments nuclear entry of FoxO1 to increase insulin transcription via upregulation of NeuroD and MafA transcription factors ( 163 , 164 ). Moreover, studies indicates that as insulin resistance and OS progresses, FoxO1 acts to combat these conditions but over time its protein levels decline causing β-cell dedifferentiation and marking a molecular switch to T2D pathology ( 165 , 166 ). Furthermore, the GLP-1RA exenatide decreases inflammation and boosts β-cell function by improving the balance between CD4+ T-helper 17 (Th17) cells and regulatory T-cells (Tregs) ( 167 ).…”