Abstract
The pro-apoptotic kinase Mammalian Sterile 20-like kinase 1 (MST1), an integral component of the Hippo pathway, is a key regulator of organ size, stress response, and tissue homeostasis; its aberrant hyperactivation is linked to multiple pathological disorders including diabetes. Here we show that MST1 deletion in mice resulted in improved glucose tolerance and insulin secretion, and restored pancreatic β-cell mass as a result of improved β-cell survival and proliferation in the combined high fat/high sucrose and streptozotocin (HFS/STZ) model of β-cell destruction and diabetes. Importantly, the glucose-lowering effects in the MST1-knockout (KO) mice could be accounted to the enhanced β-cell mass and improved insulin secretion without changes in insulin sensitivity. Metabolic and morphological data suggest that normalization of blood glucose and insulin secretion, islet architecture, and β-cell mass by MST1 deletion in response to diabetes-induced injury occurs as a result of improved β-cell survival and proliferation establishing MST1 as potent regulator of physiological β-cell turnover.
Highlights
Since the discovery of highly activated serine/threonine kinase Mammalian Sterile 20-like kinase 1 (MST1), a core kinase in the Hippo signaling pathway, during pancreatic β-cell failure in the pancreas and diabetes progression [1], MST1 targeted therapies were designed to protect β-cells and prevent diabetic complications, such as nephropathy and cardiomyopathy [2,3,4,5,6].MST1 acts as a stimulator of caspases to initiate the apoptotic cascade
Such amplification has been observed under chronic conditions of hyperglycemia, so called glucotoxicity, in the pancreatic β-cells, leading directly to β-cell dysfunction with abolished glucose-stimulated insulin secretion (GSIS) through degradation of the important β-cell transcription factor pancreatic duodenal homebox-1 (PDX-1) and to β-cell failure and death [1]
MST1 activation and its downstream events are controlled by a cross-communication between many other signaling pathways of cellular survival and metabolism through nonlinear feedback loops to balance cellular turn-over, altogether regulating important biological processes such as tissue development, cellular differentiation, proliferation, stress response, and apoptosis [9,10,11]
Summary
The pro-apoptotic kinase Mammalian Sterile 20-like kinase 1 (MST1), an integral component of the Hippo pathway, is a key regulator of organ size, stress response, and tissue homeostasis; its aberrant hyperactivation is linked to multiple pathological disorders including diabetes. Controlled by MST1 and several other kinases, the Hippo pathway has recently been shown to regulate pancreas development, β-cell survival, proliferation, and regeneration [6], as well as stress and metabolic adaptations in metabolically active organs including liver and fat [11] and constitutes an emerging player in both cellular and systemic metabolism [11]. It is not surprising, that fluctuations in the Hippo signaling pathway are involved in the progression of diabetes with its complex and multifactorial metabolic disturbances in glucose homeostasis leading to hyperglycemia. Data are expressed as means ± SEM. *p < 0.05 MST1KO compared to WT littermates
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