PHLPP1 deletion restores pancreatic β-cell survival and normoglycemia in the db/db mouse model of obesity-associated diabetes

The Pleckstrin homology domain leucine-rich repeat protein phosphatases (PHLPPs) are novel therapeutic targets for the restoration of β-cell survival and function in diabetes. Their upregulation and activation in β-cells under conditions of both type 1 and type 2 diabetes directly correlates with β-cell failure; β-cell death and loss of insulin secretory function through disturbance of cell survival control mechanisms. PHLPPs directly dephosphorylate and regulate activities of β-cell survival-dependent kinases AKT and MST1 constituting a regulatory triangle loop to control β-cell apoptosis. PHLPP1 deletion in severely diabetic leptin receptor-deficient db/db mice restored normoglycemia and β-cell area through increased β-cell proliferation and reduced β-cell apoptosis. The beneficial effects of PHLPP1 deficiency in a severe mouse model of obesity and diabetes make PHLPP a new target for β-cell-directed diabetes therapy

Loss of Deubiquitinase USP1 Blocks Pancreatic β-Cell Apoptosis by Inhibiting DNA Damage Response

Impaired pancreatic β-cell survival contributes to the reduced β-cell mass in diabetes, but underlying regulatory mechanisms and key players in this process remain incompletely understood. Here, we identified the deubiquitinase ubiquitin-specific protease 1 (USP1) as an important player in the regulation of β-cell apoptosis under diabetic conditions. Genetic silencing and pharmacological suppression of USP1 blocked β-cell death in several experimental models of diabetes in vitro and ex vivo without compromising insulin content and secretion and without impairing β-cell maturation/identity genes in human islets. Our further analyses showed that USP1 inhibition attenuated DNA damage response (DDR) signals, which were highly elevated in diabetic β-cells, suggesting a USP1-dependent regulation of DDR in stressed β-cells. Our findings highlight a novel function of USP1 in the control of β-cell survival, and its inhibition may have a potential therapeutic relevance for the suppression of β-cell death in diabetes. Biochemical Mechanism; Endocrinology; Cell Biolog

LDHA is enriched in human islet alpha cells and upregulated in type 2 diabetes

The lactate dehydrogenase isoform A (LDHA) is a key metabolic enzyme that preferentially catalyzes the conversion of pyruvate to lactate. Whereas LDHA is highly expressed in many tissues, its expression is turned off in the differentiated adult β-cell within the pancreatic islets. The repression of LDHA under normal physiological condition and its inappropriate upregulation under a diabetogenic environment is well-documented in rodent islets/β-cells but little is known about LDHA expression in human islet cells and whether its abundance is altered under diabetic conditions. Analysis of public single-cell RNA-seq (sc-RNA seq) data as well as cell type-specific immunolabeling of human pancreatic islets showed that LDHA was mainly localized in human α-cells while it is expressed at a very low level in β-cells. Furthermore, LDHA, both at mRNA and protein, as well as lactate production is upregulated in human pancreatic islets exposed to chronic high glucose treatment. Microscopic analysis of stressed human islets and autopsy pancreases from individuals with type 2 diabetes (T2D) showed LDHA upregulation mainly in human α-cells. Pharmacological inhibition of LDHA in isolated human islets enhanced insulin secretion under physiological conditions but did not significantly correct the deregulated secretion of insulin or glucagon under diabetic conditions

Inhibition of PHLPP1/2 phosphatases rescues pancreatic β-cells in diabetes

Pancreatic β-cell failure is the key pathogenic element of the complex metabolic deterioration in type 2 diabetes (T2D); its underlying pathomechanism is still elusive. Here, we identify pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2 (PHLPP1/2) as phosphatases whose upregulation leads to β-cell failure in diabetes. PHLPP levels are highly elevated in metabolically stressed human and rodent diabetic β-cells. Sustained hyper-activation of mechanistic target of rapamycin complex 1 (mTORC1) is the primary mechanism of the PHLPP upregulation linking chronic metabolic stress to ultimate β-cell death. PHLPPs directly dephosphorylate and regulate activities of β-cell survival-dependent kinases AKT and MST1, constituting a regulatory triangle loop to control β-cell apoptosis. Genetic inhibition of PHLPPs markedly improves β-cell survival and function in experimental models of diabetes in vitro, in vivo, and in primary human T2D islets. Our study presents PHLPPs as targets for functional regenerative therapy of pancreatic β cells in diabetes

Neratinib protects pancreatic beta cells in diabetes

The loss of functional insulin-producing β-cells is a hallmark of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic β-cell death and dysfunction; its deficiency restores functional β-cells and normoglycemia. The identification of MST1 inhibitors represents a promising approach for a β-cell-protective diabetes therapy. Here, we identify neratinib, an FDA-approved drug targeting HER2/EGFR dual kinases, as a potent MST1 inhibitor, which improves β-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells. In a pre-clinical study, neratinib attenuates hyperglycemia and improves β-cell function, survival and β-cell mass in type 1 (streptozotocin) and type 2 (obese Leprdb/db) diabetic mouse models. In summary, neratinib is a previously unrecognized inhibitor of MST1 and represents a potential β-cell-protective drug with proof-of-concept in vitro in human islets and in vivo in rodent models of both type 1 and type 2 diabetes

Hippo Signaling: Key Emerging Pathway in Cellular and Whole-Body Metabolism

The evolutionarily conserved Hippo pathway is a key regulator of organ size and tissue homeostasis. Its dysregulation is linked to multiple pathological disorders. In addition to regulating development and growth, recent studies show that Hippo pathway components such as MST1/2 and LATS1/2 kinases, as well as YAP/TAZ transcriptional coactivators, are regulated by metabolic pathways and that the Hippo pathway controls metabolic processes at the cellular and organismal levels in physiological and metabolic disease states such as obesity, type 2 diabetes (T2D), nonalcoholic fatty liver disease (NAFLD), cardiovascular disorders, and cancer. In this review we summarize the connection between key Hippo components and metabolism, and how this interplay regulates cellular metabolism and metabolic pathways. The emerging function of Hippo in the regulation of metabolic homeostasis under physiological and pathological conditions is highlighted

mTORC2 Signaling: A Path for Pancreatic β Cell's Growth and Function

The mechanistic target of rapamycin (mTOR) signaling pathway is an evolutionary conserved pathway that senses signals from nutrients and growth factors to regulate cell growth, metabolism and survival. mTOR acts in two biochemically and functionally distinct complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), which differ in terms of regulatory mechanisms, substrate specificity and functional outputs. While mTORC1 signaling has been extensively studied in islet/β-cell biology, recent findings demonstrate a distinct role for mTORC2 in the regulation of pancreatic β-cell function and mass. mTORC2, a key component of the growth factor receptor signaling, is declined in β cells under diabetogenic conditions and in pancreatic islets from patients with type 2 diabetes. β cell-selective mTORC2 inactivation leads to glucose intolerance and acceleration of diabetes as a result of reduced β-cell mass, proliferation and impaired glucose-stimulated insulin secretion. Thereby, many mTORC2 targets, such as AKT, PKC, FOXO1, MST1 and cell cycle regulators, play an important role in β-cell survival and function. This indicates mTORC2 as important pathway for the maintenance of β-cell homeostasis, particularly to sustain proper β-cell compensatory response in the presence of nutrient overload and metabolic demand. This review summarizes recent emerging advances on the contribution of mTORC2 and its associated signaling on the regulation of glucose metabolism and functional β-cell mass under physiological and pathophysiological conditions in type 2 diabetes

mTORC1 Signaling: A Double-Edged Sword in Diabetic β Cells

The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of metabolic and nutrient cues that integrates environmental inputs into downstream signaling pathways to control cellular metabolism, growth, and survival. While numerous in vitro and in vivo studies reported the positive functions of mTORC1 in the regulation of β cell survival and proliferation under physiological conditions, more recent work demonstrates the opposite in the long term; this is exemplified by the constitutive inappropriate hyper-activation of mTORC1 in diabetic islets or β cells under conditions of increased β cell stress and metabolic demands. These recent findings uncover mTORC1‘s importance as an emerging significant player in the development and progression of β cell failure in type 2 diabetes and suggest that mTORC1 may act as a “double edge sword” in the regulation of β cell mass and function in response to metabolic stress such as nutrient overload and insulin resistance. In this review, Ardestani et al. present the positive and negative effects of mTORC1 signaling in the β cell and discuss the implications for metabolic disease therapies. While essential for β cell development, function, and survival, mTORC1’s hyperactivation under constant metabolic stress contributes to β cell failure