STRIPAK Is a Regulatory Hub Initiating Hippo Signaling.

Signaling modules that integrate the diverse extra- and intracellular inputs to the Hippo pathway were previously unknown. By biochemical and molecular interrogation, Chen et al. established a molecular framework, the RhoA-RHPN-NF2/Kibra-STRIPAK axis, that regulates the status of Hippo core kinases and connects upstream signals to initiate and orchestrate the Hippo pathway.

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 ß-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/ß-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 ß-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.

Matrix Metalloproteinase-3 is Key Effector of TNF-α-Induced Collagen Degradation in Skin.

Inflammatory processes in the skin augment collagen degradation due to the up-regulation of matrix metalloproteinases (MMPs). The aim of the present project was to study the specific impact of MMP-3 on collagen loss in skin and its interplay with the collagenase MMP-13 under inflammatory conditions mimicked by the addition of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). Skin explants from MMP-3 knock-out (KO) mice or from transgenic (TG) mice overexpressing MMP-3 in the skin and their respective wild-type counterparts (WT and WTT) were incubated ex vivo for eight days. The rate of collagen degradation, measured by released hydroxyproline, was reduced (p < 0.001) in KO skin explants compared to WT control skin but did not differ (p = 0.47) between TG and WTT skin. Treatment with the MMP inhibitor GM6001 reduced hydroxyproline media levels from WT, WTT and TG but not from KO skin explants. TNF-α increased collagen degradation in the WT group (p = 0.0001) only. More of the active form of MMP-13 was observed in the three MMP-3 expressing groups (co-incubation with receptor-associated protein stabilized MMP-13 subforms and enhanced detection in the media). In summary, the innate level of MMP-3 seems responsible for the accelerated loss of cutaneous collagen under inflammatory conditions, possibly via MMP-13 in mice.

An SCFFBXO28 E3 Ligase Protects Pancreatic ß-Cells from Apoptosis.

Loss of pancreatic ß-cell function and/or mass is a central hallmark of all forms of diabetes but its molecular basis is incompletely understood. ß-cell apoptosis contributes to the reduced ß-cell mass in diabetes. Therefore, the identification of important signaling molecules that promote ß-cell survival in diabetes could lead to a promising therapeutic intervention to block ß-cell decline during development and progression of diabetes. In the present study, we identified F-box protein 28 (FBXO28), a substrate-recruiting component of the Skp1-Cul1-F-box (SCF) ligase complex, as a regulator of pancreatic ß-cell survival. FBXO28 was down-regulated in ß-cells and in isolated human islets under diabetic conditions. Consistently, genetic silencing of FBXO28 impaired ß-cell survival, and restoration of FBXO28 protected ß-cells from the harmful effects of the diabetic milieu. Although FBXO28 expression positively correlated with ß-cell transcription factor NEUROD1 and FBXO28 depletion also reduced insulin mRNA expression, neither FBXO28 overexpression nor depletion had any significant impact on insulin content, glucose-stimulated insulin secretion (GSIS) or on other genes involved in glucose sensing and metabolism or on important ß-cell transcription factors in isolated human islets. Consistently, FBXO28 overexpression did not further alter insulin content and GSIS in freshly isolated islets from patients with type 2 diabetes (T2D). Our data show that FBXO28 improves pancreatic ß-cell survival under diabetogenic conditions without affecting insulin secretion, and its restoration may be a novel therapeutic tool to promote ß-cell survival in diabetes.

Reciprocal regulation of mTOR complexes in pancreatic islets from humans with type 2 diabetes.

AIMS/HYPOTHESIS: Mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of nutritional status at the cellular and organismic level. While mTORC1 mediates beta cell growth and expansion, its hyperactivation has been observed in pancreatic islets from animal models of type 2 diabetes and leads to beta cell loss. We sought to determine whether such mTORC1 activation occurs in humans with type 2 diabetes or in metabolically stressed human islets and whether mTORC1 blockade can restore beta cell function of diabetic islets. METHODS: Human islets isolated from non-diabetic controls and individuals with type 2 diabetes, as well as human islets and INS-1E cells exposed to increased glucose (22.2 mmol/l), were examined for mTORC1/2 activity by western blotting analysis of phosphorylation of mTORC1 downstream targets ribosomal protein S6 kinase 1 (S6K1), S6 and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) and mTORC2 downstream targets Akt and N-myc downstream regulated 1 (NDRG1). mTORC1/2 complexes' integrity was assessed by immunoprecipitation and subsequent western blot analysis. Cell-type specific expression of activated mTORC1 in human islets was examined by immunostaining of pS6 (Ser 235/236) in human islet sections. Beta cell function was measured by glucose-stimulated insulin secretion (GSIS). RESULTS: While mTORC2 signalling was diminished, mTORC1 activity was markedly increased in islets from patients with type 2 diabetes and in islets and beta cells exposed to increased glucose concentrations. Under high-glucose conditions in metabolically stressed human islets, we identified a reciprocal regulation of different mTOR complexes, with functional upregulation of mTORC1 and downregulation of mTORC2. pS6 immunostaining showed beta cell-specific upregulation of mTORC1 in islets isolated from patients with type 2 diabetes. Inhibition of mTORC1-S6K1 signalling improved GSIS and restored mTORC2 activity in islets from patients with type 2 diabetes as well as in islets isolated from diabetic db/db mice and mice fed a high-fat/high-sucrose diet. CONCLUSIONS/INTERPRETATION: Our data show the aberrant mTORC1 activity in islets from patients with type 2 diabetes, in human islets cultured under diabetes-associated increased glucose conditions and in diabetic mouse islets. This suggests that elevated mTORC1 activation is a striking pathogenic hallmark of islets in type 2 diabetes, contributing to impaired beta cell function and survival in the presence of metabolic stress.

Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function.

In this article, Figure 2F was incorrect. The correct panel is shown below. The authors sincerely apologise for this error.

MST1: a promising therapeutic target to restore functional beta cell mass in diabetes.

The loss of insulin-producing beta cells by apoptosis is a hallmark of all forms of diabetes mellitus. Strategies to prevent beta cell apoptosis and dysfunction are urgently needed to restore the insulin-producing cells and to prevent severe diabetes progression. We recently identified the serine/threonine kinase known as mammalian sterile 20-like kinase 1 (MST1) as a critical regulator of apoptotic beta cell death and dysfunction. MST1 activates several apoptotic signalling pathways, which further stimulate its own cleavage, leading to a vicious cycle of cell death. This led us to hypothesise that MST1 signalling is central to the initiation of beta cell death in diabetes. We found that MST1 is strongly activated in a diabetic beta cell and induces not only its death but also directly impairs insulin secretion through promoting proteasomal degradation of key beta cell transcription factor, pancreatic and duodenal homeobox 1 (PDX1), which is critical for insulin production.Pre-clinical studies in various animal models of diabetes have reported that MST1 deficiency remarkably restores normoglycaemia and beta cell function and prevents the development of diabetes. Importantly, MST1 deficiency can revert fully diabetic beta cells to a non-diabetic state. MST1 may serve as a target for the development of novel therapies for diabetes that trigger the cause of the disease, namely, the destruction of the beta cells. The major current focus of our investigation is to identify and test the efficacy of potent inhibitors of this death signalling pathway to protect beta cells against the effects of autoimmune attack in type 1 diabetes and to preserve beta cell mass and function in type 2 diabetes. This review summarises a presentation given at the 'Can we make a better beta cell?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Heiko Lickert and colleagues, DOI: 10.1007/s00125-016-3949-9 , and by Harry Heimberg and colleagues, DOI: 10.1007/s00125-016-3879-6 ) and a commentary by the Session Chair, Shanta Persaud (DOI: 10.1007/s00125-016-3870-2 ).

Possible role of interleukin-1ß in type 2 diabetes onset and implications for anti-inflammatory therapy strategies.

Increasing evidence of a role of chronic inflammation in type 2 diabetes progression has led to the development of therapies targeting the immune system. We develop a model of interleukin-1ß dynamics in order to explain principles of disease onset. The parameters in the model are derived from in vitro experiments and patient data. In the framework of this model, an IL-1ß switch is sufficient and necessary to account for type 2 diabetes onset. The model suggests that treatments targeting glucose bear the potential of stopping progression from pre-diabetes to overt type 2 diabetes. However, once in overt type 2 diabetes, these treatments have to be complemented by adjuvant anti-inflammatory therapies in order to stop or decelerate disease progression. Moreover, the model suggests that while glucose-lowering therapy needs to be continued all the way, dose and duration of the anti-inflammatory therapy needs to be specifically controlled. The model proposes a framework for the discussion of clinical trial outcomes.

TLR2/6 and TLR4-activated macrophages contribute to islet inflammation and impair beta cell insulin gene expression via IL-1 and IL-6.

AIMS/HYPOTHESIS: Inflammation contributes to pancreatic beta cell dysfunction in type 2 diabetes. Toll-like receptor (TLR)-2 and -4 ligands are increased systemically in recently diagnosed type 2 diabetes patients, and TLR2- and TLR4-deficient mice are protected from the metabolic consequences of a high-fat diet. Here we investigated the role of macrophages in TLR2/6- and TLR4-mediated effects on islet inflammation and beta cell function. METHODS: Genetic and pharmacological approaches were used to determine the effects of TLR2/6 and TLR4 ligands on mouse islets, human islets and purified rat beta cells. Islet macrophages were depleted and sorted by flow cytometry and the effects of TLR2/6- and TLR4-activated bone-marrow-derived macrophages (BMDMs) on beta cell function were assessed. RESULTS: Macrophages contributed to TLR2/6- and TLR4-induced islet Il1a/IL1A and Il1b/IL1B mRNA expression in mouse and human islets and IL-1ß secretion from human islets. TLR2/6 and TLR4 ligands also reduced insulin gene expression; however, this occurred in a non-beta cell autonomous manner. TLR2/6- and TLR4-activated BMDMs reduced beta cell insulin secretion partly via reducing Ins1, Ins2, and Pdx1 mRNA expression. Antagonism of the IL-1 receptor and neutralisation of IL-6 completely reversed the effects of activated macrophages on beta cell gene expression. CONCLUSIONS/INTERPRETATION: We conclude that islet macrophages are major contributors to islet IL-1ß secretion in response to TLR2/6 and TLR4 ligands. BMDMs stimulated with TLR2/6 and TLR4 ligands reduce insulin secretion from pancreatic beta cells, partly via IL-1ß- and IL-6-mediated decreased insulin gene expression.

Proapoptotic effects of the chemokine, CXCL 10 are mediated by the noncognate receptor TLR4 in hepatocytes.

UNLABELLED: Aberrant expression of the chemokine CXC chemokine ligand (CXCL)10 has been linked to the severity of hepatitis C virus (HCV)-induced liver injury, but the underlying molecular mechanisms remain unclear. In this study, we describe a yet-unknown proapoptotic effect of CXCL10 in hepatocytes, which is not mediated through its cognate chemokine receptor, but the lipopolysaccharide receptor Toll-like receptor 4 (TLR4). To this end, we investigated the link of CXCL10 expression with apoptosis in HCV-infected patients and in murine liver injury models. Mice were treated with CXCL10 or neutralizing antibody to systematically analyze effects on hepatocellular apoptosis in vivo. Direct proapoptotic functions of CXCL10 on different liver cell types were evaluated in detail in vitro. The results showed that CXCL10 expression was positively correlated with liver cell apoptosis in humans and mice. Neutralization of CXCL10 ameliorated concanavalin A-induced tissue injury in vivo, which was strongly associated with reduced liver cell apoptosis. In vitro, CXCL10 mediated the apoptosis of hepatocytes involving TLR4, but not CXC chemokine receptor 3 signaling. Specifically, CXCL10 induced long-term protein kinase B and Jun N-terminal kinase activation, leading to hepatocyte apoptosis by caspase-8, caspase-3, and p21-activated kinase 2 cleavage. Accordingly, systemic application of CXCL10 led to TLR4-induced liver cell apoptosis in vivo. CONCLUSION: The results identify CXCL10 and its noncognate receptor, TLR4, as a proapoptotic signaling cascade during liver injury. Antagonism of the CXCL10/TLR4 pathway might be a therapeutic option in liver diseases associated with increased apoptosis.

Mitochondrial aldehyde dehydrogenase-2 coordinates the hydrogen sulfide - AMPK axis to attenuate high glucose-induced pancreatic ß-cell dysfunction by glutathione antioxidant system.

Progression of ß-cell loss in diabetes mellitus is significantly influenced by persistent hyperglycemia. At the cellular level, a number of signaling cascades affect the expression of apoptotic genes, ultimately resulting in ß-cell failure; these cascades have not been elucidated. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) plays a central role in the detoxification of reactive aldehydes generated from endogenous and exogenous sources and protects against mitochondrial deterioration in cells. Here we report that under diabetogenic conditions, ALDH2 is strongly inactivated in ß-cells through CDK5-dependent glutathione antioxidant imbalance by glucose-6-phosphate dehydrogenase (G6PD) degradation. Intriguingly, CDK5 inhibition strengthens mitochondrial antioxidant defense through ALDH2 activation. Mitochondrial ALDH2 activation selectively preserves ß-cells against high-glucose-induced dysfunction by activating AMPK and Hydrogen Sulfide (H2S) signaling. This is associated with the stabilization and enhancement of the activity of G6PD by SIRT2, a cytoplasmic NAD+-dependent deacetylase, and is thereby linked to an elevation in the GSH/GSSG ratio, which leads to the inhibition of mitochondrial dysfunction under high-glucose conditions. Furthermore, treatment with NaHS, an H2S donor, selectively preserves ß-cell function by promoting ALDH2 activity, leading to the inhibition of lipid peroxidation by high-glucose concentrations. Collectively, our results provide the first direct evidence that ALDH2 activation enhances H2S-AMPK-G6PD signaling, leading to improved ß-cell function and survival under high-glucose conditions via the glutathione redox balance.

A small molecule MST1/2 inhibitor accelerates murine liver regeneration with improved survival in models of steatohepatitis.

Dysfunctional liver regeneration following surgical resection remains a major cause of postoperative mortality and has no therapeutic options. Without targeted therapies, the current treatment paradigm relies on supportive therapy until homeostasis can be achieved. Pharmacologic acceleration of regeneration represents an alternative therapeutic avenue. Therefore, we aimed to generate a small molecule inhibitor that could accelerate liver regeneration with an emphasis on diseased models, which represent a significant portion of patients who require surgical resection and are often not studied. Utilizing a clinically approved small molecule inhibitor as a parent compound, standard medicinal chemistry approaches were utilized to generate a small molecule inhibitor targeting serine/threonine kinase 4/3 (MST1/2) with reduced off-target effects. This compound, mCLC846, was then applied to preclinical models of murine partial hepatectomy, which included models of diet-induced metabolic dysfunction-associated steatohepatitis (MASH). mCLC846 demonstrated on target inhibition of MST1/2 and reduced epidermal growth factor receptor inhibition. The inhibitory effects resulted in restored pancreatic beta-cell function and survival under diabetogenic conditions. Liver-specific cell-line exposure resulted in Yes-associated protein activation. Oral delivery of mCLC846 perioperatively resulted in accelerated murine liver regeneration and improved survival in diet-induced MASH models. Bulk transcriptional analysis of regenerating liver remnants suggested that mCLC846 enhanced the normal regenerative pathways and induced them following liver resection. Overall, pharmacological acceleration of liver regeneration with mCLC846 was feasible, had an acceptable therapeutic index, and provided a survival benefit in models of diet-induced MASH.

TCF7L2 splice variants have distinct effects on beta-cell turnover and function.

Type 2 diabetes manifests when the ß-cell fails to secrete sufficient amounts of insulin to maintain normoglycemia and undergoes apoptosis. The disease progression results from an interplay of environmental factors and genetic predisposition. Polymorphisms in T-cell factor 7-like 2 (TCF7L2) strongly correlate with type 2 diabetes mellitus (T2DM). While TCF7L2 mRNA is upregulated in islets in diabetes, protein levels are downregulated. The loss of TCF7L2 induces impaired function and apoptosis. By analyzing human isolated islets, we provide three explanations for this opposite regulation and the mechanisms of TCF7L2 on ß-cell function and survival. (i) We found TCF7L2 transcripts in the human ß-cell, which had opposite effects on ß-cell survival, function and Wnt signaling activation. While TCF7L2 clone B1, which lacks exons 13, 14, 15 and 16 induced ß-cell apoptosis, impaired function and inhibited glucagon-like peptide 1 response and downstream targets of Wnt signaling, clones B3 and B7 which both contain exon 13, improved ß-cell survival and function and activated Wnt signaling. (ii) TCF7L2 mRNA is extremely unstable and is rapidly degraded under pro-diabetic conditions and (iii) TCF7L2 depletion in islets induced activation of glycogen synthase kinase 3-ß, but this was independent of endoplasmic reticulum stress. We demonstrated function-specific transcripts of TCF7L2, which possessed distinct physiological and pathophysiological effects on the ß-cell. The presence of deleterious TCF7L2 splice variants may be a mechanism of ß-cell failure in T2DM.

Correction: Angiopoetin-2 Signals Do Not Mediate the Hypervascularization of Islets in Type 2 Diabetes.

[This corrects the article DOI: 10.1371/journal.pone.0161834.].

Enteroviral infections are not associated with type 2 diabetes.

Introduction: For more than a century, enteroviral infections have been associated with autoimmunity and type 1 diabetes (T1D). Uncontrolled viral response pathways repeatedly presented during childhood highly correlate with autoimmunity and T1D. Virus responses evoke chemokines and cytokines, the "cytokine storm" circulating through the body and attack cells especially vulnerable to inflammatory destruction. Intra-islet inflammation is a major trigger of ß-cell failure in both T1D and T2D. The genetic contribution of islet inflammation pathways is apparent in T1D, with several mutations in the interferon system. In contrast, in T2D, gene mutations are related to glucose homeostasis in ß cells and insulin-target tissue and rarely within viral response pathways. Therefore, the current study evaluated whether enteroviral RNA can be found in the pancreas from organ donors with T2D and its association with disease progression. Methods: Pancreases from well-characterized 29 organ donors with T2D and 15 age- and BMI-matched controls were obtained from the network for pancreatic organ donors with diabetes and were analyzed in duplicates. Single-molecule fluorescence in-situ hybridization analyses were performed using three probe sets to detect positive-strand enteroviral RNA; pancreas sections were co-stained by classical immunostaining for insulin and CD45. Results: There was no difference in the presence or localization of enteroviral RNA in control nondiabetic and T2D pancreases; viral infiltration showed large heterogeneity in both groups ranging from 0 to 94 virus+ cells scattered throughout the pancreas, most of them in the exocrine pancreas. Very rarely, a single virus+ cell was found within islets or co-stained with CD45+ immune cells. Only one single T2D donor presented an exceptionally high number of viruses, similarly as seen previously in T1D, which correlated with a highly reduced number of ß cells. Discussion: No association of enteroviral infection in the pancreas and T2D diabetes could be found. Despite great similarities in inflammatory markers in islets in T1D and T2D, long-term enteroviral infiltration is a distinct pathological feature of T1D-associated autoimmunity and in T1D pancreases.

Neutralizing interleukin-1beta (IL-1beta) induces beta-cell survival by maintaining PDX1 protein nuclear localization.

The transcription factor PDX1 plays a critical role during ß-cell development and in glucose-induced insulin gene transcription in adult ß-cells. Acute glucose exposure leads to translocalization of PDX1 to the nucleoplasm, whereas under conditions of oxidative stress, PDX1 shuttles from the nucleus to the cytosol. Here we show that cytosolic PDX1 expression correlated with ß-cell failure in diabetes. In isolated islets from patients with type 2 diabetes and from diabetic mice, we found opposite regulation of insulin and PDX1 mRNA; insulin was decreased in diabetes, but PDX1 was increased. This suggests that elevated PDX1 mRNA levels may be insufficient to regulate insulin. In diabetic islets, PDX1 protein was localized in the cytosol, whereas in non-diabetic controls, PDX1 was in the nucleus. In contrast, overexpression of either IL-1 receptor antagonist or shuttling-deficient PDX1 restored ß-cell survival and function and PDX1 nuclear localization. Our results show that nuclear localization of PDX1 is essential for a functional ß-cell and provides a novel mechanism of the protective effect of IL-1 receptor antagonist on ß-cell survival and function.

MST1 deletion protects ß-cells in a mouse model of diabetes.

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 ß-cell mass as a result of improved ß-cell survival and proliferation in the combined high fat/high sucrose and streptozotocin (HFS/STZ) model of ß-cell destruction and diabetes. Importantly, the glucose-lowering effects in the MST1-knockout (KO) mice could be accounted to the enhanced ß-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 ß-cell mass by MST1 deletion in response to diabetes-induced injury occurs as a result of improved ß-cell survival and proliferation establishing MST1 as potent regulator of physiological ß-cell turnover.

How ß cells can smell insulin fragments.

In this issue of Cell Metabolism, Cheng et al. identify olfactory receptor Olfr109 in ß cells with increased expression in islets from mouse models of obesity and type 1 and type 2 diabetes. Binding of a small insulin fragment to Olfr109 fosters islet inflammation, ß cell failure, and diabetes progression.

Correction: UCP-2 and UCP-3 Proteins Are Differentially Regulated in Pancreatic Beta-Cells.

[This corrects the article DOI: 10.1371/journal.pone.0001397.].

Case Report: Neratinib Therapy Improves Glycemic Control in a Patient With Type 2 Diabetes and Breast Cancer.

A critical decline of functional insulin-producing pancreatic ß-cells is the central pathologic element of both type 1 and type 2 diabetes. Mammalian Sterile 20-like kinase 1 (MST1) is a key mediator of ß-cell failure and the identification of neratinib as MST1 inhibitor with potent effects on ß-cell survival represents a promising approach for causative diabetes therapy. Here we report a case of robust glycemia and HbA1c normalization in a patient with breast cancer-T2D comorbidity under neratinib, a potent triple kinase inhibitor of HER2/EGFR and MST1. The patient, aged 62 years, was enrolled in the plasmaMATCH clinical trial and received 240 mg neratinib once daily. Neratinib therapy correlated with great improvement in glucose and HbA1c both to physiological levels during the whole treatment period (average reduction of random glucose from 13.6 ± 0.4 to 6.3 ± 0.5 mmol/l and of HbA1c from 82.2 ± 3.9 to 45.6 ± 4.2 mmol/mol before and during neratinib). 18 months later, when neratinib was withdrawn, random glucose rapidly raised together with high blood glucose fluctuations, which reflected in elevated HbA1c levels. This clinical case reports the combination of HER2/EGFR/MST1-inhibition by neratinib for the pharmacological intervention to effectively restore normoglycemia in a patient with poorly controlled T2D and suggests neratinib as potent therapeutic regimen for the cancer-diabetes comorbidity.