Maintaining Effective Beta Cell Function in the Face of Metabolic Syndrome-Associated Glucolipotoxicity—Nutraceutical Options

In people with metabolic syndrome, episodic exposure of pancreatic beta cells to elevated levels of both glucose and free fatty acids (FFAs)—or glucolipotoxicity—can induce a loss of glucose-stimulated insulin secretion (GSIS). This in turn can lead to a chronic state of glucolipotoxicity and a sustained loss of GSIS, ushering in type 2 diabetes. Loss of GSIS reflects a decline in beta cell glucokinase (GK) expression associated with decreased nuclear levels of the pancreatic and duodenal homeobox 1 (PDX1) factor that drives its transcription, along with that of Glut2 and insulin. Glucolipotoxicity-induced production of reactive oxygen species (ROS), stemming from both mitochondria and the NOX2 isoform of NADPH oxidase, drives an increase in c-Jun N-terminal kinase (JNK) activity that promotes nuclear export of PDX1, and impairs autocrine insulin signaling; the latter effect decreases PDX1 expression at the transcriptional level and up-regulates beta cell apoptosis. Conversely, the incretin hormone glucagon-like peptide-1 (GLP-1) promotes nuclear import of PDX1 via cAMP signaling. Nutraceuticals that quell an increase in beta cell ROS production, that amplify or mimic autocrine insulin signaling, or that boost GLP-1 production, should help to maintain GSIS and suppress beta cell apoptosis in the face of glucolipotoxicity, postponing or preventing onset of type 2 diabetes. Nutraceuticals with potential in this regard include the following: phycocyanobilin—an inhibitor of NOX2; agents promoting mitophagy and mitochondrial biogenesis, such as ferulic acid, lipoic acid, melatonin, berberine, and astaxanthin; myo-inositol and high-dose biotin, which promote phosphatidylinositol 3-kinase (PI3K)/Akt activation; and prebiotics/probiotics capable of boosting GLP-1 secretion. Complex supplements or functional foods providing a selection of these agents might be useful for diabetes prevention.

Suppressive role of E3 ubiquitin ligase FBW7 in type I diabetes in non-obese diabetic mice through mediation of ubiquitination of EZH2

The current study tried to uncover the molecular mechanism of E3 ubiquitin ligase F-box and WD repeat domain-containing 7 (FBW7) in a heritable autoimmune disease, type I diabetes (T1D). After streptozotocin-induced T1D model establishment in non-obese diabetic (NOD) mouse, the protein expression of FBW7, enhancer of zeste homolog 2 (EZH2), and Zinc finger and BTB domain containing 16 (ZBTB16) was quantified. Next, splenocytes and pancreatic beta cells were isolated to measure the production of pro-inflammatory cytokines in splenocytes, as well as islet beta-cell apoptosis. Additionally, the stability of EZH2 induced by FBW7 was analyzed by cycloheximide chase assay. The binding affinity of FBW7 and EZH2 and the consequence of ubiquitination were monitored by co-immunoprecipitation assay. Last, a chromatin immunoprecipitation assay was employed to analyze the accumulation of EZH2 and H3K27me3 at the ZBTB16 promoter region. Our study demonstrated downregulated FBW7 and ZBTB16 and upregulated EZH2 in diabetic NOD mice. Overexpression of FBW7 in the NOD mice inhibited pro-inflammatory cytokine release in the splenocytes and the apoptosis of islets beta cells. FBW7 destabilized EZH2 and accelerated ubiquitin-dependent degradation. EZH2 and H3K27me3 downregulated the ZBTB16 expression by accumulating in the ZBTB16 promoter and methylation. FBW7 upregulates the expression of ZBTB16 by targeting histone methyltransferase EZH2 thus reducing the occurrence of T1D.

Apoptosis in Type 2 Diabetes, Can It be Prevented?

Diabetes mellitus is a heterogeneous disease of complex etiology and pathogenesis. Hyperglycemia leads to many serious complications, but also directly initiates the process of β cell apoptosis. A potential strategy for the preservation of pancreatic β cells in diabetes may be to inhibit the implementation of pro-apoptotic pathways or to enhance the action of pancreatic protective factors. The HIPPO signaling pathway is proposed and selected as a target to manipulate the activity of its core proteins in therapy - basic research. MST1 and LATS2 as major upstream signaling kinases of the Hippo pathway are considered as target candidates for pharmacologically induced tissue regeneration and inhibition of apoptosis. Manipulating the activity of components of the HiPPO pathway offers a wide range of possibilities, and thus is a potential tool in the treatment of diabetes and the regeneration of β cells. Therefore, it is important to fully understand the processes involved in apoptosis in diabetic states and to fully characterize the role of this pathway in diabetes. Therapy consisting in slowing down or stopping the mechanisms of apoptosis may be an important direction of diabetes treatment shortly.

Soluble Klotho Is Decreased in Children With Type 1 Diabetes and Correlated With Metabolic Control

Klotho concentration may be considered as a prognostic factor in the development of chronic complications of diabetes. Moreover, decrease in sKlotho concentration may contribute to beta cell apoptosis and type 1 diabetes development. The aim of this study was to evaluate if sKlotho protein concentration in children with type 1 diabetes (T1D) and its correlation with classical risk factors of chronic complications of diabetes: dysglycemia and endothelial dysfunction.Material and methodsIn a cross-section single center study the levels of soluble Klotho protein in 80 T1D (37 boys) and 34 healthy children (controls, 15 boys). Micro- and macroangiopathy were excluded and renal function was normal in all participants. Serum sKlotho, sICAM-1, sVCAM-1 and E-selectin levels were measured.ResultsThe concentration of sKlotho was lower in T1D than in the controls (2041.9 ± 1017.6 pg/mL vs. 2790.3 ± 1423.9 pg/mL, p=0.0113). sICAM-1, sVCAM-1 and E-selectin concentrations were comparable in patients and controls. In T1D, sKlotho was not correlated with the duration of diabetes. Klotho and E-selectin were correlated with HbA1c (r=-0.31, P=0.0066 and r=0.25, P=0.0351, respectively), but not with AVBG and blood glucose SD. Correlations of sKlotho with total cholesterol (r=0.31, P=0.0129), HDL-cholesterol (r=0.43, P=0.0011) and LDL-cholesterol (r=0.28, P=0.0412), but not with triglycerides, were found. Likewise, Klotho was not correlated with sICAM-1, sVCAM-1, and E-selectin concentrations.ConclusionsThis study reports the significantly lower level of s-Klotho in children with type 1 diabetes, correlated with HbA1c and HDL cholesterol, but not with the adhesion molecules concentrations nor the duration of the disease. Negative correlation between the levels of HbA1c and soluble Klotho may suggest its possible involvement in the development of chronic diabetes complications.

The Link between Type 2 Diabetes Mellitus and the Polymorphisms of Glutathione-Metabolizing Genes Suggests a New Hypothesis Explaining Disease Initiation and Progression

The present study investigated whether type 2 diabetes (T2D) is associated with polymorphisms of genes encoding glutathione-metabolizing enzymes such as glutathione synthetase (GSS) and gamma-glutamyl transferase 7 (GGT7). A total of 3198 unrelated Russian subjects including 1572 T2D patients and 1626 healthy subjects were enrolled. Single nucleotide polymorphisms (SNPs) of the GSS and GGT7 genes were genotyped using the MassArray-4 system. We found that the GSS and GGT7 gene polymorphisms alone and in combinations are associated with T2D risk regardless of sex, age, and body mass index, as well as correlated with plasma glutathione, hydrogen peroxide, and fasting blood glucose levels. Polymorphisms of GSS (rs13041792) and GGT7 (rs6119534 and rs11546155) genes were associated with the tissue-specific expression of genes involved in unfolded protein response and the regulation of proteostasis. Transcriptome-wide association analysis has shown that the pancreatic expression of some of these genes such as EDEM2, MYH7B, MAP1LC3A, and CPNE1 is linked to the genetic risk of T2D. A comprehensive analysis of the data allowed proposing a new hypothesis for the etiology of type 2 diabetes that endogenous glutathione deficiency might be a key condition responsible for the impaired folding of proinsulin which triggered an unfolded protein response, ultimately leading to beta-cell apoptosis and disease development.

Metabolic reprogramming of cytotoxic T lymphocytes by high glucose enhances pancreatic beta cell apoptosis via TRAIL

Cytotoxic T lymphocytes (CTLs) are involved in development of diabetes. However, the impact of excessive glucose on CTL effector functions remains largely elusive. Here, we report that metabolic processes in CTLs are reprogrammed by high glucose (HG). TNF-related apoptosis inducing ligand (TRAIL) is substantially up-regulated in CTLs in environments with HG both in vitro and in vivo in a diabetic mouse model and in diabetic patients. The PI3K-Akt-NFκB axis and non-mitochondrial reactive oxygen species (ROS) are both involved in HG-induced TRAIL upregulation in CTLs. TRAILhigh CTLs induce apoptosis of insulin-producing beta cells. Metformin and Vitamin D synergistically reduce HG-enhanced expression of TRAIL in CTLs and coherently protect beta cells from TRAIL-mediated apoptosis. Our work not only reveals a novel mechanism of CTL involvement in progression of diabetes, but also establishes CTLs as a target for combined metformin and vitamin D therapy to protect pancreatic beta cells of diabetic patients.

Prenatal nicotine exposure leads to decreased histone H3 lysine 9 (H3K9) methylation and increased p66shc expression in the neonatal pancreas

Prenatal exposure to nicotine, tobacco’s major addictive constituent, has been shown to reduce birth weight and increases apoptosis, oxidative stress, and mitochondrial dysfunction in the postnatal pancreas. Given that upregulated levels of the pro-oxidative adapter protein p66shc is observed in growth-restricted offspring and is linked to beta-cell apoptosis, the goal of this study was to investigate whether alterations in p66shc expression underlie the pancreatic deficits in nicotine-exposed offspring. Maternal administration of nicotine in rats increased p66shc expression in the neonatal pancreas. Similarly, nicotine treatment augmented p66shc expression in INS-1E pancreatic beta cells. Increased p66shc expression was also associated with decreased histone H3 lysine 9 methylation. Finally, nicotine increased the expression of Kdm4c, a key histone lysine demethylase, and decreased Suv39h1, a critical histone lysine methyltransferase. Collectively, these results suggest that upregulation of p66shc through posttranslational histone modifications may underlie the reported adverse outcomes of nicotine exposure on pancreatic function.

Mechanisms of Beta-Cell Apoptosis in Type 2 Diabetes-Prone Situations and Potential Protection by GLP-1-Based Therapies

Type 2 diabetes (T2D) is characterized by chronic hyperglycemia secondary to the decline of functional beta-cells and is usually accompanied by a reduced sensitivity to insulin. Whereas altered beta-cell function plays a key role in T2D onset, a decreased beta-cell mass was also reported to contribute to the pathophysiology of this metabolic disease. The decreased beta-cell mass in T2D is, at least in part, attributed to beta-cell apoptosis that is triggered by diabetogenic situations such as amyloid deposits, lipotoxicity and glucotoxicity. In this review, we discussed the molecular mechanisms involved in pancreatic beta-cell apoptosis under such diabetes-prone situations. Finally, we considered the molecular signaling pathways recruited by glucagon-like peptide-1-based therapies to potentially protect beta-cells from death under diabetogenic situations.

Lipotoxicity induced pancreatic beta cell damage is associated with GPR119/MST1/FoxO1 Pathway

IntroductionG-protein-coupled receptor 119 (GPR119) is emerging as a potential therapeutic target against type 2 diabetes with beneficial effects on glucose homeostasis. However, the function of GRP119 in lipotoxicity induced pancreatic beta cell apoptosis and the molecular mechanism remains largely unknown.Material and methodsImpact of GPR119 on pancreatic islet beta cell apoptosis was evaluated in INS-1 cells treated with palmitate. The subsequent modulation of the MST1-FOXO1-Pdx1 signaling pathway and pro-apoptotic caspase-3 system were determined by measuring the target protein and mRNA expression. Dyslipidemia mice with gain and loss of GPR119 function by the application of specific lenti-viral vector was utilized to evaluate the impact of GPR119 on pancreas function in vivo. Lipid metabolism, glucose and insulin response, morphological changes as well as activation/inhibition of MST1-FOXO1-Pdx1 signaling pathway in pancreas were analyzed systematically.ResultsPalmitate treatment stimulated pro-apoptotic response in INS-1 cells, accompanied by inhibition of GPR119 expression and the subsequent activation of the MST1-FOXO1 combined with inhibition of Pdx1 signaling cascade. Activation of GPR119 by MBX prevents INS-1 cell from lipotoxicity induced apoptosis by targeting the MST1-FOXO1-Pdx1 pathway. Moreover, overexpression of GPR119 significantly attenuates the dyslipidemia and dysfunction of the pancreas. In contrast, inactivation of GPR119 by lentiviral vector in mice results in accelerated pancreas apoptosis and malfunction. The protective effects of GRP119 on lipotoxicity induced pancreas dysfunction are associated with modulating the MST1-FOXO1-Pdx1 signaling cascade.ConclusionsGPR119 alleviates lipotoxicity induced pancreatic beta cell apoptosis and malfunction through regulating MST1-FOXO1-Pdx1 signaling pathway.

Bergenin protects pancreatic beta cells against cytokine-induced apoptosis in INS-1E cells

Beta cell apoptosis induced by proinflammatory cytokines is one of the hallmarks of diabetes. Small molecules which can inhibit the cytokine-induced apoptosis could lead to new drug candidates that can be used in combination with existing therapeutic interventions against diabetes. The current study evaluated several effects of bergenin, an isocoumarin derivative, in beta cells in the presence of cytokines. These included (i) increase in beta cell viability (by measuring cellular ATP levels) (ii) suppression of beta cell apoptosis (by measuring caspase activity), (iii) improvement in beta cell function (by measuring glucose-stimulated insulin secretion), and (iv) improvement of beta cells mitochondrial physiological functions. The experiments were carried out using rat beta INS-1E cell line in the presence or absence of bergenin and a cocktail of proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon- gamma) for 48 hr. Bergenin significantly inhibited beta cell apoptosis, as inferred from the reduction in the caspase-3 activity (IC50 = 7.29 ± 2.45 μM), and concurrently increased cellular ATP Levels (EC50 = 1.97 ± 0.47 μM). Bergenin also significantly enhanced insulin secretion (EC50 = 6.73 ± 2.15 μM) in INS-1E cells, presumably because of the decreased nitric oxide production (IC50 = 6.82 ± 2.83 μM). Bergenin restored mitochondrial membrane potential (EC50 = 2.27 ± 0.83 μM), decreased ROS production (IC50 = 14.63 ± 3.18 μM), and improved mitochondrial dehydrogenase activity (EC50 = 1.39 ± 0.62 μM). This study shows for the first time that bergenin protected beta cells from cytokine-induced apoptosis and restored insulin secretory function by virtue of its anti-inflammatory, antioxidant and anti-apoptotic properties. To sum up, the above mentioned data highlight bergenin as a promising anti-apoptotic agent in the context of diabetes.