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A±F. Localisation of PPARg in alpha, beta and delta cells of pancreatic human islets by immunohistochemistry. Simple immunolabelling of PPARg (A and B), insulin (C), glucagon (D) and somatostatin (E) on adjacent sections with AEC (red), and double immunolabelling of PPARg with BCIP/NBT (blue) and insulin with AEC (F). Arrows indicate cells in which PPARg is co-localized with insulin (beta), glucagon (alpha) or somatostatin (delta). The bar represent 50 mm
Source publication
Aims/hypothesis. Thiazolidinediones are reported to improve pancreatic islet morphology and beta-cell function in rodents, supporting the
hypothesis of a direct action of thiazolidinediones on endocrine islet cells. In this study we examined the expression of
the peroxisome proliferator-activated receptor γ, a nuclear receptor that is activated by...
Contexts in source publication
Context 1
... of PPARg in human pancreatic tissue. Expression of PPARg in pancreatic tissue was stud- ied next by immunohistochemistry on human pan- creatic sections. Simple immunolabelling of PPARg using the same antibody as used for the western blots confirmed that this nuclear receptor was highly expressed in islets (Fig. 2). Immunola- belling on adjacent sections of glucagon, insulin and somatostatin, hormones that are specific to al- pha, beta and delta cells, respectively, showed the presence of PPARg in all three cell types of hu- man islets (Fig. 2). Expression of PPARg in beta cells was confirmed by double immunolabelling of PPARg and insulin in the ...
Context 2
... same antibody as used for the western blots confirmed that this nuclear receptor was highly expressed in islets (Fig. 2). Immunola- belling on adjacent sections of glucagon, insulin and somatostatin, hormones that are specific to al- pha, beta and delta cells, respectively, showed the presence of PPARg in all three cell types of hu- man islets (Fig. 2). Expression of PPARg in beta cells was confirmed by double immunolabelling of PPARg and insulin in the same pancreatic section (Fig. ...
Context 3
... on adjacent sections of glucagon, insulin and somatostatin, hormones that are specific to al- pha, beta and delta cells, respectively, showed the presence of PPARg in all three cell types of hu- man islets (Fig. 2). Expression of PPARg in beta cells was confirmed by double immunolabelling of PPARg and insulin in the same pancreatic section (Fig. ...
Citations
... In contrast with the ubiquitous expression of PPARG1, human PPARG2 mRNA is only present in human adipose tissue. Even at that location, human PPARG2 mRNA is less abundant than PPARG1 in both visceral and subcutaneous adipose tissue [87][88][89][90][92][93][94][95]. As mentioned, human PPAR-γ promotes adipocyte differentiation and consequently fat deposition in the subcutaneous adipose tissue. ...
The risk for metabolic and cardiovascular complications of obesity is defined by body fat distribution rather than global adiposity. Unlike subcutaneous fat, visceral fat (including hepatic steatosis) reflects insulin resistance and predicts type 2 diabetes and cardiovascular disease. In humans, available evidence indicates that the ability to store triglycerides in the subcutaneous adipose tissue reflects enhanced insulin sensitivity. Prospective studies document an association between larger subcutaneous fat mass at baseline and reduced incidence of impaired glucose tolerance. Case-control studies reveal an association between genetic predisposition to insulin resistance and a lower amount of subcutaneous adipose tissue. Human peroxisome proliferator-activated receptor-gamma (PPAR-γ) promotes subcutaneous adipocyte differentiation and subcutaneous fat deposition, improving insulin resistance and reducing visceral fat. Thiazolidinediones reproduce the effects of PPAR-γ activation and therefore increase the amount of subcutaneous fat while enhancing insulin sensitivity and reducing visceral fat. Partial or virtually complete lack of adipose tissue (lipodystrophy) is associated with insulin resistance and its clinical manifestations, including essential hypertension, hypertriglyceridemia, reduced HDL-c, type 2 diabetes, cardiovascular disease, and kidney disease. Patients with Prader Willi syndrome manifest severe subcutaneous obesity without insulin resistance. The impaired ability to accumulate fat in the subcutaneous adipose tissue may be due to deficient triglyceride synthesis, inadequate formation of lipid droplets, or defective adipocyte differentiation. Lean and obese humans develop insulin resistance when the capacity to store fat in the subcutaneous adipose tissue is exhausted and deposition of triglycerides is no longer attainable at that location. Existing adipocytes become large and reflect the presence of insulin resistance.
... PPARs represent the second way of diabetic disorder improvement regulated by SERCA and are important targets in diabetes therapy. PPAR is expressed in a variety of tissues, including the islet beta-cell [57,58]. It may play a role in beta-cell insulin release, is able to improve islet function, and may directly activate genes encoding SERCAs [59]. ...
Many redox diseases, including diabetes, are associated with an imbalance of calcium homeostasis, regulated mainly by a Ca2+-ATPase pump (SERCA). Dysfunction of this enzyme may be prevented by natural polyphenolic compounds, representing a possible supporting treatment. Compounds that increase SERCA activity/expression may be useful for the treatment of diabetic complications. Stimulation of SERCA1 activity was analyzed experimentally and by molecular modeling. SERCA1 activity under methylglyoxal- and palmitate-induced oxidative stress was evaluated. The viability of INS-1E cells and insulin secretion were determined. [6]-Gingerol, resveratrol, and ellagic acid increased SERCA1 activity and exerted a protective effect under oxidative stress in the noncellular system. We found for the first time that the binding of polyphenols ([6]-gingerol, resveratrol, ellagic acid) to Glu439 in the SERCA1 P-domain may be critical for the stimulation of its activity. Moreover, this binding may also be important in the protective effects against oxidative stress. Direct stimulation of SERCA1 activity by ellagic acid was observed for the first time. In INS-1E cells, these compounds increased insulin secretion.
... In patients with T2DM, serum levels of PPAR-γ were lower than in healthy controls, and this was accompanied by reduced NRF2 and SOD activity in the PBMC nuclear extracts of these patients (Mohamed and Schaalan, 2018). High expression levels of both PPAR-γ mRNA and protein are found in human islet cells, and PPAR-γ agonists directly target these pancreatic islet cells (Dubois et al., 2000). Activating PPAR-γ in pancreatic RIN-m5F cells induced NRF2 activity and ameliorated pancreatic dysfunction via decreased inflammation (Hsu and Pan, 2014). ...
Evidence supports a strong bidirectional association between depression and Type 2 diabetes mellitus (T2DM). The harmful impact of oxidative stress and chronic inflammation on the development of both disorders is widely accepted. Nuclear factor erythroid 2-related factor 2 (NRF2) is a pertinent target in disease management owing to its reputation as the master regulator of antioxidant responses. NRF2 influences the expression of various cytoprotective phase 2 antioxidant genes, which is hampered in both depression and T2DM. Through interaction and crosstalk with several signaling pathways, NRF2 endeavors to contain the widespread oxidative damage and persistent inflammation involved in the pathophysiology of depression and T2DM. NRF2 promotes the neuroprotective and insulin-sensitizing properties of its upstream and downstream targets, thereby interrupting and preventing disease advancement. Standard antidepressant and antidiabetic drugs may be powerful against these disorders, but unfortunately, they come bearing distressing side effects. Therefore, exploiting the therapeutic potential of NRF2 activators presents an exciting opportunity to manage such bidirectional and comorbid conditions.
... Chronic hyperlipidaemia (a consequence of insulin resistance) injures β-cells via the generation of cytotoxic intracellular metabolites (such as saturated free fatty acids, ceramides and reactive oxidative species) that activate inflammatory pathways and lead to β-cell dysfunction and death 152 . Pancreatic islets also show abundant expression of proteins (including PPARγ, PDE3B and SIRT1) involved in insulin production that serve as known substrates for S-nitrosylation in at least one situation [153][154][155] ; these SNO proteins might therefore act as potential mediators of pancreatic insulin resistance induced by hyperlipidaemia and inflammation in at least some situations (Fig. 5). ...
Insulin, which is released by pancreatic islet β-cells in response to elevated levels of glucose in the blood, is a critical regulator of metabolism. Insulin triggers the uptake of glucose and fatty acids into the liver, adipose tissue and muscle, and promotes the storage of these nutrients in the form of glycogen and lipids. Dysregulation of insulin synthesis, secretion, transport, degradation or signal transduction all cause failure to take up and store nutrients, resulting in type 1 diabetes mellitus, type 2 diabetes mellitus and metabolic dysfunction. In this Review, we make the case that insulin signalling is intimately coupled to protein S-nitrosylation, in which nitric oxide groups are conjugated to cysteine thiols to form S-nitrosothiols, within effectors of insulin action. We discuss the role of S-nitrosylation in the life cycle of insulin, from its synthesis and secretion in pancreatic β-cells, to its signalling and degradation in target tissues. Finally, we consider how aberrant S-nitrosylation contributes to metabolic diseases, including the roles of human genetic mutations and cellular events that alter S-nitrosylation of insulin-regulating proteins. Given the growing influence of S-nitrosylation in cellular metabolism, the field of metabolic signalling could benefit from renewed focus on S-nitrosylation in type 2 diabetes mellitus and insulin-related disorders.
... Gastaldelli et al. [131] and Tripathy et al. [132] reported an improved β-cell function measured as disposition index upon pioglitazone administration for 4 and 6 months, respectively. How pioglitazone would improve β-cell function is unknown, but it may J o u r n a l P r e -p r o o f involve direct (expression of PPAR-γ in pancreatic islets cells [133]) or indirect effects related to the marked improvements in insulin sensitivity by pioglitazone (see below). ...
Background
Type 2 diabetes is a syndrome defined by hyperglycaemia that is the result of various degrees of pancreatic β-cell failure and reduced insulin sensitivity. Despite the fact that diabetes can be caused by multiple metabolic dysfunctions, the majority of patients are defined as having either type 1 or type 2 diabetes. Recently, Ahlqvist and colleagues proposed a new way to classify patients with adult-onset diabetes, taking the heterogenous metabolic phenotype of the disease into account. This new classification system could be useful for a more personalized treatment based on the underlying metabolic disruption of the disease, although so far no prospective intervention studies have generated data to support such a claim.
Scope of Review
In this review, we first provide a short overview of the phenotype and pathogenesis of type 2 diabetes, and discuss the current and new classification system. Further, we aim to review the effects of different antidiabetic medication classes on insulin sensitivity and β-cell function and discuss future treatment strategies based on the subgroups proposed by Ahlqvist et al.
Conclusions
The proposed novel subgroups of type 2 diabetes provide an interesting concept that could lead to a better understanding of the pathophysiology of the broad group of type 2 diabetes paving the way for personalized treatment choices based on understanding the root cause of the disease. We conclude that all novel subgroups of adult-onset diabetes would benefit from antidiabetic medication that take into account the main pathophysiology of the disease and thereby prevent of end-organ damage. However, we are just in the beginning of personalized treatment of type 2 diabetes and studies to investigate effects of current and novel drugs in subgroups with different metabolic phenotypes is needed in order to develop personalized treatment of the syndrome.
... PPAR-γ is a member of the nuclear receptor superfamily that has been identified to exist in human and rodent pancreatic islet and INS-1 cells [18]. Previous researches have been reported that the expression of PPAR-γ is increased in the diabetic state and PPAR-γ is involved in insulin secretion [19,20]. However, studies on the effects of PPAR-γ on insulin secretion are contradictory. ...
Peroxisome proliferator-activated receptor-γ (PPAR-γ) is expressed in pancreatic β cells and is involved in insulin secretion. However, the precise mechanisms remain unclear. Calcium/calmodulin-dependent serine protein kinase (CASK), which plays a vital role in the anchoring of insulin granules on pancreatic β cell membrane, is probably a downstream of the transcription factor PPAR-γ. The aim of the present study was to investigate the correlation among PPAR-γ, CASK and insulin secretion. We found that rosiglitazone (RSG) had a positive effect on the expression of CASK and PPAR-γ in INS-1 cells as shown by real-time polymerase chain reaction (PCR) and western blot analysis, but did not change the cellular location of CASK as shown by immunofluorescence assay. Knockdown of PPAR-γ significantly attenuated the mRNA and protein expression levels of CASK. ChIP-qPCR and luciferase assays showed that PPAR-γ bound with the Cask promoter, and promoter activity of Cask was elevated by RSG. RSG significantly enhanced the insulin secretion with potassium stimulation, but did not alter the insulin content as shown by potassium-stimulated insulin secretion assay. In addition, with RSG pretreatment, knockdown of Cask did not significantly affect the PPAR-γ activation-mediated insulin secretion. Moreover, electron microscopy demonstrated that with RSG pretreatment, silence of Cask did not change the number of vesicles anchored on the cell membranes compared with those in siCask-treated cells. Overall, the present study identifies that CASK is one of the PPAR-γ downstream targets and PPAR-γ exerts a positive effect on the expression of CASK in INS-1 cells. PPAR-γ activation increases insulin secretion independent of the upregulation of CASK.
... These compounds work through activation of the nuclear transcription factor peroxisome proliferator-activated receptor-c (PPAR-c). PPAR-c expression has been confirmed in rodent and human pancreatic islets [8,9]. Several large clinical trials such as the Diabetes Prevention Program (DPP), Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial and A Diabetes Outcome Progression Trial (ADOPT) trial supported the idea that TZDs may have a protective effect on pancreatic beta cells [10][11][12]. ...
Aims:
The direct effects of thiazolidinediones (TZDs) on pancreatic beta cells have been controversial. The aim of this study was to find out whether a novel TZD, lobeglitazone, has beneficial effects on pancreatic beta cells and db/db mice compared to those of other TZDs.
Methods:
INS-1 cells were incubated at a high-glucose concentration with various concentrations of troglitazone, rosiglitazone, pioglitazone, and lobeglitazone. Apoptosis and proliferation of beta cells, markers for ER stress and glucose-stimulated insulin secretion (GSIS) were assessed. In addition, C57BL/6 db/db mice were treated with pioglitazone or lobeglitazone for 4 weeks, and metabolic parameters and the configuration of pancreatic islets were also examined.
Results:
Lobeglitazone and other TZDs decreased INS-1 cell apoptosis in high-glucose conditions. Lobeglitazone and other TZDs significantly decreased hyperglycemia-induced increases in ER stress markers and increased GSIS. Metabolic parameters showed greater improvement in db/db mice treated with pioglitazone and lobeglitazone than in control mice. Islet size, cell proliferation, and beta cell mass were increased, and collagen surrounding the islets was decreased in treated mice.
Conclusions:
Lobeglitazone showed beneficial effects on beta cell survival and function against hyperglycemia. The prosurvival and profunction effects of lobeglitazone were comparable to those of other TZDs.
... Higher levels of PPARG mRNA and protein in human islet endocrine cells were observed [36]. PPARG overexpression directly repressed insulin secretion under the conditions of stimulatory glucose concentration in the rodent models [37]. ...
Background:
Previous studies suggested that the single nucleotide polymorphisms of Pro12Ala located within the PPARG gene were significantly associated with the T2DM. Recently, the genetic studies on Pro12Ala were conducted in the different ethnic groups and the results of each study were shown to be inconsistent. Moreover, the systematic review has not been updated since 2000.
Objective:
To further validate the risk of Pro12Ala for T2DM disease based on the genetic data.
Methods:
The genetic studies on the Pro12Ala in the T2DM were searched in the PubMed and PMC database from January 2000 to October 2017. The meta-analysis was conducted with the CMA software.
Results:
The meta-analysis collected 14 studies including 20702 cases and 36227 controls. The combined analysis of all studies found that Pro12Ala was shown to be significantly associated with T2DM and the Ala allele played the increasing risks for the disease. Nevertheless, publication bias was detected in the combined analysis. The subgroup analysis indicated that Pro12Ala was still shown significant in the Caucasian and Chinese population. There was no heterogeneity and publication bias in these two groups, Conclusion: The meta-analysis confirmed the evidence that the Pro12Ala was the susceptible variant for the decreasing risks for the T2DM.
... It has also been suggested that PPARγ agonist administration preserves islet mass in animal models, but this has been considered to be a systemic effect of PPARγ activation, not a direct effect on pancreatic β-cells. Despite the known importance of PPARγ expression [21], its specific and direct role in β-cells is less well known. PPARγ, a nuclear receptor, is expressed in various tissues, including fat, muscle, and the liver, and is involved in the regulation of various genes contributing to glucose and lipid metabolism and insulin signaling [22]. ...
Background:
The nuclear receptor peroxisome proliferator-activator gamma (PPARγ) is a useful therapeutic target for obesity and diabetes, but its role in protecting β-cell function and viability is unclear.
Methods:
To identify the potential functions of PPARγ in β-cells, we treated mouse insulinoma 6 (MIN6) cells with the PPARγ agonist pioglitazone in conditions of lipotoxicity, endoplasmic reticulum (ER) stress, and inflammation.
Results:
Palmitate-treated cells incubated with pioglitazone exhibited significant improvements in glucose-stimulated insulin secretion and the repression of apoptosis, as shown by decreased caspase-3 cleavage and poly (adenosine diphosphate [ADP]-ribose) polymerase activity. Pioglitazone also reversed the palmitate-induced expression of inflammatory cytokines (tumor necrosis factor α, interleukin 6 [IL-6], and IL-1β) and ER stress markers (phosphor-eukaryotic translation initiation factor 2α, glucose-regulated protein 78 [GRP78], cleaved-activating transcription factor 6 [ATF6], and C/EBP homologous protein [CHOP]), and pioglitazone significantly attenuated inflammation and ER stress in lipopolysaccharide- or tunicamycin-treated MIN6 cells. The protective effect of pioglitazone was also tested in pancreatic islets from high-fat-fed KK-Ay mice administered 0.02% (wt/wt) pioglitazone or vehicle for 6 weeks. Pioglitazone remarkably reduced the expression of ATF6α, GRP78, and monocyte chemoattractant protein-1, prevented α-cell infiltration into the pancreatic islets, and upregulated glucose transporter 2 (Glut2) expression in β-cells. Moreover, the preservation of β-cells by pioglitazone was accompanied by a significant reduction of blood glucose levels.
Conclusion:
Altogether, these results support the proposal that PPARγ agonists not only suppress insulin resistance, but also prevent β-cell impairment via protection against ER stress and inflammation. The activation of PPARγ might be a new therapeutic approach for improving β-cell survival and insulin secretion in patients with diabetes mellitus.
... The PPARγ receptor is primarily expressed in adipose tissue, but also in pancreatic islet cells. 85 TZDs inhibit gluconeogenesis and enhance insulin sensitivity resulting in reduced fasting and postprandial glucose. 86 TZDs also promote FFA uptake and storage in adipose tissue and reduce FFA release from adipocytes by enhancing the antilipolytic effect of insulin. ...
Type 2 diabetes (T2D) is widely considered a chronic and progressive disease without cure. As beta-cell function progressively declines over time, blood glucose rises. Current management of T2D involves incremental introduction of dietary and drug therapies to achieve normoglycaemia. However, recent studies have demonstrated remission of T2D following bariatric surgery, very low calorie diet or intensive insulin therapy, raising the possibility that the declining beta-cell function in T2D may be arrested or even reversed. The point at which such interventions are introduced in the course of T2D is key for clinical benefit. Future treatment strategies should be revised to target early beta-cell preservation and thus disease remission. This article reviews the pathogenesis of beta-cell dysfunction and evidence for the clinical benefit of preserving beta-cell function in T2D, and discusses the evidence for beta-cell preservation of current glucose-lowering therapies with particular reference to their effect when initiated at the time of diagnosis of T2D.
