Immunomodulator FTY720 Rejuvenates β-cell and Ameliorates Cardiorenal Complications in Nonhuman Primate Model of Diabetes

2021 ◽  
Author(s):  
Yixin (Jim) Wang ◽  
Xiaoli Wang ◽  
Annie An ◽  
Mingfa Zang ◽  
Ling Xu ◽  
...  
Keyword(s):  
Nonhuman Primate ◽  
Cell Function ◽  
Therapeutic Potential ◽  
Systolic Function ◽  
Cell Mass ◽  
Spontaneous Diabetes ◽  
Left Ventricular ◽  
Model Assessment ◽  
Β Cell ◽  
Blood Concentrations

Abstract Inadequate β-cell mass is essential for the pathogenesis of type 2 diabetes (T2D). Previous report showed that an immunomodulator FTY720, a sphingosine 1-phosphate (S1P) receptor modulator sustainably normalized hyperglycemia by stimulating β-cell in vivo regeneration in db/db mice. To further evaluate the therapeutic potential, we examined the effects of FTY720 on glucose homeostasis in a translational nonhuman primate (NHP) model of spontaneous diabetes. Daily administration of FTY720 (5 mg/kg) effectively lowered HbA1c, blood concentrations of fasting glucose (FBG) and insulin, hence, decreased homeostatic model assessment of insulin resistance (HOMA-IR); ameliorated glucose intolerance and restored glucose-stimulated insulin release, which was largely diminished in the vehicle-treated diabetic NHPs. Importantly, after discontinuation of FTY720, FBG and HbA1c remained at the reduced levels in washout period for 8 weeks. Accompanied by the glucose lowering effects, echocardiography revealed that FTY720 significantly improved cardiac left ventricular systolic function measured by increase in ejection fraction and fractional shortening, which was compromised in the diabetic NHPs. Finally, flow cytometry analysis detected that FTY720 significantly reduced CD4+ and increased DC cells. These data strongly suggest that immunomodulator FTY720 may be a novel immunotherapy to reverse T2D progression via rejuvenation of β-cell function with benefit to improve the cardiac function.

scholarly journals VMP1-related autophagy induced by a fructose-rich diet in β-cells: its prevention by incretins

2017 ◽  
Vol 131 (8) ◽  
pp. 673-687 ◽  
Author(s):  
Bárbara Maiztegui ◽  
Verónica Boggio ◽  
Carolina L. Román ◽  
Luis E. Flores ◽  
Héctor Del Zotto ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Cell Function ◽  
Cell Damage ◽  
Cell Mass ◽  
Ultrastructural Changes ◽  
Mrna Levels ◽  
Model Assessment ◽  
Β Cells ◽  
Β Cell ◽  
Insulin Mrna

The aim of the present study was to demonstrate the role of autophagy and incretins in the fructose-induced alteration of β-cell mass and function. Normal Wistar rats were fed (3 weeks) with a commercial diet without (C) or with 10% fructose in drinking water (F) alone or plus sitagliptin (CS and FS) or exendin-4 (CE and FE). Serum levels of metabolic/endocrine parameters, β-cell mass, morphology/ultrastructure and apoptosis, vacuole membrane protein 1 (VMP1) expression and glucose-stimulated insulin secretion (GSIS) were studied. Complementary to this, islets isolated from normal rats were cultured (3 days) without (C) or with F and F + exendin-4 or chloroquine. Expression of autophagy-related proteins [VMP1 and microtubule-associated protein light chain 3 (LC3)], apoptotic/antiapoptotic markers (caspase-3 and Bcl-2), GSIS and insulin mRNA levels were measured. F rats developed impaired glucose tolerance (IGT) and a significant increase in plasma triacylglycerols, thiobarbituric acid-reactive substances, insulin levels, homoeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and β-cell function (HOMA-β) indices. A significant reduction in β-cell mass was associated with an increased apoptotic rate and morphological/ultrastructural changes indicative of autophagic activity. All these changes were prevented by either sitagliptin or exendin-4. In cultured islets, F significantly enhanced insulin mRNA and GSIS, decreased Bcl-2 mRNA levels and increased caspase-3 expression. Chloroquine reduced these changes, suggesting the participation of autophagy in this process. Indeed, F induced the increase of both VMP1 expression and LC3-II, suggesting that VMP1-related autophagy is activated in injured β-cells. Exendin-4 prevented islet-cell damage and autophagy development. VMP1-related autophagy is a reactive process against F-induced islet dysfunction, being prevented by exendin-4 treatment. This knowledge could help in the use of autophagy as a potential target for preventing progression from IGT to type 2 diabetes mellitus.

Sitagliptin prevents the development of metabolic and hormonal disturbances, increased β-cell apoptosis and liver steatosis induced by a fructose-rich diet in normal rats

2010 ◽  
Vol 120 (2) ◽  
pp. 73-80 ◽  
Author(s):  
Bárbara Maiztegui ◽  
María I. Borelli ◽  
Viviana G. Madrid ◽  
Héctor Del Zotto ◽  
María A. Raschia ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Cell Function ◽  
Liver Steatosis ◽  
Cell Mass ◽  
Oral Glucose ◽  
Model Assessment ◽  
Metabolic Disturbances ◽  
Β Cell ◽  
Commercial Diet ◽  
Triacylglycerol Content

The aim of the present study was to test the effect of sitagliptin and exendin-4 upon metabolic alterations, β-cell mass decrease and hepatic steatosis induced by F (fructose) in rats. Normal adult male Wistar rats received a standard commercial diet without (C) or with 10% (w/v) F in the drinking water (F) for 3 weeks; animals from each group were randomly divided into three subgroups: untreated (C and F) and simultaneously receiving either sitagliptin (CS and FS; 115.2 mg/day per rat) or exendin-4 (CE and FE; 0.35 nmol/kg of body weight, intraperitoneally). Water and food intake, oral glucose tolerance, plasma glucose, triacylglycerol (triglyceride), insulin and fructosamine concentration, HOMA-IR [HOMA (homoeostasis model assessment) for insulin resistance], HOMA-β (HOMA for β-cell function) and liver triacylglycerol content were measured. Pancreas immunomorphometric analyses were also performed. IGT (impaired glucose tolerance), plasma triacylglycerol, fructosamine and insulin levels, HOMA-IR and HOMA-β indexes, and liver triacylglycerol content were significantly higher in F rats. Islet β-cell mass was significantly lower in these rats, due to an increase in the percentage of apoptosis. The administration of exendin-4 and sitagliptin to F animals prevented the development of all the metabolic disturbances and the changes in β-cell mass and fatty liver. Thus these compounds, useful in treating Type 2 diabetes, would also prevent/delay the progression of early metabolic and tissue markers of this disease.

scholarly journals An autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jinyoung Kim ◽  
Kihyoun Park ◽  
Min Jung Kim ◽  
Hyejin Lim ◽  
Kook Hwan Kim ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Function ◽  
Therapeutic Potential ◽  
Therapeutic Modality ◽  
Protective Effects ◽  
Β Cells ◽  
Β Cell ◽  
Islet Amyloid ◽  
Amyloid Accumulation ◽  
Human Diabetes

AbstractWe have reported that autophagy is crucial for clearance of amyloidogenic human IAPP (hIAPP) oligomer, suggesting that an autophagy enhancer could be a therapeutic modality against human diabetes with amyloid accumulation. Here, we show that a recently identified autophagy enhancer (MSL-7) reduces hIAPP oligomer accumulation in human induced pluripotent stem cell-derived β-cells (hiPSC-β-cells) and diminishes oligomer-mediated apoptosis of β-cells. Protective effects of MSL-7 against hIAPP oligomer accumulation and hIAPP oligomer-mediated β-cell death are significantly reduced in cells with knockout of MiTF/TFE family members such as Tfeb or Tfe3. MSL-7 improves glucose tolerance and β-cell function of hIAPP+ mice on high-fat diet, accompanied by reduced hIAPP oligomer/amyloid accumulation and β-cell apoptosis. Protective effects of MSL-7 against hIAPP oligomer-mediated β-cell death and the development of diabetes are also significantly reduced by β-cell-specific knockout of Tfeb. These results suggest that an autophagy enhancer could have therapeutic potential against human diabetes characterized by islet amyloid accumulation.

scholarly journals Leptin Levels, β-Cell Function, and Insulin Sensitivity in Families with Congenital and Acquired Generalized Lipoatropic Diabetes1

1998 ◽  
Vol 83 (2) ◽  
pp. 503-508
Author(s):  
Victor C. Pardini ◽  
Ivana M. N. Victória ◽  
Selma M. V. Rocha ◽  
Danielle G. Andrade ◽  
Aline M. Rocha ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Temporal Relationship ◽  
Cell Function ◽  
Model Assessment ◽  
Homeostasis Model Assessment ◽  
Β Cell ◽  
Insulin Levels ◽  
Β Cell Function ◽  
Plasma Leptin ◽  
Specific Insulin

Lipoatropic diabetes (LD) designates a group of syndromes characterized by diabetes mellitus with marked insulin resistance and either a localized or generalized absence of adipose tissue. In this study, we evaluated plasma leptin levels in subjects with congenital generalized lipoatropic diabetes (CGLD, n = 11) or acquired generalized lipoatropic diabetes (AGLD, n = 11), and assessed correlations between leptin levels and estimations of insulin secretion and insulin sensitivity using homeostasis model assessment (HOMA). Leptin levels were 0.86 ± 0.32, 1.76 ± 0.78, and 6.9 ± 4.4 ng/mL in subjects with CGLD, AGLD, and controls (n = 19), respectively (ANOVA P < 0.0001). Specific insulin levels were 154 ± 172, 177 ± 137 and 43 ± 22 pmol/L, respectively (P < 0.0001). Insulin sensitivity was significantly decreased in both groups with LD (P< 0.0001), whereas HOMA β-cell function was not significantly different when compared with controls. Leptin levels were significantly correlated with body mass index, insulin levels, and HOMA β-cell function, and inversely correlated with insulin sensitivity in control subjects but not in subjects with generalized LD. In conclusion, decreased leptin levels were observed in subjects with generalized LD, with a trend towards lower levels in the acquired than in the congenital form (P = 0.06). The temporal relationship between the decrease in leptin levels and the development of lipoatrophy should be investigated in at-risk young relatives of subjects with the acquired forms to assess the usefulness of leptin levels as a marker of lipoatrophy.

scholarly journals The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror

2021 ◽  
Vol 22 (17) ◽  
pp. 9504
Author(s):  
María Sofía Martínez ◽  
Alexander Manzano ◽  
Luis Carlos Olivar ◽  
Manuel Nava ◽  
Juan Salazar ◽  
...  
Keyword(s):  
Cell Function ◽  
Cell Mass ◽  
Glucagon Secretion ◽  
Endocrine Regulation ◽  
Β Cell ◽  
Cell Hyperplasia ◽  
Dipeptidyl Peptidase 4 ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
Glucagon Like Peptide 1 ◽  
Chronic Hyperglycaemia

Type 2 Diabetes Mellitus (T2DM) is one of the most prevalent chronic metabolic disorders, and insulin has been placed at the epicentre of its pathophysiological basis. However, the involvement of impaired alpha (α) cell function has been recognized as playing an essential role in several diseases, since hyperglucagonemia has been evidenced in both Type 1 and T2DM. This phenomenon has been attributed to intra-islet defects, like modifications in pancreatic α cell mass or dysfunction in glucagon’s secretion. Emerging evidence has shown that chronic hyperglycaemia provokes changes in the Langerhans’ islets cytoarchitecture, including α cell hyperplasia, pancreatic beta (β) cell dedifferentiation into glucagon-positive producing cells, and loss of paracrine and endocrine regulation due to β cell mass loss. Other abnormalities like α cell insulin resistance, sensor machinery dysfunction, or paradoxical ATP-sensitive potassium channels (KATP) opening have also been linked to glucagon hypersecretion. Recent clinical trials in phases 1 or 2 have shown new molecules with glucagon-antagonist properties with considerable effectiveness and acceptable safety profiles. Glucagon-like peptide-1 (GLP-1) agonists and Dipeptidyl Peptidase-4 inhibitors (DPP-4 inhibitors) have been shown to decrease glucagon secretion in T2DM, and their possible therapeutic role in T1DM means they are attractive as an insulin-adjuvant therapy.

scholarly journals Impaired Pancreatic β-Cell Function in Critically Ill Children

2021 ◽  
Vol 9 ◽  
Author(s):  
Shereen A. Mohamed ◽  
Nora E. Badawi ◽  
Hoiyda A. AbdelRasol ◽  
Hossam M. AbdelAziz ◽  
Nirvana A. Khalaf ◽  
...  
Keyword(s):  
Cell Function ◽  
Multivariate Logistic Regression Analysis ◽  
Pediatric Intensive Care ◽  
Glucose Production ◽  
Critically Ill Children ◽  
Model Assessment ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Β Cell Function

Critical illness hyperglycemia (CIH) is common in the pediatric intensive care unit (PICU). Increased glucose production, insulin resistance (IR), and pancreatic β-cell dysfunction are responsible mechanisms. We aimed to investigate β-cell function in the PICU and to uncover its relation to clinical and laboratory variables and ICU mortality. We prospectively recruited 91 children. Pancreatic β-cell function was assessed by using a homeostasis model assessment (HOMA)-β. Patients with β-cell function <40.0% had significantly higher Pediatric Risk of Mortality III (PRISM III) scores, higher rates of a positive C-reactive protein (CRP), lower IR, and a longer hospital stay. The patients with 40–80% β-cell function had the highest IR. Intermediate IR was found when the β-cell function was >80%. ICU survivors had better β-cell function than ICU non-survivors. A multivariate logistic regression analysis revealed that higher PRISM III score and HOMA-β <80.0% were significant predictors of mortality. In conclusion, β-cell dysfunction is prevalent among PICU patients and influences patient morbidity and mortality.

scholarly journals Herbal Medicines Targeting the Improved β-Cell Functions and β-Cell Regeneration for the Management of Diabetes Mellitus

2021 ◽  
Vol 2021 ◽  
pp. 1-32
Author(s):  
Akurange Sujeevi Dammadinna Wickramasinghe ◽  
Pabasara Kalansuriya ◽  
Anoja Priyadarshani Attanayake
Keyword(s):  
Diabetes Mellitus ◽  
Cell Function ◽  
Herbal Medicines ◽  
Cell Regeneration ◽  
Model Assessment ◽  
Β Cells ◽  
Β Cell ◽  
Cell Functions ◽  
Glucose Transporter 2 ◽  
Β Cell Function

There is an increasing trend of investigating natural bioactive compounds targeting pancreatic β-cells for the prevention/treatment of diabetes mellitus (DM). With the exploration of multiple mechanisms by which β-cells involve in the pathogenesis of DM, herbal medicines are gaining attention due to their multitasking ability as evidenced by traditional medicine practices. This review attempts to summarize herbal medicines with the potential for improvement of β-cell functions and regeneration as scientifically proven by in vivo/in vitro investigations. Furthermore, attempts have been made to identify the mechanisms of improving the function and regeneration of β-cells by herbal medicines. Relevant data published from January 2009 to March 2020 were collected by searching electronic databases “PubMed,” “ScienceDirect,” and “Google Scholar” and studied for this review. Single herbal extracts, polyherbal mixtures, and isolated compounds derived from approximately 110 medicinal plants belonging to 51 different plant families had been investigated in recent years and found to be targeting β-cells. Many herbal medicines showed improvement of β-cell function as observed through homeostatic model assessment-β-cell function (HOMA-β). Pancreatic β-cell regeneration as observed in histopathological and immunohistochemical studies in terms of increase of size and number of functional β-cells was also prominent. Increasing β-cell mass via expression of genes/proteins related to antiapoptotic actions and β-cell neogenesis/proliferation, increasing glucose-stimulated insulin secretion via activating glucose transporter-2 (GLUT-2) receptors, and/or increasing intracellular Ca2+ levels were observed upon treatment of some herbal medicines. Some herbal medicines acted on various insulin signaling pathways. Furthermore, many herbal medicines showed protective effects on β-cells via reduction of oxidative stress and inflammation. However, there are many unexplored avenues. Thus, further investigations are warranted in elucidating mechanisms of improving β-cell function and mass by herbal medicines, their structure-activity relationship (SAR), and toxicities of these herbal medicines.

scholarly journals Uric acid lowering improves insulin sensitivity and lowers blood pressure: a meta-analysis of randomized parallel-controlled clinical trials

2021 ◽  
Vol 21 (1) ◽  
pp. 82-95
Author(s):  
Qunchuan Zong ◽  
Guanyi Ma ◽  
Tao Wang
Keyword(s):  
Blood Pressure ◽  
Uric Acid ◽  
Insulin Sensitivity ◽  
Cell Function ◽  
Meta Analysis ◽  
Model Assessment ◽  
Controlled Clinical Trials ◽  
Homeostasis Model Assessment ◽  
Β Cell ◽  
Β Cell Function

Objectives: This meta-analysis aimed to investigate whether uric acid lowering treatment can improve β-cell function and insulin sensitivity. Methods: PubMed, Cochrane Library, EMBASE and China Biology Medicine were searched up to March 1, 2020. Rand- omized controlled clinical trials of urate lowering therapy in hyperuricemia patients were included in meta-analysis. Effect size was estimated as mean difference with 95% confidence interval (CI). Results: Our search yielded 7 eligible trials with 503 participants. This meta-analysis showed that uric acid-lowering thera- py decreased fasting insulin -1.43 μIU/ml (weighted mean differences (WMD, 95% CI -2.78 to -0.09), homeostasis model assessment of insulin resistance -0.65 (WMD, 95% CI -1.05 to -0.24), systolic blood pressure -2.45 mm Hg (WMD, 95%CI -4.57 to -0.33) and diastolic blood pressure -3.41 mm Hg (WMD, 95%CI -3.87 to -2.95). However, the treatment had no significant effect on fasting plasma glucose (WMD -0.19 mmol/L, 95%CI -0.42 to 0.05), homeostasis model assessment of β-cell function index (WMD -0.02, 95%CI -0.28 to 0.24), total cholesterol (WMD 0.18 mg/dl; 95%CI, -1.39 to 1.75) and triglyceride (WMD 3.15 mg/dl, 95% CI -9.83 to 16.14). Conclusion: Uric acid-lowering therapies might improve insulin sensitivity and lower blood pressure, but had no significant effect on HOMA-β and serum lipids. Keywords: Hyperuricemia; uric acid lowering treatment; β-cell function; insulin sensitivity.

scholarly journals Follow-up of GK rats during prediabetes highlights increased insulin action and fat deposition despite low insulin secretion

2008 ◽  
Vol 294 (1) ◽  
pp. E168-E175 ◽  
Author(s):  
Jamileh Movassat ◽  
Danièle Bailbé ◽  
Cécile Lubrano-Berthelier ◽  
Françoise Picarel-Blanchot ◽  
Eric Bertin ◽  
...  
Keyword(s):  
Body Composition ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Cell Function ◽  
Cell Mass ◽  
The Body ◽  
Whole Body ◽  
Β Cell ◽  
Gk Rats

The adult Goto-Kakizaki (GK) rat is characterized by impaired glucose-induced insulin secretion in vivo and in vitro, decreased β-cell mass, decreased insulin sensitivity in the liver, and moderate insulin resistance in muscles and adipose tissue. GK rats do not exhibit basal hyperglycemia during the first 3 wk after birth and therefore could be considered prediabetic during this period. Our aim was to identify the initial pathophysiological changes occurring during the prediabetes period in this model of type 2 diabetes (T2DM). To address this, we investigated β-cell function, insulin sensitivity, and body composition in normoglycemic prediabetic GK rats. Our results revealed that the in vivo secretory response of GK β-cells to glucose is markedly reduced and the whole body insulin sensitivity is increased in the prediabetic GK rats in vivo. Moreover, the body composition of suckling GK rats is altered compared with age-matched Wistar rats, with an increase of the number of adipocytes before weaning despite a decreased body weight and lean mass in the GK rats. None of these changes appeared to be due to the postnatal nutritional environment of GK pups as demonstrated by cross-fostering GK pups with nondiabetic Wistar dams. In conclusion, in the GK model of T2DM, β-cell dysfunction associated with increased insulin sensitivity and the alteration of body composition are proximal events that might contribute to the establishment of overt diabetes in adult GK rats.

scholarly journals NKX6.1 transcription factor: a crucial regulator of pancreatic β cell development, identity, and proliferation

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Idil I. Aigha ◽  
Essam M. Abdelalim
Keyword(s):  
Transcription Factor ◽  
Cell Function ◽  
Disease Modeling ◽  
Critical Role ◽  
Cell Mass ◽  
Cell Development ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

Abstract Understanding the biology underlying the mechanisms and pathways regulating pancreatic β cell development is necessary to understand the pathology of diabetes mellitus (DM), which is characterized by the progressive reduction in insulin-producing β cell mass. Pluripotent stem cells (PSCs) can potentially offer an unlimited supply of functional β cells for cellular therapy and disease modeling of DM. Homeobox protein NKX6.1 is a transcription factor (TF) that plays a critical role in pancreatic β cell function and proliferation. In human pancreatic islet, NKX6.1 expression is exclusive to β cells and is undetectable in other islet cells. Several reports showed that activation of NKX6.1 in PSC-derived pancreatic progenitors (MPCs), expressing PDX1 (PDX1+/NKX6.1+), warrants their future commitment to monohormonal β cells. However, further differentiation of MPCs lacking NKX6.1 expression (PDX1+/NKX6.1−) results in an undesirable generation of non-functional polyhormonal β cells. The importance of NKX6.1 as a crucial regulator in MPC specification into functional β cells directs attentions to further investigating its mechanism and enhancing NKX6.1 expression as a means to increase β cell function and mass. Here, we shed light on the role of NKX6.1 during pancreatic β cell development and in directing the MPCs to functional monohormonal lineage. Furthermore, we address the transcriptional mechanisms and targets of NKX6.1 as well as its association with diabetes.

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