Adipsin is an adipokine that improves ? cell function in diabetes.
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ABSTRACT:
SUBMITTER: Lo JC
PROVIDER: S-EPMC4128197 | biostudies-literature | 2014 Jul
REPOSITORIES: biostudies-literature
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Adipsin is an adipokine that improves β cell function in diabetes.
Lo James C JC Ljubicic Sanda S Leibiger Barbara B Kern Matthias M Leibiger Ingo B IB Moede Tilo T Kelly Molly E ME Chatterjee Bhowmick Diti D Murano Incoronata I Cohen Paul P Banks Alexander S AS Khandekar Melin J MJ Dietrich Arne A Flier Jeffrey S JS Cinti Saverio S Blüher Matthias M Danial Nika N NN Berggren Per-Olof PO Spiegelman Bruce M BM
Cell 20140701 1
A hallmark of type 2 diabetes mellitus (T2DM) is the development of pancreatic β cell failure, which results in insulinopenia and hyperglycemia. We show that the adipokine adipsin has a beneficial role in maintaining β cell function. Animals genetically lacking adipsin have glucose intolerance due to insulinopenia; isolated islets from these mice have reduced glucose-stimulated insulin secretion. Replenishment of adipsin to diabetic mice treated hyperglycemia by boosting insulin secretion. We id ...[more]
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Project description:Background/Objectives: Adipsin, an adipokine, is known to play an important role in maintaining the function of pancreatic beta cells in mice. This study aimed to investigate whether adipsin could be a circulating biomarker for evaluating the function of beta cells in patients with type 2 diabetes (T2D). Methods: Plasma adipsin concentrations were measured using immunoassay in three distinct subject groups: normoglycemia, T2D without insulin treatment (T2D-w/o-insulin), and T2D treated with insulin (T2D-with-insulin). Adipsin expressions were evaluated in three distinct mouse groups: normal diet (ND), high-fat diet (HFD), and HFD with streptozotocin (STZ) and nicotinamide (NA). Results: The T2D-with-insulin group exhibited a significant decrease in plasma adipsin concentration (3.91 ± 1.51 μg/mL) compared to the T2D-w/o-insulin group (5.11 ± 1.53 μg/mL; p < 0.001), whereas the T2D-w/o-insulin group showed a significantly increased plasma adipsin concentration compared to the normoglycemia group (4.53 ± 1.15 μg/mL). Plasma adipsin concentration was positively correlated with fasting C-peptide level (p < 0.001), 2-h C-peptide level (p < 0.001), and 2-h C-peptidogenic index (p < 0.001) in the diabetic groups. HFD mice showed a significant increase in pancreatic islet size, plasma insulin and adipsin levels, as well as adipsin expression in white adipose tissue (WAT) compared to ND mice. In contrast, the insulin-deficient T2D model (HFD-STZ-NA) demonstrated a marked reduction in pancreatic islet size, plasma insulin and adipsin concentrations, and adipsin expression in WAT compared to the HFD mice. Conclusions: plasma adipsin may be useful for evaluating pancreatic beta cell function in patients with T2D.
| S-EPMC11642166 | biostudies-literature
Project description:Background and purposeGlycogen phosphorylase (GP) is the key enzyme for glycogen degradation. GP inhibitors (GPi-s) are glucose lowering agents that cause the accumulation of glucose in the liver as glycogen. Glycogen metabolism has implications in beta cell function. Glycogen degradation can maintain cellular glucose levels, which feeds into catabolism to maintain insulin secretion, and elevated glycogen degradation levels contribute to glucotoxicity. The purpose of this study was to assess whether influencing glycogen metabolism in beta cells by GPi-s affects the function of these cells.Experimental approachThe effects of structurally different GPi-s were investigated on MIN6 insulinoma cells and in a mouse model of diabetes.Key resultsGPi treatment increased glycogen content and, consequently, the surface area of glycogen in MIN6 cells. Furthermore, GPi treatment induced insulin receptor β (InsRβ), Akt and p70S6K phosphorylation, as well as pancreatic and duodenal homeobox 1(PDX1) and insulin expression. In line with these findings, GPi-s enhanced non-stimulated and glucose-stimulated insulin secretion in MIN6 cells. The InsRβ was shown to co-localize with glycogen particles as confirmed by in silico screening, where components of InsR signalling were identified as glycogen-bound proteins. GPi-s also activated the pathway of insulin secretion, indicated by enhanced glycolysis, mitochondrial oxidation and calcium signalling. Finally, GPi-s increased the size of islets of Langerhans and improved glucose-induced insulin release in mice.Conclusion and implicationsThese data suggest that GPi-s also target beta cells and can be repurposed as agents to preserve beta cell function or even ameliorate beta cell dysfunction in different forms of diabetes.Linked articlesThis article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.
| S-EPMC5758390 | biostudies-literature
Project description:BackgroundDiabetic cardiomyopathy (DCM) causes the myocardium to rely on fatty acid β-oxidation for energy. The accumulation of intracellular lipids and fatty acids in the myocardium usually results in lipotoxicity, which impairs myocardial function. Adipsin may play an important protective role in the pathogenesis of DCM. The aim of this study is to investigate the regulatory effect of Adipsin on DCM lipotoxicity and its molecular mechanism.MethodsA high-fat diet (HFD)-induced type 2 diabetes mellitus model was constructed in mice with adipose tissue-specific overexpression of Adipsin (Adipsin-Tg). Liquid chromatography-tandem mass spectrometry (LC-MS/MS), glutathione-S-transferase (GST) pull-down technique, Co-immunoprecipitation (Co-IP) and immunofluorescence colocalization analyses were used to investigate the molecules which can directly interact with Adipsin. The immunocolloidal gold method was also used to detect the interaction between Adipsin and its downstream modulator.ResultsThe expression of Adipsin was significantly downregulated in the HFD-induced DCM model (P < 0.05). Adipose tissue-specific overexpression of Adipsin significantly improved cardiac function and alleviated cardiac remodeling in DCM (P < 0.05). Adipsin overexpression also alleviated mitochondrial oxidative phosphorylation function in diabetic stress (P < 0.05). LC-MS/MS analysis, GST pull-down technique and Co-IP studies revealed that interleukin-1 receptor-associated kinase-like 2 (Irak2) was a downstream regulator of Adipsin. Immunofluorescence analysis also revealed that Adipsin was co-localized with Irak2 in cardiomyocytes. Immunocolloidal gold electron microscopy and Western blotting analysis indicated that Adipsin inhibited the mitochondrial translocation of Irak2 in DCM, thus dampening the interaction between Irak2 and prohibitin (Phb)-optic atrophy protein 1 (Opa1) on mitochondria and improving the structural integrity and function of mitochondria (P < 0.05). Interestingly, in the presence of Irak2 knockdown, Adipsin overexpression did not further alleviate myocardial mitochondrial destruction and cardiac dysfunction, suggesting a downstream role of Irak2 in Adipsin-induced responses (P < 0.05). Consistent with these findings, overexpression of Adipsin after Irak2 knockdown did not further reduce the accumulation of lipids and their metabolites in the cardiac myocardium, nor did it enhance the oxidation capacity of cardiomyocytes expose to palmitate (PA) (P < 0.05). These results indicated that Irak2 may be a downstream regulator of Adipsin.ConclusionsAdipsin improves fatty acid β-oxidation and alleviates mitochondrial injury in DCM. The mechanism is related to Irak2 interaction and inhibition of Irak2 mitochondrial translocation.
| S-EPMC10712050 | biostudies-literature
Project description:Physical activity is important for type 2 diabetes treatment, yet the underlying mechanisms for these beneficial effects of exercise are not fully understood. Here, we investigated the effects of exercise training on biphasic β-cell insulin secretory function, a key factor regulating blood glucose. Adults with type 2 diabetes (7F/3M, age 49 ± 5 years, BMI 30 ± 3 kg/m2) completed a 10-week moderate-intensity exercise program and multiple components of glucose homeostasis were measured. Training improved glycemic control, insulin sensitivity, and processing of proinsulin-to-insulin. Training increased late phase β-cell function by 38% (p = 0.01), which was correlated with changes in VO2peak suggesting training response-dependent effects. Ras-Responsive Element Binding Protein 1 (RREB1) concentrations, a protein postulated to increase type 2 diabetes risk, were inversely correlated with increases in training-induced late-phase disposition index, consistent with an inhibitory role of RREB1 on insulin secretion. Moderate-intensity exercise training improves late-phase β-cell function and glycemic control in adults with type 2 diabetes.
| S-EPMC10362261 | biostudies-literature
Project description:The progression from insulin resistance to type 2 diabetes is caused by the failure of pancreatic beta cells to produce sufficient levels of insulin to meet the metabolic demand. Recent studies indicate that nutrient fluctuations and insulin resistance increase proinsulin synthesis in beta cells beyond the capacity for folding of nascent polypeptides within the endoplasmic reticulum (ER) lumen, thereby disrupting ER homeostasis and triggering the unfolded protein response (UPR). Chronic ER stress promotes apoptosis, at least in part through the UPR-induced transcription factor C/EBP homologous protein (CHOP). We assessed the effect of Chop deletion in multiple mouse models of type 2 diabetes and found that Chop-/- mice had improved glycemic control and expanded beta cell mass in all conditions analyzed. In both genetic and diet-induced models of insulin resistance, CHOP deficiency improved beta cell ultrastructure and promoted cell survival. In addition, we found that isolated islets from Chop-/- mice displayed increased expression of UPR and oxidative stress response genes and reduced levels of oxidative damage. These findings suggest that CHOP is a fundamental factor that links protein misfolding in the ER to oxidative stress and apoptosis in beta cells under conditions of increased insulin demand.
| S-EPMC2528909 | biostudies-literature
Project description:UnlabelledPhysical activity improves the regulation of glucose homeostasis in both type 2 diabetes (T2D) patients and healthy individuals, but the effect on pancreatic β cell function is unknown. We investigated glycaemic control, pancreatic function and total fat mass before and after 8 weeks of low volume high intensity interval training (HIIT) on cycle ergometer in T2D patients and matched healthy control individuals. Study design/method: Elderly (56 yrs±2), non-active T2D patients (n = 10) and matched (52 yrs±2) healthy controls (CON) (n = 13) exercised 3 times (10×60 sec. HIIT) a week over an 8 week period on a cycle ergometer. Participants underwent a 2-hour oral glucose tolerance test (OGTT). On a separate day, resting blood pressure measurement was conducted followed by an incremental maximal oxygen uptake (VO2max) cycle ergometer test. Finally, a whole body dual X-ray absorptiometry (DXA) was performed. After 8 weeks of training, the same measurements were performed. Results: in the T2D-group, glycaemic control as determined by average fasting venous glucose concentration (p = 0.01), end point 2-hour OGTT (p = 0.04) and glycosylated haemoglobin (p = 0.04) were significantly reduced. Pancreatic homeostasis as determined by homeostatic model assessment of insulin resistance (HOMA-IR) and HOMA β cell function (HOMA-%β) were both significantly ameliorated (p = 0.03 and p = 0.03, respectively). Whole body insulin sensitivity as determined by the disposition index (DI) was significantly increased (p = 0.03). During OGTT, the glucose continuum was significantly reduced at -15 (p = 0.03), 30 (p = 0.03) and 120 min (p = 0.03) and at -10 (p = 0.003) and 0 min (p = 0.003) with an additional improvement (p = 0.03) of its 1st phase (30 min) area under curve (AUC). Significant abdominal fat mass losses were seen in both groups (T2D: p = 0.004 and CON: p = 0.02) corresponding to a percentage change of -17.84%±5.02 and -9.66%±3.07, respectively. Conclusion: these results demonstrate that HIIT improves overall glycaemic control and pancreatic β cell function in T2D patients. Additionally, both groups experienced abdominal fat mass losses. These findings demonstrate that HIIT is a health beneficial exercise strategy in T2D patients.Trial registrationClinicalTrials.gov NCT02333734 http://clinicaltrials.gov/ct2/show/NCT02333734.
| S-EPMC4530878 | biostudies-literature
Project description:BackgroundAdipsin (complement factor D, CFD), as the first described adipokine, is well-known for its regulatory effects in diabetic cardiovascular complications. However, its role in diabetic hind-limb ischemia was not clarified. This study aimed to evaluate the possible therapeutic effect of Adipsin in hind-limb ischemia in type 2 diabetic mice and to elucidate the molecular mechanisms involved.MethodsA high-fat diet and streptozotocin (HFD/STZ)-induced diabetic mouse model, and a transgenic mouse model with adipose tissue-specific overexpression of Adipsin (Adipsin-Tg) were employed. Hindlimb ischemia was established by femoral artery ligation, and blood flow recovery was monitored using Laser Doppler perfusion imaging. Molecular mechanisms underlying Adipsin-potentiated angiogenesis were examined using RNA sequencing and co-immunoprecipitation/mass spectrometry (Co-IP/MS) analyses.ResultsAdipsin expression was upregulated in non-diabetic mice following HLI, while suppressed in diabetic mice, indicating its potential role in ischemic recovery which is impaired in diabetes. Adipsin-Tg mice exhibited significantly improved blood flow recovery, increased capillary density, and enhanced muscle regeneration in comparison with non-transgenic (NTg) diabetic mice. Adipsin facilitated proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) under hyperglycemic and hypoxic conditions. Additionally, it enhanced phosphorylation of AKT, ERK, and eNOS pathways both in vivo and in vitro. RNA sequencing and co-immunoprecipitation/mass spectrometry (Co-IP/MS) analyses identified that Adipsin promoted angiogenesis by interacting with SERBP1, which disrupted the binding of SERBP1 to SERPINE1 mRNA, resulting in reduced SERPINE1 expression and the subsequent activation of the VEGFR2 signaling cascade.ConclusionsAdipsin promotes angiogenesis and facilitates blood perfusion recovery in diabetic mice with HLI by downregulating SERPINE1 through interaction with SERBP1. These findings elucidate a novel therapeutic potential for Adipsin in the management of PAD in diabetic patients, highlighting its role in enhancing angiogenesis and tissue repair.
| S-EPMC11613494 | biostudies-literature
Project description:ObjectiveThis study tested the hypothesis that phosphodiesterase 5 inhibition alone or in combination with ACE inhibition improves glucose homeostasis and fibrinolysis in individuals with metabolic syndrome.Research design and methodsInsulin sensitivity, beta-cell function, and fibrinolytic parameters were measured in 18 adults with metabolic syndrome on 4 separate days after a randomized, crossover, double-blind, 3-week treatment with placebo, ramipril (10 mg/day), tadalafil (10 mg o.d.), and ramipril plus tadalafil.ResultsRamipril decreased systolic and diastolic blood pressure, ACE activity, and angiotensin II and increased plasma renin activity. Ramipril did not affect insulin sensitivity or beta-cell function. In contrast, tadalafil improved beta-cell function (P = 0.01). This effect was observed in women (331.9 +/- 209.3 vs. 154.4 +/- 48.0 32 micro x mmol(-1) x l(-1), respectively, for tadalafil treatment vs. placebo; P = 0.01) but not in men. There was no effect of any treatment on fibrinolysis. CONCLUSIONS Phosphodiesterase 5 inhibition may represent a novel strategy for improving beta-cell function in metabolic syndrome.
| S-EPMC2671107 | biostudies-literature
Project description:Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function1,2. Currently, there are no therapies proven to prevent beta cell loss and some, namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes3,4. The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion5. In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db/db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes.
| S-EPMC7256970 | biostudies-literature
Project description:ContextNovel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control and weight loss (WL) compared with selective GLP-1RA dulaglutide.ObjectiveExplore mechanisms of glucose control by tirzepatide.DesignPost hoc analyses of fasting biomarkers and multiple linear regression analysis.SettingForty-seven sites in 4 countries.Patients or other participantsThree hundred and sixteen subjects with type 2 diabetes.InterventionsTirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo.Main outcome measuresAnalyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks.ResultsHomeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (P ≤ .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (P ≤ .007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (P ≤ .033) and tirzepatide 10 mg significantly decreased HOMA2-IR (P = .004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by 1 or more doses of tirzepatide (P < .05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and glycated hemoglobin A1c was conducted. WL significantly (P ≤ .028) explained only 13% and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg, respectively.ConclusionsTirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.
| S-EPMC7823251 | biostudies-literature