Treatment of type 2 diabetic db/db mice with a novel PPARγ agonist improves cardiac metabolism but not contractile function

Hearts from insulin-resistant type 2 diabetic db/db mice exhibit features of a diabetic cardiomyopathy with altered metabolism of exogenous substrates and reduced contractile performance. Therefore, the effect of chronic oral administration of 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (COOH), a novel ligand for peroxisome proliferator-activated receptor-γ that produces insulin sensitization, to db/db mice (30 mg/kg for 6 wk) on cardiac function was assessed. COOH treatment reduced blood glucose from 27 mM in untreated db/db mice to a normal level of 10 mM. Insulin-stimulated glucose uptake was enhanced in cardiomyocytes from COOH-treated db/db hearts. Working perfused hearts from COOH-treated db/db mice demonstrated metabolic changes with enhanced glucose oxidation and decreased palmitate oxidation. However, COOH treatment did not improve contractile performance assessed with ex vivo perfused hearts and in vivo by echocardiography. The reduced outward K+ currents in diabetic cardiomyocytes were still attenuated after COOH. Metabolic changes in COOH-treated db/db hearts are most likely indirect, secondary to changes in supply of exogenous substrates in vivo and insulin sensitization.

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Abstract 543: Increased Aortic Pulse Wave Velocity in Type 2 Diabetic db/db Mice is Dependent on Blood Pressure

Hypertension ◽

10.1161/hyp.64.suppl_1.543 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Mircea Anghelescu ◽

Keith J Gooch ◽

Aaron J Trask

Keyword(s):

Blood Pressure ◽

Pulse Wave Velocity ◽

Wave Velocity ◽

Aortic Stiffness ◽

Pulse Wave ◽

Ex Vivo ◽

Aortic Pulse Wave Velocity ◽

Type 2 Diabetic

Pulse wave velocity (PWV) is the gold standard for in vivo aortic stiffness measurements but can be dependent upon blood pressure and/or heart rate. Previous studies from our and other labs have shown increased aortic PWV in type 2 diabetic db/db mice. Moreover, preliminary ex vivo pressure myography data from our lab has also shown a lack of increase in passive aortic stiffness, suggesting that increased PWV in vivo , and therefore, increased stiffness in db/db mice may be dependent upon other mechanisms. In this study, we tested the hypothesis that increased aortic pulse wave velocity measured in db/db mice in vivo is blood pressure dependent under anesthesia. 16-wk old normal Db/db (n=9) and type 2 diabetic db/db (n=5) mice were anesthetized with 2% isoflurane and instrumented with two 1.2F pressure-tip catheters: one inserted in the left carotid artery and advanced to the thoracic aorta, the other inserted into the left femoral artery and advanced into the abdominal aorta. Blood pressure was continuously recorded and PWV was calculated using the foot-to-foot method. A microcannula was inserted into the right jugular vein for the administration of drugs. After a stabilization period of 25-30 mins, baseline BPs and PWVs were measured, after which mice were infused with increasing doses of phenylephrine (Phe, 100-500 nmol/kg/min) and sodium nitroprusside (SNP, 100-500 nmol/kg/min) to increase and decrease blood pressure, respectively. At baseline (prior to the infusion of any drugs), mean arterial pressure and aortic PWV were significantly elevated in db/db mice under anesthesia (MAP; Db/db: 77±5 vs. db/db: 100±4 mmHg, p <0.05; PWV; Db/db: 0.31±0.01 vs. db/db: 0.35±0.01 cm/ms, p <0.05). The increase in aortic PWV in db/db mice at baseline was completely abrogated when measured at equivalent MAPs ranging from 40-120 mmHg during the Phe and SNP infusions ( p >0.05). In both Db/db and db/db mice, aortic PWV was significantly correlated with MAP (Db/db: r=0.94, p <0.001; db/db: r=0.97, p <0.0001). These data show that increased aortic PWV, and therefore increased aortic stiffness in db/db mice in vivo is dependent upon blood pressure.

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Identifying potential PPARγ agonist/partial agonist from plant molecules to control type 2 diabetes using in silico and in vivo models

Medicinal Chemistry Research ◽

10.1007/s00044-016-1621-z ◽

2016 ◽

Vol 25 (9) ◽

pp. 1980-1992 ◽

Cited By ~ 4

Author(s):

Antony Stalin ◽

Santiagu Stephen Irudayaraj ◽

Dhandapani Ramesh Kumar ◽

Kedike Balakrishna ◽

Savarimuthu Ignacimuthu ◽

...

Keyword(s):

Type 2 Diabetes ◽

In Silico ◽

Partial Agonist ◽

In Vivo Models ◽

Pparγ Agonist

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High amount of visceral fat mass is associated with multiple metabolic changes in offspring of type 2 diabetic patients

International Journal of Obesity ◽

10.1038/sj.ijo.0803041 ◽

2005 ◽

Vol 29 (12) ◽

pp. 1464-1470 ◽

Cited By ~ 14

Author(s):

U Salmenniemi ◽

E Ruotsalainen ◽

M Vänttinen ◽

I Vauhkonen ◽

J Pihlajamäki ◽

...

Keyword(s):

Fat Mass ◽

Visceral Fat ◽

Metabolic Changes ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

Type 2 Diabetic

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Skeletal muscle attenuation determined by computed tomography is associated with skeletal muscle lipid content

Journal of Applied Physiology ◽

10.1152/jappl.2000.89.1.104 ◽

2000 ◽

Vol 89 (1) ◽

pp. 104-110 ◽

Cited By ~ 434

Author(s):

Bret H. Goodpaster ◽

David E. Kelley ◽

F. Leland Thaete ◽

Jing He ◽

Robert Ross

Keyword(s):

Skeletal Muscle ◽

Lipid Content ◽

Ct Scans ◽

Lipid Concentration ◽

Muscle Lipid ◽

Muscle Attenuation ◽

Good Concordance ◽

Type 2 Diabetic

The purpose of this investigation was to validate that in vivo measurement of skeletal muscle attenuation (MA) with computed tomography (CT) is associated with muscle lipid content. Single-slice CT scans performed on phantoms of varying lipid concentrations revealed good concordance between attenuation and lipid concentration ( r 2 = 0.995); increasing the phantom's lipid concentration by 1 g/100 ml decreased its attenuation by ∼1 Hounsfield unit (HU). The test-retest coefficient of variation for two CT scans performed in six volunteers was 0.51% for the midthigh and 0.85% for the midcalf, indicating that the methodological variability is low. Lean subjects had significantly higher ( P < 0.01) MA values (49.2 ± 2.8 HU) than did obese nondiabetic (39.3 ± 7.5 HU) and obese Type 2 diabetic (33.9 ± 4.1 HU) subjects, whereas obese Type 2 diabetic subjects had lower MA values that were not different from obese nondiabetic subjects. There was also good concordance between MA in midthigh and midcalf ( r = 0.60, P < 0.01), psoas ( r = 0.65, P < 0.01), and erector spinae ( r = 0.77, P < 0.01) in subsets of volunteers. In 45 men and women who ranged from lean to obese (body mass index = 18.5 to 35.9 kg/m2), including 10 patients with Type 2 diabetes mellitus, reduced MA was associated with increased muscle fiber lipid content determined with histological oil red O staining ( P = −0.43, P < 0.01). In a subset of these volunteers ( n = 19), triglyceride content in percutaneous biopsy specimens from vastus lateralis was also associated with MA ( r = −0.58, P = 0.019). We conclude that the attenuation of skeletal muscle in vivo determined by CT is related to its lipid content and that this noninvasive method may provide additional information regarding the association between muscle composition and muscle function.

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Dysfunction of muscle contraction with impaired intracellular Ca2+ handling in skeletal muscle and the effect of exercise training in male db/db mice

Journal of Applied Physiology ◽

10.1152/japplphysiol.00048.2018 ◽

2019 ◽

Vol 126 (1) ◽

pp. 170-182 ◽

Cited By ~ 6

Author(s):

Hiroaki Eshima ◽

Yoshifumi Tamura ◽

Saori Kakehi ◽

Kyoko Nakamura ◽

Nagomi Kurebayashi ◽

...

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Exercise Training ◽

Muscle Contraction ◽

Contractile Function ◽

Contractile Force ◽

Contractile Dysfunction ◽

Muscle Contractile ◽

Type 2 Diabetic

Type 2 diabetes is characterized by reduced contractile force production and increased fatigability of skeletal muscle. While the maintenance of Ca2+ homeostasis during muscle contraction is a requisite for optimal contractile function, the mechanisms underlying muscle contractile dysfunction in type 2 diabetes are unclear. Here, we investigated skeletal muscle contractile force and Ca2+ flux during contraction and pharmacological stimulation in type 2 diabetic model mice ( db/db mice). Furthermore, we investigated the effect of treadmill exercise training on muscle contractile function. In male db/db mice, muscle contractile force and peak Ca2+ levels were both lower during tetanic stimulation of the fast-twitch muscles, while Ca2+ accumulation was higher after stimulation compared with control mice. While 6 wk of exercise training did not improve glucose tolerance, exercise did improve muscle contractile dysfunction, peak Ca2+ levels, and Ca2+ accumulation following stimulation in male db/db mice. These data suggest that dysfunctional Ca2+ flux may contribute to skeletal muscle contractile dysfunction in type 2 diabetes and that exercise training may be a promising therapeutic approach for dysfunctional skeletal muscle contraction. NEW & NOTEWORTHY The purpose of this study was to examine muscle contractile function and Ca2+ regulation as well as the effect of exercise training in skeletal muscle in obese diabetic mice ( db/db). We observed impairment of muscle contractile force and Ca2+ regulation in a male type 2 diabetic animal model. These dysfunctions in muscle were improved by 6 wk of exercise training.

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Ncor2/PPARα-dependent upregulation of MCUb in the type 2 diabetic heart impacts cardiac metabolic flexibility and function

10.2337/figshare.13342229 ◽

2020 ◽

Author(s):

Ada Admin ◽

Federico Cividini ◽

Brian T Scott ◽

Jorge Suarez ◽

Darren E. Casteel ◽

...

Keyword(s):

Contractile Function ◽

Pyruvate Dehydrogenase Complex ◽

Dominant Negative ◽

Diabetic Heart ◽

Acid Oxidation ◽

Cardiac Contractile Function ◽

Mitochondrial Fatty Acid Oxidation ◽

Mitochondrial Fatty Acid ◽

Type 2 Diabetic

The contribution of altered mitochondrial Ca2+ handling to metabolic and functional defects in type 2 diabetic (T2D) mouse hearts is not well understood. Here, we show that the T2D heart is metabolically inflexible and almost exclusively dependent on mitochondrial fatty acid oxidation as a consequence of mitochondrial calcium uniporter complex (MCUC) inhibitory subunit MCUb overexpression. Using a recombinant endonuclease-deficient Cas9 (dCas9)-based gene promoter pull-down approach coupled with mass spectrometry we found that MCUb is upregulated in the T2D heart due to loss of glucose homeostasis regulator nuclear receptor co-repressor 2 (Ncor2) repression, and ChIP assays identified PPARα as a mediator of MCUb gene expression in T2D cardiomyocytes. Upregulation of MCUb limits mitochondrial matrix Ca2+ uptake and impairs mitochondrial energy production via glucose oxidation, by depressing Pyruvate Dehydrogenase Complex (PDC) activity. Gene therapy displacement of endogenous MCUb with a dominant-negative MCUb transgene (MCUbW246R/V251E) in vivo rescued T2D cardiomyocytes from metabolic inflexibility, and stimulated cardiac contractile function and adrenergic responsiveness by enhancing phospholamban (PLN) phosphorylation via Protein Kinase A (PKA). We conclude that MCUb represents one newly-discovered molecular effector at the interface of metabolism and cardiac function, and its repression improves the outcome of the chronically-stressed diabetic heart.

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Multinucleated giant cells in adipose tissue are specialized in adipocyte degradation

10.2337/figshare.13168862 ◽

2020 ◽

Author(s):

Ada Admin ◽

Julia Braune ◽

Andreas Lindhorst ◽

Janine Fröba ◽

Constance Hobusch ◽

...

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Ex Vivo ◽

Giant Cells ◽

Low Grade ◽

Adipose Tissue Macrophages ◽

Visceral Adipose ◽

Low Grade Inflammation

Obesity is associated with a chronic low-grade inflammation in visceral adipose tissue (AT) characterized by an increasing number of adipose tissue macrophages (ATMs) and linked to type 2 diabetes. AT inflammation is histologically indicated by the formation of so-called crown-like structures (CLS), as accumulation of ATMs around dying adipocytes, and the occurrence of multi-nucleated giant cells (MGCs). However to date, the function of MGCs in obesity is unknown. Hence, the aim of this study was to characterize MGCs in AT and unravel the function of these cells. We demonstrate that MGCs occur in obese patients and after 24 weeks of high fat diet (HFD) in mice, accompanying signs of AT inflammation and then represent ~3% of ATMs in mice. Mechanistically, we found evidence that adipocyte death triggers MGC formation. Most importantly, MGCs in obese AT have a higher capacity to phagocytose oversized particles, such as adipocytes, as shown by live-imaging of AT, 45 µm bead uptake ex vivo and a higher lipid content in vivo. Finally, we show that IL-4 treatment is sufficient to increase the number of MGCs in AT, whereas other factors maybe more important for endogenous MGC formation in vivo.

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Improvements in HOMA indices and pancreatic endocrinal tissues in type 2-diabetic rats by DPP-4 inhibition and antioxidant potential of an ethanol fruit extract of Withania coagulans

10.21203/rs.3.rs-69981/v2 ◽

2021 ◽

Author(s):

Heera Ram ◽

Pramod Kumar ◽

Ashok Purohit ◽

Priya Kashyap ◽

Suresh Kumar ◽

...

Keyword(s):

Diabetic Rats ◽

Model Assessment ◽

Fruit Extract ◽

Protein Ligands ◽

Homeostatic Model Assessment ◽

Docking Protein ◽

Type 2 Diabetic

Abstract Context: Withania coagulans (Stocks) Dunal fruits are used in the therapeutics of several ailments due to possessing of potent phytoconstituents which is also used traditionally for curing the diabetes. Objective: The present study was assessing the amelioration potential of the phytochemicals of an ethanol fruit extract of Withania coagulans (Stocks) Dunal in the HOMA (Homeostatic model assessment) indices and pancreatic endocrinal tissues by inhibition of DPP-4 and antioxidants activities.Material and methods: The identification of phytoconstituents of the test extract was performed by LCMS. Further, assessments of in-vitro, in-vivo and in-silico were achieved by following standard methods. In-vivo studies were conducted on type-2 diabetic ratsResults: The chosen extract inhibited DPP-4 activity by 63.2% in an in vitro assay as well as significantly inhibit serum DPP-4 levels. Accordingly, the administration of the ethanol fruit extract resulted in a significant (𝑃≤ 0.001) alterations in the lipid profile, antioxidant levels, and HOMA indices. Moreover, pancreatic endocrinal tissues (islet of Langerhans) appeared to have the restoration of normal histoarchitecture as evidenced by increased cellular mass. Molecular docking (Protein - ligands) of identified phytoconstituents with DPP-4 (target enzyme) shown incredibly low binding energy (Kcal/mol) as required for ideal interactions. ADMET analysis of the pharmacokinetics of the identified phytoconstituents indicated an ideal profile as per Lipinski laws. Conclusion: It can be concluded that the phytoconstituents of an ethanol fruit extract of Withania coagulans have the potential to inhibit DPP-4 which result in improved glucose homeostasis and restoration of pancreatic endocrinal tissues in type-2 diabetic rats.

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STAT subtype specificity and ischemic preconditioning in mice: is STAT-3 enough?

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00231.2010 ◽

2011 ◽

Vol 300 (2) ◽

pp. H522-H526 ◽

Cited By ~ 10

Author(s):

Michael D. Goodman ◽

Sheryl E. Koch ◽

Muhammad R. Afzal ◽

Karyn L. Butler

Keyword(s):

Ischemic Preconditioning ◽

Ischemia Reperfusion Injury ◽

Contractile Function ◽

Ex Vivo ◽

Ischemia Reperfusion ◽

Cardiac Performance ◽

Subtype Specificity ◽

Developed Pressure ◽

Perfused Hearts

The role of other STAT subtypes in conferring ischemic tolerance is unclear. We hypothesized that in STAT-3 deletion alternative STAT subtypes would protect myocardial function against ischemia-reperfusion injury. Wild-type (WT) male C57BL/6 mice or mice with cardiomyocyte STAT-3 knockout (KO) underwent baseline echocardiography. Langendorff-perfused hearts underwent ischemic preconditioning (IPC) or no IPC before ischemia-reperfusion. Following ex vivo perfusion, hearts were analyzed for STAT-5 and -6 phosphorylation by Western blot analysis of nuclear fractions. Echocardiography and postequilibration cardiac performance revealed no differences in cardiac function between WT and KO hearts. Phosphorylated STAT-5 and -6 expression was similar in WT and KO hearts before perfusion. Contractile function in WT and KO hearts was significantly impaired following ischemia-reperfusion in the absence of IPC. In WT hearts, IPC significantly improved the recovery of the maximum first derivative of developed pressure (+dP/d tmax) compared with that in hearts without IPC. IPC more effectively improved end-reperfusion dP/d tmax in WT hearts compared with KO hearts. Preconditioned and nonpreconditioned KO hearts exhibited increased phosphorylated STAT-5 and -6 expression compared with WT hearts. The increased subtype activation did not improve the efficacy of IPC in KO hearts. In conclusion, baseline cardiac performance is preserved in hearts with cardiac-restricted STAT-3 deletion. STAT-3 deletion attenuates preconditioning and is not associated with a compensatory upregulation of STAT-5 and -6 subtypes. The activation of STAT-5 and -6 in KO hearts following ischemic challenge does not provide functional compensation for the loss of STAT-3. JAK-STAT signaling via STAT-3 is essential for effective IPC.

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P–100 Metabolic, hormonal, and inflammatory status in sub-fertile men with obesity and diabetes

Human Reproduction ◽

10.1093/humrep/deab130.099 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

S Abbasihormozi ◽

A Kouhkan ◽

A Shahverdi ◽

A Parhizkar ◽

Z Zolfaghary ◽

...

Keyword(s):

Semen Analysis ◽

Metabolic Changes ◽

Semen Parameters ◽

Computer Assisted ◽

Obesity And Diabetes ◽

Hormonal Dysfunction ◽

Hs Crp ◽

Type 2 Diabetic

Abstract Study question To evaluate the association between sperm functionality parameters and biochemical, hormonal, and inflammatory indices in obese and diabetic men. Summary answer Metabolic changes,hormonal dysfunction,and the presence of inflammatory mediators might be considered possible mechanisms in the development of sub-fertility in obese and diabetic sub-fertile men What is known already Although the higher prevalence of subfertility in obese and diabetic men during the reproductive age is evident, the mechanisms by which obesity and diabetes mellitus (DM) cause male infertility are not entirely understood. Several pathways might be involved in the role of obesity in semen quality, thereby inducing alterations in hormonal profiles, abnormal lipid metabolism, and possibly the formation of inflammatory cytokines, ultimately leading to impaired sperm function Study design, size, duration We enrolled normal weight (BMI<25 kg/m2) and non-type–2 diabetic (control=40), obese and non- type–2 diabetic (obese=40), non-obese and type–2 diabetic (Lean-DM=35), and obese and type–2 diabetic (Obese-DM=35) sub-fertile men, aged 20–50 years, referring to Royan infertility clinic (Tehran, Iran) from March to September 2014 Participants/materials, setting, methods After enrollment and receiving informed consent, all men underwent face-to-face private interviews. The obesity-associated markers, insulin resistance, beta-cell function, hormonal and lipid profile, inflammatory indices, and semen analysis were assessed in four experimental groups. Semen analysis was examined after 2–5 days of sexual analysis).abstinence based on WHO-recommended methods by CASA system (computer-assisted sperm Main results and the role of chance Main results and the role of chance: Our finding showed that diabetic markers were significantly increased in two diabetic groups, while obesity indices were markedly increased in two obese groups. Conventional sperm parameters were significantly lower in obese DM, lean DM, and obese groups compared with the control (p < 0.05). Serum levels of total testosterone (TT) and sex hormone-binding globulin (SHBG) were significantly lower in men with obesity and DM compared with the control (p < 0.05).There was a significant difference in the concentration of high-sensitivity C-reactive protein (hs-CRP) among four experimental groups. Moreover, serum leptin was significantly increased in obese DM, lean DM, and obese groups. Serum insulin levels had a positive correlation with metabolic-associated indices (WC, BMI, FBS,HbA1c,and HOMA-IR), as well as hs-CRP levels, whereas it had a negative correlation with count, motility, and morphology. There is also a negative association between metabolic-associated indices (WC, BMI, FBS, HbA1c, and HOMA-IR) and semen parameters. Limitations, reasons for caution It was better to evaluate inflammatory biomarkers be examined in other tissues Wider implications of the findings: The results of this study demonstrated the association of metabolic changes, hormonal dysfunction, and inflammatory responses with the semen parameters of sub-fertile men with obesity and diabete. Trial registration number Not applicable

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