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1.
J Assoc Physicians India ; 69(8): 11-12, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34472814

RESUMO

Around 300- 400 AD, ancient Indian physicians described a condition akin to diabetes mellitus which was called "Madhumeha". Sushrutha and Charaka, are also credited with describing two types of diabetes which would roughly correspond to type 1 diabetes and type 2 diabetes. However, little is known about the history of diabetes in India between the first and 19th century AD. A thorough search of literature revealed a large number of publications on diabetes from India in the 1800s and early 1900s, mostly from Calcutta and the Madras Presidency, suggesting that the prevalence of diabetes was high in these two places. Building on the observations made by a number of English physicians, Chunilal Bose in 1907 suggested the link between diabetes and lifestyle in India. Amazingly, India did not have to wait long after the discovery of insulin by Banting and Best at Toronto in 1921, to get its own supply. Around this time, Dr. J.P. Bose, eminent physician and diabetologist from Calcutta made remarkable contributions to the study of diabetes in India. He was also the first to describe the dramatic effects of insulin administration to children with type 1 diabetes in India. All these facts have remained largely forgotten which prompted the authors to delve deep into the history of diabetes in pre-independence India. This has led to the unearthing of several pearls of knowledge which are presented in this article as a fitting tribute to the 100th year of Insulin Discovery.


Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Médicos , Criança , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , História do Século XX , Humanos , Índia/epidemiologia , Insulina , Masculino
2.
Artigo em Inglês | MEDLINE | ID: mdl-34569820

RESUMO

Objective To compare the clinical profile of long-term survivors and non-survivors with T1D(T1D) in India. Research design and methods This is a retrospective study of 76 individuals with T1D who had survived for at least 40 years ('survivors') and 51 individuals with T1D who had died with shorter duration of diabetes ('non-survivors'), from diabetes clinics in different cities of India. Prevalence of complications in both groups and causes of death of the non-survivors were analyzed. Retinopathy was diagnosed by retinal photography; chronic kidney disease (CKD) by urinary albumin excretion (micro- or macroalbuminuria) and estimated glomerular filtration rate; peripheral vascular disease (PVD) by Doppler measurement of ankle-brachial pressure index; coronary artery disease (CAD) based on history of myocardial infarction or coronary revascularization and neuropathy by biothesiometry. Results Mean glycated hemoglobin (8.4±1.5 vs 10.7±2.2%, p<0.001), serum low density lipoprotein-cholesterol (91±29 vs 107±22mg/dl, p=0.004) and systolic blood pressure (135±16 vs 153±37mmHg, p=0.003) were lower, and high density-lipoprotein cholesterol (51±11 vs 43±15mg/dl, p=0.002) higher, among survivors compared to non-survivors. Diabetic retinopathy, CKD, neuropathy, PVD and CAD were more frequent among non-survivors. CAD [25.5%] and renal failure [23.5%] were the most frequent causes of death. Conclusions In this first report of long-term survivors with T1DM from India, we report that survivors had better glycemic and blood pressure control, more favorable lipid profiles and lower prevalence of complications compared to non-survivors. However, there could be other protective factors as well, which merit further studies.

3.
Indian J Pathol Microbiol ; 64(3): 571-574, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34341276

RESUMO

Composite phaeochromocytomas (CP) are extremely uncommon adrenal medullary tumours where phaeochromocytoma coexists with another adrenal medullary tumour also of neural crest origin. CP includes combination of phaeochromocytoma along with a component of neuroblastoma, ganglioneuroblastoma, ganglioneuroma, benign nerve sheath tumour or a malignant peripheral nerve sheath tumour (MPNST). Here we describe the morphological and immunohistochemical details of a case of CP with MPNST in a 30 years old lady, without history of neurofibromatosis. Only 6 cases of CP with MPNST have been reported so far. We have tabulated a summary of these prior published cases of phaeochromocytoma with MPNST. To our knowledge, this is the first literature review describing the clinico-pathological characteristics of these rare tumours.

4.
Arch Osteoporos ; 16(1): 102, 2021 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-34176015

RESUMO

The Indian Society for Bone and Mineral Research (ISBMR) has herein drafted clinical practice guidelines for the diagnosis and management of osteoporosis for the people of India. Implementation of the position statement in clinical practice is expected to improve the overall care of patients with osteoporosis in India. PURPOSE: In India, osteoporosis is a major public health problem. However, in the absence of any robust regional guidelines, the screening, treatment, and follow-up of patients with osteoporosis are lagging behind in the country. METHODS: The Indian Society for Bone and Mineral Research (ISBMR), which is a multidisciplinary group of physicians, researchers, dietitians, and epidemiologists and who study bone and related tissues, in their annual meeting, drafted the guidelines for the diagnosis and management of osteoporosis that would be appropriate in a resource constraint setting like India. RESULTS: Diagnosis of osteoporosis can be made in a patient with minimal trauma fracture without the aid of any other diagnostic tools. In others, bone mineral density measured by dual-energy X-ray absorptiometry remains the modality of choice. Data indicates that osteoporotic fractures occur at an earlier age in Indians than in the West; hence, screening for osteoporosis should begin at an earlier age. FRAX can be used for fracture risk estimation; however, it may underestimate the risk of future fractures in our population and still needs validation. Maintaining optimum serum 25-hydroxyvitamin D levels is essential, which, in most cases, would require regular vitamin D supplementation. Pharmacotherapy should be guided by the presence/absence of vertebral/hip fractures or the severity of risk based on clinical factors, although bisphosphonates remain the first choice in most cases. Regular follow-up is essential to ensure adherence and response to therapy. CONCLUSIONS: Implementation of the position statement in clinical practice is expected to improve the overall care of patients with osteoporosis in India.


Assuntos
Osteoporose , Fraturas por Osteoporose , Absorciometria de Fóton , Adulto , Densidade Óssea , Humanos , Minerais , Osteoporose/diagnóstico por imagem , Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/diagnóstico , Fatores de Risco
5.
Diabet Med ; 38(9): e14590, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33930215
6.
Endocr Pract ; 27(7): 710-715, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33685668

RESUMO

OBJECTIVE: Primary hyperparathyroidism (PHPT) is a common endocrine disorder in women which becomes more prevalent after menopause. In this study, we compared the demographic, clinical, and biochemical variables between premenopausal (pre-M) and postmenopausal (post-M) women with PHPT. METHODS: A retrospective analysis (from 2005 to 2019) of enrolled women PHPT patients from an online Indian PHPT registry. RESULTS: Of the women with PHPT, 232 and 122 were pre-M and post-M, respectively. The number of post-M PHPT cases registered had a 3.3-fold increase in 2015-2019 from 2005-2009 compared with only a 2.5-fold increase in pre-M cases in the same duration. The majority were symptomatic (90%), although pre-M had a higher proportion of symptomatic than post-M (92% vs 85%; P = .04). Pre-M women showed more prevalence of osteitis fibrosa cystica than post-M women (28% vs 13%; P = .03), although hypertension and gallstone disease were seen more frequently in post-M PHPT women. Pre-M women had a significantly higher median PTH (403 vs 246 pg/mL; P = .02) and median alkaline phosphatase (202 vs 145 pg/mL; P = .02) than post-M women, and vitamin D deficiency was more common in pre-M women (58% vs 45%; P = .03). Gland localization, tumor weight, and disease cure rates did not differ according to menopausal status. CONCLUSION: PHPT was more prevalent in pre-M women, although the number of post-M cases had significantly increased in the last 10 years. Pre-M women had generally more severe clinical and biochemical variables than post-M PHPT women.


Assuntos
Hiperparatireoidismo Primário , Deficiência de Vitamina D , Cálcio , Feminino , Humanos , Hiperparatireoidismo Primário/complicações , Hiperparatireoidismo Primário/epidemiologia , Índia/epidemiologia , Hormônio Paratireóideo , Pós-Menopausa , Estudos Retrospectivos , Deficiência de Vitamina D/epidemiologia
7.
Indian Pediatr ; 58(1): 34-37, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33452775

RESUMO

OBJECTIVE: To describe clinical features in Indian girls with Turner syndrome along with the phenotype-karyotype correlation. METHODS: 103 girls with Turner syndrome were divided into karyotype-groups: Classic (45X), 45,X/46,XX mosaics, isochromosomeXq (46,X,iXq and 45,X/46,X,iXq mosaics), 45,X/46,XYmosaics and structural defects, and analyzed for phenotypic differences. RESULTS: Majority (44.1%) had classic karyotype followed by isochromosome-Xq (26.5%). Classic Turner syndrome had higher prevalence of most skeletal and cutaneous stigmata, cubitus valgus (68.3%) and multiple nevi (68.2%) being the commonest. Bicuspid aortic valve was most common in 45,X/46,XX mosaics (5/15, 33.3%), and aortic coarctation in classic TS (3/42, 7.2%). Congenital renal anomalies occurred mostly in classic TS (6/42,14.3%). Overt hypothyroidism, conductive deafness and recurrent otitis media were commonest in isochromosomes (P<0.03). 45,X/46,XY mosaics had highest IQ (P<0.005). CONCLUSIONS: We report some novel associations of karyotype with non-endocrine parameters in Turner syndrome. In resource-limited settings, underlying karyotype may help prioritize screening investigations in girls with Turner syndrome.


Assuntos
Doença da Válvula Aórtica Bicúspide , Síndrome de Turner , Feminino , Humanos , Cariótipo , Cariotipagem , Fenótipo , Síndrome de Turner/epidemiologia , Síndrome de Turner/genética
9.
Biochim Biophys Acta Mol Basis Dis ; 1867(4): 166050, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33359696

RESUMO

Obesity induced insulin resistance is primarily regulated by the inhibitory phosphorylation of peroxisome proliferator-activated receptor γ at serine 273 (PPARγS273) which has been shown to be regulated by MEK and ERK. An upstream regulatory molecule of this pathway could be a therapeutic option. Here we analyzed the involvement of Fetuin-A (FetA), a key hepato-adipokine implicated in insulin resistance, as an upstream regulator molecule for the regulation of PPARγ inhibitory phosphorylation. Mice fed with standard diet (SD), high fat diet (HFD) and HFD with FetA knockdown (HFD-FetAKD) were used to examine the role of FetA on PPARγS273 phosphorylation in adipocytes. The mechanism of regulation and its effect on skeletal muscle were studied using primary adipocytes, 3T3-L1 (preadipocyte) and C2C12 (myotube) cell lines. Increased FetA in HFD mice strongly correlated with augmentation of PPARγS273 phosphorylation in inflamed adipocytes while knockdown of FetA suppressed it. This effect of FetA was mediated through the activation of Ras which in turn activated MEK and ERK. On addressing how FetA could stimulate activation of Ras, we found that FetA triggered TNFα in inflamed adipocytes which induced Ras activation. The ensuing sharp fall in adiponectin level attenuated AMPK activation in skeletal muscle cells affecting mitochondrial ATP production. Our data reveal the essential role of FetA induced activation of Ras in regulating PPARγ inhibitory phosphorylation through Ras-MEK-ERK pathway which downregulates adiponectin disrupting skeletal muscle mitochondrial bioenergetics. Thus, FetA mediated PPARγ inactivation has adverse consequences upon adipocyte-myocyte crosstalk leading to disruption of energy homeostasis and loss of insulin sensitivity.


Assuntos
Resistência à Insulina , Sistema de Sinalização das MAP Quinases , Obesidade/metabolismo , PPAR gama/metabolismo , alfa-2-Glicoproteína-HS/metabolismo , Células 3T3-L1 , Animais , Células Cultivadas , Metabolismo Energético , Masculino , Camundongos , Mitocôndrias/metabolismo , Fosforilação
10.
Diabetes Ther ; 11(12): 2791-2827, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33025397

RESUMO

Diabetic kidney disease (DKD) occurs in approximately 20-40% of patients with type 2 diabetes mellitus. Patients with DKD have a higher risk of cardiovascular and all-cause mortality. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and antihyperglycemic drugs form the mainstay of DKD management and aim to restrict progression to more severe stages of DKD. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) control hyperglycemia by blocking renal glucose reabsorption in addition to preventing inflammation, thereby improving endothelial function and reducing oxidative stress; consequently, this class of prescription medicines is emerging as an important addition to the therapeutic armamentarium. The EMPA-REG OUTCOME, DECLARE TIMI 58, and CANVAS trials demonstrated the renoprotective effects of SGLT2i, such as restricting decline in glomerular filtration rate, in the progression of albuminuria, and in death due to renal causes. The renoprotection provided by SGLT2i was further confirmed in the CREDENCE study, which showed a 30% reduction in progression of chronic kidney disease, and in the DELIGHT study, which demonstrated a reduction in albuminuria with dapagliflozin compared with placebo (- 21.0%, confidence interval [CI] - 34.1 to - 5.2, p = 0.011). Furthermore, a meta-analysis demonstrated a reduced risk of dialysis, transplantation, or death due to kidney disease (relative risk 0.67; 95% CI 0.52-0.86; p = 0.0019) and a 45% risk reduction in worsening of renal function, end-stage renal disease, or renal death (hazard ratio 0.55, CI 0.48-0.64, p < 0.0001) with SGLT2i, irrespective of baseline estimated glomerular filtration rate. Thus, there is emerging evidence that SGLT2i may be used to curb the mortality and improve the quality of life in patients with DKD. However, clinicians need to effectively select candidates for SGLT2i therapy. In this consensus statement, we have qualitatively synthesized evidence demonstrating the renal effects of SGLT2i and proposed recommendations for optimal use of SGLT2i to effectively manage and delay progression of DKD.

11.
Int J Low Extrem Wounds ; : 1534734620952245, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32907433

RESUMO

Hyperglycemia impairs healing of diabetic foot ulcer (DFU). But there is no evidence regarding benefit of intensive glucose control for healing of DFU. We plan to conduct a randomized, parallel arm, controlled study to assess the role of intensive glycemic management in comparison to conventional glucose control for healing of DFU. Participants with neuropathic DFU (infected or uninfected) having hemoglobin A1c (HbA1c) >8% and without evidence of osteomyelitis from 7 tertiary care hospitals will be enrolled. They will undergo a 2-week run-in phase for optimization of comorbidities, ulcer debridement, and counseling regarding self-monitoring of blood glucose (SMBG). Subsequently, they will be randomized to "intensive glycemic control" arm defined by glycemic targets of fasting blood glucose (FBG) <130 mg/dL, postprandial BG <180 mg/dL, and HbA1c <8%, with basal-bolus insulin regimen and frequent titration of insulin to achieve glycemic targets. The "conventional" arm will continue on prior treatment (oral antidiabetic drugs) with no titration unless meeting rescue criteria. Ulcer area will be calculated by automated wound assessment device (WoundlyClinial app) weekly for first 4 weeks, and less frequently until the 24th week. Standard treatment for DFU, off-loading, and counseling for foot care will be provided in both arms. The primary outcome measure will be number of wounds closed at 12th and 24th weeks. A multivariate regression analysis will be performed to identify the predictors of wound healing with baseline HbA1c, diabetes duration, wound size, wound duration, and background therapies as independent variable. This study will provide the much needed guidance to set optimum glucose targets in people with DFU.

12.
Diagn Cytopathol ; 48(11): 1003-1012, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32445510

RESUMO

BACKGROUND: Cytology of the adrenal gland is a less performed technique even in tertiary care centres; yet cytological evaluation is an important diagnostic tool for assessment of adrenal lesions. Our objective was to evaluate the diagnostic utility of FNAC smears and cellblock with immunohistochemistry (IHC) in lesions of the adrenal. MATERIAL AND METHODS: We had a total of 50 cases over a period of 2 years where both FNAC smears and cellblocks were taken. The smears and cellblocks were examined for adequacy. They were subsequently categorised into four groups: unsatisfactory, benign, suspicious of malignancy and malignant. The diagnostic accuracy of FNAC smears and cellblock with IHC were evaluated and compared, taking histopathology, wherever available, as the gold standard, RESULT: We had 50 cases with age ranging from 6 to 53 years with a median of 7.5 years. Of these, 54% were cytologically malignant and neuroblastoma was the commonest lesion. Histopathology was available in 23 cases only, where the diagnostic accuracy was evaluated. The sensitivity and specificity of FNAC smear was 100% and 85.71%, respectively whereas the sensitivity and specificity of cellblock with IHC was 100% and 92.86%, respectively. CONCLUSION: Cellblock together with IHC provides a higher degree of specificity, reduces the unsatisfactory rate and improves the diagnostic accuracy in lesions of the adrenal gland. Immunohistochemistry is an important adjunctive tool.

13.
Proc Natl Acad Sci U S A ; 117(12): 6509-6520, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32152128

RESUMO

Among all of the Super Elongation Complex (SEC) components, ELL1 (also known as ELL) is the only bona fide elongation factor that directly stimulates transcription elongation by RNA polymerase II. However, the mechanism(s) of functional regulation of ELL1 (referred to as ELL hereafter), through its stabilization, is completely unknown. Here, we report a function of human DBC1 in regulating ELL stability involving HDAC3, p300, and Siah1. Mechanistically, we show that p300-mediated site-specific acetylation increases, whereas HDAC3-mediated deacetylation decreases, ELL stability through polyubiquitylation by the E3 ubiquitin ligase Siah1. DBC1 competes with HDAC3 for the same binding sites on ELL and thus increases its acetylation and stability. Knockdown of DBC1 reduces ELL levels and expression of a significant number of genes, including those involved in glucose metabolism. Consistently, Type 2 diabetes patient-derived peripheral blood mononuclear cells show reduced expression of DBC1 and ELL and associated key target genes required for glucose homeostasis. Thus, we describe a pathway of regulating stability and functions of key elongation factor ELL for expression of diverse sets of genes, including ones that are linked to Type 2 diabetes pathogenesis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína p300 Associada a E1A/metabolismo , Regulação da Expressão Gênica , Histona Desacetilases/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Elongação da Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Acetilação , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Sítios de Ligação , Linhagem Celular , Diabetes Mellitus Tipo 2/patologia , Proteína p300 Associada a E1A/genética , Técnicas de Silenciamento de Genes , Glucose/metabolismo , Histona Desacetilases/genética , Humanos , Leucócitos Mononucleares/metabolismo , Mutação , Ligação Proteica , Estabilidade Proteica , Transcrição Genética , Fatores de Elongação da Transcrição/química , Fatores de Elongação da Transcrição/genética , Ubiquitinação
14.
J Lab Physicians ; 11(4): 323-329, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31929698

RESUMO

BACKGROUND OR CONTEXT: Pituitary adenoma (PA) is the most common pathology of the pituitary gland. Pituitary tumors were historically considered benign, however, from recent advances in pathological and molecular analyses, numerous prognostic markers have been identified, allowing a better characterization of tumor behavior and prediction of response to treatment and recurrences. AIMS AND OBJECTIVES: Evaluation of the epidemiological occurrence of pituitary tumors in our center and prediction of the benign, aggressive, or malignant nature of the tumor with the help of immunohistochemical markers (IHC) Ki-67, P53, and O-6-methylguanine-DNA methyltransferase (MGMT) along with radiology. MATERIALS AND METHODS: A prospective study was done in 33 cases. Patients with clinically suspected pituitary tumors and related symptoms and signs are referred from the endocrine outpatient department and subsequently operated at the neurosurgery department were selected. We have studied the clinical features, radiology, histopathology, and IHC with the help of Ki-67, P53, and MGMT of PA over 2 years. RESULTS: We have 94% (31/33) cases of PA among them 94% (29/31) cases are macroadenoma. The IHC was conducted on 30 cases (excluding 1 case of pituitary apoplexy) where Ki-67, p53, and MGMT have been used for IHC in order to analyze the prognosis of the PA, irrespective of the immunological subtype of the PA. In our study, only 13% (4 patients) had MGMT score 0 and 2 patients, among these 4 patients having above cutoff level of Ki-67 and p53 value, considered as aggressive (in case of Ki-67 >3% and >50% in case of p53). When comparing MGMT expression with recurrence, a high degree of significance was found (Mann-Whitney U-test, P = 0.0038). Most of the recurrent tumors (6/9) had MGMT score 1 or below and most of the nonrecurring tumor had MGMT score 2 or above. When comparing MGMT expression with aggressiveness, a high degree of significance was found (Mann-Whitney U-test, P < 0.0001). Finally, combining the radiological Ki-67, p53, and MGMT values, two cases of aggressive adenoma have been seen in our study, the remaining being benign adenomas (WHO classification 2004). We did not encounter any case of pituitary carcinoma. MGMT did not show any significant correlation with radiological grading and histology. CONCLUSION: The benign, aggressive, or malignant nature of PA can be effectively predicted with the help of IHC, such as Ki-67, p53, and MGMT. This helps in better patient management and predicts recurrences and prognosis.

16.
Indian J Endocrinol Metab ; 22(3): 347-354, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30090726

RESUMO

Background and Objectives: Nonalcoholic fatty liver disease (NAFLD) and dysglycemia are public health challenges. There is urgent need for anthropometric surrogates for NAFLD screening. This study evaluated role of neck circumference (NC) and neck-height ratio (NHtR) as predictors of liver stiffness measure (LSM) in individuals with prediabetes (IPD). Methods: In a cross-sectional study, 188 IPD from 1130 screened individuals underwent anthropometry, ultrasonography, Fibroscan® for LSM, dyslipidemia, insulin resistance (IR), and fetuin-A assessment. Results: Hypertension, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), metabolic syndrome (MetS), NAFLD, and significant liver stiffness (SLS) (LSM >8.5kPa) were observed in 53.7%, 31.4%, 71.3%, 73.9%, 24.5%, and 11.2% prediabetes individuals, respectively. Prediabetes with NAFLD had significantly higher body mass index (BMI), NC, NHtR, glycated hemoglobin, triglycerides, fatty liver index (FLI), and LSM. Prediabetes in highest NHtR quartile had significantly higher BMI, hypertension, MetS, fasting glucose, glycated hemoglobin, homeostatic model assessment-IR, NAFLD, LSM, SLS, and lower HDL-C. Stepwise forward linear regression revealed that NHtR, FLI, and LDL-C were best predictors of LSM, at baseline (Model-1), after adjusting for age and sex (Model-2), and adjusting model-2 plus systolic and diastolic blood pressure (Model-3). NHtR and NC (in females) and NHtR and BMI (in males) had largest area under the curves for predicting LSM, NAFLD, and MetS. NHtR ≥21.54 cm/m (sensitivity: 90%; specificity: 52.5%; females) and ≥21.62 cm/m (sensitivity: 80%; specificity: 49.4%; males) was best predictor of SLS. Interpretation and Conclusion: NHtR is a reliable tool for community screening of NAFLD and liver stiffness in prediabetes.

17.
Biochem Biophys Res Commun ; 501(3): 771-778, 2018 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-29763604

RESUMO

Accumulation and polarization of anti-inflammatory M2 to proinflammatory M1 macrophage in the adipose tissue of obese diabetic mice is an important pathogenic signature. It worsens lipid induced inflammation and insulin resistance. Here we demonstrate that a small molecule, a peroxyvanadate compound i.e. DmpzH [VO(O2)2 (dmpz)] or dmp, could robustly decrease macrophage infiltration, accumulation and their polarization in high fat diet (HFD) induced obese diabetic mice. In searching the underlying mechanism it was revealed that SIRT1 level was strikingly low in the inflamed adipose tissue of HFD mice as compared to mice fed with standard diet (SD). Administration of dmp markedly increased SIRT1 level by inducing its gene expression with a consequent decrease in macrophage population. Elevation of SIRT1 coincided with the decrease of MCP1, Fetuin-A (FetA) and IFNγ. Since MCP1 and FetA drive macrophage to inflamed adipose tissue and IFNγ promotes M2 to M1 transformation, both recruitment and M1 induced inflammation were found to be significantly repressed by dmp. In addressing the question about how dmp induced excess SIRT1 could reduce MCP1, FetA and IFNγ levels, we found that it was due to the inactivation of NFκB because of its deacetylation by SIRT1. Since NFκB is the transcriptional regulator of these molecules, their expressions were significantly suppressed and that caused sharp decline in macrophage recruitment and their polarity to M1. This effected a marked fall in proinflammatory cytokine level which significantly improved insulin sensitivity. dmp is likely to be the first molecule that rescues inflammatory burden contributed by macrophage in obese diabetic mice adipose tissue which causes significant increase in insulin sensitivity therefore it may be a meaningful choice to treat type 2 diabetes.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Resistência à Insulina , Macrófagos/efeitos dos fármacos , Obesidade/complicações , Obesidade/tratamento farmacológico , Vanadatos/uso terapêutico , Animais , Polaridade Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Inflamação/complicações , Inflamação/tratamento farmacológico , Inflamação/patologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Obesos , Obesidade/patologia , Células RAW 264.7
19.
Cell Signal ; 42: 67-76, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29030114

RESUMO

Although several reports demonstrated that accumulation of excess lipid in adipose tissue produces defects in adipocyte which leads to the disruption of energy homeostasis causing severe metabolic problems, underlying mechanism of this event remains yet unclear. Here we demonstrate that FetuinA (FetA) plays a critical role in the impairment of two metabolic sensors, SIRT1 and AMPK, in inflamed adipocytes of high fat diet (HFD) mice. A linear increase in adipocyte hypertrophy from 10 to 16 week was in tandem with the increase in FetA and that coincided with SIRT1 cleavage and decrease in pAMPK which adversely affects PGC1α activation. Knock down (KD) of FetA gene in HFD mice could significantly improve this situation indicating FetA's contribution in the damage of energy sensors in inflamed adipocyte. However, FetA effect was not direct, it was mediated through TNF-α which again is dependent on FetA as FetA augments TNF-α expression. FetA being an upstream regulator of TNF-α, its suppression prevented TNF-α mediated Caspase-1 activation and cleavage of SIRT1. FetA induced inactivation of PGC1α due to SIRT1 cleavage decreased PPARϒ, adiponectin, NRF1 and Tfam expression. All these together caused a significant fall in mitochondrial biogenesis and bioenergetics that disrupted energy homeostasis resulting loss of insulin sensitivity. Taken together, our findings revealed a new dimension of FetA, it not only induced inflammation in adipocyte but also acts as an upstream regulator of SIRT1 cleavage and AMPK activation. Intervention of FetA may be worthwhile to prevent metabolic imbalance that causes insulin resistance and type 2 diabetes.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Adipócitos/metabolismo , Metabolismo Energético/genética , Obesidade/genética , Sirtuína 1/genética , alfa-2-Glicoproteína-HS/genética , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/patologia , Adiponectina/genética , Adiponectina/metabolismo , Animais , Caspase 1/genética , Caspase 1/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Grupo de Alta Mobilidade/metabolismo , Homeostase/genética , Resistência à Insulina , Masculino , Camundongos , Fator 1 Nuclear Respiratório/genética , Fator 1 Nuclear Respiratório/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , PPAR gama/genética , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Cultura Primária de Células , Proteólise , Transdução de Sinais , Sirtuína 1/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , alfa-2-Glicoproteína-HS/metabolismo
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