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There are 47 results for Insulin (displaying 1 to 10).

Defective NOD2 peptidoglycan sensing promotes diet‐induced inflammation, dysbiosis, and insulin resistance

Pattern recognition receptors link metabolite and bacteria‐derived inflammation to insulin resistance during obesity. We demonstrate that NOD 2 detection of bacterial cell wall peptidoglycan ( PGN ) regulates metabolic inflammation and insulin sensitivity. An obesity‐promoting high‐fat diet ( HFD ) increased NOD 2 in hepatocytes and adipocytes, and NOD 2 −/− mice have increased adipose tissue and liver inflammation and exacerbated insulin resistance during a HFD . This effect is independent …

A, BBody mass (A), blood glucose, and the cumulative area under the curve (AUC) (B) during insulin tolerance tests (ITT; 1.0 IU/kg i.p.) in NOD2+/+ (n = 8) and NOD2−/− (n = 10) littermate mice fed a HFD for 16 weeks, *P = 0.001. CBlood glucose and the cumulative AUC during insulin tolerance tests (ITT; 0.5 IU/kg i.p.) in chow‐fed WT (n = 6) and NOD2−/− (n = 6) mice. DHOMA insulin resistance (IR) index in weight‐matched chow‐ (n = 7) or HFD‐fed (n = 10) WT and NOD2−/− mice, #P = 0.0001 (WT …

… (n = 5) and HFD‐fed (n = 11) WT and NOD2−/− mice, *P = 0.02. I, JQuantification (I) and immunoblots (J) of insulin‐stimulated pFOXO1Ser256 in liver lysates after vena cava injection of insulin (0.5 IU/kg) in HFD‐fed WT (n = 4) and NOD2−/− (n = 4) mice, *P = 0.0498. KBlood glucose and quantification of the AUC during a 120‐min pyruvate tolerance test (PTT, 2.0 g/kg pyruvate, i.p.) in HFD‐fed WT (n = 6) and NOD2−/− mice (n = 6), *P = 0.0005. Data information: An unpaired t‐test was used …

… ‐fed (n = 5 in both genotypes) or HFD‐fed (n = 11 in both genotypes) WT and NOD2−/− mice, *P = 0.04, **P = 0.02, ##P = 0.004, and #P = 0.04. EQuantification of serum non‐esterified fatty acids (NEFA) in fasted and clamped HFD‐fed WT (n = 4) and NOD2−/− (n = 3) mice, *P = 0.0001. FQuantification of insulin‐stimulated pAktSer473 in gonadal adipose tissue at the end of the clamp in HFD‐fed WT (n = 5) and NOD2−/− mice (n = 5), *P = 0.04. GThe number of ampicillin‐resistant E. coli cfu per gram …

… Obesity is associated with an elevation in the chronic inflammatory tone of metabolic tissues. This metabolic inflammation regulates glucose homeostasis, and the underlying host immune responses are emerging (Greiner & Bäckhed, ). Accumulation of immune cells such as neutrophils, lymphocytes, and macrophages in adipose and liver tissues during obesity are associated with augmented inflammatory mediators that contribute to insulin resistance (Weisberg et al , ; Elgazar‐Carmon et al , ; Feuerer …

Emmanuel Denou et al. EMBO molecular medicine March 2015

Inhibition of insulin/IGF‐1 receptor signaling protects from mitochondria‐mediated kidney failure

Mitochondrial dysfunction and alterations in energy metabolism have been implicated in a variety of human diseases. Mitochondrial fusion is essential for maintenance of mitochondrial function and requires the prohibitin ring complex subunit prohibitin‐2 (PHB2) at the mitochondrial inner membrane. Here, we provide a link between PHB2 deficiency and hyperactive insulin/IGF‐1 signaling. Deletion of PHB2 in podocytes of mice, terminally differentiated cells at the kidney filtration barrier, caused …

Kaplan–Meier survival curve showed that an additional knockout of the insulin receptor (Insr) prolonged survival of Phb2pko mice (n = 7 for Phb2pko/Insrpko, n = 4 for Phb2pko/Insrhet, and n = 6 for Phb2pko). Kaplan–Meier survival curve revealed that the survival time of Phb2pko mice is not changed by an additional Igf1r deficiency (n = 6 for Phb2pko/Igf1rpko, n = 4 for Phb2pko/Igf1rhet, and n = 6 for Phb2pko). Statistical analysis comparing all genotypes with Phb2pko mice. Kaplan–Meier …

… of the insulin and IGF‐1 receptor or treatment with the mTORC1 inhibitor rapamycin partially rescued the phenotype of Phb2 knockout mice and prolonged survival. To understand the contribution of mitochondrial dysfunction to kidney disease, we deleted the Phb2 gene specifically in podocytes ( Phb2 pko ) by mating a conditional Phb2 fl/fl mouse line (Merkwirth et al , ) to podocyte‐specific Cre mice ( NPHS2.cre ) (Moeller et al , ). Mice of all genotypes were born following Mendelian rules ( ). At birth …

Christina Ising et al. EMBO molecular medicine March 2015

IGFBP1 increases β‐cell regeneration by promoting α‐ to β‐cell transdifferentiation

There is great interest in therapeutically harnessing endogenous regenerative mechanisms to increase the number of β cells in people with diabetes. By performing whole‐genome expression profiling of zebrafish islets, we identified 11 secreted proteins that are upregulated during β‐cell regeneration. We then tested the proteins' ability to potentiate β‐cell regeneration in zebrafish at supraphysiological levels. One protein, insulin‐like growth factor (Igf) binding‐protein 1 (Igfbp1), potently …

… A, BRepresentative confocal projections of the whole pancreas (dashed lines) of 35‐day‐old Tg(ins:H2B‐GFP);Tg(ins:Flag‐NTR) transgenics, with or without Tg(bactin:igfbp1a), that were subjected to β‐cell ablation between day 30 and 31 and then allowed to regenerate for 4 days. Scale bars represent 100 μm. CBody length of control and Tg(bactin:igfbp1a) zebrafish; ****P < 0.0001. D–HQuantification of β‐cell regeneration was automated with an ImageJ script. (D) Insulin‐positive area per zebrafish …

A–DCorrelations between baseline levels of fasting IGFBP1 levels and BMI (A, C) or fasting insulin levels (B, D) in men (A, B) and women (C, D). The correlations between these baseline values are significant both in subjects who developed T2D (red squares) and in controls with a normal glucose tolerance (NGT) (blue circles) at follow‐up after 8–10 years. Results are presented as individual values with linear regression. Related to Table .

A–EControl and Tg(bactin:igfbp1a)‐overexpressing larvae were treated with MTZ from 3 to 4 dpf to ablate β cells and analyzed at 6 dpf, after 2 days of regeneration. Representative confocal images (A, B) of control and Tg(bactin:igfbp1a)‐overexpressing Tg(ins:dsRed);Tg(gcg:GFP);Tg(ins:Flag‐NTR) larvae. A bihormonal glucagon‐ and insulin‐expressing cell (gcg+;ins+) is indicated by an arrow. Representative confocal images (C, D) of control and Tg(bactin:igfbp1a)‐overexpressing Tg(gcg:GFP);Tg …

… Diabetes is characterized by hyperglycemia that results from insulin deficiency, insulin resistance, or a combination of both. Insulin deficiency can be caused by a reduction in the number of insulin‐producing β cells—not only through autoimmune destruction of β cells in type‐1 diabetes (T1D) but also through stress‐induced apoptosis of β cells in type‐2 diabetes (T2D) (Weir & Bonner‐Weir, )—at which point there is a need for insulin therapy or transplantation of pancreas or islets. However …

Jing Lu et al. The EMBO Journal September 2016

Defects in mitophagy promote redox‐driven metabolic syndrome in the absence of TP53INP1

The metabolic syndrome covers metabolic abnormalities including obesity and type 2 diabetes (T2D). T2D is characterized by insulin resistance resulting from both environmental and genetic factors. A genome‐wide association study ( GWAS ) published in 2010 identified TP 53 INP 1 as a new T2D susceptibility locus, but a pathological mechanism was not identified. In this work, we show that mice lacking TP 53 INP 1 are prone to redox‐driven obesity and insulin resistance. Furthermore, we …

A, B(A, B) Immunocytofluorescent staining of TP53INP1 (red) and insulin (green) in mouse pancreatic sections (A) and single human islet beta cell (B). Scale bars represent 50 μm (A) and 10 μm (B). C–EQuantitative PCR for Tp53inp1 mRNA levels in tissues and cells from rat (C) and C57BL/6J mice fed with a normal diet (5% fat; ND) or an high‐fat diet (45% fat; HFD) (D, E). Results are expressed as the mean ± SEM and are representative of two independent experiments. n = 2 for rat liver, islets and mouse spleen; n = 4 for INS‐1E cells; n = 5 for mouse exocrine pancreas; n = 6 for Min6 cells and ND and HFD islets; n = 11 for mouse islets. *P = 0.035 for HFD versus ND.

Male TP53INP1 KO and WT mice were fed a high‐fat diet (HFD, 60% fat) or a control diet (CTRL) during 16 weeks. Mice drank tap water or NAC‐supplemented tap water (1%). A, BHistograms show blood glucose (A) or plasma insulin (B) levels of 6‐h‐fasted mice at the beginning (Week 0) and/or at the end of the protocol (Week 16). Fasting blood glucose week 16: P (−/− versus +/+; HFD) = 0.0052; P (CTRL versus HFD; −/−) = 0.000081; P (NAC versus no NAC; −/− HFD) = 0.0019; P (w16 versus w0; +/+ CTRL …

… Metabolic syndrome (MS) describes a cluster of metabolic abnormalities including obesity, insulin resistance, hypertension and dyslipidemia (Pothiwala et al , ). The prevalence of MS has been increasing exponentially in the last few decades, paralleling the obesity epidemic. Obesity, which is defined as a body mass index ≥ 30 kg/m 2 , results from accumulation of white adipose tissue. It depends on both genetic and environmental factors, in particular lifestyles featuring increased nutrient …

Marion Seillier et al. EMBO molecular medicine June 2015

mTORC2 sustains thermogenesis via Akt‐induced glucose uptake and glycolysis in brown adipose tissue

Activation of non‐shivering thermogenesis ( NST ) in brown adipose tissue ( BAT ) has been proposed as an anti‐obesity treatment. Moreover, cold‐induced glucose uptake could normalize blood glucose levels in insulin‐resistant patients. It is therefore important to identify novel regulators of NST and cold‐induced glucose uptake. Mammalian target of rapamycin complex 2 ( mTORC 2) mediates insulin‐stimulated glucose uptake in metabolic tissues, but its role in NST is unknown. We show that mTORC 2 …

Representative immunostainings for RFP of BAT from control mice infected with either AAV8‐RFP or AAV8‐empty (n = 4/group). RFP mRNA expression in BAT, liver, quadriceps, and WAT of control mice infected with either AAV8‐RFP or AAV8‐empty (n = 4/group). Plasma insulin of AdRiKO and control mice infected with either AAV8‐Akt2S474D or AAV8‐empty housed at 4°C for 4 h [n = 7 (control AAV8‐null), n = 6 (AdRiKO AAV8‐null), n = 6 (control AAV8‐AktS474D), n = 6 (AdRiKO AAV8‐AktS474D)]. Data information: Data represent mean ± SEM.

Blood glucose of AdRiKO and control mice housed at 22 or 4°C for 8 h (n = 7/group). Plasma insulin of AdRiKO and control mice housed at 22 or 4°C for 8 h (n = 6/group). Quantification of raptor‐pS792 and ACC‐pS79 band intensity relative to total raptor or total ACC band intensity shown in Fig C (n = 6/group). Data information: Data represent mean ± SEM. Statistically significant differences between AdRiKO and control mice were determined with unpaired Student's t‐test and are indicated …

… , adrenergic stimulation enhances glucose uptake and glycolysis in BAT (Greco‐Perotto et al , ; Vallerand et al , ; Hao et al , ). Due to the ability of BAT to burn energy efficiently and to reduce blood glucose levels, activation of NST has been proposed as an alternative strategy for weight loss in obese patients (Cypess et al , ; van Marken Lichtenbelt et al , ; Virtanen et al , ; Clapham & Arch, ) and for normalization of blood glucose levels in insulin‐resistant diabetic patients. Thus …

Verena Albert et al. EMBO molecular medicine February 2016

Autophagy in Myf5+ progenitors regulates energy and glucose homeostasis through control of brown fat and skeletal muscle development

Macroautophagy (MA) regulates cellular quality control and energy balance. For example, loss of MA in aP2‐positive adipocytes converts white adipose tissue (WAT) into brown adipose tissue (BAT)‐like, enhancing BAT function and thereby insulin sensitivity. However, whether MA regulates early BAT development is unknown. We report that deleting Atg7 in myogenic Myf5+ progenitors inhibits MA in Myf5‐cell‐derived BAT and muscle. Knock out (KO) mice have defective BAT differentiation and function …

Knock out (KO) mice show reduced myofiber size and impaired glucose clearance. (A) Blood glucose in 6‐ to 10‐month (mo)‐old mice (n=12–15), and (B) serum insulin levels in 10‐mo‐old fed control (Con) and KO mice (n=6). (C) Glucose tolerance tests in 10‐mo‐old chow diet (RD)‐fed (n=5), and (D) in 10‐ to 12‐mo‐old high‐fat diet (HFD)‐fed Con and KO mice (n=4–9). (E) Insulin tolerance test in 10‐mo‐old RD‐fed Con and KO mice (n=5). (F) Immunoblots for indicated proteins in skeletal muscle from 10 …

… glucose homeostasis via glucose uptake in response to insulin, and intriguingly, both tissues originate from myogenic factor 5‐positive (Myf5+) progenitors [ ]. It is thus conceivable that factors affecting Myf5+ progenitors will dysregulate energy balance through effects on BAT and SKM differentiation. Macroautophagy (MA) entails formation of LC3‐II‐positive autophagosomes that sequester and target cytoplasmic cargo for lysosomal degradation [ ]. In addition to quality control, MA regulates …

Nuria Martinez‐Lopez et al. EMBO Reports August 2013

A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity

… revealed that FXR acetylation increased proinflammatory gene expression, macrophage infiltration, and liver cytokine and triglyceride levels, impaired insulin signaling, and increased glucose intolerance. Mechanistically, acetylation of FXR blocked its interaction with the SUMO ligase PIAS y and inhibited SUMO 2 modification at K277, resulting in activation of inflammatory genes. SUMO ylation of agonist‐activated FXR increased its interaction with NF ‐κB but blocked that with RXR α, so that SUMO …

… were expressed in hepatocytes isolated from lean mice and treated with insulin for 30 min, and phospho‐ and total AKT levels were measured by IB (n = 3). Data information: Values are presented as mean ± SEM; two‐tailed Student's t‐test, *P < 0.05, **P < 0.005.

… is a sign of local hepatic inflammation in obesity (Hotamisligil, ; Olefsky & Glass, ; Chawla et al , ; Lumeng & Saltiel, ), which results in selective insulin resistance, such as sustained hepatic lipogenesis but impaired inhibition of gluconeogenesis. Notably, both mRNA levels (Fig  C and D) and protein levels detected by IHC (Fig  F and G) of the macrophage marker, F4/80, were increased in livers of lean mice expressing the K217Q Ac‐mimic mutant and decreased in obese mice expressing the K217R …

Dong‐Hyun Kim et al. The EMBO Journal January 2015

A novel thermoregulatory role for PDE10A in mouse and human adipocytes

… selective inhibitor MP ‐10 recruited BAT and potentiated thermogenesis in vivo . In diet‐induced obese mice, chronic administration of MP ‐10 caused weight loss associated with increased energy expenditure, browning of white adipose tissue, and improved insulin sensitivity. Analysis of human PET data further revealed marked levels of PDE 10A in the supraclavicular region where brown/beige adipocytes are clustered in adults. Finally, the inhibition of PDE 10A with MP ‐10 stimulated thermogenic …

… A, BThe percentage (%) change in body weight and cumulative food intake of diet‐induced obese (DIO) mice in response to daily treatment with MP‐10 (10 mg/kg) or vehicle for a week (n = 4 per group). *P = 0.0264 (day 4), ***P = 0.0002 (day 5), ***P < 0.0001 (day 6), and ***P < 0.0001 (day 7) using two‐way analysis of variance (ANOVA) with Sidak's post hoc test. CUpon completion of the chronic feeding study, an insulin tolerance test was performed on DIO mice with single treatment of 0.75 U/kg …

… adipose tissue depots (Omar et al , ; Kraynik et al , ). In WAT, PDE3B has received the most attention as a downstream target of insulin's anti‐lipolytic effects through Akt‐mediated phosphorylation and activation (Armani et al , ). Preclinical studies have also shown that long‐term inhibition of PDEs 1, 4, and 5 promotes a negative energy balance by increasing energy expenditure through either increased BAT function and/or browning of WAT (Ayala et al , ; Park et al , ; Mitschke et al , ; Pan et al …

Mohammed K Hankir et al. EMBO molecular medicine July 2016

Fission and selective fusion govern mitochondrial segregation and elimination by autophagy

insulin secretion. Pulse chase and arrest of autophagy at the pre‐proteolysis stage reveal that before autophagy mitochondria lose Δψ m and OPA1, and that overexpression of OPA1 decreases mitochondrial autophagy. Together, these findings suggest that fission followed by selective fusion segregates dysfunctional mitochondria and permits their removal by autophagy.

… ‐deficient MEF cells had maximal respiration reduced by ∼40% ( ). Treatment of C2C12 mouse myoblasts cells with 3‐MA (1 mM) resulted in a ∼16% reduction in maximal oxygen consumption ( P =0.04). The INS1 cells used here were derived from rat insulinoma (pancreatic tumor β‐cells) and are characterized by a linear relationship between insulin secretion and glucose concentration within a range of 2–10 mM ( ). At basal glucose concentration (2 mM), there was no significant difference in insulin

Gilad Twig et al. The EMBO Journal January 2008

Hepatic stellate cell‐expressed endosialin balances fibrogenesis and hepatocyte proliferation during liver damage

… by HSC and portal fibroblasts, is upregulated in liver fibrosis in mouse and man. Chronic chemically induced liver damage resulted in reduced fibrosis and enhanced hepatocyte proliferation in endosialin‐deficient ( EN KO ) mice. Correspondingly, acute‐liver‐damage‐induced hepatocyte proliferation (partial hepatectomy) was increased in EN KO mice. A candidate‐based screen of known regulators of hepatocyte proliferation identified insulin‐like growth factor 2 ( IGF 2) as selectively endosialin‐dependent hepatocyte mitogen. Collectively, the study establishes a critical role of HSC in the reciprocal regulation of fibrogenesis vs. hepatocyte proliferation and identifies endosialin as a therapeutic target in non‐neoplastic settings.

…  = 5–9 mice per group and time point). EQuantitation of Ki‐67+ hepatocytes/HPF determined 1, 2, 4, and 8 days after 2/3 PHx. FNumber of mitotic figures  days after 2/3 PHx of WT and ENKO mice (n = 5–9 mice per group and time point). GqRT–PCR analysis of total liver lysates 1 day after PHx for IGF2. HWestern blot analysis of phosphorylated insulin‐like growth factor receptor 1 (pIGFR1), phosphorylated insulin receptor substrate 1 (pIRS1) and β‐actin 2 days after PHx. IWestern blot analysis …

Carolin Mogler et al. EMBO molecular medicine March 2015
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