Search results

There are 47 results for Insulin (displaying 11 to 20).

Alzheimer‐associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation

Alzheimer's disease ( AD ) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD ‐associated Aβ oligomers (AβOs) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD . Systemically injected AβOs failed to induce glucose intolerance, suggesting AβOs target brain regions involved in peripheral metabolic control. Accordingly, we show that AβOs affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2α phosphorylation ( eIF 2α‐P). AβOs further induced eIF 2α‐P and activated pro‐inflammatory IKK β/ NF ‐κB signaling in the hypothalamus of mice and macaques. AβOs failed to trigger peripheral glucose intolerance in tumor necrosis factor‐α ( TNF ‐α) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented glucose intolerance in mice, indicating that AβOs act via a central route to affect peripheral glucose homeostasis. While the hypothalamus has been largely ignored in the AD field, our findings indicate that AβOs affect this brain region and reveal novel shared molecular mechanisms between hypothalamic dysfunction in metabolic disorders and AD.

… of vehicle or AβOs in mice. Graphs show IRS‐1pSer or IRS‐1pTyr levels normalized by total IRS‐1. In (I), *P = 0.0043; in (J), *P = 0.0275; Student's t‐test. KTwelve‐hour food intake after a single i.c.v. infusion of insulin (200 mU) in mice. Experiment was performed 7 days after i.c.v. injection of vehicle or AβOs (n = 5 PBS; 5 Veh + Insulin; 9 AβOs + Insulin), data are representative of two independent experiments with similar results. ***P < 0.0001, one‐way ANOVA followed by Bonferroni post hoc test comparing Veh‐Insulin versus PBS groups. Data information: Data are expressed as means ± SEM. In (A–J), to assess statistical significance, AβO‐injected mice were compared to vehicle‐injected mice.Source data are available online for this figure. …

… . HRepresentative images of GLUT‐4 immunofluorescence in insulin‐stimulated skeletal muscle from mice that were i.c.v.‐injected with vehicle (Veh) or 10 pmol AβOs. Bar graphs show quantification of GLUT‐4 surface immunoreactivity in skeletal muscle of mice that received intraperitoneal injections of PBS or insulin (1 IU/kg body weight) 7 days after i.c.v. injection of vehicle or AβOs, as indicated (n = 5 animals/group). Scale bar = 25 μm. *P = 0.0144, one‐way ANOVA followed by Bonferroni post hoc test. I …

… followed by Bonferroni post hoc test; right panel: *P = 0.0207, Student's t‐test. BInsulin tolerance test (1 IU insulin/kg body weight, i.p.) (n = 7 Veh; 8 AβOs). Blood levels of glucose were measured at several time points following insulin administration. Bar graph represents the kinetic constants for glucose disappearance (Kitt) calculated from the time course plot. Data are representative of two independent experiments with similar results. Left panel: *P = 0.0456 and ***P = 0.0007, two‐way ANOVA …

… Increasing evidence suggests an association between metabolic disorders, notably type 2 diabetes (T2D), and Alzheimer's disease (AD) (Craft, ; De Felice, ). Clinical and epidemiological studies indicate that diabetic patients have increased risk of developing AD (Ott et al , ; Sims‐Robinson et al , ; Wang et al , ) and AD brains exhibit defective insulin signaling (Moloney et al , ; Bomfim et al , ; Craft, ; Talbot et al , ). Recent studies have shown that soluble amyloid‐β peptide oligomers …

Julia R Clarke et al. EMBO molecular medicine February 2015

Dual melanocortin‐4 receptor and GLP‐1 receptor agonism amplifies metabolic benefits in diet‐induced obese mice

We assessed the efficacy of simultaneous agonism at the glucagon‐like peptide‐1 receptor ( GLP ‐1R) and the melanocortin‐4 receptor ( MC 4R) for the treatment of obesity and diabetes in rodents. Diet‐induced obese ( DIO ) mice were chronically treated with either the long‐acting GLP ‐1R agonist liraglutide, the MC 4R agonist RM ‐493 or a combination of RM ‐493 and liraglutide. Co‐treatment of DIO mice with RM ‐493 and liraglutide improves body weight loss and enhances glycemic control and cholesterol metabolism beyond what can be achieved with either mono‐therapy. The superior metabolic efficacy of this combination therapy is attributed to the anorectic and glycemic actions of both drugs, along with the ability of RM ‐493 to increase energy expenditure. Interestingly, compared to mice treated with liraglutide alone, hypothalamic Glp‐1r expression was higher in mice treated with the combination therapy after both acute and chronic treatment. Further, RM ‐493 enhanced hypothalamic Mc4r expression. Hence, co‐dosing with MC 4R and GLP ‐1R agonists increases expression of each receptor, indicative of minimized receptor desensitization. Together, these findings suggest potential opportunities for employing combination treatments that comprise parallel MC 4R and GLP ‐1R agonism for the treatment of obesity and diabetes.

A–IGlucose metabolic parameters were assessed following 5 days of treatment of DIO male mice with vehicle (white), liraglutide (10 nmol/kg) (gray), RM‐493 (3.6 μmol/kg) (black), or liraglutide (10 nmol/kg) and RM‐493 (3.6 μmol/kg) (checkered). (A) Fasted blood glucose levels, (B, C) glucose tolerance, (D) fasted insulin levels, (E, F) glucose‐induced insulin secretion, (G) HOMA‐IR, (H) insulin sensitivity and (I) hepatic phosphorylation of AKT (p‐AKTSer473) were analyzed. Compounds were administered by daily subcutaneous injections. To assess insulin‐stimulated p‐AKTSer473, insulin (n = 5) or saline (n = 3) was injected 10 min prior to liver sampling. Data represent means ± SEM; n = 8 in (A–H); *P < 0.05, **P < 0.01, ***P < 0.001.

… target for the development of novel, anti‐obesity pharmacotherapies (Huszar et al , ; Yeo et al , ; Farooqi et al , ). Furthermore, MC4R‐agonism enhances peripheral insulin sensitivity and improves glucose tolerance in rodents and non‐human primates (Obici et al , ; Kievit et al , ), implying that MC4R‐based drug therapies hold promise for treatment of type 2 diabetes and obesity. Unfortunately, adverse effects, including increased blood pressure and heart rate, have hampered the clinical …

Christoffer Clemmensen et al. EMBO molecular medicine March 2015

Fasting‐induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health

Recent studies have demonstrated that repeated short‐term nutrient withdrawal (i.e. fasting) has pleiotropic actions to promote organismal health and longevity. Despite this, the molecular physiological mechanisms by which fasting is protective against metabolic disease are largely unknown. Here, we show that, metabolic control, particularly systemic and liver lipid metabolism, is aberrantly regulated in the fasted state in mouse models of metabolic dysfunction. Liver transcript assays between lean/healthy and obese/diabetic mice in fasted and fed states uncovered “growth arrest and DNA damage‐inducible” GADD 45β as a dysregulated gene transcript during fasting in several models of metabolic dysfunction including ageing, obesity/pre‐diabetes and type 2 diabetes, in both mice and humans. Using whole‐body knockout mice as well as liver/hepatocyte‐specific gain‐ and loss‐of‐function strategies, we revealed a role for liver GADD 45β in the coordination of liver fatty acid uptake, through cytoplasmic retention of FABP 1, ultimately impacting obesity‐driven hyperglycaemia. In summary, fasting stress‐induced GADD 45β represents a liver‐specific molecular event promoting adaptive metabolic function.

… ) triglycerides (TG) were measured. H–JSerum TG (H), NEFA (I) and blood glucose (BG, J) concentrations during an oral lipid tolerance test in overnight fasted GADD45β+/+ (WT; n = 5) or GADD45β−/− (KO; n = 5) mice. K–NBlood glucose excursion during and intraperitoneal insulin tolerance test (K) as well as fasting blood glucose (L), serum insulin (M) and HOMA‐IR (N) in GADD45β+/+ (WT; n = 6) or GADD45β−/− (KO, n = 9) chronically fed a normal‐ (NFD) or high (HFD)‐fat diet. Data information: Data are mean ± SEM. Effect of genotype, *P < 0.05, **P < 0.01, ***P < 0.001. Effect of nutritional state: #P < 0.05, ##P < 0.01, ###P < 0.001. The statistical test used and respective P‐value outputs can be found in Appendix Table S1.

A, BMale 12‐weeks‐old wild‐type (WT; C57Bl/6J) or obese/diabetic (db/db; BKS.Cg‐m+/+ Lepr DB/J) mice with (Ad‐G45b OE) or without (Ad‐NC) prior liver‐restricted GADD45β over‐expression were fasted and insulin was injected with livers harvested shortly thereafter and subsequently liver proteins were subjected to immunoblotting for insulin signalling proteins including phosphoprotein kinase B (PKB/Akt; A) and glycogen synthase kinase beta (GSK3b; B). Inserts show representative blots (n = 6 …

A–CMale 12‐weeks‐old wild‐type (WT; C57Bl/6J) or obese/diabetic (db/db; BKS.Cg‐m+/+ Lepr DB/J) mice with (AD‐G45b OE) or without (AD‐NC) prior liver‐restricted GADD45β over‐expression were fasted, and blood glucose (A) and serum insulin (B) were measured from which HOMA‐IR was calculated (C) (n = 4–6/group). Data are mean ± SEM. Effect of genotype/viral manipulation, *P < 0.05, **P < 0.01, ***P < 0.001. Effect of nutritional state: #P < 0.05, ##P < 0.01, ###P < 0.001. D–FLiver GADD45B mRNA …

… of obesity‐driven T2D is insulin resistance (Bjorntorp, ), and thus, much effort is placed into treatments that promote “insulin sensitisation” (Connor et al , ). While there is no doubt that insulin is an important mediator of metabolic control in the prandial state (Boucher et al , ), insulin resistance likely represents a physiological feedback mechanism to actually retard the development of obesity‐driven complications (Hoehn et al , ), prompting speculation that “insulin sensitisation” may …

Jessica Fuhrmeister et al. EMBO molecular medicine May 2016

Loss of autophagy in hypothalamic POMC neurons impairs lipolysis

Autophagy degrades cytoplasmic contents to achieve cellular homeostasis. We show that selective loss of autophagy in hypothalamic proopiomelanocortin (POMC) neurons decreases α‐melanocyte‐stimulating hormone (MSH) levels, promoting adiposity, impairing lipolysis and altering glucose homeostasis. Ageing reduces hypothalamic autophagy and α‐MSH levels, and aged‐mice phenocopy, the adiposity and lipolytic defect observed in POMC neuron autophagy‐null mice. Intraperitoneal isoproterenol restores lipolysis in both models, demonstrating normal adipocyte catecholamine responsiveness. We propose that an unconventional, autophagosome‐mediated form of secretion in POMC neurons controls energy balance by regulating α‐MSH production. Modulating hypothalamic autophagy might have implications for preventing obesity and metabolic syndrome of ageing.

Loss of POMC neuronal atg7 impairs glucose tolerance. (A) Blood glucose levels in 6 mo (n=7–9) and (B) 12 mo Con and KO mice on RD (n=6), and in (C) 12‐mo‐old Con and KO mice on HFD (n=4). (D) Serum insulin levels in 6 mo, (n=7–9) and (E) 12‐mo‐old RD‐fed Con and KO mice that were fed or 6 h fasted (n=6). (F) HOMA values from 6‐h‐fasted 6‐mo‐old (n=7–9) and (G) 12‐mo‐old Con and KO mice (n=6) on RD. (H) Glucose tolerance tests in 6‐h‐fasted 6‐mo‐old mice on RD (n=4) and in (I) 6‐h‐fasted 12‐mo …

… in the lipolysis‐deficient KO mice, suggest that additional mechanisms might skew adipose macrophages towards the M1 form in a fatty acid‐independent manner. As obesity typically associates with reduced insulin sensitivity, we asked whether adiposity and inflammation in KO mice altered glucose homeostasis. To test this, we first examined basal blood glucose levels in 6‐mo‐ and 12‐mo‐old RD‐fed control and KO mice, and in 12‐mo‐old cohorts fed a HFD. The loss of autophagy in POMC neurons …

Susmita Kaushik et al. EMBO Reports February 2012

eIF4A inactivates TORC1 in response to amino acid starvation

Amino acids regulate TOR complex 1 ( TORC 1) via two counteracting mechanisms, one activating and one inactivating. The presence of amino acids causes TORC 1 recruitment to lysosomes where TORC 1 is activated by binding Rheb. How the absence of amino acids inactivates TORC 1 is less well understood. Amino acid starvation recruits the TSC 1/ TSC 2 complex to the vicinity of TORC 1 to inhibit Rheb; however, the upstream mechanisms regulating TSC 2 are not known. We identify here the eIF 4A‐containing eIF 4F translation initiation complex as an upstream regulator of TSC 2 in response to amino acid withdrawal in Drosophila . We find that TORC 1 and translation preinitiation complexes bind each other. Cells lacking eIF 4F components retain elevated TORC 1 activity upon amino acid removal. This effect is specific for eIF 4F and not a general consequence of blocked translation. This study identifies specific components of the translation machinery as important mediators of TORC 1 inactivation upon amino acid removal.

… ), or incubated with 10 μg/ml insulin for 60 min (lane 3), or 20 nM rapamycin for 30 min (lane 4), before lysis in CHAPS‐containing buffer. Representative of three biological replicates. (C′) Validation of the anti‐dRaptor antibody. Left panel: Kc167 cells were treated with the indicated dsRNAs for 5 days, prior to lysis. The band corresponding to the dRaptor protein, running at approximately 180 kDa, significantly decreases upon Raptor knockdown. Right panel: The Raptor band observed in a TOR …

… according to the Invitrogen formulation by adding or omitting the amino acids. Both homemade media were supplemented with 10% FBS that had been dialyzed using a 3,500‐Da cutoff membrane (Spectrumlabs, 132720) against PBS pH 7.4. Drugs used for cell treatments: rapamycin (Santa Cruz, sc‐3504A), oligomycin (Calbiochem, #495455), harringtonine (Abcam, ab141941), RSK inhibitor (BI‐D1870) (BioVision, #1924‐1,5), cycloheximide (Sigma, C4859), insulin (Sigma, I9278). For dsRNA treatments, cells were diluted …

Foivos‐Filippos Tsokanos et al. The EMBO Journal May 2016

Mutations in pregnancy‐associated plasma protein A2 cause short stature due to low IGF‐I availability

Mutations in multiple genes of the growth hormone/ IGF ‐I axis have been identified in syndromes marked by growth failure. However, no pathogenic human mutations have been reported in the six high‐affinity IGF ‐binding proteins ( IGFBP s) or their regulators, such as the metalloproteinase pregnancy‐associated plasma protein A2 ( PAPP ‐A2) that is hypothesized to increase IGF ‐I bioactivity by specific proteolytic cleavage of IGFBP ‐3 and ‐5. Multiple members of two unrelated families presented with progressive growth failure, moderate microcephaly, thin long bones, mildly decreased bone density and elevated circulating total IGF ‐I, IGFBP ‐3, and ‐5, acid labile subunit, and IGF ‐ II concentrations. Two different homozygous mutations in PAPPA 2 , p.D643fs25* and p.Ala1033Val, were associated with this novel syndrome of growth failure. In vitro analysis of IGFBP cleavage demonstrated that both mutations cause a complete absence of PAPP ‐A2 proteolytic activity. Size‐exclusion chromatography showed a significant increase in IGF ‐I bound in its ternary complex. Free IGF ‐I concentrations were decreased. These patients provide important insights into the regulation of longitudinal growth in humans, documenting the critical role of PAPP ‐A2 in releasing IGF ‐I from its BP s.

… The growth hormone (GH)/insulin‐like growth factor (IGF)‐I system is essential for optimal human growth. GH promotes growth via IGF‐I production and by direct actions on the growth plate. IGF‐I circulates bound to six IGF‐binding proteins (IGFBPs). After binding IGF, IGFBP‐3, and ‐5 also bind with the IGF acid labile subunit (ALS) to form a ternary complex, which further increases IGF‐I's half‐life (Baxter, ). Free IGF‐I (fIGF‐I) binds its receptor, activating signaling cascades that up …

Andrew Dauber et al. EMBO molecular medicine March 2016

H19 lncRNA alters stromal cell growth via IGF signaling in the endometrium of women with endometriosis

Endometriosis affects approximately 15% of reproductive aged women and is associated with chronic pelvic pain and infertility. However, the molecular mechanisms by which endometriosis impacts fertility are poorly understood. The developmentally regulated, imprinted H19 long noncoding RNA (lnc RNA ) functions to reduce the bioavailability of micro RNA let‐7 by acting as a molecular sponge. Here we report that H19 expression is significantly decreased in the eutopic endometrium of women with endometriosis as compared to normal controls. We show that decreased H19 increases let‐7 activity, which in turn inhibits Igf1r expression at the post‐transcriptional level, thereby contributing to reduced proliferation of endometrial stromal cells. We propose that perturbation of this newly identified H19/Let‐7/ IGF 1R regulatory pathway may contribute to impaired endometrial preparation and receptivity for pregnancy in women with endometriosis. Our finding represents the first example of a lnc RNA ‐based mechanism in endometriosis and its associated infertility, thus holding potential in the development of novel therapeutics for women with endometriosis and infertility.

… and quality of life (reviewed in Macer & Taylor, ). There is a clear association between endometriosis and infertility. Some studies suggest that 25–50% of women with infertility also have endometriosis and 30–50% of women with endometriosis are infertile (Meuleman et al , ). However, despite the well‐established link between endometriosis and infertility, the mechanism by which endometriosis impacts fertility is poorly understood. The insulin‐like growth factors, including insulin, IGF1, and IGF2 …

Sanaz Ghazal et al. EMBO molecular medicine August 2015

The nuclear cofactor DOR regulates autophagy in mammalian and Drosophila cells

The regulation of autophagy in metazoans is only partly understood, and there is a need to identify the proteins that control this process. The diabetes‐ and obesity‐regulated gene (DOR), a recently reported nuclear cofactor of thyroid hormone receptors, is expressed abundantly in metabolically active tissues such as muscle. Here, we show that DOR shuttles between the nucleus and the cytoplasm, depending on cellular stress conditions, and re‐localizes to autophagosomes on autophagy activation. We demonstrate that DOR interacts physically with autophagic proteins Golgi‐associated ATPase enhancer of 16 kDa (GATE16) and microtubule‐associated protein 1A/1B‐light chain 3. Gain‐of‐function and loss‐of‐function studies indicate that DOR stimulates autophagosome formation and accelerates the degradation of stable proteins. CG11347, the DOR Drosophila homologue, has been predicted to interact with the Drosophila Atg8 homologues, which suggests functional conservation in autophagy. Flies lacking CG11347 show reduced autophagy in the fat body during pupal development. All together, our data indicate that DOR regulates autophagosome formation and protein degradation in mammalian and Drosophila cells.

… , providing essential nutrients and energy for the developing tissues of the adult fly ( ; ). The regulation of autophagy in metazoans is only partly understood, and a relevant task is to identify further proteins that contribute to this control. Here we provide evidence that the novel protein diabetes‐ and obesity‐regulated gene (DOR) has an essential role in autophagy. We have recently reported that DOR is abundantly expressed in insulin‐sensitive tissues and highly repressed in the muscle …

Caroline Mauvezin et al. EMBO Reports December 2009

A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis ( ALS ) is the most common fatal motor neuron disease in adults. Numerous studies indicate that ALS is a systemic disease that affects whole body physiology and metabolic homeostasis. Using a mouse model of the disease ( SOD 1 G86R ), we investigated muscle physiology and motor behavior with respect to muscle metabolic capacity. We found that at 65 days of age, an age described as asymptomatic, SOD 1 G86R mice presented with improved endurance capacity associated with an early inhibition in the capacity for glycolytic muscle to use glucose as a source of energy and a switch in fuel preference toward lipids. Indeed, in glycolytic muscles we showed progressive induction of pyruvate dehydrogenase kinase 4 expression. Phosphofructokinase 1 was inhibited, and the expression of lipid handling molecules was increased. This mechanism represents a chronic pathologic alteration in muscle metabolism that is exacerbated with disease progression. Further, inhibition of pyruvate dehydrogenase kinase 4 activity with dichloroacetate delayed symptom onset while improving mitochondrial dysfunction and ameliorating muscle denervation. In this study, we provide the first molecular basis for the particular sensitivity of glycolytic muscles to ALS pathology.

… of high‐energy substrates for anaerobic exercise. Given that impaired glycolytic performance in SOD1 G86R mice cannot be explained by denervation or atrophy, we hypothesized that reduced anaerobic performance was due to defective glucose utilization. In order to verify whether glucose metabolism is altered in SOD1 G86R mice, we first analyzed their response to glucose and insulin. The glucose tolerance test ( ) showed that at 65 days, SOD1 G86R mice presented with higher blood glucose at 30 and 45 …

Lavinia Palamiuc et al. EMBO molecular medicine May 2015

Inducing mitophagy in diabetic platelets protects against severe oxidative stress

Diabetes mellitus ( DM ) is a growing international concern. Considerable mortality and morbidity associated with diabetes mellitus arise predominantly from thrombotic cardiovascular events. Oxidative stress‐mediated mitochondrial damage contributes significantly to enhanced thrombosis in DM . A basal autophagy process has recently been described as playing an important role in normal platelet activation. We now report a substantial mitophagy induction (above basal autophagy levels) in diabetic platelets, suggesting alternative roles for autophagy in platelet pathology. Using a combination of molecular, biochemical, and imaging studies on human DM platelets, we report that platelet mitophagy induction serves as a platelet protective mechanism that responds to oxidative stress through JNK activation. By removing damaged mitochondria (mitophagy), phosphorylated p53 is reduced, preventing progression to apoptosis, and preserving platelet function. The absence of mitophagy in DM platelets results in failure to protect against oxidative stress, leading to increased thrombosis. Surprisingly, this removal of damaged mitochondria does not require contributions from transcription, as platelets lack a nucleus. The considerable energy and resources expended in “prepackaging” the complex mitophagy machinery in a short‐lived normal platelet support a critical role, in anticipation of exposure to oxidative stress.

… in regulating the process of autophagy has recently been highlighted in an elegant review (Fullgrabe et al , ), autophagy/mitophagy can also occur in anucleate platelets. The basal platelet autophagy process appears to play an important role in platelet activation (Feng et al , ; Cao et al , ; Ouseph et al , ). Diabetes mellitus (DM) is a progressive and chronic metabolic disorder characterized by hyperglycemia caused by impaired insulin levels, insulin sensitivity, and/or insulin action. Currently, over …

Seung Hee Lee et al. EMBO molecular medicine July 2016
Feedback