Morris White

Morris White
Harvard Medical School | HMS · Division of Developmental Medicine/Children's Hospital Boston

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381
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Publications

Publications (381)
Article
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Inhibition of P300 acetyltransferase activity by specific inhibitor C646 has been shown to improve insulin signaling. However, the underlying molecular mechanism of this improvement remains unclear. In this study, we analyzed P300 levels of obese patients and found that they were significantly increased in liver hepatocytes. In addition, large amou...
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The hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04–1.47, p < 0.05) dur...
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The elucidation of the mechanisms whereby the liver maintains glucose homeostasis is crucial for the understanding of physiologic and pathologic states. Here, we show a novel role of hepatic transcriptional co-activator with PDZ-binding motif (TAZ) in the inhibition of glucocorticoid receptor (GR). TAZ is abundantly expressed in pericentral hepatoc...
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The discovery of insulin 100 years ago and its application to the treatment of human disease marked a major turning point in the history of medicine. With the availability of purified insulin, its physiological role for the regulation of blood glucose and ketones was established; its amino acid sequence was determined, and its structure was solved....
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Fgf21 (fibroblast growth factor 21) is a regulatory hepatokine that, in pharmacologic form, powerfully promotes weight loss and glucose homeostasis. Although “Fgf21 resistance” is inferred from higher plasma Fgf21 levels in insulin-resistant mice and humans, diminished Fgf21 function is understood primarily via Fgf21 knockout mice. By contrast, we...
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Pressure overload (PO) cardiac hypertrophy and heart failure are associated with generalized insulin resistance and hyperinsulinemia, which may exacerbate left ventricular (LV) remodeling. While PO activates insulin receptor tyrosine kinase activity that is transduced by insulin receptor substrate 1 (IRS1), the present study tested the hypothesis t...
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Understanding the neural components modulating feeding-related behavior and energy expenditure is crucial to combating obesity and its comorbidities. Neurons within the paraventricular nucleus of the hypothalamus (PVH) are a key component of the satiety response; activation of the PVH decreases feeding and increases energy expenditure, thereby prom...
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The transcription factor forkhead boxO1 (FoxO1) is a key mediator in the insulin signaling pathway and controls multiple physiological functions, including hepatic glucose production (HGP) and pancreatic β-cell function. We previously demonstrated that Ser256 in human FOXO1, equivalent to Ser253 in mouse FoxO1, is a key phosphorylation site mediati...
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Hyperglycemia and insulin resistance accelerate atherosclerosis by an unclear mechanism. The two factors down-regulate IRS-1, an intermediary of the insulin/IGF-I signaling system. We previously reported that insulin receptor substrate-1 (IRS-1) down-regulation leads to vascular smooth muscle cell (VSMC) dedifferentiation and that IRS-1 deletion fr...
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In the version of this article originally published, the y axis labels in Fig. 4b,d were incorrect. In Fig. 4b, the unit on the label was (ng mg-1). This should have been (ng/ml). In Fig. 4d, the y axis label was Serum Fst (ng ml-1). It should have been Serum insulin (ng/ml). The errors have been corrected in the HTML and PDF versions of this artic...
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Unsuppressed hepatic glucose production (HGP) contributes substantially to glucose intolerance and diabetes, which can be modeled by the genetic inactivation of hepatic insulin receptor substrate 1 (Irs1) and Irs2 (LDKO mice). We previously showed that glucose intolerance in LDKO mice is resolved by hepatic inactivation of the transcription factor...
Article
Non-small-cell lung cancer (NSCLC) is a leading cause of cancer death worldwide, with 25% of cases harboring oncogenic Kirsten rat sarcoma (KRAS). Although KRAS direct binding to and activation of PI3K is required forKRAS-driven lung tumorigenesis, the contribution of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) in the co...
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Diabetes and obesity are characterized by insulin resistance and chronic low-grade inflammation. An elevated plasma concentration of lipopolysaccharide (LPS) caused by increased intestinal permeability during diet-induced obesity promotes insulin resistance in mice. Here, we show that LPS induces endoplasmic reticulum (ER) stress and protein levels...
Chapter
Protein tyrosine kinases (PTKs) are encoded by a large multigene family. PTKs regulate many aspects of metabolism, growth, and cancer progression – including cell proliferation, differentiation, and survival, adhesion and motility, and systemic nutrient homeostasis (Schlessinger 2014; Robinson et al. 2000; Lemmon and Schlessinger 2010). Of the appr...
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Diabetes is a major risk factor for the development of atherosclerosis but the mechanism by which hyperglycemia accelerates lesion development is not well defined. Insulin and insulin like growth factor-I (IGF-I)1 signal through the scaffold protein insulin receptor substrate-1(IRS-1). In diabetes IRS-1 is down regulated and cells become resistant...
Chapter
Insulin and IGF (insulin-like growth factor) signaling integrates the storage and release of nutrients with animal growth during development and throughout adult life. It is essential for all metazoans, revealing a common mechanism used by animals to integrate metabolism, growth, and lifespan with environmental signals. The human genome encodes a s...
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GPCRs (G protein-coupled receptors)2 activate PI3K/AKT (phosphatidylinositol-3 kinase/v-AKT thymoma viral oncoprotein) to regulate many cellular functions that promote cell survival, proliferation, and growth. However, the mechanism by which GPCRs activate PI3K/AKT remains poorly understood. We used ovarian preantral granulosa cells (GCs) to elucid...
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IRS proteins are cellular adaptor molecules that mediate many of the key metabolic actions of insulin. When tyrosine is phosphorylated by the activated insulin receptor, IRS proteins recruit downstream effectors, such as phosphoinositide 3-kinase and mitogen-activated protein kinase, in order to elicit cellular responses such as glucose uptake, lip...
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Insulin receptor substrate-1 (IRS-1) is a signaling adaptor protein that interfaces with many pathways activated in lung cancer. It has been assumed that IRS-1 promotes tumor growth through its ability to activate PI3K signaling downstream of the insulin-like growth factor receptor. Surprisingly, tumors with reduced IRS-1 staining in a human lung a...
Article
The capacity of pancreatic β cells to maintain glucose homeostasis during chronic physiologic and immunologic stress is important for cellular and metabolic homeostasis. Insulin receptor substrate 2 (IRS2) is a regulated adapter protein that links the insulin and IGF1 receptors to downstream signaling cascades. Since strategies to maintain or incre...
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Constitutive activation of the mammalian target of rapamycin complex 1 and S6 kinase (mTORC1→S6K) attenuates insulin-stimulated Akt activity in certain tumors, in part through 'feedback' phosphorylation of upstream insulin receptor substrate IRS1. However, the significance of this mechanism for regulating insulin sensitivity in normal tissue remain...
Article
Inhibiting the PI3K branch of the cell signalling induced by insulin and insulin-like growth factor can extend lifespan. The finding that inhibiting the RAS branch also extends lifespan in flies suggests a new target for anti-ageing drugs
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Insulin and IGF-1 receptor signaling pathways differentially modulate cardiac growth under resting conditions and following exercise training. These effects are mediated by insulin receptor substrates (IRS) 1 and 2, which also differentially regulate resting cardiac mass. To determine the role of IRS isoforms in mediating the hypertrophic and metab...
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Binding of insulin receptor substrate proteins 1 and 2 (IRS1/2) to the insulin receptor (IR) is essential for the regulation of insulin sensitivity and energy homeostasis. However, the mechanism of IRS1/2 recruitment to the IR remains elusive. Here, we identify adaptor protein APPL1 as a critical molecule that promotes IRS1/2-IR interaction. APPL1...
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IRS1 and IRS2 are key substrates of the insulin receptor tyrosine kinase. Mass spectrometry reveals more than 50 phosphorylated IRS1 serine and threonine residues (phospho-S/Ts) in IRS1 from insulin-stimulated cells or human tissues. We investigated a subset of IRS1 phospho-S/Ts using a newly developed panel of 25 phosphospecific monoclonal antibod...
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Increased mammalian target of rapamycin complex 1 (mTORC1) activity has been suggested to play important roles in development of insulin resistance in obesity. mTORC1 hyperactivity also increases endoplasmic reticulum (ER) stress, which in turn contributes to development of insulin resistance and glucose intolerance. Increased IRS1 phosphorylation...
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Cardiac failure is a major cause of death in patients with type 2 diabetes, but the molecular mechanism that links diabetes to heart failure remains unclear. Insulin resistance is a hallmark of type 2 diabetes, and insulin receptor substrates 1 and 2 (IRS1 and IRS2) are the major insulin-signaling components regulating cellular metabolism and survi...
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The induction of autophagy in the mammalian heart during the perinatal period is an essential adaptation required to survive early neonatal starvation; however, the mechanisms that mediate autophagy suppression once feeding is established are not known. Insulin signaling in the heart is transduced via insulin and IGF-1 receptors (IGF-1Rs). We disru...
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Insulin receptor substrates (Irs1, 2, 3 and Irs4) mediate the actions of insulin/IGF1 signaling. They have similar structure, but distinctly regulate development, growth, and metabolic homeostasis. Irs2 contributes to central metabolic sensing, partially by acting in leptin receptor (LepRb)-expressing neurons. Although Irs4 is largely restricted to...
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Pyruvate dehydrogenase kinases (PDK1-4) play a critical role in the inhibition of the mitochondrial pyruvate dehydrogenase complex especially when blood glucose levels are low and pyruvate can be conserved for gluconeogenesis. Under diabetic conditions, the Pdk genes, particularly Pdk4, are often induced, and the elevation of the Pdk4 gene expressi...
Article
A major cause of death in patients with type 2 diabetes is cardiac failure and the molecular mechanism that links diabetes to cardiomyopathy remains unclear. Insulin resistance is a hallmark of type 2 diabetes and intensive insulin therapy on the patients with type 2 diabetes increases the risks of cardiovascular dysfunction. Thus, understanding th...
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Phosphatidylcholine transfer protein (PC-TP) is a phospholipid-binding protein that is enriched in liver and that interacts with thioesterase superfamily member 2 (THEM2). Mice lacking either protein exhibit improved hepatic glucose homeostasis and are resistant to diet-induced diabetes. Insulin receptor substrate 2 (IRS2) and mammalian target of r...
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In recent years there has been a growing interest in the possibility of a direct autocrine effect of insulin on the pancreatic β-cell. Indeed, there have been numerous intriguing articles and several eloquent reviews written on the subject (1-3); however, the concept is still controversial. Although many in vitro experiments, a few transgenic mouse...
Article
Diabetic nephropathy (DN) is a progressive fibrotic condition that may lead to end-stage renal disease and kidney failure. Transforming growth factor-β1 and bone morphogenetic protein-7 (BMP7) have been shown to induce DN-like changes in the kidney and protect the kidney from such changes, respectively. Recent data identified insulin action at the...
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Protein Kinase C (PKC) activation, induced by hyperglycemia and angiotensin II (AngII), inhibited insulin-induced phosphorylation of Akt/eNOS by decreasing p-Tyr-IRS2 in endothelial cells. PKC activation by phorbol ester (PMA) reduced insulin-induced p-Tyr-IRS2 by 46% ± 13% and similarly, phosphorylation of Akt/eNOS. Site-specific mutational analys...
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TrkA is a cell surface transmembrane receptor tyrosine kinase for nerve growth factor (NGF). TrkA has an NPXY motif and kinase regulatory loop similar to insulin receptor (INSR) suggesting that NGF→TrkA signaling might overlap with insulin→INSR signaling. During insulin or NGF stimulation TrkA, insulin receptor substrate-1 (IRS-1), INSR (and presum...
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Type 2 diabetes (T2D) has emerged as a major threat to human health in most parts of the world. Therapeutic strategies aimed at improving pancreatic β cell function are predicted to prove beneficial for the treatment of T2D. In the present study, we demonstrate that drug-mediated, chronic, and selective activation of β cell Gq signaling greatly imp...
Article
The insulin pathway coordinates growth, development, metabolic homoeostasis, fertility, and stress resistance, which influence life span. Compensatory hyperinsulinemia to overcome systemic insulin resistance circumvents the immediate consequences of hyperglycemia. Work on flies, nematodes, and mice indicate that excess insulin signaling damages cel...
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Background: An emerging literature suggests that environmental chemicals may play a role in the development of childhood obesity and metabolic disorders, especially when exposure occurs early in life. Objective: Here we assess the association between these health outcomes and exposure to maternal smoking during pregnancy as part of a broader effort...
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Insulin is secreted as discrete insulin secretory bursts at ~5-min intervals into the hepatic portal vein, these pulses being attenuated early in the development of type 1 and type 2 diabetes mellitus (T2DM). Intraportal insulin infusions (pulsatile, constant, or reproducing that in T2DM) indicated that the pattern of pulsatile insulin secretion de...
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Diabetic bladder dysfunction (DBD) is common and affects 80% of diabetic patients. However, the molecular mechanisms underlying DBD remain elusive because of a lack of appropriate animal models. We demonstrate DBD in a mouse model that harbors hepatic-specific insulin receptor substrate 1 and 2 deletions (double knockout [DKO]), which develops type...
Article
Irs2-mediated insulin/IGF1 signaling in the CNS modulates energy balance and glucose homeostasis; however, the site for Irs2 function is unknown. The hormone leptin mediates energy balance by acting on leptin receptor (LepR-b)-expressing neurons. To determine whether LepR-b neurons mediate the metabolic actions of Irs2 in the brain, we utilized Lep...
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Insulin controls systemic nutrient homeostasis by promoting anabolic processes in various tissues, including the stimulation of glucose influx (into muscle and adipose), protein and glycogen synthesis (in muscle and liver), lipid synthesis and storage (in liver and adipose), and the inhibition of fatty acid oxidation, glycogenolysis, gluconeogenesi...
Article
The kinase AKT has been regarded as an obligate intermediate in the insulin signaling pathway that suppresses glucose production by inhibiting the transcription factor forkhead box O1 (FoxO1) after meals. A new study shows that, without AKT-FoxO1 signaling, insulin still contributes to postprandial responses, revealing an AKT-independent pathway fo...
Chapter
Insulin-like signaling integrates the storage and release of nutrients with somatic growth during development and in adult life. It is a feature of all metazoans, revealing a common mechanism used by animals to integrate metabolism and growth with environmental signals [1, 2]. Lower animals have a wide array of insulin-like peptides—seven in fruit...
Article
Full-text available
The regulation of endothelial function by insulin is consistently abnormal in insulin-resistant states and diabetes. Protein kinase C (PKC) activation has been reported to inhibit insulin signaling selectively in endothelial cells via the insulin receptor substrate/PI3K/Akt pathway to reduce the activation of endothelial nitric-oxide synthase (eNOS...