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Derek LeRoith

Publications and source records attributed to Derek LeRoith.

51 records · Page 3Linked to original sources
PubMed2003

The insulin-like growth factor system and cancer.

The insulin-like growth factor (IGF) family of ligands, binding proteins and receptors is an important growth factor system involved in both the development of the organism and the maintenance of normal function of many cells of the body. The system also has powerful anti-apoptotic effects. More recently, evidence has accrued to demonstrate that the IGFs play an important role in cancer. Individuals with serum IGF-II levels in the upper quartile of the normal range (and IGF binding protein-3 levels in the lower quartiles) have a relative risk for developing breast, prostate, colon and lung cancer. IGF-II is commonly expressed by tumor cells and may act as an autocrine growth factor; occasionally even reaching target tissues and causing tumor-induced hypoglycemia. The IGF-I receptor is commonly (though not always) overexpressed in many cancers, and many recent studies have identified new signaling pathways emanating from the IGF-I receptor that affect cancer cell proliferation, adhesion, migration and cell death; functions that are critical for cancer cell survival and metastases. In this review, many aspects of the IGF system and its relationship to cancer will be discussed.

Animals↗
PubMed2003

Regulation of the splenic somatotropic axis by dietary protein and insulin-like growth factor-I in the rat.

Protein intake is a critical regulatory factor of the GH/IGF-I axis. Recently, it has been shown that splenic GH/IGF-I may respond to nutritional stress by preserving tissue homeostasis. To study the effects of exogenous administration of rhIGF-I on the splenic GH/IGF-I axis in protein malnourished rats, six-week-old male rats were assigned to one of four isocaloric diets differing in the protein content (0%, 4%, 12% and 20%) for a period of 12 days. Animals in the same dietary group on day 5 were randomly divided into two groups and during 7 days received a continuous subcutaneous infusion of either vehicle or rhIGF-I (300 microg/day). A low protein intake decreased the circulating levels of IGF-I, IGFBP-3, GH and insulin whereas the serum levels of IGFBP-1 were increased. Splenic IGFBP-3, -4 and -6 mRNA expression were up-regulated by protein malnutrition. Similarly, IGF-IR and GHR mRNA expression were significantly increased by the lack of dietary protein, whereas the levels of IGF-I mRNA remained unchanged. Exogenous rhIGF-I administration increased the circulating levels of IGFBP-1 and -3 in protein malnourished rats and reduced significantly the GH and insulin levels in well-fed rats. Similarly, rhIGF-I increased significantly the expression of the GHR in the spleen and splenic weight in all dietary groups, whereas nitrogen balance was enhanced only in the high-protein diet group. Among the cell subpopulations, B lymphocytes showed the highest GHR expression. These results suggest that in catabolic stress, induced by protein malnutrition the splenic GH/IGF-I axis is an important modulator and contributes to the maintenance of the homeostasis of the immune system.

Animals↗
PubMed2003

Overcoming the barriers for achieving standards of diabetes care: the formation of CADRE.

Diabetes remains one of the leading causes of death and disability in the United States. Despite significant breakthroughs in treatment of diabetes, recent reports suggest a large number of patients are not at target goals for blood pressure, lipids, and glucose levels. Failure to achieve these goals is most likely not due to the unavailability of drugs and innovations, as numerous drugs have been released over the past 10 years, and monitoring of blood glucose is now considered routine. Therefore, other obstacles must exist at the primary care level preventing adherence to suggested targets. Based on the above, the Council for the Advancement of Diabetes Research and Education (CADRE), a membership organization, was launched in an effort to address the problem of understanding diabetes and its treatment. The ultimate goal of CADRE is to expand understanding of diabetes and its treatment by providing educational programs enabling healthcare professionals to manage and empower patients with diabetes. In particular, by focusing on innovations in diabetes care, CADRE hopes to promote optimal therapy for meeting the treatment goals as outlined by governing bodies such as the American Diabetes Association. This article will focus on the formation of CADRE, and, in particular, identification of the problem contributing to the obstacles of care, and review various surveys conducted by CADRE designed in an effort to identify the problem.

Allied Health Personnel↗
PubMed2003

Microarray analysis and identification of novel molecules involved in insulin-like growth factor-1 receptor signaling and gene expression.

The insulin receptor (IR) and the insulin-like growth factor-1 receptor (IGF-1R) are members of the same subfamily of receptor tyrosine kinases. The two receptors phosphorylate many of the same substrates and activate the same signaling modules, including the mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3' kinase (PI3K) signaling pathways. Although the IR and IGF-1R share some redundant functions in metabolism, cell growth, differentiation, and apoptosis, they also exhibit distinct physiological roles. Some of these may be due to differences in tissue distribution, receptor structure, formation of hybrid receptors, or mechanisms of ligand binding. However, the divergent effects of insulin and IGF-1 also may be explained by specificity in the intracellular signals generated by insulin and IGF-1. In particular, the IR and IGF-1R are capable of triggering their own biological responses by using specific or preferential substrates, molecular adapters, or signaling pathways. In a recent study, we used cDNA microarray analysis to identify genes differentially regulated by insulin and IGF-1. Mouse NIH-3T3 fibroblasts expressing either the wild-type human IGF-1R or IR were stimulated with either IGF-1 or insulin, respectively. We identified 39 genes differentially regulated by insulin and IGF-1. Most of these genes had not been reported previously to be responsive to insulin or IGF-1. The genes induced by IGF-1 generally were involved in mitogenesis or differentiation, while the genes found to be induced by insulin did not conform to any particular category. In a separate study, immortalized breast epithelial cells were stimulated with IGF-1 and a cDNA microarray analysis was used to generate a profile of IGF-1-regulated genes. A number of genes known to be involved in angiogenesis were found to be regulated by IGF-1. These results strongly suggest that this technology may be extremely useful in identifying groups of genes that are specifically regulated by different ligands and their activated receptors.

Animals↗
PubMed2003

Insulin resistance in the liver-specific IGF-1 gene-deleted mouse is abrogated by deletion of the acid-labile subunit of the IGF-binding protein-3 complex: relative roles of growth hormone and IGF-1 in insulin resistance.

Liver IGF-1 deficient (LID) mice demonstrate a 75% reduction in circulating IGF-1 levels and a corresponding fourfold increase in growth hormone (GH) levels. At 16 weeks of age, LID mice demonstrate, using the hyperinsulinemic-euglycemic clamp, insulin insensitivity in muscle, liver, and fat tissues. In contrast, mice with a gene deletion of the acid-labile subunit (ALSKO) demonstrate a 65% reduction in circulating IGF-1 levels, with normal GH levels and no signs of insulin resistance. To further clarify the relative roles of increased GH and decreased IGF-1 levels in the development of insulin resistance, we crossed the two mouse lines and created a double knockout mouse (LID+ALSKO). LID+ALSKO mice demonstrate a further reduction in circulating IGF-1 levels (85%) and a concomitant 10-fold increase in GH levels. Insulin tolerance tests showed an improvement in insulin responsiveness in the LID+ALSKO mice compared with controls; LID mice were very insulin insensitive. Surprisingly, insulin sensitivity, while improved in white adipose tissue and in muscle, was unchanged in the liver. The lack of improvement in liver insulin sensitivity may reflect the absence of IGF-1 receptors or increased triglyceride levels in the liver. The present study suggests that whereas GH plays a major role in inducing insulin resistance, IGF-1 may have a direct modulatory role.

Adipose Tissue↗
PubMed2003

Peroxisome proliferator-activated receptor-alpha agonist treatment in a transgenic model of type 2 diabetes reverses the lipotoxic state and improves glucose homeostasis.

Abnormalities in insulin action are the characteristics of type 2 diabetes. Dominant-negative muscle-specific IGF-I receptor (MKR) mice exhibit elevated lipid levels at an early age and eventually develop type 2 diabetes. To evaluate the role of elevated lipids in the progression of the diabetic state, MKR mice were treated with WY14,643, a peroxisome proliferator-activated receptor (PPAR)-alpha agonist. WY14,643 treatment markedly reduced serum fatty acid and triglyceride levels within a few days, as well as muscle triglyceride levels, and subsequently normalized glucose and insulin levels in MKR mice. Hyperinsulinemic-euglycemic clamp analysis showed that WY14,643 treatment enhanced muscle and adipose tissue glucose uptake by improving whole-body insulin sensitivity. Insulin suppression of endogenous glucose production by the liver of MKR mice was also improved. The expression of genes involved in fatty acid oxidation was increased in liver and skeletal muscle, whereas gene expression levels of hepatic gluconeogenic enzymes were decreased in WY14,643-treated MKR mice. WY14,643 treatment also improved the pattern of glucose-stimulated insulin secretion from the perfused pancreata of MKR mice and reduced the beta-cell mass. Taken together, these findings suggest that the reduction in circulating or intracellular lipids by activation of PPAR-alpha improved insulin sensitivity and the diabetic condition of MKR mice.

Animals↗
PubMed2002

Beta-cell dysfunction and insulin resistance in type 2 diabetes: role of metabolic and genetic abnormalities.

Defects in insulin action and insulin secretion are both present in type 2 diabetes, and both are believed to be genetically predetermined. In the absence of a defect in beta-cell function, individuals can compensate indefinitely for insulin resistance with appropriate hyperinsulinemia, as observed even in obese populations such as the Pima Indians of Arizona. However, loss of beta-cell function leads eventually to the postprandial and fasting hyperglycemia that characterizes type 2 diabetes. This progression occurs despite initially effective antidiabetic therapies, a situation clearly demonstrated by the United Kingdom Prospective Diabetes Study (UKPDS). External factors (access to high-calorie foods, lack of exercise, weight gain), the increased insulin requirements imposed by insulin resistance, and toxicities from hyperglycemia and elevated free fatty acids may all contribute to beta-cell deterioration. Free fatty acids, resistin, and tumor necrosis factor (TNF)-alpha potentially worsen the insulin resistance. beta-Cell dysfunction resulting from glucose toxicity and lipotoxicity is potentially reversible with restoration of metabolic control. Therefore, attention to these toxicities may delay the deterioration of beta-cell function and suggest new approaches to the management of type 2 diabetes.

Adipose Tissue↗
PubMed2002

Insulin-like growth factor I induces MDM2-dependent degradation of p53 via the p38 MAPK pathway in response to DNA damage.

In many tissues, the insulin-like growth factor I (IGF-I) receptor (IGF-IR) is known to functionally oppose apoptosis. Recently, we demonstrated a direct role for the IGF-IR in the rescue of DNA-damaged fibroblasts by activating a DNA repair pathway (Héron-Milhavet, L., Karas, M., Goldsmith, C. M., Baum, B. J., and LeRoith, D. (2001) J. Biol. Chem. 276, 18185-18192). p53 is a nuclear transcription factor that can block progression of the cell cycle, modulate DNA repair, and trigger apoptosis. In this work, we tested the effect of IGF-I on the regulation of the p53 signaling cascade. The DNA-damaging agent 4-nitroquinoline 1-oxide was applied to NIH-3T3 cells overexpressing normal IGF-IRs (NWTb3 cells). We showed that after 4-nitroquinoline 1-oxide-induced DNA damage, IGF-I induced exclusion of the p53 protein from the nucleus and led to its degradation in the cytoplasm, whereas p53 mRNA was unaffected. Degradation of the p53 protein was associated with an increase in MDM2, an upstream modulator of the half-life and activity of the p53 protein. p53 degradation was also associated with down-regulation of p21. We further showed that the effects of IGF-I on mdm2 transcription and on MDM2/p19 ARF association were mediated by the p38 MAPK pathway. In conclusion, we describe a novel role for IGF-I in the regulation of the MDM2/p53/p21 signaling pathway during DNA damage.

Cell Line↗
PubMed2002

Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis.

It has been shown previously that slight elevations in serum levels of insulin-like growth factor-I (IGF-I) are correlated with an increased risk for developing prostate, breast, colon, and lung cancer. The aim of this study was to determine the role of serum IGF-I levels in the process of stimulating tumor growth and metastasis in a mouse model of colon cancer. Colon 38 adenocarcinoma tissue fragments were orthotopically transplanted by attachment to the surface of the cecum in control and liver-specific IGF-I-deficient (LID) mice in which serum IGF-I levels are 25% of that in control mice. A total of 156 male mice at 5 weeks of age (74 control mice and 82 LID mice) received tumor transplants. Mice were divided randomly into two groups; one group was injected i.p. with recombinant human IGF-I (2 mg/kg) twice daily for 6 weeks, and the other group received saline injections. IGF-I treatment increased the serum levels of IGF-I and IGFBP-3 in both control and LID mice. In the saline-injected group, the incidence of tumor growth on the cecum as well as the frequency of hepatic metastasis was significantly higher in control mice as compared with LID mice. Both control and LID mice treated with recombinant human IGF-I displayed significantly increased rates of tumor development on the cecum and metastasis to the liver, as compared with saline-injected mice. The number of metastatic nodules in the liver was significantly higher in control mice as compared with LID mice. The expression of vascular epithelial growth factor (VEGF) as well as vessel abundance in the cecum tumors was dependent on the levels of serum IGF-I. This study supports the hypothesis that circulating IGF-I levels play an important role in tumor development and metastasis.

Adenocarcinoma↗
PubMed2002

Insulin-like growth factor-I: compartmentalization within the somatotropic axis?

Insulin-like growth factor-I (IGF-I) is essential for normal growth; igf-1 gene mutations are associated with extreme growth retardation in mice and, very rarely, in humans. The relative contributions of tissue vs. endocrine (hepatic) IGF-I to the regulation of growth has been a fundamental question. New gene targeting technologies are providing answers for these questions.

Animals↗
PubMed2002

PTEN overexpression suppresses proliferation and differentiation and enhances apoptosis of the mouse mammary epithelium.

The phosphatase PTEN regulates growth, adhesion, and apoptosis, among many other cell processes. To investigate its role during mouse mammary gland development, we generated MK-PTEN, a transgenic mouse model in which human PTEN is overexpressed in ductal and alveolar mammary epithelium during puberty, pregnancy, lactation, and involution. No obvious phenotype was observed in mammary tissue of pubescent virgin mice. However, MK-PTEN females could not lactate normally, and approximately 30% of pups died, with survivors exhibiting growth retardation. Transgenic offspring nursed by wild-type foster mothers, conversely, developed normally. This phenotype is consistent with a reduced number of alveolar epithelial cells due to a decrease in cell proliferation and an increase in apoptosis. Using mammary-enriched cDNA microarrays, we identified several genes that were preferentially expressed in MK-PTEN mammary tissue, including the IGF-binding protein-5 (Igfbp5) gene, and others whose expression was reduced, including the genes for c-Jun amino-terminal kinase. Secretory epithelial cell differentiation was impaired, as measured by the expression of specific milk protein genes. MK-PTEN mice also exhibited a 50% decrease in the phosphorylation state of Akt. Taken together, these results suggest that PTEN controls mammary gland development and, consequently, lactation.

Animals↗
PubMed2002

Circulating levels of IGF-1 directly regulate bone growth and density.

IGF-1 is a growth-promoting polypeptide that is essential for normal growth and development. In serum, the majority of the IGFs exist in a 150-kDa complex including the IGF molecule, IGF binding protein 3 (IGFBP-3), and the acid labile subunit (ALS). This complex prolongs the half-life of serum IGFs and facilitates their endocrine actions. Liver IGF-1-deficient (LID) mice and ALS knockout (ALSKO) mice exhibited relatively normal growth and development, despite having 75% and 65% reductions in serum IGF-1 levels, respectively. Double gene disrupted mice were generated by crossing LID+ALSKO mice. These mice exhibited further reductions in serum IGF-1 levels and a significant reduction in linear growth. The proximal growth plates of the tibiae of LID+ALSKO mice were smaller in total height as well as in the height of the proliferative and hypertrophic zones of chondrocytes. There was also a 10% decrease in bone mineral density and a greater than 35% decrease in periosteal circumference and cortical thickness in these mice. IGF-1 treatment for 4 weeks restored the total height of the proximal growth plate of the tibia. Thus, the double gene disruption LID+ALSKO mouse model demonstrates that a threshold concentration of circulating IGF-1 is necessary for normal bone growth and suggests that IGF-1, IGFBP-3, and ALS play a prominent role in the pathophysiology of osteoporosis.

Animals↗
PubMedDate not supplied

Metabolic memory in diabetes--focus on insulin.

Large-scale clinical trials have demonstrated that metabolic control achieved early in the course of diabetes substantially reduces development and progression of diabetes and the associated microvascular complications. Additionally, prospective observational studies have demonstrated that atherogenic and inflammatory mediators are elevated even prior to the onset of diabetes and significantly contribute to subsequent development of macrovascular complications. Collectively, these data suggest that metabolic memories are stored early in the course of diabetes. We believe that insulin suppresses inflammation and also suppresses glucotoxicity and lipotoxicity (and the consequences thereof, such as the formation of advanced glycation end products and epigenetic phenomena), and thus has a pivotal and beneficial role. Comprehensive metabolic control, especially when instituted early, may alter the natural history of diabetic complications by affecting this metabolic memory. Thus, our overall goal is to understand in more detail the molecular mechanisms involved in these changes, thereby affording us opportunities to reduce the long-term effects of diabetes.

Diabetes Mellitus↗