Diabetes cure--is the glass half full?
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Blood Glucose↗
Biomedical subjects
Derek LeRoith
Publications and source records attributed to Derek LeRoith.
Increased tumor growth in mice with diet-induced obesity: impact of ovarian hormones.
Obesity increases the risk of many cancers in both males and females. This study describes a link between obesity, obesity-associated metabolic alterations, and the risk of developing cancer in male and female mice. The goal of this study was to evaluate the relationship between gender and obesity and to determine the role of estrogen status in obese females and its effect on tumor growth. We examined the susceptibility of C57BL/6 mice to diet-induced obesity, insulin resistance/glucose intolerance, and tumors. Mice were injected sc with one of two tumorigenic cell lines, Lewis lung carcinoma, or mouse colon 38-adenocarcinoma. Results show that tumor growth rate was increased in obese mice vs. control mice irrespective of the tumor cell type. To investigate the effect of estrogen status on tumor development in obese females, we compared metabolic parameters and tumor growth in ovariectomized (ovx) and intact obese female mice. Obese ovx female mice developed insulin resistance and glucose intolerance similar to that observed in obese males. Our results demonstrate that body adiposity increased in ovx females irrespective of the diet administered and that tumor growth correlated positively with body adiposity. Overall, these data point to more rapid tumor growth in obese mice and suggest that endogenous sex steroids, together with diet, affect adiposity, insulin sensitivity, and tumor growth in female mice.
Adenocarcinoma↗
The role of the IGF system in cancer growth and metastasis: overview and recent insights.
IGF-I receptor (IGF-IR) signaling and functions are mediated through the activities of a complex molecular network of positive (e.g., type I IGF) and negative (e.g., the type II IGF receptor, IGF-IIR) effectors. Under normal physiological conditions, the balance between the expression and activities of these molecules is tightly controlled. Changes in this delicate balance (e.g., overexpression of one effector) may trigger a cascade of molecular events that can ultimately lead to malignancy. In recent years, evidence has been mounting that the IGF axis may be involved in human cancer progression and can be targeted for therapeutic intervention. Here we review old and more recent evidence on the role the IGF system in malignancy and highlight experimental and clinical studies that provide novel insights into the complex mechanisms that contribute to its oncogenic potential. Controversies arising from conflicting evidence on the relevance of IGF-IR and its ligands to human cancer are discussed. Our review highlights the importance of viewing the IGF axis as a complex multifactorial system and shows that changes in the expression levels of any one component of the axis, in a given malignancy, should be interpreted with caution and viewed in a wider context that takes into account the expression levels, state of activation, accessibility, and functionality of other interacting components. Because IGF targeting for anticancer therapy is rapidly becoming a clinical reality, an understanding of this complexity is timely because it is likely to have an impact on the design, mode of action, and clinical outcomes of newly developed drugs.
Animals↗
Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice.
Cholangiocellular carcinoma (CC), the second most common primary liver cancer, is associated with a poor prognosis. It has been shown that CCs harbor alterations of a number of tumor-suppressor genes and oncogenes, yet key regulators for tumorigenesis remain unknown. Here we have generated a mouse model that develops CC with high penetrance using liver-specific targeted disruption of tumor suppressors SMAD4 and PTEN. In the absence of SMAD4 and PTEN, hyperplastic foci emerge exclusively from bile ducts of mutant mice at 2 months of age and continue to grow, leading to tumor formation in all animals at 4-7 months of age. We show that CC formation follows a multistep progression of histopathological changes that are associated with significant alterations, including increased levels of phosphorylated AKT, FOXO1, GSK-3beta, mTOR, and ERK and increased nuclear levels of cyclin D1. We further demonstrate that SMAD4 and PTEN regulate each other through a novel feedback mechanism to maintain an expression balance and synergistically repress CC formation. Finally, our analysis of human CC detected PTEN inactivation in a majority of p-AKT-positive CCs, while about half also lost SMAD4 expression. These findings elucidate the relationship between SMAD4 and PTEN and extend our understanding of CC formation.
Animals↗
Intensive insulin therapy in the medical ICU.
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Blood Glucose↗
Recombinant human insulin-like growth factor-I treatment inhibits gluconeogenesis in a transgenic mouse model of type 2 diabetes mellitus.
IGF-I and insulin are structurally related polypeptides that mediate a similar pattern of biological effects via receptors that display considerably homology. Administration of recombinant human IGF-I (rhIGF-I) has been proven to improve glucose control and liver and muscle insulin sensitivity in patients with type 2 diabetes mellitus (DM). The effect of rhIGF-I treatment was evaluated in a mouse model of type 2 DM (MKR mouse), which expresses a dominant-negative form of the human IGF-I receptor under the control of the muscle creatine kinase promoter specifically in skeletal muscle. MKR mice have impaired IGF-I and insulin signaling in skeletal muscle, leading to severe insulin resistance in muscle, liver, and fat, developing type 2 DM at 5 wk of age. Six-week-old MKR mice were treated with either saline or rhIGF-I for 3 wk. Blood glucose levels were decreased in response to rhIGF-I treatment in MKR mice. rhIGF-I treatment also increased body weight in MKR with concomitant changes in body composition such as a decrease in fat mass and an increase in lean body mass. Insulin, fatty acid, and triglyceride levels were not affected by rhIGF-I, nor were insulin or glucose tolerance in MKR mice. Hyperinsulinemic-euglycemic clamp analysis demonstrated no improvement in overall insulin sensitivity. Pyruvate and glutamine tolerance tests proved that there was a decrease in the rate of glucose appearance in MKR mice treated with rhIGF-I, suggesting a reduction in the gluconeogenic capacity of liver, kidney, and small intestine. Taken together these results demonstrate that the improvement of the hyperglycemia was achieved by inhibition of gluconeogenesis rather than an improvement in insulin sensitivity. Also, these results suggest that a functional IGF-I receptor in skeletal muscle is required for IGF-I to improve insulin sensitivity in this mouse model of type 2 DM.
Animals↗
MKR mice are resistant to the metabolic actions of both insulin and adiponectin: discordance between insulin resistance and adiponectin responsiveness.
Most rodent models of insulin resistance are accompanied by decreased circulating adiponectin levels. Adiponectin treatment improves the metabolic phenotype by increasing fatty acid oxidation in skeletal muscle and suppressing hepatic glucose production. Muscle IGF-I receptor (IGF-IR)-lysine-arginine (MKR) mice expressing dominant-negative mutant IGF-IRs in skeletal muscle are diabetic with insulin resistance in muscle, liver, and adipose tissue. Adiponectin levels are elevated in MKR mice, suggesting an unusual discordance between insulin resistance and adiponectin responsiveness. Therefore, we investigated the metabolic actions of adiponectin in MKR mice. MKR and ob/ob mice were treated both acutely (28 microg/g) and chronically (for 2 wk) with full-length adiponectin. Acute hypoglycemic effects of adiponectin were evident only in ob/ob mice but not in MKR mice. Chronic adiponectin treatment significantly improved both insulin sensitivity and glucose tolerance in ob/ob but not in MKR mice. Adiponectin receptor mRNA levels and adiponectin-stimulated phosphorylation of AMPK in skeletal muscle and liver were similar among MKR, wild-type, and ob/ob mice. Thus MKR mice are adiponectin resistant despite normal expression of adiponectin receptors and normal AMPK phosphorylation in muscle and liver. MKR mice may be a useful model for dissecting relationships between insulin resistance and adiponectin action in regulation of glucose homeostasis.
Adiponectin↗
Mouse models created to study the pathophysiology of Type 2 diabetes.
Obesity and Type 2 diabetes have become epidemics in the Western world. Understanding the pathophysiology of the disease should help in prevention and treatment of these disorders. A common theme is the presence of insulin resistance that eventually results in Type 2 diabetes. To understand the underlying mechanisms in the progression of the disease states, investigators have created mouse models by transgenic overexpression of a candidate gene or produced gene-deletion mouse models. This review will summarize many of the more appropriate models that study insulin resistance and Type 2 diabetes.
Adolescent↗
Leptin improves insulin resistance and hyperglycemia in a mouse model of type 2 diabetes.
Leptin has metabolic effects on peripheral tissues including muscle, liver, and pancreas, and it has been successfully used to treat lipodystrophic diabetes, a leptin-deficient state. To study whether leptin therapy can be used for treatment of more common cases of type 2 diabetes, we used a mouse model of type 2 diabetes (MKR mice) that show normal leptin levels and are diabetic due to a primary defect in both IGF-I and insulin receptors signaling in skeletal muscle. Here we show that leptin administration to the MKR mice resulted in improvement of diabetes, an effect that was independent of the reduced food intake. The main effect of leptin therapy was enhanced hepatic insulin responsiveness possibly through decreasing gluconeogenesis. In addition, the reduction of lipid stores in liver and muscle induced by enhancing fatty acid oxidation and inhibiting lipogenesis led to an improvement of the lipotoxic condition. Our data suggest that leptin could be a potent antidiabetic drug in cases of type 2 diabetes that are not leptin resistant.
AMP-Activated Protein Kinases↗
Monitoring glycemic control: the cornerstone of diabetes care.
BACKGROUND: Diabetes mellitus is associated with significant morbidity and mortality and escalating costs, and its prevalence is increasing to epidemic proportions. Studies have consistently documented the importance of glycemic control in delaying the onset and decreasing the incidence of both the short- and long-term complications of diabetes. Although glycemic control is difficult to achieve and challenging to maintain, its impact on disease outcomes is well worth the effort. OBJECTIVE: This article reviews the importance of monitoring and tightly controlling blood glucose concentrations in patients with diabetes and the methods and tools available for achieving these goals. METHODS: This clinical review was developed using 102 a MEDLINE search of the literature from 1990 to 2005 using the terms diabetes, glucose control, glucose monitoring, A(1c), and hypoglycemia. RESULTS: The complications of diabetes can be prevented or sharply curtailed through tight glycemic control, which requires frequent monitoring of blood glucose levels, careful attention to diet and exercise, and the use of medications. The progressive nature of diabetes imposes the need for frequent and regular monitoring, leading to data-driven adjustments to therapy to maintain optimal glucose levels. Failure to achieve glycemic control is often the result of a failure to educate the patient about how to monitor blood glucose levels and the importance of accuracy in doing so. CONCLUSIONS: Tight glycemic control requires an 102 educated and motivated patient, an appropriate treatment regimen, vigilant monitoring, and a close partnership between the patient and a multidisciplinary team of health care professionals to ensure accurate monitoring and appropriate actions. The growing array of monitoring devices contributes to this effort by providing increased convenience and accuracy.
Algorithms↗
Clinical relevance of systemic and local IGF-I.
The insulin-like growth factor family of ligands, receptors and binding proteins are critical for many normal physiological functions. These include normal development during fetal and post-natal development and maintenance of organ function in adult life. Circulating IGF-I is produced primarily by the liver under GH control, whereas the production of tissue IGF-I has other controls. Recent studies have demonstrated that both circulating and tissue IGF-I are important for maintaining the normal structure-function of complex organs such as bone. Circulating IGF-I is important for maintaining ambient GH levels; in its absence GH elevation is seen leading to insulin resistance. In addition, low levels of circulating IGF-I retard the progression and metastatic potential of a number of cancers.
Animals↗
Hodgkin lymphoma in temporal association with growth hormone replacement.
The association between growth hormone (GH) replacement and malignancy has long been debated. We report a case of Hodgkin lymphoma that developed in temporal association with the initiation of GH replacement in a 57-year-old woman with panhypopituitarism secondary to a non-secretory pituitary macroadenoma. Treatment of her pituitary tumor included transphenoidal surgery, external beam radiation, Bromocriptine and Cabergaline therapy. In addition to replacement steroid, thyroid and sex hormones, she insisted on GH replacement. Approximately 2 years after GH initiation, the diagnosis of Hodgkin lymphoma was made. Although the exact contribution of GH to the development of Hodgkin disease in our patient is unclear and a causal effect cannot be concluded, the temporal association is suggestive, and warrants reporting as part of ongoing surveillance for potential complications of GH replacement.
Adenoma↗
The luteinizing hormone-releasing hormone inhibits the anti-apoptotic activity of insulin-like growth factor-1 in pituitary alphaT3 cells by protein kinase Calpha-mediated negative regulation of Akt.
The luteinizing hormone-releasing hormone (LHRH) receptor is a G protein-coupled receptor involved in the synthesis and release of pituitary gonadotropins and in the proliferation and apoptosis of pituitary cells. Insulin-like growth factor-1 receptor (IGF-1R) is a tyrosine kinase receptor that has a mitogenic effect on pituitary cells. In this study, we used the alphaT3 gonadotrope cell line as a model to characterize the IGF-1R signaling pathways and to investigate whether this receptor interacts with the LHRH cascade. We found that IGF-1 activated the IGF-1R, insulin receptor substrate (IRS)-1, phosphatidylinositol 3-kinase, and Akt in a time-dependent manner in alphaT3 cells. The MAPK (ERK1/2, p38, and JNK) pathways were only weakly activated by IGF-1. In contrast, LHRH strongly stimulated the MAPK pathways but had no effect on Akt activation. Cotreatment with IGF-1 and LHRH had various effects on these signaling pathways. 1) It strongly increased IGF-1-induced tyrosine phosphorylation of IRS-1 and IRS-1-associated phosphatidylinositol 3-kinase through activation of the epidermal growth factor receptor. 2) It had an additive effect on ERK1/2 activation without modifying the phosphorylation of p38 and JNK1/2. 3) It strongly reduced IGF-1 activation of Akt. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and cell cycle analysis revealed that, in addition to having an additive effect on ERK1/2 activation, cotreatment with IGF-1 and LHRH also had an additive effect on cell proliferation. The LHRH-induced inhibition of Akt stimulated by IGF-1 was completely blocked by Safingol, a protein kinase C (PKC) alpha-specific inhibitor, and by a dominant negative form of PKCalpha. Finally, we showed that the inhibitory effect of LHRH on IGF-1-induced PKCalpha-mediated Akt activation was associated with a marked reduction in Bad phosphorylation and a substantial decrease in the ability of IGF-1 to rescue alphaT3 cells from apoptosis induced by serum starvation. Our results demonstrate for the first time that several interactions take place between IGF-1 and LHRH receptors in gonadotrope cells.
Animals↗
Hepatic CCAAT/enhancer binding protein alpha mediates induction of lipogenesis and regulation of glucose homeostasis in leptin-deficient mice.
CCAAT/enhancer binding protein alpha (C/EBP alpha) is a critical factor in glucose metabolism in the neonate as revealed by conventional C/EBP alpha-null mice that do not survive beyond the first day after birth because of severe hypoglycemia and a deficiency in hepatic glycogen accumulation. To elucidate the function of C/EBP alpha in leptin-deficient mouse (ob/ob) liver, a C/EBP alpha-liver null mouse on an ob/ob background (ob/ob-C/EBP alpha/Cre(+)) was produced using a floxed C/EBP alpha allele and Cre recombinase under control of the albumin promoter (AlbCre). The C/EBP alpha-deficient liver in ob/ob mice had significantly decreased triglyceride content compared with equivalent mice lacking the AlbCre transgene (ob/ob-C/EBP alpha/Cre(-)). Expression of genes involved in lipogenesis including fatty acid synthase, acetyl-coenzyme A carboxylase, stearoyl-coenzyme A desaturase 1 and ATP-citrate lyase dramatically decreased in ob/ob-C/EBP alpha/Cre(+) mouse liver. Induction of these lipogenic genes by a high-carbohydrate diet caused an exacerbation in the development of fatty liver and an increase in liver size, hepatic triglyceride, and cholesterol contents in ob/ob-C/EBP alpha/Cre(-) mice but not in ob/ob-C/EBP alpha/Cre(+) mice. Deficiency in hepatic C/EBP alpha expression caused an exacerbation of hyperglycemia because of decreased insulin secretion. Taken together, these results indicate that hepatic C/EBP alpha plays a critical role in the acceleration of lipogenesis in ob/ob mice and in glucose homeostasis by the indirect regulation of insulin secretion.
ATP Citrate (pro-S)-Lyase↗
Role of growth hormone (GH) in liver regeneration.
Liver regeneration is a fundamental mechanism by which the liver responds to injury. This process is regulated by endogenous growth factors and cytokines, and it involves proliferation of all mature cells that exist within the intact organ. To understand the role of the GH/IGF-I axis in liver regeneration, we performed partial hepatectomies in three groups of mice: GH antagonist (GHa) transgenic mice, in which the action of GH is blocked; liver IGF-I-deficient mice that lack IGF-I specifically in the liver and also lack the acid-labile subunit (ALS; LID+ALSKO mice), in which IGF-I levels are very low and GH secretion is increased; and control mice. Interestingly, the survival rate of GHa transgenic mice was dramatically reduced after partial hepatectomy (57%) compared with the survival rate of controls (100%) or LID+ALSKO mice (88%). In control mice, the liver was completely regenerated after 4 d, whereas liver regeneration required 7 d in LID+ALSKO mice. In contrast, in GHa mice, liver regeneration reached only 70% of the original liver mass after 4 d and did not improve thereafter. Strikingly, 36 and 48 h after hepatectomy, the livers of control and LID+ALSKO mice, respectively, exhibited intense 5-bromo-2'-deoxyuridine (BrdU) staining, whereas BrdU staining was dramatically decreased in the livers of GHa-treated mice. These results suggest that GH plays a critical role in liver regeneration, although whether it acts directly or indirectly remains to be determined.
Animals↗
Muscle-specific overexpression of CD36 reverses the insulin resistance and diabetes of MKR mice.
Insulin resistance is one of the primary characteristics of type 2 diabetes. Mice overexpressing a dominant-negative IGF-I receptor specifically in muscle (MKR mice) demonstrate severe insulin resistance with high levels of serum and tissue lipids and eventually develop type 2 diabetes at 5-6 wk of age. To determine whether lipotoxicity plays a role in the progression of the disease, we crossed MKR mice with mice overexpressing a fatty acid translocase, CD36, in skeletal muscle. The double-transgenic MKR/CD36 mice showed normalization of the hyperglycemia and the hyperinsulinemia as well as a marked improvement in liver insulin sensitivity. The MKR/CD36 mice also exhibited normal rates of fatty acid oxidation in skeletal muscle when compared with the decreased rate of fatty acid oxidation in MKR. With the reduction in insulin resistance, beta-cell function returned to normal. These and other results suggest that the insulin resistance in the MKR mice is associated with increased muscle triglycerides levels and that whole-body insulin resistance can be, at least partially, reversed in association with a reduction in muscle triglycerides levels, although the mechanisms are yet to be determined.
Animals↗
14-3-3sigma mediation of cell cycle progression is p53-independent in response to insulin-like growth factor-I receptor activation.
We investigated the role of 14-3-3sigma protein in insulin-like growth factor-I (IGF-I) receptor signaling. It has been previously shown that 14-3-3sigma negatively regulates cell cycle especially in response to p53-sensitive DNA damage. In this study we demonstrated that 14-3-3sigma is a positive mediator of IGF-I receptor-induced cell proliferation. Treatment with IGF-I increased 14-3-3sigma mRNA and protein levels about 4-fold, in a time-dependent manner in MCF-7 breast cancer cells. Preincubation with the phosphoinositide 3'-kinase inhibitor LY294002 significantly reduced the effects of IGF-I on 14-3-3sigma gene expression in these cells, suggesting that this effect of IGF-I occurs via the phosphoinositide 3'-kinase pathway. 14-3-3sigma is induced by IGF-I in MCF-7 cells, which express wild-type p53, as well as in MCF-7 cells transfected with a small interference RNA targeting duplex that reduced p53 expression levels. These results suggest that IGF-I induces 14-3-3sigma expression in a manner that is independent of p53. Using the small interference RNA strategy, we demonstrated that a 70-75% reduction of 14-3-3sigma mRNA levels resulted in a similar decrease in the effects of IGF-I on cell cycle progression and proliferation in MCF-7 cells. This effect was also associated with a reduction in IGF-I-induced cyclin D1 expression. Taken together, these results suggest that 14-3-3sigma positively mediates IGF-I-induced cell cycle progression.
14-3-3 Proteins↗