Treatment of diabetes: a clinical update on insulin trials.

The prevalence of diabetes, along with its accompanying long-term microvascular and macrovascular complications, continues to increase. Landmark studies of both type 1 and type 2 diabetes have provided the foundations on which to investigate improved treatment strategies for type 2 diabetes. Recent evidence suggests a new paradigm for treating type 2 diabetes that adds insulin earlier in the treatment process to maintain tight glycemic control.

Update on diabetes mellitus: prevention, treatment, and association with oral diseases.

Diabetes mellitus is a prevalent disease that affects millions of people worldwide and has paralleled the growing population of overweight and obese individuals. Early detection of prediabetes and diabetes, as well as lifestyle interventions including diet and exercise, are the overarching objectives in preventing and managing diabetes. For individuals who do not achieve glycemic control with lifestyle modification, there are newer medication classes that assist with weight loss, more physiologic insulins with convenient delivery systems, and old standbys like metformin and thiazolidinediones.

The role of lipocalin 2 in the regulation of inflammation in adipocytes and macrophages.

Adipose tissue-derived cytokines (adipokines) are associated with the development of inflammation and insulin resistance. However, which adipokine(s) mediate this linkage and the mechanisms involved during obesity is poorly understood. Through proteomics and microarray screening, we recently identified lipocalin 2 (LCN 2) as an adipokine that potentially connects obesity and its related adipose inflammation.

Mechanisms of disease: using genetically altered mice to study concepts of type 2 diabetes.

A wide range of genetically engineered murine models of type 2 diabetes have been created to try to understand the site of the primary defect in insulin action, and the relationship between insulin resistance and impaired beta-cell function in diabetes. Genetic disruption of various aspects known to be important in diabetes has examined specific facets, including glucose sensing, transcription factors for the insulin gene, the insulin gene itself, insulin and insulin-like growth factor receptors, downstream signaling components and some mutations that increase insulin sensitivity. This article focuses on models that have given insight into insulin resistance and impaired insulin production, especially models that examine molecules involved in the signaling pathway downstream of insulin binding its receptor.

Insulin-like growth factor-i regulates Kruppel-like factor-6 gene expression in a p53-dependent manner.

High-circulating IGF-I concentrations are associated with an increased risk for breast, prostate, and colorectal cancer. Krüppel-like factor-6 (KLF6) is a zinc finger tumor suppressor inactivated in prostate and other types of cancer. We have previously demonstrated that KLF6 is a potent transactivator of the IGF-I receptor promoter.

The benefits of tight glycemic control in type 2 diabetes mellitus.

Type 2 diabetes mellitus (DM) is associated with significantly increased risk of microvascular and macrovascular disease. Although most studies have focused on the microvascular complications of diabetes (eg, nephropathy, neuropathy, retinopathy), most patients with type 2 DM die from causes that are related to macrovascular disease (eg, myocardial infarction). Poor glycemic control increases the risk of future cardiovascular events, and prospective studies of patients with type 1 and type 2 DM have demonstrated that the incidence of vascular complications is reduced by lifestyle modifications or medications that reduce blood glucose concentrations.

Insulin resistance as the underlying cause for the metabolic syndrome.

Classically, the metabolic syndrome is characterized as group of pathologies including visceral obesity, hypertension, dyslipidemia, and impaired glucose tolerance. It is now realized that insulin resistance plays a principal role in initiating and perpetuating the pathologic manifestations of the metabolic syndrome. A more in-depth understanding of the basic pathophysiologic mechanisms underlying insulin resistance may aid clinicians in treating and possibly delaying or even preventing the onset of the metabolic syndrome and its complications.

Central actions of liver-derived insulin-like growth factor I underlying its pro-cognitive effects.

Increasing evidence indicates that circulating insulin-like growth factor I (IGF-I) acts as a peripheral neuroactive signal participating not only in protection against injury but also in normal brain function. Epidemiological studies in humans as well as recent evidence in experimental animals suggest that blood-borne IGF-I may be involved in cognitive performance. In agreement with observations in humans, we found that mice with low-serum IGF-I levels due to liver-specific targeted disruption of the IGF-I gene presented cognitive deficits, as evidenced by impaired performance in a hippocampal-dependent spatial-recognition task.

[Evaluation of adiponectin and TNFalpha genes expression in women with gestational diabetes. Preliminary results].

Objectives: Recent studies suggest the essential role of different cytokines realised from adipose tissue in pathogenesis of gestational diabetes. The aim of the study was evaluation of adiponectin (diabetes development protective factor) and TNFalpha (one of the most important insulin resistance mediator) genes expression in maternal visceral and subcutaneous adipose tissue as well as placental tissue.

Material And Methods: The study group consists of patients with gestational diabetes, healthy pregnant glucose tolerant women represented the control group.

Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1.

Insulin-like growth factor (IGF) 1 is a member of a family that is involved in growth, development, cell differentiation, and metabolism. IGF1, IGF2 and insulin act primarily through tyrosine-kinase-linked receptors--the IGF1 receptor (IGF1R) and insulin receptor (IR). The IGF1R binds IGF1 and IGF2 with high affinity and the IR binds insulin with high affinity; however, since both receptors share a high degree of structural and functional homology, the IGF1R can bind insulin and the IR can bind the IGFs with reduced affinity.

A familial insulin-like growth factor-I receptor mutant leads to short stature: clinical and biochemical characterization.

Context: IGF-I/IGF-I receptor (IGF-IR) signaling pathways play important roles in longitudinal growth. A novel Arg481Glu (R481Q) mutation in IGF-IR was detected in a family with intrauterine and postnatal growth retardation.

Objective: The objective of the study was to explore the mechanism whereby the R481Q mutation may be causative in growth retardation.

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.

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.

Epithelial-specific and stage-specific functions of insulin-like growth factor-I during postnatal mammary development.

Postnatal development of the mammary gland requires interactions between the epithelial and stromal compartments, which regulate actions of hormones and growth factors. IGF-I is expressed in both epithelial and stromal compartments during postnatal development of the mammary gland. However, little is known about how local expression of IGF-I in epithelium or stroma regulates mammary growth and differentiation during puberty and pregnancy-induced alveolar development.

Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members.

The breast cancer-associated gene-1 (BRCA1) plays many important functions in multiple biological processes/pathways. Mice homozygous for a targeted deletion of full-length BRCA1 (Brca1Delta11/Delta11) display both increased tumorigenesis and premature aging, yet molecular mechanisms underlying these defects remain elusive. Here, we show that Brca1 deficiency leads to increased expression of several insulin-like growth factor (IGF) signaling axis members in multiple experimental systems, including BRCA1-deficient mice, primary mammary tumors, and cultured human cells.

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.

Effect of adipocyte beta3-adrenergic receptor activation on the type 2 diabetic MKR mice.

The antiobesity and antidiabetic effects of the beta3-adrenergic agonists were investigated on nonobese type 2 diabetic MKR mice after injection with a beta3-adrenergic agonist, CL-316243. An intact response to acute CL-316243 treatment was observed in MKR mice. Chronic intraperitoneal CL-316243 treatment of MKR mice reduced blood glucose and serum insulin levels.

The ternary IGF complex influences postnatal bone acquisition and the skeletal response to intermittent parathyroid hormone.

The role of circulating IGF-I in skeletal acquisition and the anabolic response to PTH is not well understood. We generated IGF-I-deficient mice by gene deletions of IGF ternary complex components including: (1) liver-specific deletion of the IGF-I gene (LID), (2) global deletion of the acid-labile (ALS) gene (ALSKO), and (3) both liver IGF-I and ALS inactivated genes (LA). Twelve-week-old male control (CTL), LID, ALSKO, and LA mice were treated with vehicle (VEH) or human PTH(1-34) for 4 weeks.

Insulin-like growth factor 1 receptor signaling regulates skin development and inhibits skin keratinocyte differentiation.

The insulin-like growth factor 1 receptor (IGF-1R) is a multifunctional receptor that mediates signals for cell proliferation, differentiation, and survival. Genetic experiments showed that IGF-1R inactivation in skin results in a disrupted epidermis. However, because IGF-1R-null mice die at birth, it is difficult to study the effects of IGF-1R on skin.

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 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.