Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-like growth factor-I (IGF-I) has significant structural homology with proinsulin. IGF-I binds to insulin receptors, stimulates insulin-like actions and enhances insulin sensitivity. However, because circulating IGF-I is bound to high-affinity binding proteins and has relatively low affinity for insulin receptors, most of its ability to alter insulin sensitivity is mediated indirectly (i.e. through suppression of growth hormone, a known insulin antagonist). Direct effects of IGF-I on insulin actions are tissue specific, occurring principally in skeletal muscle and kidney. Genetic manipulations in experimental mouse models have been used to analyze the role of endogenous IGF-I on insulin action. These studies have shown that suppression of growth hormone is important for enhancing insulin action in the liver and that deletion of the IGF-I receptor in skeletal muscle results in severe insulin resistance. IGF-I also suppresses renal gluconeogenesis, which might contribute to its glucose-lowering actions. In humans, IGF-I enhances insulin sensitivity and lowers blood glucose in patients with either extreme insulin resistance or type 2 diabetes. It also decreases insulin requirement in patients with insulin-deficient diabetes. Taken together, these findings suggest that IGF-I is functioning coordinately with insulin to regulate glucose homeostasis.
 ...
PMID:Involvement of insulin-like growth factor-I in the control of glucose homeostasis. 1703 15

Pituitary gigantism, a condition of endogenous growth hormone (GH) hypersecretion prior to epiphyseal closure, is a rare condition. In the adult condition of GH excess, acromegaly, the occurrence of type 2 diabetes mellitus (T2DM) and diabetic ketoacidosis (DKA) have been reported, with resolution following normalization of GH levels. We report the case of a 16-year-old male with pituitary gigantism due to a large invasive suprasellar adenoma who presented with T2DM and DKA. Despite surgical de-bulking, radiotherapy and medical treatment with cabergoline and pegvisomant, GH and insulin-like growth factor-I (IGF-I) levels remained elevated. However, the T2DM and recurrent DKA were successfully managed with metformin and low-dose glargine insulin, respectively. We review the pathophysiology of T2DM and DKA in growth hormone excess and available treatment options.
 ...
PMID:Management of type 2 diabetes mellitus associated with pituitary gigantism. 1762 84

Size at birth and patterns of postnatal weight gain have been associated with adult risk for the development of type 2 diabetes in many populations, but the putative pathophysiological link remains unknown. Studies of contemporary populations indicate that rapid infancy weight gain, which may follow fetal growth restriction, is an important risk factor for the development of childhood obesity and insulin resistance. Data from the Avon Longitudinal Study of Pregnancy and Childhood shows that rapid catch-up weight gain can lead to the development of insulin resistance, as early as 1 year of age, in association with increasing accumulation of central abdominal fat mass. In contrast, the disposition index, which reflects the beta-cells ability to maintain insulin secretion in the face of increasing insulin resistance, is much more closely related to ponderal index at birth than postnatal catch-up weight gain. Infants with the lowest ponderal index at birth show a reduced disposition index at aged 8 years associated with increases in fasting NEFA levels. The disposition index is also closely related to childhood height gain and insulin-like growth factor-I (IGF-I) levels; reduced insulin secretory capacity being associated with reduced statural growth, and relatively short stature with reduced IGF-I levels at age 8 years. IGF-I may have an important role in the maintenance of beta-cell mass, as demonstrated by recent studies of pancreatic beta-cell IGF-I receptor knock-out and adult observational studies indicating that low IGF-I levels are predictive of subsequent risk for the development of type 2 diabetes. However, as insulin secretion is an important determinant of IGF-I levels, cause and effect may be difficult to establish. In conclusion, although rapid infancy weight gain and increasing rates of childhood obesity will increase the risk for the development of insulin resistance, prenatal and postnatal determinants of beta-cell mass may ultimately be the most important determinants of an individual's ability to maintain insulin secretion in the face of increasing insulin resistance, and thus risk for the development of type 2 diabetes.
 ...
PMID:Session 7: Early nutrition and later health early developmental pathways of obesity and diabetes risk. 1763 98

Patients with insulin resistance and type 2 diabetes have an excessive risk of cardiovascular disease (CVD); this increased risk is not fully explained by traditional risk factors such as hypertension and dyslipidaemias. There is now compelling evidence to suggest that abnormalities of insulin-like growth factor-I (IGF-I) and one of its binding proteins, insulin-like growth factor-binding protein-1 (IGFBP-1), occur in insulin-resistant states and may be significant factors in the pathophysiology of CVD. We reviewed articles and relevant bibliographies following a systematic search of MEDLINE for English language articles between 1966 and the present, using an initial search strategy combining the MeSH terms: IGF, diabetes and CVD. Our aim was first to review the role of IGF-I in vascular homeostasis and to explore the mechanisms by which it may exert its effects. We also present an overview of the physiology of the IGF-binding proteins, and finally, we sought to summarize the evidence to date describing the changes in the insulin/IGF-I/IGFBP-1 axis that occur in type 2 diabetes and CVD; in particular, we have focused on the potential vasculoprotective effects of both IGF-I and IGFBP-1. We conclude that this system represents an interesting and novel therapeutic target in the prevention of CVD in type 2 diabetes.
 ...
PMID:The role of IGF-I and its binding proteins in the development of type 2 diabetes and cardiovascular disease. 1826 35

During the past decade, the immune and endocrine systems have been discovered to interact in controlling physiologic processes as diverse as cell growth and differentiation, metabolism, and even human and animal behavior. The interaction between these two major physiological systems is a bi-directional process. While it has been well documented that hormones, including prolactin (PRL), growth hormone (GH), insulin-like growth factor-I (IGF-I), and thyroid-stimulating hormone (TSH), regulate a variety of immune events, a great deal of data have accumulated supporting the notion that cytokines from the innate immune system also affect the neuroendocrine system. Communication between these two systems coordinates processes that are necessary to maintain homeostasis. Proinflammatory cytokines often act as negative regulatory signals that temper the action of hormones and growth factors. This system of 'checks and balances' is an active, ongoing process, even in healthy individuals. Dysregulation of this process has been implicated as a potential pathogenic factor in the development of co-morbid conditions associated with several chronic inflammatory diseases, including type 2 diabetes, cardiovascular disease, cerebrovascular disease, inflammatory bowel disease, rheumatoid arthritis, major depression, and even normal aging. Over the past decade, research in our laboratory has focused on the ability of the major proinflammatory cytokines, tumor necrosis factor (TNF)alpha and interleukin (IL)-1beta, to induce a state of IGF resistance. This review will highlight these and other new findings by explaining how proinflammatory cytokines induce resistance to the major growth factor, insulin-like growth factor-I (IGF-I). We also highlight that IGF-I can induce resistance or reduce sensitivity to brain TNFalpha and discuss how TNFalpha, IL-1beta, and IGF-I interact to regulate several aspects of behavior and cognition.
 ...
PMID:Regulation of IGF-I function by proinflammatory cytokines: at the interface of immunology and endocrinology. 1832 86

We investigated the relationship between serum dehydroepiandrosterone-sulfate (DHEA-S) and insulin-like growth factor-I (IGF-I) to various parameters for atherosclerosis in type 2 diabetes. The levels of DHEA-S and IGF-I are known to decrease with aging and thereby might be associated with an increased risk of cardiovascular disease. One hundred forty-eight men and 106 postmenopausal women with type 2 diabetes were assessed in a cross-sectional study. Serum DHEA-S and IGF-I concentrations were measured and brachial-ankle pulse wave velocity (baPWV) and ultrasonographically-evaluated intima-media thickness (IMT) were assessed. Although simple regression analysis showed that log(DHEA-S) and IGF-I in men and log(DHEA-S) in women were significantly and inversely correlated with baPWV and IMT, only log(DHEA-S) in women was still significantly and inversely correlated with these atherosclerotic parameters after multiple regression analysis was adjusted for age, duration of diabetes, BMI, HbA(1C), systolic blood pressure, LDL-Cholesterol (C), serum creatinine, and smoking (Brinkman index). Serum DHEA-S level seemed to be associated with atherosclerosis in diabetic postmenopausal women independent of age, body stature, diabetic status, and other atherosclerotic risk factors, and might be a useful addition to other parameters for assessing the risk of atherosclerosis in this population.
 ...
PMID:Serum DHEA-S level is associated with the presence of atherosclerosis in postmenopausal women with type 2 diabetes mellitus. 1849 2

Therapeutics based on the actions of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), have recently been introduced for the treatment of type 2 diabetes mellitus. The serine/threonine kinase Akt is a major mediator of incretin action on the pancreatic islet, increasing beta-cell mass and function and promoting beta-cell survival. The mechanisms underlying incretin activation of Akt are thought to involve an essential phosphoinositide 3-kinase-mediated phosphorylation of threonine 308, similar to the prototypical Akt activator, insulin-like growth factor-I (IGF-I). In this study, using activity assays on immunoprecipitated Akt, we discovered that GIP and GLP-1 were capable of stimulating Akt in the INS-1 beta-cell line and isolated mouse islets via a mechanism that did not require phosphoinositide 3-kinase or phosphorylation of Thr(308) and Ser(473), and this pathway involved the production of cAMP. Furthermore, we found that GIP stimulated anti-apoptotic signaling via this alternate mode of Akt activation. We conclude that incretins can activate Akt via a novel noncanonical mechanism that may provide an alternative therapeutic target for the treatment of type 2 diabetes mellitus and have broader implications for Akt physiology in human health and disease.
 ...
PMID:Noncanonical activation of Akt/protein kinase B in {beta}-cells by the incretin hormone glucose-dependent insulinotropic polypeptide. 1923 42

We examined whether or not BMD or bone markers were useful for assessing the risk of vertebral fractures in 248 Japanese men with type 2 diabetes. We analyzed the relationships between bone markers (osteocalcin [OC], bone-specific alkaline phosphatase [BAP], urinary N-terminal cross-linked telopeptide of type-I collagen) or BMD and HbA(1c), urinary C-peptide, insulin-like growth factor-I (IGF-I), parathyroid hormone, 1,25(OH)(2) vitamin D, and the presence of prevalent vertebral fractures. Multiple regression analysis adjusted for age, body height, weight, duration of diabetes, and serum creatinine showed that serum OC and OC/BAP ratio were correlated negatively with HbA(1c) (P < 0.01) and positively with IGF-I (P < 0.01). Multivariate logistic regression analysis adjusted for the above parameters showed that serum OC/BAP ratio was inversely associated with the presence of vertebral fractures (odds ratio = 0.695, P < 0.05). This association was still significant after additional adjustment for lumbar or femoral neck BMD. Our results suggest that poor diabetic control and lower IGF-I level are linked to impaired bone formation and resultant reduction in OC/BAP ratio in men with type 2 diabetes. The OC/BAP ratio could be clinically useful for assessing the risk of vertebral fractures independent of BMD in diabetic men.
 ...
PMID:Serum osteocalcin/bone-specific alkaline phosphatase ratio is a predictor for the presence of vertebral fractures in men with type 2 diabetes. 1964 39

Epidemiologic studies suggest that type 2 diabetes (T2D) increases breast cancer risk and mortality, but there is limited experimental evidence supporting this association. Moreover, there has not been any definition of a pathophysiological pathway that diabetes may use to promote tumorigenesis. In the present study, we used the MKR mouse model of T2D to investigate molecular mechanisms that link T2D to breast cancer development and progression. MKR mice harbor a transgene encoding a dominant-negative, kinase-dead human insulin-like growth factor-I receptor (IGF-IR) that is expressed exclusively in skeletal muscle, where it acts to inactivate endogenous insulin receptor (IR) and IGF-IR. Although lean female MKR mice are insulin resistant and glucose intolerant, displaying accelerated mammary gland development and enhanced phosphorylation of IR/IGF-IR and Akt in mammary tissue, in the context of three different mouse models of breast cancer, these metabolic abnormalities were found to accelerate the development of hyperplastic precancerous lesions. Normal or malignant mammary tissue isolated from these mice exhibited increased phosphorylation of IR/IGF-IR and Akt, whereas extracellular signal-regulated kinase 1/2 phosphorylation was largely unaffected. Tumor-promoting effects of T2D in the models were reversed by pharmacological blockade of IR/IGF-IR signaling by the small-molecule tyrosine kinase inhibitor BMS-536924. Our findings offer compelling experimental evidence that T2D accelerates mammary gland development and carcinogenesis,and that the IR and/or the IGF-IR are major mediators of these effects.
 ...
PMID:Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. 2006 49

The relationship between diabetes and bone disease is complex. While low bone mineral density (BMD) is consistently observed in type 1 diabetes (T1DM), in type 2 diabetes (T2DM) bone mineral density is similar to or higher than in non diabetic subjects. Yet, for both types of diabetes bone appears to be more fragile for a given density. Recent meta-analyses and cohort studies confirm that T1DM and T2DM are associated with higher fracture risk. Many factors influence the probability of fractures. Diabetes can affect bone through multiple pathways including obesity, changes in insulin levels, higher concentrations of advanced glycation end products in collagen, increased urinary excretion coupled with lower intestinal absorption of calcium, inappropriate homeostatic response of parathyroid hormone secretion, complex alterations of vitamin D regulation, reduced renal function, lower insulin-like growth factor-I, microangiopathy, and inflammation. Data on cellular mechanisms and experimental models are extensive, but the relevance of each one of these factors to the clinical situation is unclear. In this article we review the pathophysiological mechanisms potentially involved in the altered BMD found in diabetic patients, show data on the increased risk of fractures, and speculate on the potential causes of the increased risk of fractures in this context. Finally, we comment on the prevention and treatment of osteoporosis in diabetes, although the lack of trials testing the use of pharmacotherapy on preventing fractures in this context is emphasized.
 ...
PMID:Bone disease in diabetes. 2038 Jun 29


<< Previous 1 2 3 4 5 6 Next >>