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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fetal growth demands a coordinated increase in size of the fetus and the placenta, and both are determined, in part, by locally produced peptide growth factors. The availability of growth factors to individual tissues may be due to local changes in gene expression, but it is also controlled by proteolytic release from extracellular matrix stores. Members of the fibroblast growth factor (FGF) family are stored within basement membranes, while insulin-like growth factors (IGFs) are stored in association with specific binding proteins (IGFBPs). Insulin is a major trophic hormone in utero, and pancreatic beta-cell mass is determined by locally produced IGF-II and members of the FGF family. The mitogenic effects of IGF-II on beta-cells are determined by IGFBPs, which are themselves expressed with a distinct ontogeny within the islets of Langerhans. Overexpression of IGF-II or IGFBP-I can result in nesidioblastosis. Shortly after birth in rodents, many pancreatic beta-cells are destroyed by a process of apoptosis but are simultaneously replaced as a result of beta-cell neogenesis. This process may enrich the pancreas in beta-cells suited to the metabolic demands of postnatal life. The wave of beta-cell apoptosis coincides with a dramatic decrease in the local expression of IGF-II. These events may be functionally linked, because exogenous IGF-II will protect isolated islets from cytokine-induced apoptosis. FGF-2 is also widely expressed within fetal tissues and may be an important regulator of placental angiogenesis. FGF-2 appears in the maternal circulation during pregnancy, with peak values late in the 2nd trimester. It is associated with a circulating binding protein derived from the extracellular domain of the FGFR1 receptor. Levels of FGF-2 in maternal serum correlate positively with fetal size both in the 2nd trimester and at term. The expression of FGF-2 in placenta and its presence in maternal blood are elevated in pregnancies complicated by diabetes and are greatest in diabetic pregnancies associated with retinopathy. Thus, maternal FGF-2 may be a useful indicator of both fetal development and the risk of maternal pathology in pregnancies complicated by diabetes.
Diabetes Care 1998 Aug
PMID:Growth factors and the regulation of fetal growth. 970 29

The expression of a number of genes encoding key players in insulin signalling and action, including insulin, insulin receptor (IR), downstream signalling molecules such as insulin receptor substrate-1 (IRS-1) and IRS-2, glucose transporters (GLUT4, GLUT2) and important metabolic enzymes such as glucokinase, has now been altered in transgenic or knockout mice. Such mice presented with phenotypes ranging from mild defects, revealing complementarity between key molecules or pathways, to severe diabetes with ketoacidosis and early postnatal death. Insulin action could also be improved by overproduction of proteins acting at regulatory steps. The development of diabetes by combining mutations, which alone do not lead to major metabolic alterations, validated the 'diabetogenes' concept of non-insulin-dependent diabetes mellitus. Genes encoding insulin-like growth factors (IGF-I and IGF-II) and their type I receptor (IGF-IR) have also been disrupted. It appears that although IR and IGF-IR are both capable of metabolic and mitogenic signalling, they are not fully redundant. However, IR could replace IGF-IR if efficiently activated by IGF-II. Studies with cell lines lacking IR or IGF-IR lend support to such conclusions. Concerning the issues of specificity and redundancy, studies with cell lines derived from IRS-1-deficient mice showed that IRS-1 and IRS-2 are also not completely interchangeable.
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PMID:Genetic engineering in mice: impact on insulin signalling and action. 976 14

Chromium (Cr) depletion may exacerbate hyperglycemia and negative outcomes of pregnancy in the streptozotocin (STZ) diabetic pregnant rat model through the regulation of the insulin-like growth factor (IGF) system. To test this hypothesis, 40 female rats, all fed a low Cr diet (i.e., 70 microgram Cr/kg diet ) from 21 d of age, were randomly assigned one of four treatments, applied on Day 1 of pregnancy, in a 2 x 2 factorial design: 1) very low Cr diet (40 microgram Cr/kg diet) + citrate buffer injection, 2) very low Cr diet + STZ injection (30 mg STZ/kg body wt in citrate buffer), 3) adequate Cr diet (2 mg Cr [from added CrK(SO4)2]/kg diet) + citrate buffer injectionand 4) adequate Cr diet + STZ injection. Blood and tissues were collected on Day 20 of pregnancy. Chromium depletion increased (P < 0.05) urinary hydroxyproline excretion, 22-kDa IGF binding protein (IGFBP) concentration and litter size but decreased (P < 0. 05) placental wt, percentage of protein per fetus, and fetal IGF-I and -II concentrations. Chromium had no effect (P > 0.10) on maternal hormones, 32-kDa IGFBP, glucose, or placental and fetal hydroxyproline concentrations. Diabetes decreased (P < 0.05) maternal wt gain, embryonic survival, litter size, mean pup wt and maternal insulin concentrations, increased (P < 0.05) maternal blood glucose, IGF-I concentrations and maternal hydroxyproline excretion but did not affect fetal concentrations of hormones, IGFBP, glucose or hydroxyproline. Interaction between chromium and diabetes tended (P < 0.10) to affect maternal IGF-II concentrations, but had no effect on other maternal or fetal variables. In conclusion, maternal chromium depletion did not exacerbate hyperglycemia or pregnancy outcome in STZ-induced diabetic rats, but may negatively affect fetal protein content by decreasing fetal IGF-II concentrations. Diabetes may negatively affect fetal growth through its effect on maternal glucose, insulin and IGF-I.
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PMID:Maternal and fetal insulin-like growth factor system and embryonic survival during pregnancy in rats: interaction between dietary chromium and diabetes. 986 79

Bone contains several growth factors, including bone morphogenetic proteins (BMPs), transforming growth factor beta (TGF-beta), insulin-like growth factors I and II (IGF-I and IGF-II), platelet derived growth factor (PDGF) and basic and acidic fibroblast growth factor (bFGF and aFGF). The BMPs are the only factors known to provoke bone formation heterotopically by making undifferentiated mesenchymal cells differentiate into osteoblasts (osteoinduction). Much of our knowledge of osteoinduction derives from studies in rodents of heterotopically implanted demineralised bone which contains various growth factors, including BMPs. This model has been used to examine the effect on osteoinduction of different factors, including the type of host soft tissue, age and species of donor and recipient, demineralisation procedure, storage and sterilisation procedures, experimental diabetes, dietary factors, hormones, growth factors, caffeine, biphosphonates, indomethacin and biomaterials. Demineralised bone enhances bone formation experimentally in various animal models, including cranio-maxillofacial reconstructions, healing of diaphyseal defects, and spinal fusion; demineralised bone has also been used in a limited way clinically. However, sufficient osteoinduction in humans may require a higher concentration of BMPs and other growth factors than those found in demineralised bone.
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PMID:Osteoinduction by demineralised bone. 991 41

The soluble form of the insulin-like growth factor II/mannose 6-phosphate (IGF-II/M6-P) receptor has been detected in serum from a variety of mammalian species. We report the development of a highly sensitive quantitative human IGF-II/M6-P receptor immunoassay. Antibodies raised to receptor purified from a human hepatoma cell line by phosphomannan affinity chromatography were used to develop a specific enzyme-linked immunosorbent assay. In this assay, the serum level of soluble receptor for healthy adult subjects was 0.70 +/- 0.23 mg/L. We have shown that soluble receptor is developmentally regulated, with levels in infant (1.12 +/- 0.28 mg/L) and prepubertal (1.18 +/- 0.6 mg/L) subjects dropping by 40% during adolescence (0.73 +/- 0.61 mg/L) and remaining constant throughout adulthood. Further, the receptor is gestationally regulated, with a highly significant association between gestational age and maternal serum receptor levels (r = 0.947; P < 0.0001). Noninsulin-dependent diabetes mellitus (0.98 +/- 0.25 mg/L) and insulin-dependent diabetes mellitus (0.98 +/- 0.25 mg/L) mildly elevated soluble receptor levels, whereas end-stage renal failure (0.75 +/- 0.23 mg/L) and acromegaly (0.79 +/- 0.25 mg/L) did not affect receptor levels. Additionally, we have shown that soluble receptor is present in amniotic fluid, but at a 100-fold lower concentration than serum levels. The ability to quantitate soluble IGF-II/M6-P receptor levels in serum and other fluids provides a valuable tool that will help to further elucidate the role of the receptor in human physiology and disease states.
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PMID:Regulation of soluble insulin-like growth factor II/mannose 6-phosphate receptor in human serum: measurement by enzyme-linked immunosorbent assay. 1002 25

Recent evidence from animal models of diabetes and human diabetic subjects suggests that the reduced availability of neurotrophic factors may contribute to the pathogenesis of diabetic peripheral neuropathy (DPN). Of these proteins, nerve growth factor (NGF), brain-derived neurotrophic factor, neurotrophin (NT-3) and NT-4/5 appear to be important for the development and maintenance of peripheral neurons, but others, including insulin-like growth factors (IGFs), may also be involved. Studies with NGF, NT-3, IGF-I and IGF-II both in vitro and in animal models of neuropathies (including DPN) suggest that these factors ameliorate nerve degeneration. Recombinant human NGF is the first neurotrophic factor to enter clinical trials for DPN and is currently being tested in two phase III studies.
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PMID:Neurotrophic factors and diabetic peripheral neuropathy. 1002 26

Insulin-like growth factors (IGFs) and their receptors regulate embryonic and post-natal growth. Genetic evidence derived from targeted mouse mutants indicates that both the insulin receptor (IR) and IGF-I receptors (IGF-IRs) are required for mouse embryonic growth. However, the roles of IRs and IGF-IRs are functionally distinct, with IGF-IRs mediating both IGF-I and IGF-II actions, and IRs mediating IGF-II, rather than insulin, action. The combined interactions of IGF-IRs and IRs with IGF-I and IGF-II account for the entirety of the growth effects of these two ligands, and provide the molecular basis for IGFs-mediated intrauterine growth and differentiation. Genetic ablation experiments of insulin receptor substrate-1 (IRS-1) and -2 (IRS-2), two important molecules in the IR and IGF-IR signaling pathways, are also beginning to shed light onto the mechanisms accounting for the specificity of IR and IGF-IR signaling. IRS-1-deficient mice are growth retarded, while IRS-2-deficient mice develop diabetes, indicating that the two molecules play a more specific role than previously recognized in IGF-IR and IR signaling.
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PMID:Targeted gene mutations define the roles of insulin and IGF-I receptors in mouse embryonic development. 1041 63

A large number of neurotrophic factors that exert effects on specific neuronal populations in the peripheral nervous system have been discovered. Some of these factors may prove useful for the treatment of diabetic peripheral neuropathy. Among the most promising are members of the neurotrophin gene family (nerve growth factor [NGF], brain-derived neurotrophic factor, neurotrophin [NT]-3, and NT-4/5), insulin-like growth factor (IGF)-I and IGF-II, and glial cell-derived neurotrophic factor. Of these, NGF and the IGFs have been tested most extensively in animal models of diabetic neuropathy, with encouraging results. Recombinant human nerve growth factor (rhNGF) has been tested in phase II clinical trials for treatment of patients with diabetes, and the results have been encouraging. Phase III trials of rhNGF have been completed, and clinical trials of other neurotrophic factors are likely to be conducted in the next few years.
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PMID:Neurotrophic factors in the therapy of diabetic neuropathy. 1048 43

In patients with acromegaly, clinical improvement has been reported after octreotide (OCT) treatment, even in cases of only a moderate suppression of growth hormone (GH) levels. In rats, OCT suppresses IGF-I mRNA expression and generation of serum and tissue IGF-I levels. A direct effect of OCT on the IGF system could have therapeutical implications in diabetes mellitus, cardiovascular disease, and certain malignancies in which IGF-I might be involved. The aim of this study was to examine possible GH-independent effects of OCT on IGF components in humans. Six GH-deficient (GHD) patients were studied for 24 h after each of the following treatment regimens (each of 1 weeks duration): (a) daily s.c. GH injection (2 IU/m(2)); (b) as (a) + continuous s.c. infusion of OCT (200 microg/24 h) by means of a portable pump (Nordic Infuser); (c) no treatment. Serum GH binding protein (GHBP) levels tended to be lower after GH and OCT than after GH alone (P =0.10). OCT reduced the GH induced increase in serum IGF-I levels (P<0.05, ANOVA). Mean integrated levels (microg/l) were 359.1+/-49.6 (GH), and 301.6+/-58.9 (GH+OCT). OCT did not significantly reduce serum IGFBP-3 levels (microg/l) [3460+/-270 (GH), and 3112+/-435 (GH+/-OCT);P =0.14]. Serum levels of free IGF-I (P =0.39), IGF-II (P =0.54), and of the acid-labile subunit (ALS) of the ternary complex (P =0.50) were similar during GH+/-OCT as compared with GH alone. After 1 week off GH treatment, significantly lower levels of IGF-I, IGF-II, IGFBP-3, and ALS were recorded (P<0.001). Serum IGFBP-1 levels were significantly higher after GH+OCT than after GH alone (P<0.0001), and levels were even higher without GH. Serum insulin levels (pmol/l) were significantly higher after GH alone as compared with no GH (P<0.05, ANOVA), whereas OCT partly suppressed the insulinotropic effect of GH (P<0. 05) [mean: 114.5+/-33.0 (GH), 91.3+/-29.6 (GH+OCT), 65.9+/-22.5 (no GH)]. This was also reflected in higher blood glucose levels during GH+OCT. Finally, GH+OCT reduced glucagon levels significantly as compared with GH alone (P =0.02). In conclusion, 7 days' administration of OCT to GH-treated GHD patients slightly attenuated serum IGF-I generation, and tended to decrease levels of the other components of the 150 kDa ternary complex. Whether these effects are mediated directly by OCT or indirectly via the accompanying changes in insulin levels remains to be investigated.
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PMID:Effects of a 7-day continuous infusion of octreotide on circulating levels of growth factors and binding proteins in growth hormone (GH)-treated GH-deficient patients. 1062 66

Hypoglycemia is a clinical and biological syndrome, caused by an abnormal decrease in plasma glucose levels to below 0.55 g/l (3.0 mmol/l). Hypoglycemia is responsible for non-specific signs and symptoms which should be noted in a particular pathological context, and for secretion of counterregulatory hormones (mainly glucagon and catecholamines). Difficulty in identifying the etiology is variable, based upon history and physical examination, and hormonal investigations or imaging procedures, according to the results. Drug-related hypoglycemia is the most frequent observed cause (mainly in insulin-treated diabetic patients, but many drugs may be involved), followed par toxicity (alcohol mainly). Tumor-induced hypoglycemia is secondary to inappropriate insulin secretion by a beta-cell pancreatic tumor (insulinoma), and, rarely to an extrapancreatic mesenchymal large tumor secreting IGF-II. Hypoglycemia is present in other diseases, such as hormonal deficiencies, hepatic, or renal failure, or acute cardiac insufficiency. Multifactorial hypoglycemia seems to be underdiagnosed, mainly in hospitalized, underfed older patients with severe disease or sepsis. Autoimmune hypoglycemia is rare, due to insulin or insulin-receptor autoantibodies. Reactive hypoglycemia is observed after gastrectomy, but true primitive hypoglycemia appears to be rare, with false excess diagnosis in the majority of the cases.
Diabetes Metab 1999 Dec
PMID:Hypoglycemia in adults. 1063 72


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