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

The role of insulin in the control of somatomedin release has been investigated in people with Type 1 diabetes. Six patients underwent insulin-induced hypoglycaemia of 20 min duration and 8 patients were studied using the hyperinsulinaemic euglycaemic clamp technique at insulin infusion rates of 0.25, 1.25, 2.5, and 0.25 mU kg-1 min-1 for 1 h at each rate. In the first study plasma insulin concentrations rose from (median, range) 23 (10-36) to 114(60-200) mU l-1 at the onset of hypoglycaemia, and fell to 53 (23-100) mU l-1 after 20 min hypoglycaemia and 30 (15-73) mU l-1 on return to normoglycaemia. Plasma IGF-1 rose from 140 (96-292) to 179 (127-352) micrograms l-1 (p less than 0.05) at the onset of hypoglycaemia and fell to 131 (125-173) micrograms l-1 after 20 min and to 154 (121-287) micrograms l-1 at the end of the study. During hyperinsulinaemia plasma insulin rose from 23 (19-40) mU l-1 at the lowest infusion rate to 61 (33-84) and 148 (68-200) mU l-1 at the two higher infusion rates. Over the same period, plasma IGF-1 increased from 91 (13-203) to 123 (98-182) micrograms l-1 (p less than 0.05) and 109 (84-160) micrograms l-1. There was no correlation between growth hormone levels and IGF-1 in either study. These results suggest that insulin produces short-term increases in IGF-1 levels in man in the absence of a growth hormone response.
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PMID:Insulin increases plasma somatomedin C (IGF-1) concentrations in adult type 1 diabetic patients. 252 86

Diabetes is associated with a fall in serum levels of insulin-like growth factor-1/somatomedin-C (IGF-1/Sm-C) and a rise in somatomedin inhibitor, a factor which antagonizes somatomedin action. We attempted to determine if the presence of glucocorticoids was required for diabetes-related alterations in these circulating growth factors. Diabetes was induced with streptozotocin in intact or adrenalectomized rats. Adrenalectomized-nondiabetic and adrenalectomized-diabetic rats were given either no glucocorticoids or daily hydrocortisone acetate at 0.5 or 50 mg/kg body weight, and killed 48 hours after streptozotocin treatment. After serum fractionation via size exclusion high performance liquid chromatography (HPLC), IGF-1/Sm-C was determined by radioimmunoassay, and somatomedin inhibitor by bioassay according to the ability of serum fractions to blunt cartilage stimulation by normal serum. Intact-diabetic rats had 22% weight loss, glucose 427 mg/dL, and beta-hydroxybutyrate 7.2 mmol/L (all P less than .001 v control). Serum IGF-1/Sm-C levels in intact-diabetic rats were decreased 71%, while somatomedin inhibitor rose to 470% of the control values (both P less than .004). Adrenalectomized-diabetic rats displayed comparable hyperglycemia (greater than 400 mg/dL) and decline in IGF-1/SmC, with or without glucocorticoid replacement. However, adrenalectomized-diabetic rats had greatly reduced weight loss (10%), beta-hydroxybutyrate (1.5 mmol/L), and somatomedin inhibitor (59% of control), all P less than .01 v intact-diabetic. Hydrocortisone 0.5 mg/kg in these animals increased weight loss but had no significant effect on beta-hydroxybutyrate or somatomedin inhibitor levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glucocorticoid effects on IGF-1/somatomedin-C and somatomedin inhibitor in streptozotocin-diabetic rats. 272 99

Sera and their IgG from 10/104 diabetic patients (five with insulin-dependent and five with noninsulin-dependent diabetes, NIDDM), contained antibodies that bound 125I-labeled purified human insulin receptors. 9 of these 10 sera failed to inhibit insulin binding (to rat hepatocytes and human placental membranes), did not stimulate glucose oxidation (by isolated rat adipocytes), and did not bind human placental IGF-1 receptors. Only one serum (and its IgG) modestly inhibited insulin binding and stimulated glucose oxidation. We conclude (a) that sera from 9/104 diabetics (five insulin-dependent and four noninsulin-dependent) contained a newly identified species of IgG antiinsulin receptor autoantibodies (AIRA), which bound to the insulin receptor at a locus different from the insulin binding site and did not inhibit insulin binding; and (b) that only 1/104 diabetic sera contained low-titer "conventional" antiinsulin receptor autoantibodies that bound to the insulin receptor at or near the insulin binding site, inhibited insulin binding and caused a clinical condition, which was difficult to distinguish from typical NIDDM.
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PMID:Nonbinding inhibitory antiinsulin receptor antibodies. A new type of autoantibodies in human diabetes. 296 69

Poor growth in diabetes involves low circulating levels of somatomedins/insulin-like growth factors (IGFs), largely reflecting decreased growth factor release by the liver. To define regulatory mechanisms, circulating IGF-1 was compared with levels of a high mol wt putative hepatic IGF-1 precursor and hepatic IGF-1 mRNA in a model of progressive severity of diabetes in rats. Streptozotocin administered at 36, 72, 144, and 288 mg/kg produced graded metabolic decompensation 2 days later, from minimal hyperglycemia with continued weight gain at 36 mg/kg, to marked hyperglycemia, ketonemia, and weight loss at 288 mg/kg (all P less than 0.001). Total serum IGF-1 measured by RIA was unchanged with the 36 and 72 mg/kg doses of streptozotocin (471 +/- 19 and 439 +/- 27 ng/ml, respectively, vs. 517 +/- 27 ng/ml in controls) despite serum glucose greater than 400 mg/dl. With streptozotocin 144 and 288 mg/kg, serum IGF-1 fell to 131 +/- 27 and 142 +/- 10 ng/ml, respectively (both P less than 0.005 vs. controls). Serum IGF-1 was correlated strongly with serum beta-hydroxybutyrate and body weight (r = -0.88 and 0.91, respectively, P less than 0.0001), and less strongly with serum glucose (r = -0.59, P less than 0.0002). Extractable hepatic content of a high mol wt form of immunoreactive IGF-1 (a putative precursor) was unchanged at the two lowest doses of streptozotocin (68 +/- 4 and 83 +/- 9 ngeq/g vs. 67 +/- 4 in controls), but decreased to 16 +/- 3 and 29 +/- 4 ng/g at the two highest doses (both P less than 0.001 vs. controls).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nutrition and somatomedin. XIX. Molecular regulation of insulin-like growth factor-1 in streptozotocin-diabetic rats. 297 56

Insulin and the insulin-like growth factors IGF-I and IGF-II are thought to exert their mitogenic effects in cultured chick embryo fibroblasts and human skin fibroblasts via IGF receptors rather than via insulin receptors. These effects appear to be mediated by the type I subtype of IGF receptor, which is structurally similar to the insulin receptor and exhibits significant cross-reactivity with insulin. As a first step in our long-range goal of defining those features of the IGF-I and IGF-II molecules that confer enhanced mitogenic activity and reactivity with these mitogenic type I IGF receptors, we have prepared two hybrid insulin-IGF molecules and examined their mitogenic and binding activities: (1) A27-insulin, containing an elongated 27-residue A-chain (in which the 6-residue D-domain of IGF-II was added to the carboxy-terminus of the 21-residue A-chain of insulin) combined with the B-chain of insulin; and (2) A insulin-B IGF-1, containing the A-chain of insulin and the synthetic 30-residue B-domain of IGF-I. Both hybrid molecules stimulated DNA synthesis and inhibited 125I-IGF-I binding to type I IGF receptors in both chick embryo and human fibroblast cultures. A27-insulin had considerably greater mitogenic potency and binding potency than A insulin-B IGF-I. Neither hybrid molecule was more potent in these assays than insulin, indicating that the presence of D IGF-II or B IGF-I by itself was not sufficient to increase the mitogenic potency of insulin in fibroblasts. By contrast, A insulin-B IGF-I showed enhanced reactivity with an antiserum to IGF-I. A27-insulin retained significant insulin-like metabolic activity despite the presence of the D-domain of IGF-II.
Diabetes 1986 Mar
PMID:Mitogenic activity and receptor reactivity of hybrid molecules containing portions of the insulin-like growth factor I (IGF-I), IGF-II, and insulin molecules. 300 95

We have reviewed the role of insulin in ovarian physiology. Clinical observations and experimental data strongly support the hypothesis that insulin possesses gonadotropic activity, when acting alone or with FSH or LH. This idea is further supported by the recent discovery of insulin in follicular fluid. The idea that insulin has gonadotropic function can explain a variety of clinical observations, which otherwise are difficult to understand. For example, manifestations of ovarian hypofunction (primary amenorrhea, late menarche, anovulation, low pregnancy rate, and early menopause) in IDDM can be understood if it is accepted that insulin is necessary for the ovary to reach its full steroidogenic potential. The idea that insulin affects ovarian steroidogenesis also helps to understand the observation that hyperandrogenism frequently accompanies each of the various insulin-resistant states, regardless of the latter's etiology (e.g. genetic deficiency in the number of insulin receptors, antiinsulin receptor antibodies, obesity, etc.). The explanation for this association is based on the idea that hyperinsulinemia intensifies ovarian steroidogenesis, which manifests clinically as hyperandrogenism. Continuous stimulation of the ovary by insulin over a long period of time possibly produces morphological ovarian changes, such as hyperthecosis or polycystic changes; these changes commonly are observed among women with insulin resistance. The effects of insulin on ovarian cells are mediated possibly through binding of the peptide to its own receptor or to the IGF-1 receptor (the specificity spillover phenomenon). The latter could be an important mechanism in cases of insulin resistance. Potential mechanisms underlying the gonadotropic activity of insulin include direct effects on steroidogenic enzymes, modulation of FSH or LH receptor number, synergism with FSH or LH, or nonspecific enhancement of cell viability. The gonadotropic function of insulin adds yet another note to what has been termed a symphony of insulin action. Further investigation into this new area may yield greater insights not only into normal ovarian physiology, but also into the pathogeneses of such diverse entities as PCO, obesity, diabetes mellitus, and the syndromes of insulin resistance and acanthosis nigricans.
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PMID:The gonadotropic function of insulin. 330 17

The suggestion of a role for the abnormally regulated growth hormone (GH) in the pathogenesis of diabetes mellitus (DM), implicates also the somatomedins, as mediators of some of GH actions. The present study was aimed at assessing the somatomedin response to exogenous GH administration in diabetes type II (NIDDM) subjects as well as its possible relationship with the degree of control of diabetes. Twenty-two subjects (seven controls and 15 NIDDM patients), matched for sex and age, underwent human GH infusion (0.1 U/kg b.w.) over a one-hour period (time 0 to 1 hour). Total somatomedins (SMs) were measured by human placental membrane radioreceptor assay (in which all SMs crossreact) and Somatomedin-C (SM-C) was determined by a specific RIA. Values were obtained from plasma samples at times 0, 1, 4, 6, and 24 hours. Glycosylated hemoglobin (HbA1a-c) measurements were done from blood samples obtained at time 0. The increase in SMs following GH infusion in NIDDM group was not significantly different from that of the controls. In contrast, the SM-C increase at time 6 and 24 hours were significantly higher than in controls (p less than 0.05 and p less than 0.01, respectively). No significant difference was found between SMs or SM-C response to GH infusion in patients with HbA1a-c greater than 10% vs. less than 10%. These results indicate an exaggerated and prolonged increase in SM-C synthesis following exogenous GH infusion in NIDDM subjects, apparently unrelated to the degree of control of diabetes.
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PMID:Exaggerated somatomedin-C response to human growth hormone infusion in patients with type II diabetes mellitus. 653 51

Biosynthetic human insulin (BHI) was compared to pancreatic human insulin and sperm whale insulin in terms of ability to stimulate incorporation of glucose into isolated rat adipocytes and thymidine into DNA in chick embryo fibroblasts. The human insulins were identical in their effects in both assays. Sperm whale insulin was more potent than the human insulins in stimulating glucose incorporation into rat adipocytes. All three insulins showed identical stimulation of DNA synthesis in the fibroblast assay. That action, however, is mediated via the receptor for insulin-like growth factor (IGF-I). Therefore, both human insulins were evaluated in terms of binding to the IGF-1 receptor in chick embryo fibroblasts. The two human insulins behaved identically (and agreed with previous findings for sperm whale insulin). All insulins, however, were approximately 200-fold less potent than IGF-I itself in this binding assay.
Diabetes Care
PMID:Comparison of pancreatic human and biosynthetic human insulin with respect to their action on adipocytes and chick embryo fibroblasts. 701 41

To evaluate the effect of IGF-1 on the autoimmune process of beta cell destruction, permissive non-obese diabetic (NOD) recipients were adoptively transferred with 7 x 10(6) autoreactive T cells from diabetic NOD mice and were administered subcutaneously 10 micrograms rhIGF-1, twice daily for 3 weeks. Administration of rhIGF-1 reduced the final incidence of successful transfers of diabetes observed in only 6/24 mice (25%) versus 12/21 (57%) in control mice. A marked reduction of insulitis during histological analysis of pancreatic glands was also observed. Mice treated with rhIGF-1 had a higher percentage of intact islets (48.6 +/- 12% versus 1.6 +/- 1.1%, P = 0.001) and a lower percentage of infiltrated islets. Islets from rhIGF-1-treated mice had a more intense insulin staining reflecting a higher beta cell mass, but no difference was observed in the amount of insulin content of pancreatic extracts and in the amounts of mRNA transcripts for proinsulin. No difference was also observed in the titres of three islet cell antibody (ICA)-positive sera and in the pattern of A2B5 staining. Some mice developed diabetes and severe islet cell infiltration despite rhIGF-1, thus indicating that some committed T cells were still able to invade the islets and cause beta cell destruction. The percentages of CD4+ and CD8+ T cells in the spleen of experimental mice were similar. To evaluate the effects of rhIGF-1 on cell trafficking in recipient mice, T cells from diabetic NOD Thy-1,2 mice injected into congenic NOD-N Thy-1,1 mice were monitored 3 weeks after adoptive cell transfer. The percentage of Thy-1,2+ T cells was significantly reduced in the spleen (10.8 +/- 1.3% versus 17.2 +/- 3.9%, P = 0.004) of rhIGF-1 treated mice in contrast to the thymus (68.4 +/- 7.9% versus 72.87 +/- 6.2%, P = 0.306), suggesting that rhIGF-1 could influence T cell trafficking to the lymphoid organs. The findings that rhIGF-1 has protective effects in autoimmune diabetes opens new perspectives for future experiments as well as for preventive strategies in human type I diabetes.
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PMID:Insulin-like growth factor-1 (IGF-1) protects NOD mice from insulitis and diabetes. 758 87

NIDDM is likely to have a major genetic component in view of the different prevalence between ethnic groups, the familial clustering, and the high concordance in monozygotic twins. Linkage analysis of extended pedigrees of patients with maturity-onset diabetes of the young (MODY) identified the glucokinase gene mutations. Specific phenotypes have also led to the discovery of the insulin gene mutations in patients with high insulin or proinsulin levels, to the insulin receptor mutations in patients with marked insulin resistance, and to the mutations in mitochondrial DNA associated with deafness and maternal inheritance. These four types of diabetogenic gene mutations account for only a minor proportion of NIDDM. Direct screening for mutations in candidate genes with single-strand conformation polymorphism or heteroduplex screening or with direct sequencing in the diabetic patients with the appropriate pathophysiological abnormality can be a successful strategy. Genetic diagnosis provides clear definite diagnosis and specific therapies, such as IGF-1 for the insulin receptor mutations and coenzyme Q10 for the mitochondrial gene mutations.
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PMID:[Genetic diagnosis of diabetes mellitus]. 778 64


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