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

The disease association of autoantibodies to proinsulin and insulin was compared in patients with Type 1 (insulin-dependent) diabetes mellitus and first-degree relatives. Following the recommendation of the Fourth International Workshop on the Standardization of insulin autoantibodies, autoantibodies were determined by fluid-phase radioimmunoassay using equimolar concentrations of mono-125I-A14-insulin or -proinsulin to detect insulin or proinsulin autoantibodies, respectively. A higher prevalence of proinsulin autoantibodies vs insulin autoantibodies was found in 97 patients with Type 1 diabetes prior to insulin treatment (34.0% vs 22.7%, p less than 0.05) and in 16 islet cell antibody-positive relatives (43.8% vs 31.3%, NS). There was only one serum positive for insulin and proinsulin autoantibodies in 110 islet cell antibody-negative first degree relatives (0.9%). None of 88 normal sera contained proinsulin autoantibodies or insulin autoantibodies. There was a close correlation of proinsulin autoantibody and insulin autoantibody titres in individual sera (r = 0.95, p less than 0.01) due to crossreaction of all insulin autoantibodies with proinsulin. However, some proinsulin autoantibodies did not crossreact with insulin. Background binding in normal sera was lower for proinsulin autoantibodies. We conclude that proinsulin autoantibodies have a higher association to acute Type 1 diabetes than insulin autoantibodies.
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PMID:Proinsulin autoantibodies are more closely associated with type 1 (insulin-dependent) diabetes mellitus than insulin autoantibodies. 176 42

Insulin was radioiodinated with 123I (123I-tyrosine-(A14)-insulin) to a specific activity of 1 micrograms/mCi, corresponding to 0.025 I.U. of insulin/mCi. This preparation was used for in vitro binding experiments with adipose tissue, showing active binding to the two subunits of the known insulin receptor. In a preliminary clinical investigation, 5 adipose patients with (n = 2) and without (n = 3) diabetes mellitus Type II, were subject to in vivo injection of the same radiolabeled product using 3 mCi/patient. During the first minutes of dynamic imaging, the liver was the major organ of tracer uptake in all patients. Furthermore, the pancreas, and in one patient the kidneys, were visualised. Further studies on insulin in vivo kinetics and quantification are under way.
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PMID:123I-tyrosine-(A14)-insulin: preparation and preliminary clinical studies. 177

Factors associated with diabetes onset were analysed for their predictive value in 708 first-degree relatives of Type 1 (insulin-dependent) diabetic patients including 374 parents and 308 siblings of Type 1 diabetic patients. Relatives were prospectively followed for 2,304 subject years with blood samples for specific autoantibody evaluation. Islet cell cytoplasmic autoantibody titres were quantified in Juvenile Diabetes Foundation units with a threshold of positivity of 5 units. Insulin autoantibodies were determined using Tyr-A14 iodinated human insulin. HLA typing was performed in 92% of the relatives. During the time of study, 17 of 646 (2.6%) relatives showed islet cell antibodies. During follow-up, eight relatives developed diabetes, including six with high islet cell antibody titre. Taking titres above 20 units increased the positive predictive value from 35% to 75% whereas the presence of insulin autoantibodies did not increase the positive predictive value for the disease. Analysis of metabolic profiles months before the onset of diabetes by either oral or intravenous glucose loads, indicated a considerable level of heterogeneity with relatives with a high islet cell antibody titre who rapidly developed insulin-dependent diabetes, whereas other remained insulin-independent during the same observation period despite comparable titres. This study clearly indicates that initial islet cell antibody titre is not sufficient to predict individual outcome. Follow-up samples are clearly needed to monitor progression of the disease. Few relatives with persistent immunologic positivity progress to clinical Type 1 diabetes, suggesting that non-progressive and sub-clinical Beta-cell dysfunction is common.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Autoantibodies and genetic factors associated with the development of type 1 (insulin-dependent) diabetes mellitus in first degree relatives of diabetic patients. 188 91

To describe quantitatively the in vivo distribution and elimination of insulin, high-performance liquid chromatography (HPLC) separation was applied to the pharmacokinetic study of human insulin labeled with 125I at tyrosine A14 (A14-125I-insulin) as a tracer. Intact A14-125I-insulin levels were determined by HPLC and trichloroacetic acid (TCA) precipitation in plasma and various tissues after its intravenous bolus injection into mice. TCA precipitation consistently overestimated the intactness of A14-125I-insulin compared with HPLC, possibly due to the presence of both a TCA-precipitable intermediate degradation product of labeled insulin found in HPLC elution profiles and reported high-molecular-weight forms of labeled insulin in plasma. Thus, TCA precipitation gave a considerably lower total plasma clearance (Cltot) value than HPLC. The half-life of A14-125I-insulin was prolonged by a simultaneous injection of 8 U/kg unlabeled insulin, and labeled insulin behaved similarly to [14C]inulin (an extracellular fluid marker). The concentration time profiles of HPLC-separated labeled insulin in plasma were analyzed by a noncompartmental moment method, and both Cltot and steady-state apparent volume distribution (VDss) of A14-125I-insulin were considerably decreased by unlabeled insulin coadministration. In particular, VDss of labeled insulin decreased by 79%, similar to that of inulin (181 ml/kg), suggesting that the nonspecific binding of labeled insulin to tissues was so small that VDss of labeled insulin was reduced to the extracellular fluid volume (approximately 20% of the body weight) when its receptor binding was blocked effectively by unlabeled insulin.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1990 May
PMID:Application of HPLC in disposition study of A14-125I-labeled insulin in mice. 218 7

Methylcholanthrene-induced sarcomas (MCA-S) have different growth patterns in diabetic (D) and nondiabetic (ND) rats. Diabetes delays the early phase of tumor growth and prolongs survival. This study evaluated MCA-S growth and its relation to insulin receptors (IR) and glucose uptake. Fisher 344 rats 150-200 g were assigned to two groups: Diabetic tumor bearers (DTB, n = 26) and nondiabetic tumor bearers (NDTB, n = 18). Diabetes was induced with iv streptozocin (40 mg/kg); MCA-S was inoculated (1 X 10(6) cells) subcutaneously 10 days later. Animals were sacrificed during early growth (tumor volume less than or equal to 20 cc) or logarithmic growth (tumor volume greater than 20 cc). IR assay was performed (0-10(5) ng/ml cold insulin, 25 X 10(3) cpm/tube A14 125I-insulin, 90 min, 15 degrees C, pH 7.8) on a single cell preparation. Serum glucose milligrams per deciliter and insulin nanograms per milliliter were assayed. Glucose uptake (dpm/g tissue/hr) was assayed 2 hr after an ip injection of 0.5 microCi 3-O[14C]methylglucose. Diabetic, tumor-bearing animals had a significantly increased number of insulin receptors at the small [less than or equal to 20 cc, 28.7 (D) vs 8.3 (ND)] and large [greater than 20 cc, 82.8 (D) vs 27.8 (ND)] tumor volumes. Glucose uptake was increased in the tumor at both volumes in the non-diabetic animals compared to the diabetic animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Changes in insulin receptors on methylcholanthrene-induced sarcoma during growth. 219 Nov 69

This study investigated the relative effect of obesity alone and in combination with non-insulin-dependent diabetes mellitus (NIDDM) on the intracellular processing of insulin and evaluated the effect of metformin therapy on this process. Monocytes from 11 obese hyperinsulinemic subjects, 13 obese hyperinsulinemic NIDDM patients, and 7 nondiabetic control subjects were incubated with A14-125I-labeled insulin for 60 min at 37 degrees C, and intracellular insulin degradation was characterized by high-performance liquid chromatography. Total cell-associated insulin (insulin binding) and internalized and degraded insulin were decreased in obese subjects and significantly decreased in obese NIDDM patients compared with nondiabetic control subjects. In NIDDM patients, intracellular insulin degradation was inversely correlated with fasting plasma glucose (P less than 0.01). Eight obese subjects and 9 obese NIDDM patients were restudied after 4 wk of therapy with metformin (850 mg twice a day). Plasma levels of the drug were superimposable in the two groups. Metformin therapy did not change glucose and insulin levels in obese subjects but caused a decrease in blood glucose in obese NIDDM patients. Total cell-associated radioactivity (insulin binding) significantly increased in both groups (P less than 0.01). On the contrary, internalized radioactivity increased (0.83 +/- 0.3 vs. 1.31 +/- 0.35%, P less than 0.01), and similarly, insulin degradation was enhanced (54.6 +/- 8.9 vs. 74.22 +/- 9.15%, P less than 0.01) only in monocytes from obese NIDDM patients. However, the levels of these parameters were still lower than in control subjects (internalization, 2.94 +/- 0.68%; degradation, 93.03 +/- 3.7%).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1990 Jul
PMID:Improvement with metformin in insulin internalization and processing in monocytes from NIDDM patients. 219 88

In an earlier study, we described the presence of a retroendocytotic pathway for insulin in a cultured kidney epithelial cell line. Derived from the opossum kidney (OK), these cells possess many features of proximal tubule epithelium, which is the major site of kidney insulin metabolism. We studied the interaction between the retroendocytotic and the degradative pathways with bacitracin as a pharmacological probe. Monolayers of OK cells were loaded with 125I-labeled insulin over 30 min, acid washed to remove membrane-bound insulin, then incubated in fresh medium for 60 min while the release of intracellular radioactivity was monitored. In experiments carried out in the presence of bacitracin (2 mM), there was a two-thirds increase in intracellular radioactivity at the end of the loading phase. Measurements made during the subsequent release phase showed that bacitracin reduced the release of degradation products. Thus, although controls released 72.1 +/- 8.1% of the internalized radioactivity as trichloroacetic acid (TCA)-soluble products, bacitracin-treated cells released 59.2 +/- 9.4% (P less than 0.02). In contrast, release of TCA-precipitable insulin increased from 15.2 +/- 4.6% in controls to 25.8 +/- 3.7% in bacitracin-treated cells (P less than 0.01). In separate experiments analyzed by gel-exclusion chromatography, 6.4 +/- 0.6% of radioactivity released from preloaded control cells into medium over 60 min was insulin sized compared to 29.7 +/- 1.4% in bacitracin-treated cells. High-performance liquid chromatography revealed that 61.5 +/- 3.5% of this insulin-sized material released from control cells preloaded with A14-insulin eluted as intact insulin and the remainder as unidentified intermediate degradation products.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1990 Nov
PMID:Effect of bacitracin on retroendocytosis and degradation of insulin in cultured kidney epithelial cell line. 222 8

The effects of free fatty acids (FFA) on insulin receptor binding and processing (internalization, degradation, dissociation, and release) were examined in hepatocytes isolated from 12-week-old female rats. Animals were fasted for 24 h to deplete liver glycogen and lipid content. Cells were preincubated for 30 min or 3 h at 37 degrees C in media containing 10 mM lactate, 1 mM pyruvate, and 3.5 percent albumin with increasing concentrations of palmitate (0.00, 0.05, 0.2, 0.5, 1.0 and 2.0 mM). Under these conditions palmitate is the primary substrate for cellular metabolism, and its major fate is oxidation. Equilibrium binding was determined after 18-20 h of incubation at 4 degrees C with radiolabeled insulin and increasing concentrations of unlabeled hormone. With increasing palmitate concentration, a dose-dependent decline in cell-surface insulin receptor binding was observed. Binding decreased by 35 percent and 44 percent after 30 min and 3 h of preincubation with 2 mM palmitate, respectively. This decrease was due to a reduction in insulin receptor number. Receptor-mediated insulin processing was evaluated in cells prelabeled at 4 degrees C with 125I (A14)-monoiodoinsulin at an insulin concentration of 100 pM and reincubated at 37 degrees C for up to 30 min. The amount of internalized insulin was decreased by preincubation of hepatocytes with palmitate. This decrease was proportional to the reduction in cell-surface insulin receptor density at palmitate concentrations of 0.05-0.5 mM, but was disproportionally greater at higher fatty acid concentrations. Receptor-mediated insulin degradation decreased at palmitate concentrations between 0.05 and 1.0 mM. At 2 mM, however, insulin degradation was enhanced. This enhancement was observed after 30 min or 3 h of exposure to the fatty acid. Dissociation and/or release of cell-associated internalized insulin was not influenced by the FFA exposure. The effects of FFA on hepatocyte insulin binding and processing were contingent upon cellular metabolism, since no changes were noted when cells were preincubated with palmitate at 4 degrees C under otherwise similar conditions. Thus the in vitro exposure of hepatocytes to FFA influences both receptor and postreceptor events mediating insulin metabolism. These effects may account for the altered hepatic insulin extraction and sensitivity that accompany abdominal obesity and its progression to diabetes.
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PMID:Receptor and postreceptor effects of free fatty acids (FFA) on hepatocyte insulin dynamics. 226 78

T cell autoreactivity to insulin in type I diabetic and related non-diabetic individuals was analyzed. Peripheral T lymphocytes from both insulin-treated diabetic and untreated non-diabetic members of four families were found to proliferate in vitro in response to human insulin. T cell autoreactivity to insulin therefore does not appear to be diagnostic of the onset of type I diabetes. Highest T cell responses to human insulin were usually detected in insulin-dependent type I diabetes patients treated with a mixture of beef and pork insulin than with self insulin, the greater the dose of animal insulin the higher the T cell response. The T cell repertoires for self insulin appear to be similar in diabetics and non-diabetics based on their patterns of T cell reactivity to beef insulin, port insulin, human insulin, and various peptide of human insulin. The autoreactive T cells analyzed recognize two conformational epitopes of human insulin formed by interactions between A chain and B chain residues. One epitope is associated with the A chain loop and is present in the A1-A14/B1-B16 peptide, and the other epitope consists mainly of B chain residues located in the A16-A21/B10-B25 peptide. These two epitopes are present in amphipathic alpha-helical regions of insulin. HLA-DR (DR3, DR4, and DR5) and HLA-DQ (DQw2/DQw3) Ag can restrict these T cell responses to human insulin epitopes. The ability to detect insulin-specific autoreactive T cells in healthy non-diabetic individuals supports the hypothesis that autoreactive lymphocytes do not necessarily elicit autoimmune disease if present in an environment in which their activity is immunoregulated.
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PMID:T cell autoreactivity to insulin in diabetic and related non-diabetic individuals. 245 92

To clarify the significance of insulin autoantibodies (IAA) in insulin-dependent diabetes mellitus, we measured the IAA longitudinally in non-obese diabetic (NOD) mice, and in high-dose streptozotocin-induced diabetes (high-SZ) and EMC virus-induced diabetes (EMC) in mice, and compared the data with the occurrence of insulitis. The IAA were detected by the polyethylene glycol (PEG) method using 125I-(Tyr A14) human insulin. The IAA were found in 38% of NOD mice and correlated with the occurrence of insulitis. The prevalence of IAA was 0% before the appearance of insulitis, 80% at 12-14 weeks of age and 30% after 20 weeks of age in female NOD mice. In male NOD mice, IAA were found in 45% at 12-14 weeks of age and 20% after 20 weeks. In high-SZ mice, IAA were detected in several mice while insulitis was not present. In EMC-virus induced diabetic mice, IAA and lymphocytic infiltration into the islets were detected 4-14 days after EMC virus infection. These results suggest that (a) IAA are markers for islet autoimmunity in NOD mice, (b) the presence of IAA does not always reflect insulitis, (c) the presence of IAA is not sufficient for the development of overt diabetes and (d) the appearance of IAA may reflect a difference of the immune response genotype.
Diabetes Res 1989 Jun
PMID:Insulin autoantibodies in mouse models of insulin-dependent diabetes. 262 Apr 86


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