Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-dependent diabetes mellitus (IDDM) is associated with insulin deficiency and insulin-resistant glucose uptake in skeletal muscle. To investigate the molecular mechanisms for this insulin resistance, we examined the expression of GLUT1 and GLUT4, glucose transporter genes in vastus lateralis muscle from 20 IDDM subjects and 10 nondiabetic controls. Both groups had a mean age of 34 yr and were nonobese. Fasting free plasma insulin levels were similar in control and IDDM subjects but hemoglobin A1c (HbA1c), fasting plasma glucose and free fatty acid levels were significantly higher in IDDM subjects. Euglycemic clamp studies over a range of insulin concentrations in these IDDM subjects previously showed both decreased insulin sensitivity and decreased maximally insulin stimulated glucose utilization. In this study, Northern blotting of muscle ribonucleic acid (RNA) revealed a single 3.0-3.5 kb transcript for both GLUT1 and GLUT4 with no change in messenger RNA (mRNA) size or abundance with IDDM. In IDDM subjects, GLUT1 mRNA levels correlated positively with HbA1c whereas GLUT4 mRNA levels correlated negatively with fasting plasma glucose but not with HbA1c. Neither mRNA correlated with fasting plasma insulin or free fatty acid levels or with daily insulin dose. Immunoblotting of total muscle membranes for GLUT4 showed a single band of mol mass of approximately 45 kilodaltons with no change in size or abundance with IDDM. There was no significant correlation between GLUT4 polypeptide levels and HbA1c, fasting plasma glucose, insulin, or free fatty acids, daily insulin dose, duration of diabetes, or subject age but in IDDM subjects GLUT4 protein levels correlated negatively with body mass index. Thus, impaired expression of glucose transporters in muscle is not essential for the pathogenesis of insulin-resistant glucose uptake in IDDM. No direct regulatory role of chronic glycemic control or plasma insulin levels on GLUT4 expression is evident. In contrast, recent ambient glucose levels may affect levels of GLUT4 mRNA but not GLUT4 protein, suggesting important posttranscriptional regulation of this protein. Since glucose transport has been shown to be rate limiting for glucose utilization in muscle in IDDM, these results suggest impaired translocation or activation of glucose transporters in IDDM.
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PMID:Expression of GLUT1 and GLUT4 glucose transporters in skeletal muscle of humans with insulin-dependent diabetes mellitus: regulatory effects of metabolic factors. 156 56

Type 1 diabetes seems to be an autoimmune disease in which T cells have a substantial role. A possible target antigen was suggested by the proliferation of CD4 T cells from a newly diagnosed patient in response to a 38 kD polypeptide of the insulin-secretory-granule membrane. To see whether this reactivity is widespread at disease onset, we have generated T-cell lines in vitro from peripheral blood mononuclear cells of nineteen children of caucasoid origin with newly diagnosed type 1 diabetes and sixteen healthy controls matched for age and HLA antigens. The procedure involved two cycles of incubation with a rat beta-cell tumour subcellular fraction enriched in secretory granules and plasma membrane components, followed by a proliferation assay. Fourteen (74% [95% confidence interval 49-91%]) of the patients' cell lines showed a positive proliferative response on subsequent exposure to the islet-cell antigen preparation compared with only two (13% [2-38%]) of the controls (p = 3 x 10(-4); difference 61% [44-87%]). Two subjects who had high titres of islet-cell autoantibodies (ICA) without clinical diabetes produced responsive T-cell lines. Reactivity towards the 38 kD fraction of insulin-secretory-granule membranes was found only in patients (eight of ten responders tested; 95% CI 44-98%) and one ICA-positive non-diabetic subject. Detection of an ongoing autoimmune T-cell response might be useful diagnostically and could lead to prevention of diabetes through specific immunotherapy.
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PMID:T-cell reactivity to 38 kD insulin-secretory-granule protein in patients with recent-onset type 1 diabetes. 167 18

Recent observations suggest a role for interleukin-1 (IL-1), a polypeptide product of macrophage/monocytic cells, in the immune-mediated destruction of pancreatic islet beta-cells observed in type 1 diabetes. In this study, we investigated the effects of IL-1 on both alpha- and beta-cell secretory functions in rat islet cell monolayer cultures. Insulin release was 97% inhibited after 6 h of incubation in RPMI-1640 medium (11 mM glucose) containing 1 U/ml IL-1 and 96% inhibited after 24 h of incubation in medium containing 0.1 U/ml IL-1. The cell content of insulin in the monolayers was decreased by 66% (P less than 0.01) after 4 days of incubation in 10 U/ml IL-1; however, after a further 8-day incubation in IL-1-free medium, cell insulin content recovered fully. In contrast, cell glucagon content was decreased by 77% (P less than 0.001) after 4 days of incubation in 10 U/ml IL-1 and did not recover after a further 8-day incubation in IL-1-free medium. After an 18-h preincubation in medium with 0.1 and 1 U/ml IL-1, insulin release responses to 16.7 mM glucose were abolished in 4-h incubations, whereas responses to 0.1 mM 3-isobutyl-1-methylxanthine were normal, and after a further 2 and 5 days of incubation in IL-1-free medium, insulin responses to 16.7 mM glucose recovered fully. Similarly, the inhibitory effect of 16.7 mM glucose on glucagon release was lost after an 18-h preincubation in 0.1 and 1 U/ml IL-1, and did not recover fully after 2 and 5 days in IL-1-free medium, whereas the stimulatory effect of 3-isobutyl-1-methylxanthine on glucagon release was not affected by IL-1. We conclude that 1) IL-1 inhibits glucose-dependent and not cAMP-dependent mechanisms of insulin and glucagon release; 2) inhibition of glucose-stimulated insulin release by IL-1 is reversible, whereas the effect on glucose-modulated glucagon release is not; and 3) IL-1 causes a reversible decrease in the insulin content of islet cells and an irreversible decrease in glucagon content. These actions of IL-1 do not appear to account for the beta-cell-specific destruction of islets characteristic of type 1 diabetes.
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PMID:Interleukin-1 inhibits glucose-modulated insulin and glucagon secretion in rat islet monolayer cultures. 245 40

The peptide C, polypeptide secreted by the pancreas at the same time as insulin, presents a great interest in the evaluation of diabetic patients. First it allows a differentiation between insulin dependent diabetes (IDD) and non insulin dependent (NDD). A low and non stimulated levels of peptide C signifies an insulin dependence. Within the group of IDD patients the peptide C was low when the diabetes was discovered at a younger age and its secretion diminished as the diabetes progresses. The peptide C has also a prognostic interest in IDD. Low and non stimulable levels of peptide C signifies a difficult control of diabetes which needs two injections per day while high and stimulable levels will be seen in diabetes easy to control with one injection of insulin. Finally, values of peptide C does not permit to predict the onset of diabetic complications (retinopathy, acidocetosis) as well as the control of patients.
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PMID:[Importance of peptide C determination in diabetes]. 251 29

Amylin, the major peptide component of the islet amyloid commonly found in the pancreases of patients with type 2 (non-insulin-dependent) diabetes mellitus (NIDDM), is a recently discovered islet polypeptide. This peptide has many structural and functional features suggesting that it is a novel hormone, which may control carbohydrate metabolism in partnership with insulin and other glucoregulatory factors. Amylin is synthesised in, and probably secreted from, the beta-cells of the islets of Langerhans, where it has recently been immunolocalised to secretory granules. DNA cloning studies indicate that in the human and the rat, amylin is generated from a precursor, preproamylin, which displays a typical signal peptide followed by a small prohormone-like sequence containing the amylin sequence. The presence of the signal peptide suggests that amylin is secreted and plays a physiological role. Amylin is probably generated by proteolytic processing similar to that for proinsulin and other islet prohormones. The human amylin gene encodes the complete polypeptide precursor in two exons which are separated by an intron of approx. 5 kb, and is located on chromosome 12. Amylin is a potent modulator of glycogen synthesis and glucose uptake in skeletal muscle, and is capable of inducing an insulin-resistant state in this tissue in vitro, and perhaps also in the liver in vivo. In normal metabolism, amylin could act in concert with insulin as a signal for the body to switch the site of carbohydrate disposal from glycogen to longer-term stores in adipose tissue, by making skeletal muscle relatively insulin-resistant, whilst at the same time leaving rates of insulin-stimulated carbohydrate metabolism in adipose tissue unaltered. Several lines of evidence now implicate elevated amylin levels in the pathogenic mechanisms underlying NIDDM, and suggest to us that the obesity which frequently accompanies this syndrome is a result of, rather than a risk factor for, NIDDM. Following the beta-cell destruction which occurs in type 1 (insulin-dependent) diabetes mellitus (IDDM), it is probable that amylin secretion disappears in addition to that of insulin. As patients with insulin-treated IDDM frequently experience problems with hypoglycaemia, and as amylin acts to modulate the action of insulin in various tissues, it is possible that amylin deficiency may contribute to morbidity in insulin-treated IDDM, perhaps through the loss of a natural damping mechanism which guards against hypoglycaemia under conditions of normal physiology.
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PMID:Amylin and the amylin gene: structure, function and relationship to islet amyloid and to diabetes mellitus. 269 Sep 58

The perivascular autonomic nerves of the major blood vessels on the ventral surface of the brain were studied in the streptozotocin-induced diabetic rat, an animal model for juvenile onset of diabetes. Histochemical and immunohistochemical techniques were used to determine the pattern and density of perivascular nerves containing catecholamine, 5-hydroxytryptamine (5-HT), vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY). A significant reduction in the density and/or fluorescence intensity of 5-HT-immunoreactive nerves was observed in the circle of Willis and its main arterial branches namely: basilar, superior cerebellar, internal carotid, posterior communicating, middle cerebral and anterior cerebral arteries, while a significant reduction of VIP-immunoreactive nerves was observed in the internal carotid, middle cerebral and anterior cerebral arteries, but not in the basilar, superior cerebellar and posterior communicating arteries 8 weeks after the onset of diabetes. However, no changes were observed in the density of NPY- and catecholamine-containing nerves. The results are discussed in relation to autonomic neuropathy of the cerebral blood vessels in diabetes.
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PMID:Reduction of nerves containing vasoactive intestinal polypeptide and serotonin, but not neuropeptide Y and catecholamine, in cerebral blood vessels of the 8-week streptozotocin-induced diabetic rat. 329 10

Somatostatin, as an adjunct to insulin in the treatment of poorly controlled type 1 diabetes, has been recently suggested. However, some authors, after injection of the polypeptide, detected a reduction in number and aggregation of platelets, others instead, reported a proaggregatory effect of the drug. To answer these questions, the plasma levels of proaggregatory thromboxane A2 and of B-thromboglobulin, marker of the platelet activation, were studied in nine control subjects and in thirteen insulin dependent diabetic patients before and during the endovenous injection, for three hours, of somatostatin (250 micrograms in bolus followed by infusion of 100 micrograms/h). In both groups, 30 min after the infusion of somatostatin, a fall of thromboxane B2, stable metabolite of thromboxane A2 and an increase of B-thromboglobulin were respectively observed. Their greatest figure was reached after 120 min and their levels did not return to basal values within the end of the observation. In diabetics, during the infusion of somatostatin, thromboxane B2 presented normal percentual falls while B-thromboglobulin showed increases which were lower than controls. In conclusion, the effect of somatostatin implied in the relative lower increase of B-thromboglobulin, seems connected to the precedent continuous activation of circulating platelets, the one, responsible for the decrease of thromboxane B2, instead, seems linked to a direct action of somatostatin, independently on the deranged metabolic conditions found in diabetic patients.
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PMID:Effects of somatostatin on the behavior of thromboxane B2 and B-thromboglobulin in type 1 diabetes. 608 13

The human HLA-D histocompatibility region encodes class II antigens each of which consists of two polypeptide chains (alpha and beta) inserted in the plasma membrane. These molecules are implicated in the regulation of the immune response but several human diseases are also found to be associated with certain HLA-DR antigens. The occurrence of insulin-dependent (type I) diabetes (IDDM) is strongly associated with HLA-DR3 and/or 4 (ref. 5). The class II antigens, however, show a marked genetic polymorphism associated with the beta-chains which seem, from hybridization studies, to be encoded by several genes. We have therefore used the beta-chain cDNA probe, pDR-beta-1 (refs 8, 10) to test whether there are differences in hybridization pattern between DNA from healthy individuals and diabetic patients, after digestion with restriction endonucleases. Among the HLA-DR 4 and 3/4 individuals, the IDDM patients showed an increased frequency of a PstI 18 kilobase (kb) fragment. A BamHI 3.7 kb fragment, frequent among controls (30-40%), was rarely detected in the IDDM patients (0-2%). These differences may be related to susceptibility to develop the disease.
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PMID:HLA-D region beta-chain DNA endonuclease fragments differ between HLA-DR identical healthy and insulin-dependent diabetic individuals. 630 68

The C-peptide is a polypeptide generated from enzymatic cleavage of proinsulin into insulin in pancreatic B. cell. C-peptide and insulin are secreted in an equimolar ratio. For this reason. C-peptide radio-immunoassay in blood or urine reflects the insulin secretion when direct insulin determination cannot be done (insulin treatment, circulating insulin antibodies). This assay is mainly used in clinical and investigational studies of insulin dependent diabets. It enabled demonstation of residual secretion of insulin in numerous insulin dependent patients (70% during the first year and 15% after the 15th year of the disease). Persistence of insulin secretion may play a role in the natural history of diabetes since patients with detectable C-peptide immunoreactivity have more stable diabetes, are controlled by lower insulin dose and are less ketosis prone than the others. Factors which influence persistence of B. cell activity in some IDD remain unknown.
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PMID:[The clinical value of C-peptide assay (author's transl)]. 700 55

Interleukin-1 beta (IL-1 beta) is a polypeptide produced by a variety of cells of hematological, dermal and neural origin. We have investigated the effect of type I diabetes mellitus and insulin treatment on tissue levels of IL-1 beta using streptozotocin (STZ)-treated mouse as an animal model. Diabetes affected IL-1 beta in a tissue specific manner. For example, IL-1 beta levels (as measured by ELISA) were markedly decreased in the liver and spleen of the STZ diabetic mice. In contrast, the levels of this cytokine remained unalatered in other tissues including kidney, testis, hippocampus and pituitary. Insulin treatment restored the diabetes-related decreases in liver and spleen IL-1 beta levels. Overall, the present data suggest that the abnormalities in hepatic and splenic IL-1 beta levels may contribute, at least in part, to the immunodeficiency and increased susceptibility to infection in diabetes mellitus.
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PMID:Insulin-dependent reduction in hepatic and splenic contents of interleukin-1 beta in experimental diabetes. 759 Jun 11


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