Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Highly purified regular porcine insulin was given by portable insulin pumps through indwelling vena caval catheters to 17 (13 normal, and 4 pancreatectomized) dogs initially weighing 15 +/- 2 kg at rates ranging from 2 to 10 mU/min (total 17-250 mg) over time periods ranging from 37 to 252 days. During the course of the study, many of the animals lost weight and became anemic. Since these conditions persisted and weight loss progressed even after cessation of insulin infusion, as many of the dogs as possible (15 of 17) were autopsied for microscopic studies. Large amounts of amyloid were demonstrated in the liver, kidney, spleen, and/or pancreas in 55% (6/11) of normal, and in 75% (3/4) of pancreatectomized dogs. The amyloid deposits were Congo red positive, exhibited classical apple green fluorescence under polarized light, and possessed the characteristic ultrastructural features of amyloid. Massive deposits of amyloid were observed in animals receiving as little as 17 mg of insulin over a time span of 52 days. In those animals with hepatic amyloid, marked hepatomegaly was present (i.e., 1200 +/- 250, X +/- SD, versus 300 +/- 25 g for normal animals) and preterminal serum alkaline phosphatase levels were markedly elevated (434 +/- 285 versus 30 +/- 14 IU/L for animals without hepatic amyloid). The magnitude of the hepatic amyloid deposits precludes the possibility that they represent insulin aggregates or insulin-derived products per se. No evidence of amyloid was present in any of the tissue biopsy specimens obtained prior to insulin infusion. Moreover, the possibility that this represents an immune response to the injected porcine insulin has to be viewed in light of the fact that the amino acid sequences of dog and porcine insulins are identical. It is of particular interest that the affinity of the amyloid deposits for Congo red stain was totally abolished by prior permanganate treatment, suggesting that the amyloid was derived from serum amyloid A protein rather than from immunoglobulin light chains or insulin aggregates per se. Further evidence that the protein was of the AA-type came from the initial biochemical characterization. Gel filtration on Sephadex G100 in 6 M guanidine hydrochloride identified two small molecular weight peaks of about 13,000 and 25,000 daltons, both of which inhibited the radioimmunoassay for human AA protein.(ABSTRACT TRUNCATED AT 400 WORDS)
Diabetes 1983 Dec
PMID:Unanticipated amyloidosis in dogs infused with insulin. 636 Jul 58

Fatty acid metabolism in the myocardium is affected by metabolic disorders such as diabetes mellitus. We evaluated 123I-beta-methyl-iodophenyl-pentadecanoic acid (BMIPP) myocardial scintigraphy in 15 diabetes mellitus patients without overt coronary heart disease. Patients with overt coronary heart disease were excluded by careful history taking, resting electrocardiography, treadmill exercise testing, echocardiography and resting 201Tl scintigraphy. Patients with remarkably impaired left ventricular (LV) systolic function (%FS < 30%) were also excluded. BMIPP uptake scores as the ratio of heart/mediastinum (H/M) and liver/mediastinum (L/M) at 20 minutes after injection were analyzed and compared with clinical profile, serum parameters, and LV parameters obtained from echocardiography. Five of the 15 patients showed abnormal BMIPP images; two patients showed a decreased uptake in the inferior segments, while three showed a diffuse decrease in BMIPP uptake. Body mass index (BMI), fasting blood sugar (FBS), HbAlc, IRI, and LV end-diastolic diameter (LVEDD) were higher in these five patients with abnormal BMIPP findings (abnormal BMIPP group vs normal BMIPP group, BMI: 29 vs 23 kg/m2, p < 0.05; FBS: 178 vs 114 mg/dl, p < 0.01; HbAlc: 7.6 vs 6.2%, p < 0.01; IRI: 18.5 vs 9.5 microU/ml, p < 0.01; LVEDD: 52 vs 44 mm, p < 0.05). 123I-metaiodobenzyl-guanidine (MIBG) scintigraphy in the five patients with abnormal BMIPP uptake showed more severe defects than in the 10 patients with normal BMIPP imaging. BMIPP scintigraphy demonstrated a significant correlation between H/M and L/M by BMIPP (r = 0.74, p < 0.01). Furthermore, correlation between H/M by BMIPP scintigraphy and clinical parameters (BMI, systolic blood pressure, FBS, HbAlc, IRI) were found, suggesting that diabetes mellitus patients without over coronary heart disease show abnormal BMIPP imaging when their general glucose utility and 123I-MIBG uptake are severely impaired (progression of insulin resistance and sympathetic nerve involvement). BMIPP scintigraphy may be useful in investigating the pathogenesis and subclinical abnormality of diabetic heart.
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PMID:[123I-beta-methyl-iodophenyl-pentadecanoic acid myocardial scintigraphy in diabetic patients without overt ischemic heart disease]. 766 41

This study was undertaken to compare the ability of two guanidine compounds (aminoguanidine and methylguanidine), with different in vitro effects on NO synthase activity and AGE formation, to inhibit diabetic vascular dysfunction developing early after the onset of diabetes. In rats with STZ-induced diabetes of 5-wk duration, regional vascular [125I]albumin permeation was increased about two- to threefold in ocular tissues, sciatic nerve, and aorta; in general, both guanidine compounds normalized albumin permeation in diabetic rats without affecting it in controls. Methylguanidine was only approximately 7% as effective as aminoguanidine as an inhibitor of AGE formation from L-lysine and G6P; both compounds were poor inhibitors of AR. Methylguanidine was approximately 1-5% as potent as aminoguanidine and L-NMMA as an inhibitor of the cytokine- and endotoxin-inducible isoform of NO synthase. In contrast, the potency of methylguanidine as an inhibitor of the constitutive isoform of NO synthase was comparable to that of aminoguanidine, and both guanidine compounds were much less effective than L-NMMA. These observations suggest a role for a relative or absolute increase in NO production in the pathogenesis of early diabetic vascular dysfunction and raise the possibility that inhibition of diabetic vascular functional changes by aminoguanidine may reflect inhibition of NO synthase activity rather than, or in addition to, prevention of AGE formation.
Diabetes 1993 Feb
PMID:Prevention of diabetic vascular dysfunction by guanidines. Inhibition of nitric oxide synthase versus advanced glycation end-product formation. 767 25

Studies were performed to examine the effect of experimental diabetes (4-6 weeks duration) on both the passive elastic and active myogenic properties of isolated skeletal muscle arterioles. Studies were conducted on untreated streptozotocin (60 mg/kg)-induced diabetic rats and in similar rats treated daily with either amino-guanidine (25 mg/kg) or methylguanidine (25 mg/kg). First-order cremaster muscle arterioles were isolated, cannulated, and pressurized in the absence of intraluminal flow. Video microscopy was used to determine relationships between arteriolar diameter and intraluminal pressure both in the active and passive (o mmol/l Ca(2+)-2 mmol/l EGTA superfusated) tes. The measurements were used to calculate active myogenic responses, arteriolar distensibility, and stress-strain relationships. Under passive conditions, arterioles from untreated diabetic animals appeared to be stiffer and less distensible compared with similar arterioles from control animals. Under active conditions, i.e., in the presence of extracellular Ca2+, arterioles from the untreated diabetic group showed impaired myogenic reactivity as evidenced by a significant (P < 0.001) reduction in the negative slope of the pressure-diameter relationship over a physiological range of intraluminal pressures. Chronic treatment with aminoguanidine prevented the diabetes-induced changes in the active and passive properties of the isolated arterioles while treatment with methylguanidine appeared ineffective. Vasodilator responses to topically applied acetylcholine (10(-8) to 5 x 10(-6) mol/l) were significantly impaired in diabetic animals irrespective of treatment with aminoguanidine. The data indicate that experimental diabetes is associated with a decreased passive distensibility, or stiffening, of skeletal muscle arterioles that, in addition, may contribute to impaired active myogenic responses.
Diabetes 1994 Dec
PMID:Active and passive mechanical properties of isolated arterioles from STZ-induced diabetic rats. Effect of aminoguanidine treatment. 795 98

Non-enzymatic protein glycosylation is the first stage of the reaction described by L.C. Maillard. When the reaction progresses beyond that stage the long half-life molecules are damaged by formation of intermolecular crosslinking. The recent discovery of pentosidine, a crosslink between lysine and arginine residues, has demonstrated that advanced Maillard reaction is accelerated in diabetic patients with severe complications. Moreover, high tissue and plasma levels of pentosidine have been found in uraemia. The formation of advanced Maillard end-products (AGE) in plasma proteins constitutes a source of cell stimulation which induces macrophages to secrete cytokines, interleukin-1 and tumoral necrosis factor. Similarly, endothelial cells are induced to increase the permeability and production of the procoagulant factor. These mechanisms are thought to play an important role in the pathogenesis of atherosclerosis, nephropathy and thromboembolic disorders of diabetes. The discovery of beneficial effects of amino-guanidine, an inhibitor of advanced Maillard reaction, in the prevention of experimental diabetic complications opens a new line of investigation and new hopes for diabetics.
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PMID:[Non-enzymatic glycosylation of proteins. Complications of diabetes mellitus, aging and kidney failure]. 824 84

To evaluate the long-held concept that acidic guanidines lack glycemic effects, guanidinoalkanoic acids and the biguanide metformin (positive control) were administered to KKAy mice, a model of noninsulin-dependent diabetes. Two acidic guanidines, 3-guanidinopropionic acid (3-GPA) and guanidinoacetic acid, decreased the plasma glucose level; other compounds were ineffective. 3-GPA was more potent than even metformin. Insulin suppression tests in KKAy mice indicated that improved insulin sensitivity was the mode of action for 3-GPA. Glycemic effects in KKAy mice resulted from increased glucose disposal whereas gluconeogenesis, hepatic glycogen content and intestinal glucose absorption were unchanged. 3-GPA's glycemic effect was corroborated in two other models of noninsulin-dependent diabetes. In ob/ob mice, the compound reduced hyperglycemia, polyuria, glycosuria and hyperinsulinemia. In insulin-resistant rhesus monkeys, it increased the disappearance of i.v. glucose. The glycemic action of 3-GPA required the presence of some circulating insulin as well as hyperglycemia because the compound was ineffective in normoglycemic mice, insulinopenic Chinese hamsters and streptozotocin-diabetic rats. These data indicate that acidic guanidine derivatives can ameliorate hyperglycemia in animal models of noninsulin-dependent diabetes. Because acidic derivatives uniquely lack the propensity of guanidine compounds for inducing lactic acidosis, our finding suggests a new approach for developing improved antidiabetes compounds from this chemical class.
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PMID:Antihyperglycemic action of guanidinoalkanoic acids: 3-guanidinopropionic acid ameliorates hyperglycemia in diabetic KKAy and C57BL6Job/ob mice and increases glucose disappearance in rhesus monkeys. 837 Nov 49

The relationship between cardiosympathetic neuropathy and cardioparasympathetic neuropathy was investigated in 103 patients with non-insulin-dependent diabetes mellitus. Cardioparasympathetic nerve function was assessed by comparing electrocardiographically the expiratory and inspiratory R-R interval ratios, during a period of deep breathing, and the coefficients of variation of the R-R intervals. Cardiosympathetic nerve function was assessed by determining the uptake of [123I]metaiodobenzyl guanidine into the myocardium. The results indicate that there is no significant correlation between cardioparasympathetic and cardiosympathetic nerve function.
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PMID:Cardiosympathetic neuropathy is independent of cardioparasympathetic neuropathy in patients with non-insulin-dependent diabetes mellitus. 852 79

Aminoguanidine, nucleophilic hydrazine derivative, has been shown to inhibit diamine oxidase, the formation of advanced glycation endproducts, nitric oxide synthase, and catalase. Prompted by the reports that aminoguanidine also inhibits aldose reductase (AR), we have investigated the effect of aminoguanidine, 1,3-diaminoguanidine, and methylguanidine on AR activity in vitro, and in vivo. In vitro, we have measured the inhibition of AR isolated from bovine lenses; in vivo, we have examined the effect on the galactitol levels in the red blood cells, sciatic nerve, retina, and lens of rats administered the test compounds for 11 days in the drinking water and, for the last 4 days, given access to a 20% galactose diet. Two known, structurally distinct AR inhibitors, tolrestat and compound WAY-121,509, were used as reference. In vitro, at concentrations up to 1.0 mmol/L, none of the tested guanidine derivatives had any effect on AR. As a corollary, in vivo, at doses ranging from 201 to 349 mg/kg/day, none of the guanidine derivatives affected tissular galactitol levels. We conclude that, in short-term galactose-fed rats, at the doses tested, aminoguanidine, 1,3-diaminoguanidine, and methylguanidine do not inhibit AR.
J Diabetes Complications
PMID:Aminoguanidine does not inhibit aldose reductase activity in galactose-fed rats. 863 71

The relationship between cardiac autonomic neuropathy and diabetic microangiopathies and macroangiopathy was investigated in 103 patients with non-insulin-dependent diabetes mellitus. Cardiac autonomic nerve function was assessed by determining the uptake of [123I]metaiodobenzyl-guanidine into the myocardium. Cardioparasympathetic nerve function was assessed by comparing electrocardiographically the expiratory and inspiratory respiratory rate (RR) interval ratios, during a period of deep breathing, and the coefficients of variation of the RR intervals. Nerve conduction velocity measurements were used to assess diabetic somatic neuropathy, and measurement of pulse-wave velocity provided an indication of the extent of aortic sclerosis. The only correlations between the parameters of cardiac autonomic neuropathy and parameters of diabetic microangiopathies and macroangiopathy were between the expiratory to inspiratory RR interval ratio and both the conduction velocity of the tibial nerve and pulse-wave velocity, and between the heart to lung ratio (cardiac autonomic nerve function) and nephropathy. These correlations may have occurred by chance; alternatively they may indicate a difference in the onset mechanisms of cardiac parasympathetic and sympathetic neuropathies in diabetics.
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PMID:Relationship between cardiac autonomic neuropathy and diabetic microangiopathies and macroangiopathy in patients with non-insulin-dependent diabetes mellitus. 867 5

The purpose of this study was to clarify any association between clinically detectable silent myocardial ischemia (SMI) and myocardial 123I-metaiodobenzyl-guanidine (MIBG) uptake. Subjects of this study were (1) patients with SMI with diabetes (n = 15), (2) patients with angina pectoris with diabetes (n = 15), (3) patients with SMI without diabetes (n = 8) and (4) normal subjects (n = 23). Subjects underwent planar and single photon-emission-computed tomography (SPECT) imaging 15 min and 3 hours after injection of 123I-MIBG. H/M ratio was significantly lower in diabetic SMI (2.1 +/- 0.3) and non-diabetic SMI (2.3 +/- 0.3) than control subjects (2.6 +/- 0.3). The inferior-to-anterior wall count ratio (I/A) in diabetic SMI group was the lowest among all groups (p < 0.05). A significant difference was observed in relative regional uptake in the inferior segment of the distal left ventricle between SMI and angina group in patients with diabetes mellitus (p < 0.05). The decreased MIBG uptake in the inferior wall may be an important sign of cardiac sympathetic dysfunction, suggesting the abnormalities in cardiac nervous system play an important role in the mechanism of diabetic silent myocardial ischemia.
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PMID:[Characteristics of regional sympathetic innervation in diabetic patients with silent myocardial ischemia assessed by 123I-metaiodobenzylguanidine imaging]. 869 17


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