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)

OBJECTIVE: To compare kinetics and accumulation of 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) in primary lung cancer between diabetic and non-diabetic patients using positron emission tomography (PET).METHODS: Five diabetic patients and 21 non-diabetic patients underwent dynamic FDG-PET to image untreated primary lung cancers. Standardized uptake value normalized for lean body mass (SUL) was determined in tumor, blood, muscle, and lung. A 3-compartment metabolic model was applied to FDG kinetics in tumors in 24 of 26 patients.RESULTS: At the time of PET scans, serum glucose levels were elevated in 5 diabetic patients, while 21 non-diabetic patients showed normal glucose levels. In diabetic patients, tumor SUL, tumor/blood and tumor/muscle SUL ratios were significantly decreased (P < 0.02) and also tumor/lung SUL ratio declined (P = 0.064), as compared to non-diabetic patients. In addition, the rate constant for FDG phosphorylation (k3) and influx constant (Ki) in diabetic patients were significantly lower than those in non-diabetic patients (P < 0.02).CONCLUSION: In diabetic patients, the rate of FDG accumulation in tumors is decreased, and tumor targeting with FDG is impaired. Diabetes may reduce the sensitivity of FDG-PET for lung cancer detection.
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PMID:Diabetes Decreases FDG Accumulation in Primary Lung Cancer. 1451 52

The pancreas is one of the most heavily innervated peripheral organs in the body. Parasympathetic and sympathetic neurons terminate in the pancreas and provide tight control of endocrine and exocrine functions. The aim of this study was to determine whether the pancreas can be imaged with a radioligand that binds to specific neuroreceptors. Using fluorine-18 4-fluorobenzyltrozamicol (FBT), which binds to the presynaptic vesicular acetylcholine transporter, positron emission tomography scans were performed in four adult mice, two adult rhesus monkeys, and one adult human. In these mammals, the pancreas is intensely FBT avid, with uptake greater than in any other organ at 30, 60, and 90 min. The maximum standardized uptake value (SUV) ratios of pancreas to liver, for example, ranged from 1.4 to 1.7 in rhesus monkeys (mean 1.6; median 1.7) and from 1.9 to 4.7 (mean 3.24; median 3.02) in mice. The maximum SUV ratio of pancreas to liver in the human was 1.8. These data suggest that neuroreceptor imaging of the pancreas in vivo is feasible in animal models and humans. This imaging could allow researchers to interrogate functions under control of the autonomic nervous system in the pancreas, with applications possible in transplanted and native pancreata. Also, as beta cell function is intimately related to parasympathetic cholinergic input, FBT activity in the pancreas may correlate with insulin-producing beta cell mass. This could ultimately provide a method of in vivo imaging in animal models and humans for diabetes research.
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PMID:Neurofunctional imaging of the pancreas utilizing the cholinergic PET radioligand [18F]4-fluorobenzyltrozamicol. 1512 9

Aldose reductase, the first and rate-limiting enzyme of the polyol pathway, is a target for drug design for the treatment of diabetes complications. The structures of aldose reductase in complex with the cyclic imide inhibitors Fidarestat and Minalrestat were recently determined at ultra-high resolution (Proteins 2004, 55, 805). We have used the detailed structural information revealed at atomic resolution, including the assignment of protonation states for the inhibitors and active site residues, together with molecular modelling and noncovalent mass spectrometry to characterise the type and strength of the interactions between the enzyme and the inhibitors, and to attempt the design of novel potential inhibitors with enhanced binding energies of the complexes. The VC(50) values measured by mass spectrometry (accelerated voltage of ions needed to dissociate 50% of a noncovalent complex in the gas phase) for the aldose reductase inhibitors correlate with the IC(50) values (concentration of inhibitor giving 50% inhibition in solution) and with the electrostatic binding energies calculated between the active site residues Tyr48, His110 and Trp111 and the inhibitors, suggesting that electrostatic interactions play a major role in inhibitor binding. Our molecular modelling and design studies suggest that the replacement of the fluorine atom in Minalrestat's bromo-fluorobenzyl group with nitro, amide and carboxylate functional groups enhanced the predicted net binding energies of the complexes by 16%, 31% and 68%, respectively. When the carbamoyl group of Fidarestat was replaced with a nitro, 4-hydroxyl phenyl and carboxylate functional groups, the predicted net binding energies of the complexes were enhanced by 13%, 34% and 46%, respectively.
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PMID:Probing the ultra-high resolution structure of aldose reductase with molecular modelling and noncovalent mass spectrometry. 1521 Jan 46

The epidemic of obesity is worldwide. It will be followed by an epidemic of diabetes. Although there is a genetic basis for obesity and diabetes, the current epidemic reflects the failure of our ancient genes to cope with a modern toxic environment. To put it another way, the genetic background loads the gun, but the environment pulls the trigger. Diet, lifestyle and exercise are the cornerstones of current approaches to treating obesity. However, these approaches that depend on individuals making lifestyle changes have been ineffective in preventing the epidemic. An alternative model views obesity as an epidemiological disease with food(s) and other environmental agents acting on the host to produce disease. The consumption patterns for many foods have changed over the past 30 years, but the increase in the consumption of high-fructose corn syrup (HFCS) for soft drinks is far and away the largest. Moreover, the rise in HFCS intake is an environmental insult that has occurred at exactly the same time as obesity began to increase in prevalence. Rising soft drink consumption is associated with a decrease in milk consumption and a decrease in calcium intake, which has an inverse relationship to body mass index (BMI). To combat the epidemic of obesity, we need new strategies that flow from the epidemiological model. The Fluoride Hypothesis for obesity proposes that we can make environmental changes that when made, will reduce the epidemic of obesity, in much the same way as fluoride reduced the incidence of dental disease. Fluoride-like strategies can work without the personal effort required by changes in lifestyle. In this context, fluoride is also an acronym for treatment and prevention of obesity: For Lowering Universal Obesity Rates are Implement ideas that Don't demand Effort (FLUORIDE).
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PMID:The epidemic of obesity and changes in food intake: the Fluoride Hypothesis. 1523 99

Diabetic neuropathy (DN) is a complication of diabetes that affects the distal terminals of lengthy-projecting sensory axons. To determine whether diabetes-induced axonal degeneration induces gene expression similar to nerve injury, the expression of activating transcription factor 3 (ATF3) by primary sensory neurons was examined in an experimental mouse model of DN. Diabetes was induced using streptozotocin in C57BL/6 mice, and ATF3 expression in lumbar dorsal root ganglia was assessed at different time points and correlated with the markers of unmyelinated and myelinated neuronal populations. ATF expression was first evident 3 weeks after diabetes induction in both small unmyelinated and large myelinated neurons, but it was more prevalent in larger neurons. At 6 weeks, ATF3 was expressed by neurons among smaller size ranges, but this shift occurred principally within myelinated populations. The retrograde labeling of neurons innervating the flank and paw skin using Fluoro-Gold labeled appropriate percentages of ATF3-positive neurons at 3 weeks, suggesting ATF3 is expressed by neurons capable of transporting substances. However, the percentage of double-labeled neurons was substantially reduced at 6 weeks, suggesting this capacity decreases during disease progression. Finally, behavioral responses to noxious cutaneous stimuli were assessed. Although no differences to radiant heat were observed, diabetic mice developed severe mechanical hypoalgesia 4-5 weeks after diabetes induction. These results demonstrate that the diabetes-induced damage of sensory axons can induce the expression of genes linked to peripheral nerve injury and may identify neurons undergoing nerve damage. Finally, the ability to detect sensory deficits in diabetic mice occurs after the expression of injury-related gene ATF3, suggesting that nerve damage may be underway prior to the appearance of behavioral deficits.
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PMID:Diabetes-induced expression of activating transcription factor 3 in mouse primary sensory neurons. 1557 37

Intensive insulin therapy in patients with type 1 diabetes mellitus reduces long-term complications; however, intensive therapy is also associated with a three-fold increase in hypoglycemic episodes. The present study in conscious rats characterizes the physiologic and neuropathologic consequences of a single episode of moderate hypoglycemia. In this model, intravenous insulin is used to reduce plasma glucose to 30 to 35 mg/dL for 75 mins. This single hypoglycemic insult acutely induces hypoglycemia-associated autonomic failure (HAAF), with epinephrine responses to hypoglycemia reduced more than 36% from control. Neuropathology after this insult includes the appearance of dying cells, assessed with the marker Fluoro-jade B (FJ). After hypoglycemic insult, FJ+ cells were consistently seen in subdivisions of the medial prefrontal cortex, the orbital cortex, and the piriform cortex. There was a significant correlation between depth of hypoglycemia and number of FJ+ cells, suggesting that there is a critical threshold below which vulnerable cells begin to die. These data suggest that there is a population of cells that are vulnerable to moderate levels of hypoglycemia commonly experienced by patients with insulin-treated diabetes. These cells, which may be neurons, are primarily found in cortical regions implicated in visceral perception and autonomic control, raising the possibility that their loss contributes to clinically reported deficits in autonomic and perceptual responses to hypoglycemia.
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PMID:Cortical Fluoro-Jade staining and blunted adrenomedullary response to hypoglycemia after noncoma hypoglycemia in rats. 1590 94

We assessed the value of positron emission tomography to predict long-term outcome in patients with diabetes and ischemic left ventricular (LV) dysfunction. Circumferential profiles of nitrogen-13 ammonia (NH3) and fluorine-18 fluorodeoxyglucose uptakes were obtained in 61 patients who had diabetes and ischemic LV dysfunction. Patient profiles were compared with those from a normal database. NH3 and fluorine-18 fluorodeoxyglucose defect sizes and extent of perfusion-metabolism mismatch (percentage of myocardium with fluorine-18 fluorodeoxyglucose uptake minus NH3 uptake >2 SD above the normal difference) were determined. Patients were followed every 6 months. Over a mean follow-up of 4.3 years, cardiac death occurred in 52% of patients who underwent revascularization and 61% of those who underwent medical therapy (p = 0.69). No clinical or imaging variables predicted cardiac death in patients who underwent revascularization. In those who received medical therapy, mismatch in > or =3% of the left ventricle (risk ratio 4.0, p = 0.01) was the only multivariate predictor of cardiac death. Revascularization improved survival of patients who had mismatch of > or =3% at 4 years (p = 0.003) and at 8 years (p = 0.012) of follow-up. Patients who had mismatch > or =3% and ejection fraction <30% had the greatest improvement in survival with revascularization compared with medical therapy (p <0.0001). Revascularization also improved 4-year survival of patients who had NH3 perfusion defects of > or =25% of the left ventricle (p = 0.02). In conclusion, mismatch identifies medically treated patients who have diabetes and LV dysfunction, who are at high risk for cardiac death. Intermediate- and long-term survival of patients who have diabetes and mismatch may be improved with revascularization, and those who have significant mismatch and severe LV dysfunction have the greatest benefit.
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PMID:Usefulness of positron emission tomography in predicting long-term outcome in patients with diabetes mellitus and ischemic left ventricular dysfunction. 1597 22

Pancreatic islet cell mass (PICM) is a major determinant of the insulin secretory capacity in humans. Currently, the only method for accurate assessment of the PICM is an autopsy study. Thus, development of a technique allowing the non-invasive quantification of PICM is of great interest. The aim of this study was to develop such a non-invasive technique featuring novel fluorine- and (99m)Tc-labelled glibenclamide derivatives. Despite the structural modifications necessary to introduce fluorine into the glibenclamide molecule, all derivatives retained insulin stimulating capacity as well as high affinity binding to human SUR1 when compared to the original glibenclamide. Contrastingly, the lipophilicity of the fluorine-labelled derivatives was altered depending on the particular modification. In the human PET-study a constant but weak radioactive signal could be detected in the pancreas using a fluorine-labelled glibenclamide derivative. However, a reliable assessment and visualisation of the PICM could not be obtained. It can be assumed that the high uptake of the fluorine-labelled tracer e.g. into the the liver and the high plasma protein binding leads to a relatively low signal-to-noise ratio. In case of the presented fluorine-labelled glibenclamide based compounds this could be the result of their invariably high lipophilicity. The development of a (99 m)Tc-labelled glibenclamide derivative with a lower lipophilicity and differing in vivo behaviour, glibenclamide based compounds for non-invasive imaging of the pancreatic islet cell mass may be possible.
Exp Clin Endocrinol Diabetes 2005 Jul
PMID:In vitro and in vivo evaluation of novel glibenclamide derivatives as imaging agents for the non-invasive assessment of the pancreatic islet cell mass in animals and humans. 1602

Congenital hyperinsulinism (HI) is the most important cause of hypoglycaemia in early infancy. The inappropriate oversecretion of insulin is responsible for profound hypoglycaemias requiring aggressive treatment to prevent severe and irreversible brain damage. Several classifications of HI can be attempted, based on: 1) the onset of hypoglycemia in the neonatal period or later in infancy; 2) the histological lesion: focal or diffuse; 3) the genetic transmission: sporadic, recessive, or less frequently dominant. The most common underlying mechanism of HI is dysfunction of the pancreatic ATP-sensitive potassium channel (K(+)(ATP)). The 2 subunits of the K(+)(ATP) channel are encoded by either the sulfonylurea receptor gene (SUR1 or ABCC8) or the inward-rectifying potassium channel gene (KIR6.2. or KCNJ11), both located in the 11p15.1 region. Focal CHI has been shown to result from a paternally inherited mutation on the SUR1 or KIR6.2 gene and loss of the maternal 11p15 allele restricted to the pancreatic lesion. Diffuse HI, frequently due to mutations of the SUR1 or KIR6.2 genes of autosomal recessive inheritance is genetically heterogeneous. The distinction between the focal and the diffuse HI is very important, because the treatments are different. To distinguish between focal and diffuse HI, transhepatic catheterisation with pancreatic venous sampling was the reference technique, but will likely be replaced by [(18)F] Fluoro-L-Dopa PET scan, which is easier to perform. In absence of response to the medical treatment (diazoxide) a limited pancreatectomy permits to cure focal HI, while a diffuse HI requires a subtotal pancreatectomy with high risk of subsequent diabetes mellitus.
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PMID:[Congenital hyperinsulinism in newborn and infant]. 1619 94

The hippocampus, an important integration center for learning and memory in the mammalian brain, undergoes neurological changes in response to a variety of stimuli that are suggestive of ongoing synaptic reorganization. Accordingly, the aim of this study was to identify markers of synaptic plasticity using rapid and reliable techniques such as radioimmunocytochemistry and confocal microscopy, thereby providing a "birds-eye view" of the whole hippocampus under hypercorticosteronemic conditions. The regulation of microtubule-associated protein 2, synaptophysin and postsynaptic density-95 was examined in two different animal models of hypercorticosteronemia: corticosterone administration and streptozotocin-induced diabetes using both a short-term (1 week) and long-term (5 weeks) treatment. Glucocorticoids and/or hyperglycemia increased synaptophysin expression in CA1, CA3 and the dentate gyrus, regions that exhibit synaptic plasticity in response to glucocorticoid exposure. In these models, postsynaptic density-95 expression increased in the CA3 region, particularly in the diabetic rats, while microtubule-associated protein 2 exhibited more selective changes. Fluoro-Jade histochemistry did not detect neuronal damage, suggesting that glucocorticoids and/or hyperglycemia induce plastic and not irreversible neuronal changes at these time points. Collectively, these results demonstrate that changes in the expression and distribution of synaptic proteins provide another measure of synaptic plasticity in the rat hippocampus in response to glucocorticoid exposure, changes that may accompany or contribute to neuroanatomical, neurochemical, and behavioral changes observed in experimental models of type 1 diabetes.
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PMID:Immunocytochemical analysis of synaptic proteins provides new insights into diabetes-mediated plasticity in the rat hippocampus. 1622 81


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