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)

There are two insulin receptor (IR) isoforms (designated type A and type B), derived from alternative splicing of exon 11 of the IR gene. Recently, we reported (Huang Z., Bodkin N.L., Ortmeyer H.K., Hansen B.C., Shuldiner A. R., 1994, J Clin Invest, 94:1289-1296) that an increase in the exon 11- (i.e. lacking exon 11) (type A) IR messenger RNA (mRNA) variant in muscle is associated with hyperinsulinemia, an early risk factor for noninsulin-dependent diabetes mellitus (NIDDM), in the spontaneously obese, diabetic rhesus monkey. To explore further the role of IR mRNA splicing in insulin resistance of NIDDM, we studied liver, another target organ that is resistant to insulin action in NIDDM. The relative amounts of the two IR mRNA-splicing variants in liver were quantitated by RT-PCR in normal, prediabetic, and diabetic (NIDDM) monkeys. The percentage of the exon 11- mRNA variant in liver (n = 24) was significantly correlated with fasting plasma glucose (r = 0.55, P < 0.01) and intravenous glucose disappearance rate (r = -0.45, P < 0.05). The exon 11- mRNA variant was increased significantly from 29.8 +/- 1.6% in monkeys with normal fasting glucose to 39.2 +/- 2.9% in monkeys with elevated fasting glucose (P < 0.01). These studies provide the first direct evidence in vivo that the relative expression of the two IR mRNA-splicing variants is altered in liver and suggest that increased expression of the exon 11- IR isoform may contribute to hepatic insulin resistance and NIDDM or may compensate for some yet unidentified defect.
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PMID:Altered insulin receptor messenger ribonucleic acid splicing in liver is associated with deterioration of glucose tolerance in the spontaneously obese and diabetic rhesus monkey: analysis of controversy between monkey and human studies. 863 66

Endogenous nerve growth factor (NGF) levels were studied in patients with nerve trauma, diabetes mellitus and leprosy, the most common causes of human peripheral neuropathy. In diabetics, there was an early length-dependent dysfunction of small-diameter sensory fibres, with depletion of skin NGF and the sensory neuropeptide substance P. The NGF depletion correlated significantly with decreased skin axon-reflex vasodilatation, which is mediated by small sensory fibres at least partly via substance P release. Immunostaining showed depletion of NGF in keratinocytes in diabetic skin. In injured nerves, NGF levels were reduced when compared to intact nerve, except acutely distal to injury; NGF-immunostaining was seen in Schwann cells in distal segments, including neuromas. NGF levels were decreased in leprosy-affected skin and nerve. The role of neurotrophins in the rational treatment of human neuropathies is discussed e.g. loss of nociception and axon-reflex vasodilatation contribute to skin ulceration, a major and serious complication, for which NGF may provide prophylaxis.
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PMID:Neurotrophins and peripheral neuropathy. 873 Jul 84

Peripheral neuropathy is an important factor of disability in the elderly. In order to learn more on the usefulness of intensive evaluation of patients over 65 years of age with subacute or chronic disabling peripheral neuropathy, we reviewed the clinical and nerve biopsy findings of the last 100 patients of this age group who suffered from a peripheral neuropathy severe enough to justify performance of a nerve biopsy for a diagnostic or prognostic purpose. Normal nerve biopsy findings led to the diagnosis of lower motor neuron disease in three patients and pointed to lesions of the spinal roots in six other patients. Necrotizing arteritis was demonstrated in the biopsy specimens of 23 patients, and non-necrotizing vasculitis in five. In five additional patients the diagnosis of vasculitic neuropathy was kept in spite of non-contributive biopsy findings. In two diabetic patients who had a multifocal neuropathy the biopsy also revealed the presence of vasculitis. Thus 35% of the patients included in this series had one form or another of vasculitic neuropathy. Fourteen patients had a chronic inflammatory demyelinating polyneuropathy. In 11 patients the neuropathy was associated with monoclonal gammopathy, which was benign in nine and associated with malignant plasma cell dyscrasia in two. Among the six patients with diabetes mellitus, two patients who presented with a multifocal neuropathy were found to have vasculitis in the nerve specimen; in the others the biopsy was performed because of uncommonly severe pains or motor involvement due to an extremely severe diabetic neuropathy. Six patients suffered from a long-lasting disability secondary to a drug-induced neuropathy. The remaining 15% had neuropathies of different origin, including amyloidosis, lepromatous leprosy, carcinomatous neuropathy and alcoholic neuropathy. Six patients had a mild, non-progressive or slowly progressive axonopathy of unknown origin, ageing of the peripheral nervous system may have played a role in its development. Our findings show that vasculitis is an important and treatable cause of disabling neuropathy in the elderly and that the proportion of patients with severe neuropathy of unknown origin is small.
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PMID:Contribution of nerve biopsy findings to the diagnosis of disabling neuropathy in the elderly. A retrospective review of 100 consecutive patients. 881 73

Emerging emphases on systems of care, cost containment, and preventive interventions require the CNS to recognize risk factors and change health behaviors before complications develop. To lower substantially the rate of nontraumatic lower extremity amputation, high-risk populations must be screened and must receive appropriate management, including education and self-care interventions. In this article, two studies that examined foot risk factors in ambulatory elderly with intact feet are compared. American Diabetes Association and Gillis W. Long Hansen's Disease Center risk criteria were applied to both datasets. Recommendations for education, management, and referrals based on the calculated level of risk are presented.
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PMID:Evolving role of CNSs in developing risk-anchored preventive interventions. 884 53

Among principal causes of acrodystrophic neuropathy-ie, leprosy, diabetes, amyloid neuropathy, hereditary sensory neuropathies-alcoholism is controversial since first descriptions (Bureau et al, 1957) incriminating heavy drinking. This retrospective review of 38 cases occurring in West-Indian rhum abusers, tends however to confirm its etiologic role. Patients present with three non specific signs or symptoms of the lower extremities: anaesthetic foot, plantar ulcers, and chronic, indolent, mutilating arthropathies. Motor function is spared. Male gender, massive (> or = 150 g pure alcohol daily) and prolonged (> or = 12 years) rhum intake, hygiene deficiency, poverty and social distress, exposition to repeated foot microtrauma and a protracted, non fatal, but disabling course leading to amputation, are the main features of this syndrome. The pathophysiology is poorly documented, and many questions remain unanswered including a genetic predisposition or a particular neuro-toxicity of West Indian rhum. However, the clinical and epidemiologic data presented here favour the concept of an "alcoholic foot" or true alcoholic acrodystrophic neuropathy, quite different from the most common sensory-motor form.
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PMID:[Mutilating acrodystrophic neuropathy of alcoholic origin in the French West Indies]. 895 26

Dapsone (4,4'-diaminodiphenyl sulfone) has a large clinical experience due to its antimicrobial effects against Mycobacterium leprae, the causative agent of leprosy, and is used clinically where inflammation mediated by neutrophils is perceived to play a role. We administered dapsone in two concentrations (0.001% and 0.0001% w/w of diet) to 30 female non-obese diabetic (NOD) mice to explore the effect of dapsone on the development of IDDM following either a 1-week pulse or 20 weeks of continuous oral dapsone administration. Those mice receiving either the high or low doses of dapsone in the continuous group had a significantly reduced cumulative percentage of onset of IDDM. One of the seven mice given 0.0001% dapsone became diabetic (age 25 weeks), while none of the eight high dose (0.001%) mice developed the disease. Histological examination of pancreatic sections revealed islet infiltration in all groups of animals. The pulse and continuous experiments showed no statistically significant difference in the frequency or severity of lymphocytic infiltration. Dapsone administration did not inhibit growth, and growth rates were greater in those animals receiving the higher dapsone dose compared with the lower dose comparable to controls. We studied whether dapsone influenced murine lymphocyte function in addition to the published effects of the drug on neutrophils. At doses approximating those achieved in vivo (0.4 and 2 micrograms/ml), dapsone was found to inhibit murine splenocyte IL-2 and IL-4 secretion in response to concanavalin A. In view of the wide clinical experience with dapsone, randomized trials of the drug in new onset diabetes may be warranted.
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PMID:Dapsone decreases the cumulative incidence of diabetes in non-obese diabetic female mice. 920 62

Thirty-two cases of ankle fractures associated with fibular fractures above the distal tibiofibular syndesmosis were studied. All were treated with open reduction and internal fixation. The average follow-up was 25 months. The results of the postoperative evaluation were rated, based on subjective clinical criteria, as good, fair, and poor. According to the Lauge-Hansen classification, there were 17 (53%) cases of supination-external rotation injury (2 stage 2 and 15 stage 4), 9 (28%) cases of stage 3 pronation-abduction injury, and 6 (19%) cases of pronation-external rotation injury (3 stage 3 and 3 stage 4). All cases could be classified as Weber type C or as suprasyndesmotic, fibular diaphyseal fracture (44-C) according to the Orthopaedic Trauma Association classification. In 18 (56%) cases, the fracture was associated with ankle dislocation. There were seven (22%) open fractures, (two grade I, four grade II, and one grade IIIA). Syndesmotic screws were used in 23 (72%) cases (12 supination-external rotation injury, 6 pronation-external rotation injury, and 5 pronation-abduction injury). The syndesmotic screw was removed after an average of 9 weeks. Four (13%) nonunions and two (6%) delayed unions of the fibula were treated with bone grafting and/or hardware revision and eventually healed. Three of the nonunions had poor clinical results because of degenerative ankle joint arthritis in two (one of them ended in arthrodesis) and deep infection, which was eventually cured, in the third. The fourth nonunion had a fair result. One of the delayed unions had a fair result (an obese patient) and the other had a good result. Two patients developed deep infections; one ended in gangrene and amputation in a diabetic patient, and the other was a patient with fibular nonunion that eventually healed. Three patients had superficial infections that were treated successfully. Of the 32 cases, 23 (72%) showed good results, 4 (13%) showed fair results, and 5 (16%) showed poor results. The cases with poor results included three fibular nonunions, one deep infection, and one recurrent superficial infection and wound dehiscence after hardware removal. A syndesmotic screw is usually needed in cases of fracture-dislocations. Two patients with occult fibular nonunions developed diastasis of the syndesmosis after removal of the syndesmotic screw. It was found that reduction and temporary pinning of the distal tibiofibular joint helps achieve fibular length, which is crucial to restoring the biomechanics of the ankle joint. It seems advisable not to remove the syndesmotic screw until there are signs of healing of fibular fracture to avoid diastasis of the distal tibiofibular joint. Bone grafting should be considered in high energy fractures with comminution. These complex injuries are associated with higher rates of complications. Poor results can be attributed to fracture factors, e.g., open fractures, infections; patient factors, e.g., obesity, lowered immunity as in diabetes, and noncompliance; and iatrogenic factors, e.g., early removal of syndesmotic screws.
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PMID:Ankle fractures involving the fibula proximal to the distal tibiofibular syndesmosis. 927 48

Dapsone (4,4'-diaminodiphenyl sulfone) is a compound that has a large clinical experience due to its antimicrobial effects against mycobacterium leprae, the causative agent of leprosy. It is increasingly used in a number of clinical situations where inflammation may play an ancillary role. An inhibitory effect of the drug or lack thereof in the cumulative incidence or propagation of diabetes mellitus in the NOD mouse has mechanistic as well as therapeutic implications. We previously showed that dapsone administered continuously as a percentage of food to NOD mice inhibits the cumulative incidence of diabetes in a dose dependent fashion. In the present experiment, female NOD litter mates were randomized to receive dapsone (0.001% w/w as a percentage of food) at onset of diabetes. There were no differences in weight, blood glucose, or glycated hemoglobin at 10 weeks of age among the animals that were ultimately to receive dapsone (n = 10), mouse chow alone (n = 9), or those who did not develop diabetes (n = 3). The mean time to onset of diabetes, mean blood glucose at onset, and mean glycated hemoglobin at onset did not differ between animals who did or did not receive dapsone. Animals receiving dapsone had significantly (p < or = 0.03) lower glycated hemoglobin at weeks 2, 3, and 4 following the onset of diabetes and lived significantly longer following diagnosis of diabetes (7 vs. 4 weeks, p < 0.05). In conclusion, dapsone modulates the progression of autoimmune diabetes in the NOD mouse even when administered after the initiation of hyperglycemia.
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PMID:Dapsone at onset of diabetes lowers glycated hemoglobin and delays death in NOD mice. 986 28

The Nramp1 gene was originally described as Ity/Lsh/Bcg, a single gene controlling resistance and susceptibility of inbred mice to a range of intramacrophage pathogens. Functional studies demonstrated that Ity/Lsh/Bcg had multiple pleiotropic effects on macrophage activation pathways, broadening interest in the gene to include its candidacy as an autoimmune disease susceptibility gene. In 1993 the gene was positionally cloned and found to encode a polytopic integral membrane protein of unknown function. Subsequent studies have localized the protein to late endosomal and lysosomal compartments, and demonstrated that it functions as an iron transporter. Precisely how this function influences macrophage activation pathways is still under investigation, but is likely to include direct effects on pathogen survival in the endosomal/lysosomal compartment as well as influences on intracellular signalling pathways and in regulating mRNA stability. Several studies now provide evidence for a role for NRAMP1 in determining human susceptibility to autoimmune (rheumatoid arthritis. juvenile rheumatoid arthritis, diabetes, Crohn's disease) and infectious (tuberculosis, leprosy) diseases. Amongst these. data are accumulating to support the hypothesis that a functional Z-DNA forming repeat polymorphism in the promoter region of human NRAMP1 contributes directly to disease susceptibility. Four alleles have been observed, alleles 1 and 4 are rare (gene frequencies approximately equal to 0.001), alleles 2 and 3 occur at gene frequencies approximately 0.25 and approximately 0.75, respectively. In the absence of exogenous stimuli, alleles 1, 2 and 4 are poor promoters of gene expression in a luciferase reporter gene system; allele 3 drives high expression. Allele 3 shows allelic association with autoimmune disease susceptibility, allele 2 with infectious disease susceptibility. Hence, balancing selection is likely to be maintaining these two alleles in human populations. Although the association of NRAMP1 with autoimmune disease susceptibility may be related to any one of the multiple pleiotropic effects associated with macrophage activation, the function of NRAMP1 as an iron transporter now prompts more interesting speculation that regulation of iron transport may contribute directly to the disease phenotype in arthritic disease. Patients suffering from rheumatoid arthritis show increased deposition of iron in the synovial membrane, which may contribute to free radical generation and local inflammation. Further analysis of NRAMP1 function will continue to be of importance in understanding the molecular basis to autoimmune and infectious disease susceptibility.
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PMID:Genetic regulation of macrophage activation: understanding the function of Nramp1 (=Ity/Lsh/Bcg). 1006 30

The purpose of this pictorial essay is to illustrate the radiologic spectrum of imaging findings of neuropathic osteoarthropathy. Typical findings include joint destruction, disorganization, and effusion with osseous debris. A variety of other imaging findings related to neuropathic osteoarthropathy such as resorption of the ends of tubular bones and neuropathic fracture are shown. The two prevailing theories for the pathophysiology of neuropathic bone and joint disease, the neurovascular and neurotraumatic theories, are briefly described. Examples of osteoarthropathy from diverse causes are presented including syringomyelia, spinal cord injury, meningomyelocele, diabetes mellitus, congenital insensitivity to pain, steroid injections, syphilis, leprosy, and others. The discussion focuses on key imaging features with emphasis on disease patterns and differential diagnosis, which vary by skeletal location.
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PMID:Neuropathic osteoarthropathy: diagnostic dilemmas and differential diagnosis. 1104 79


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