Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As part of the four-center NIMH Genetics Initiative on Bipolar Disorder we carried out a genomic scan of chromosomes 3, 5, 15, 16,17, and 22. Genotyping was performed on a set of 540 DNAs from 97 families, enriched for affected relative pairs and parents where available. We report here the results of the initial 74 markers that have been typed on this set of DNAs. The average distance between markers (theta) was 12.3 cM. Nonparametric analysis of excess allele sharing among affected sibling pairs used the SIBPAL program of the S.A.G.E. package to test three hierarchical models of affected status. D16S2619 gave some evidence of linkage to bipolar disorder, with P = 0.006 for Model II (in which bipolar 1, bipolar 2 and schizoaffective-bipolar type individuals are considered affected). Nearby markers also showed increased allele sharing. A second interesting region was toward the telomere of chromosome 5q, where D5S1456 and nearby markers showed increased allele sharing; for D5S1456, P = 0.05, 0.015 and 0.008 as the models of affected status become more broad. MOD score analysis also supported the possible presence of a susceptibility locus in this region of chromosome 5. A pair of adjacent markers on chromosome 3, D3S2405 and D3S3038, showed a modest increased allele sharing in the broad model. Several isolated markers had excess allele sharing at the P < 0.05 level under a single model. D15S217 showed a MOD score of 2.37 (P < 0.025). Multipoint analysis flagged the region of chromosome 22 around D22S533 as the most interesting. Thus, several regions showed modest evidence for linkage to bipolar disorder in this initial genomic scan of these chromosomes, including broad regions near previous reports of possible linkage.
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PMID:Initial genomic scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 3, 5, 15, 16, 17, and 22. 918 5

A 45-year-old man, with a 10-year history of manic depression treated with lithium, was admitted with hyperosmolar, nonketotic coma. He gave a five-year history of polyuria and polydipsia, during which time urinalysis had been negative for glucose. After recovery from hyperglycaemia, he remained polyuric despite normal blood glucose concentrations; water deprivation testing indicated nephrogenic diabetes insipidus, likely to be lithium-induced. We hypothesize that when this man developed type 2 diabetes, chronic polyuria due to nephrogenic diabetes insipidus was sufficient to precipitate hyperosmolar dehydration.
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PMID:Hyperosmolar nonketotic coma precipitated by lithium-induced nephrogenic diabetes insipidus. 953 87

Mutations in the melanocortin 4 receptor gene (MC4R) are the most common cause of monogenic human obesity. As part of our ongoing project entitled 'Turkish Obesity Genome Study' we determined the nucleotide sequence of the entire coding region of the MC4R gene in 40 morbidly obese subjects from independent families. Here we report a novel heterozygous mutation (N274S) in an adult female obese individual (age: 52 yrs, BMI 41.7 kg/m(2), height 158 cm, weight: 104 Kg). The sister of the index case (age: 55 yrs, height: 160 cm, weight: 110 Kg, BMI: 43 kg/m(2)) also carries the same mutation. Although both sisters were morbidly obese and hypertensive the index case had normal plasma insulin and fasting blood glucose levels whereas her sister had type 2 diabetes mellitus. No abnormalities of the reproductive function were present. Despite marked hyperphagia in childhood both sisters had a history of relatively diminished intensity of appetite after the age of 20. Of notice, index case was diagnosed to have cyclothymia whereas her sister was being treated for bipolar affective disorder. Detailed clinical evaluation revealed normal bone mineral density and serum calcium parameters as well as intact thyroid axis and hypothalamus-pituitary-adrenal axis in both patients. The human MC4-R deficient phenotype resembles the murine deficient state with regard to preserved reproductive function although hyperphagia, increased linear growth and absence of diabetes in mice are not observed in humans. Affected individuals have hyperphagia in childhood, which looses intensity later in life, and they also present with normal height and diabetes mellitus. Accumulating evidence indicate that melanocortin endocrine system or defective melanocortin signaling has inherently different characteristics in mice and humans resembling the variation observed with regard to leptin deficiency in both species.
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PMID:A novel melanocortin 4 receptor (MC4R) gene mutation associated with morbid obesity. 1144 23

Patients receiving treatment with atypical antipsychotics commonly experience weight gain, which can cause considerable distress and can have deleterious effects on cardiovascular health. Because of the associated weight gain and potential direct effects on glucose metabolism, atypical antipsychotics have also been linked to the development of type II diabetes mellitus. Data on long-term treatment with these agents show that clozapine and olanzapine, followed by risperidone, were associated with the greatest degree of weight gain. A large body of data suggests that during long-term treatment, patients receiving the atypical antipsychotic quetiapine experience minimal weight gain. Data also suggest that quetiapine treatment does not increase the risk of developing type II diabetes. The use of atypical antipsychotics is increasing, as these agents are being prescribed for schizophrenia in lieu of conventional antipsychotics. Furthermore, these drugs have efficacy for treating other conditions such as bipolar disorder. Physicians prescribing atypical antipsychotics must be aware of the risk of weight gain and its associated comorbidities.
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PMID:The implications of weight changes with antipsychotic treatment. 1283 46

Glycogen synthase kinase-3 (GSK-3) has perplexed signal transduction researchers since its detection in skeletal muscle 25 years ago. The enzyme confounds most of the rules normally associated with protein kinases in that it exhibits significant activity, even in resting, unstimulated cells. However, the protein is highly regulated and potently inactivated in response to signals such as insulin and polypeptide growth factors. The enzyme also displays a distinct and unusual preference for substrates that have been previously phosphorylated by other protein kinases which provides obvious opportunities for cross-talk. Its substrates are diverse and are predominantly regulatory molecules. The molecular cloning of the kinase revealed it to be encoded by two related but distinct genes. Moreover, the mammalian proteins showed remarkable similarity to a fruitfly protein isolated on the basis of its role in cell fate determination. From these humble beginnings, study of the enzyme has accrued further surprises such as its inhibition by lithium, its regulation by serine and tyrosine phosphorylation and its implication in several human disorders including Alzheimers disease, bipolar disorder, cancer and diabetes. Most recently, small molecule inhibitors of GSK-3 have been developed and assessed for therapeutic potential in several of models of pathophysiology. The question is whether modulation of such an "involved" enzyme could lead to selective restoration of defects without multiple unwanted side effects. This review summarizes current knowledge of GSK-3 with respect to its known functions, together with an assessment of its real-life potential as a drug target for chronic conditions such as type 2 diabetes.
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PMID:Physiological roles of glycogen synthase kinase-3: potential as a therapeutic target for diabetes and other disorders. 1468 59

With the widespread use of atypical antipsychotics over the past several years, adverse metabolic effects have emerged as the most serious medical consequences of pharmacotherapy with some of these agents. Initially, weight gain and obesity were observed (especially with clozapine and olanzapine), but subsequently, type 2 diabetes and dyslipidemia became apparent as well. Further, many reports suggest that sudden and severe (occasionally fatal) diabetes ketoacidosis (DKA) can emerge during treatment with some atypical antipsychotics, even in the absence of adiposity. A marked increase of serum lipids (especially triglycerides) has also been reported, to varying degrees, with different atypicals. This article reviews the data regarding metabolic dysfunction in patients with psychosis (schizophrenia and bipolar disorder). Populations with psychosis have a 2-3-fold higher prevalence of diabetes even before treatment with any antipsychotics, suggesting a possible genetic linkage or comorbidity; this was confirmed with glucose regulation studies in schizophrenia and mania. The induction of type 2 diabetes with atypicals has further increased the prevalence of noninsulin-dependent diabetes from about 6% to 8% to 11% to 15% according to recent studies, and even higher rates of subclinical hyperglycemia. Serious weight gain (eg, 26-29 lbs after 1 year of clozapine or olanzapine treatment) is an important risk factor, but sudden DKA has now been reported in patients with minimal weight gain, suggesting alternative mechanisms, such as insulin resistance, as a direct effect of some atypicals. Psychiatrists can reduce the risk of metabolic disorders in schizophrenia and bipolar disorder by avoiding the use of certain atypicals as first-line treatment in patients with a personal or family history of diabetes, obesity, and hyperlipidemias. Regulatory agencies in some countries have already taken action in this regard.
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PMID:Factors in antipsychotic drug selection: tolerability considerations. 1497 55

Diabetic and psychiatric symptoms often appear in patients with Wolfram syndrome, and obligate carriers of WFS1 have increased prevalence of type 2 diabetes and are more likely to require hospitalization for psychiatric illness including bipolar disorder. To identify the polymorphisms in Japanese, we examined a region of approximately 50 kb covering the entire WFS1 gene, and evaluated the patterns of linkage disequilibrium. We found a total of 42 variations including 8 novel coding single nucleotide polymorphisms (A6T, A134A, N159N, T170T, E237K, R383C, V412L, and V503G), 14 novel non-coding polymorphisms, and 2 linkage disequilibrium blocks. We also performed association studies in patients with type 2 diabetes mellitus and patients with bipolar disorder. The haplotype comprising R456 and H611 was most associated with type 2 diabetes (p = 0.013) and the haplotype comprising g. -15503C/T and g. 16226G/A was most associated with bipolar disorder (p = 0.006), but neither reached significant difference after multiple adjustment. These genetic variations and linkage disequilibrium patterns in WFS1 in Japanese should be useful in further investigation of genetic diversities of WFS1 and various related disorders.
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PMID:Genetic variations in the WFS1 gene in Japanese with type 2 diabetes and bipolar disorder. 1523 38

In the United States, the risk of type 2 diabetes is currently growing to epidemic proportions, with many physicians unaware that disorders such as schizophrenia and bipolar disorder naturally place patients at an increased risk for diabetes. Another serious concern for physicians is the development of metabolic syndrome, also known as syndrome X, in patients suffering from schizophrenia. Metabolic syndrome often encompasses medical conditions such as weight gain, hypertriglyceridemia, and increased insulin, glucose, and low-density lipoprotein cholesterol levels. Treatment with atypical antipsychotics may increase the risk of metabolic syndrome and diabetes, and physicians need to be proactive when treating patients with schizophrenia. Physicians should be aware that the treatment of schizophrenia involves the right balance for the patient in terms of adverse effects versus benefit, and failing to treat a patient's mental illness because of potential medical problems may place the patient at an increased risk for more serious problems.
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PMID:Metabolic changes associated with antipsychotic use. 1600 Oct 95

Lifestyle, illness and treatment factors in people with bipolar disorder (BD) may confer additional risk of morbidity and mortality to the increasing rates of obesity, metabolic syndrome, diabetes mellitus and cardiovascular mortality in the general population.The aim of this review is to examine whether the risk of obesity and related morbidity and mortality are raised in BD, and possible contributory effects of lifestyle, illness and treatment factors to this risk.Systematic search of Medline and Cochrane Collaboration for relevant studies followed by a critical review of literature was carried out.Mortality from cardiovascular causes and pulmonary embolism (standardized mortality ratio approximately 2.0), and morbidity from obesity and type 2 diabetes mellitus may be increased in BD compared to the general population. Reduced exercise and poor diet, frequent depressive episodes, comorbidity with substance misuse and poor quality general medical care contribute to the additional risk of these medical problems in people with BD. There is no evidence that patients with BD are more sensitive than other patients to weight gain and medical problems associated with long-term use of psychotropic medication; in fact long-term treatment with lithium, antipsychotics and tricyclic antidepressants may reduce overall mortality. Psychiatrists, general practitioners and other health professionals should work together to systematically assess and manage weight gain and related medical problems to reduce the morbidity and mortality associated with obesity in BD. There is insufficient evidence to associate any of these factors with specific drug treatments. More research is required to understand how BD changes the risk for physical health comorbidity.
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PMID:Metabolism, lifestyle and bipolar affective disorder. 1628 Mar 42

We present the findings of a large linkage study of bipolar affective disorder (BPAD) that involved genomewide analysis of 52 families (448 genotyped individuals) of Spanish, Romany, and Bulgarian descent and further fine mapping of the 1p34-p36, 4q28-q31, and 6q15-q24 regions. An additional sample of 56 German families (280 individuals) was included for this fine-mapping step. The highest nonparametric linkage scores obtained in the fine mapping were 5.49 for 4q31 and 4.87 for 6q24 in the Romany families and 3.97 for 1p35-p36 in the Spanish sample. MOD-score (LOD scores maximized over genetic model parameters) analysis provided significant evidence of linkage to 4q31 and at least borderline significance for the 1p and 6q regions. On the basis of these results and previous positive research findings, 4q31 and 6q24 should now be considered confirmed BPAD susceptibility loci, and 1p35-p36 is proposed as a new putative locus that requires confirmation in replication studies.
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PMID:Genomewide scan and fine-mapping linkage studies in four European samples with bipolar affective disorder suggest a new susceptibility locus on chromosome 1p35-p36 and provides further evidence of loci on chromosome 4q31 and 6q24. 1638 Sep 20


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