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)

Resistance to thyroid hormone (RTH) is usually inherited in a dominant fashion, and is characterized by elevated serum thyroid hormone levels and failure to suppress pituitary secretion of thyroid-stimulating hormone, with variable refractoriness to hormone action in peripheral tissues. Two major forms of the disorder are recognized: asymptomatic individuals with generalized resistance (GRTH) and patients with thyrotoxic features suggesting predominant pituitary resistance (PRTH). In over 100 families with GRTH or PRTH, we have identified heterozygous mutations in the thyroid hormone receptor beta isoform (TRbeta), which localize to three regions (amino acids 234-282, 310-353 and 429-461) of the hormone-binding domain of the receptor. The mutant receptors are transcriptionally impaired, due either to reduced ligand binding or to attenuated interaction with co-activators, and inhibit wild-type TR action in a dominant-negative manner. In the TRbeta crystal structure, most RTH mutations cluster around the hormone-binding pocket, with receptor regions that mediate functions (DNA binding, dimerization, co-repressor recruitment) required for dominant-negative activity being devoid of natural mutations. The pathogenesis of variable tissue resistance is not fully understood, but may be related to the differing tissue distributions of TRalpha and TRbeta, and to variable dominant-negative activity of mutant receptors on different target genes. The nuclear receptor peroxisome-proliferator-activated receptor gamma (PPARgamma) regulates adipogenesis and mediates the action of thiazolidinediones - novel anti-diabetic agents which enhance tissue insulin sensitivity. The PPARgamma gene was screened in 85 subjects with severe insulin resistance, and two different heterozygous receptor mutations (P467L and V290M) were identified in three affected individuals. The PPARgamma mutants are markedly transcriptionally impaired due to altered ligand binding and co-activator recruitment. Analogous to RTH, they inhibit the function of wild-type PPARgamma when co-expressed, and such dominant-negative inhibition is linked to their ability to silence basal gene transcription via aberrant interaction with co-repressors. In addition to insulin resistance, all three affected subjects developed Type II diabetes mellitus and hypertension at an unusually early age. Our findings provide compelling evidence that PPARgamma is important in the control of insulin sensitivity, glucose homoeostasis and blood pressure in humans. Future studies aim to elucidate the mechanism by which this receptor regulates insulin action and vascular tone.
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PMID:Resistance to thyroid hormone, and peroxisome-proliferator-activated receptor gamma resistance. 1135 59

Molecular diagnostic techniques provide an unsurpassed opportunity to understand the pathophysiological basis of endocrine disorders. Diseases have been associated with mutations in almost every gene known to have a role in either the production or secretion of a hormone or the mediators of hormone signalling. Even though most of these mutations are rare and account for only a small fraction of endocrine diseases, molecular diagnostics offers a valuable tool for the clinician in these cases. The most common endocrine disorders such as autoimmune thyroiditis, type 2 diabetes mellitus, osteoporosis, growth disorders, and obesity have all major genetic components, but these are mostly unknown. In this review the clinical implications of molecular diagnostics are illustrated for some endocrine diseases: congenital adrenal hyperplasia, congenital hypothyroidism, thyroid hormone resistance, familial hypocalciuric hypercalcaemia, growth hormone deficiency and resistance, and monogenic obesity. Improved diagnostic specificity has direct implications for treatment and follow up in these syndromes. Molecular diagnostics in endocrine tumours and diabetes are presented in two other articles in this series.
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PMID:[Molecular diagnostics in endocrine diseases]. 1647 3

This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders.
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PMID:Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement. 2995 30

Thyroid function and type 2 diabetes mellitus (T2DM) are both associated with increased risks of adverse clinical outcomes in nonalcoholic fatty liver disease (NAFLD). Our study is aimed at evaluating the association between thyroid function and NAFLD in T2DM patients with normal thyroid function (euthyroid) and analyzing the potential effects of metformin on the pathological process. Overall, 369 T2DM patients were enrolled between July 2017 and September 2018 and stratified into NAFLD and non-NAFLD groups. Data on age, gender, body mass index (BMI, kg/m2), metformin use, and basal metabolic rate (BMR) were obtained from participants' records. All patients were tested for biochemical markers, indexes of glucose metabolism, lipid metabolism, bone metabolism, and thyroid function at baseline. Multivariate analyses detected increased odds of NAFLD among individuals with T2DM per unit increase in their BMI and free triiodothyronine (FT3) and thyroid stimulating hormone (TSH); the odds ratios (OR) were 1.25, 3.02, and 1.58, respectively (all p < 0.05). Positive correlations were detected between alanine aminotransferase (ALT) and FT3 (r = 0.221, p = 0.010), and negative correlations were noted between TSH and BMR (r = -0.618, p < 0.001) and between BMR and FT3 (r = -0.452, p < 0.001) in T2DM subjects with NAFLD. A significant difference in serum FT3 (t = 2.468, p = 0.0167) and TSH (t = 2.658, p = 0.010) levels was found between obese individuals with NAFLD who used and did not use metformin. The pathological mechanism of T2DM complicated by NAFLD in euthyroid patients may be associated with insulin resistance and a thyroid hormone resistance-like manifestation, i.e., relevant hypothyroidism. Metformin can potentially decrease the double-resistance situation, especially in obese individuals.
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PMID:Association between Thyroid Function and Nonalcoholic Fatty Liver Disease in Euthyroid Type 2 Diabetes Patients. 3296 54