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)

Nutrient oxidation in beta cells generates a rise in [ATP]:[ADP] ratio. This reduces K(ATP) channel activity, leading to depolarization, activation of voltage-dependent Ca(2+) channels, Ca(2+) entry and insulin secretion. Consistent with this paradigm, loss-of-function mutations in the genes (KCNJ11 and ABCC8) that encode the two subunits (Kir6.2 and SUR1, respectively) of the ATP-sensitive K(+) (K(ATP)) channel underlie hyperinsulinism in humans, a genetic disorder characterized by dysregulated insulin secretion. In mice with genetic suppression of K(ATP) channel subunit expression, partial loss of K(ATP) channel conductance also causes hypersecretion, but unexpectedly, complete loss results in an undersecreting, mildly glucose-intolerant phenotype. When challenged by a high-fat diet, normal mice and mice with reduced K(ATP) channel density respond with hypersecretion, but mice with more significant or complete loss of K(ATP) channels cross over, or progress further, to an undersecreting, diabetic phenotype. It is our contention that in mice, and perhaps in humans, there is an inverse U-shaped response to hyperexcitabilty, leading first to hypersecretion but with further exacerbation to undersecretion and diabetes. The causes of the overcompensation and diabetic susceptibility are poorly understood but may have broader implications for the progression of hyperinsulinism and type 2 diabetes in humans.
Diabetes Obes Metab 2007 Nov
PMID:beta-cell hyperexcitability: from hyperinsulinism to diabetes. 1791 82

Prader-Willi syndrome (PWS) is a complex genetic disorder localized to chromosome 15 and is considered the most common genetic cause of the development of life-threatening obesity. Although some morbidities associated with PWS, including respiratory disturbance/hypoventilation, diabetes, and stroke, are commonly seen in obesity, others such as osteoporosis, growth hormone deficiency, and hypogonadism, and also altered pain threshold and inability to vomit, pose unique issues. Various bariatric procedures have been used to cause gastric stasis, decrease gastric volume, and induce malabsorption, with poor results in PWS patients in comparison with normal obese individuals.
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PMID:Critical analysis of bariatric procedures in Prader-Willi syndrome. 1816 38

Three general genetic models for the development of the polycystic ovary syndrome (PCOS) can be proposed, namely: (1) the "single-gene Mendelian" model, which considers the majority of defects present in PCOS to be unique; (2) the "multifactorial" model, which suggests that the defects present in PCOS are not unique, and simply represent the conglomeration of abnormalities already present separately, and to a significant degree, in the general population (e.g. as in cardiovascular disease and non-insulin-dependent diabetes); and (3) the "variable expression-single gene" model, a modified version of the above two. Overall, our data support this third model, suggesting that PCOS is a familial disorder, with a single autosomal dominant gene effect, and a variable phenotype. Family history can then be considered as an important factor determining the risk of developing PCOS. Our preliminary data indicate that a woman's risk of developing PCOS is approximately 40% if her sister is affected. Alternatively, only 19% of mothers were affected, suggesting that the inheritance of PCOS may be preferentially paternal, although expanded clinical studies will be required to confirm these findings. Considering PCOS to be a dominant genetic disorder with a high degree of expressivity, we propose that the risk of developing the disorder is governed by family history and the degree of exposure to the selected environmental and/or other genetic influences.
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PMID:The development of the polycystic ovary syndrome: family history as a risk factor. 1840 41

DIDMOAD or Wolfram syndrome is a hereditary disorder characterized by early onset diabetes and optic atrophy. Besides these features, a variety of other symptoms have been described including psychiatrical abnormalities leading to hospitalization in about 25% of all patients. To our knowledge, until now, a detailed characterization of these psychiatric symptoms does not exist. Here we describe a 21-year-old male patient with deficits of frontal lobe function, such as impaired impulse control and learning deficits. Magnetic resonance imaging (MRI) of the brain showed a bilateral optic atrophy, but no signs of frontal brain atrophy. Neuropsychological tests revealed performance deficits in complex planning (e.g., Tower of London). Also his capacities in memorizing logically connected information after a short and delayed period of time were significantly reduced. Since histopathological studies did not reveal frontal brain abnormalities, but did show thalamic neuronal loss and gliosis, we interpret our findings as representative of thalamic dysfunction. In addition, hypoglycaemia seemed to trigger rapid mood swings. As soon as blood glucose levels improved, the patient stabilized emotionally and assaultive behaviour disappeared while the cognitive deficits remained unchanged.
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PMID:Psychiatric symptoms in a patient with Wolfram syndrome caused by a combination of thalamic deficit and endocrinological pathologies. 1909 Apr 13

We study the functional characteristics of a two-gene motif consisting of a double positive feedback loop and an autoregulatory negative feedback loop. The motif appears in the gene regulatory network controlling the functional activity of pancreatic beta-cells. The model exhibits bistability and hysteresis in appropriate parameter regions. The two stable steady states correspond to low (OFF state) and high (ON state) protein levels, respectively. Using a deterministic approach, we show that the region of bistability increases in extent when the copy number of one of the genes is reduced from 2 to 1. The negative feedback loop has the effect of reducing the size of the bistable region. Loss of a gene copy, brought about by mutations, hampers the normal functioning of the beta-cells giving rise to the genetic disorder, maturity-onset diabetes of the young (MODY). The diabetic phenotype makes its appearance when a sizable fraction of the beta-cells is in the OFF state. Using stochastic simulation techniques we show that, on reduction of the gene copy number, there is a transition from the monostable ON to the ON state in the bistable region of the parameter space. Fluctuations in the protein levels, arising due to the stochastic nature of gene expression, can give rise to transitions between the ON and OFF states. We show that as the strength of autorepression increases, the ON --> OFF state transitions become less probable whereas the reverse transitions are more probable. The implications of the results in the context of the occurrence of MODY are pointed out.
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PMID:Functional characteristics of a double positive feedback loop coupled with autorepression. 1909 61

We describe two sisters with type A insulin resistance. In contrast to common situation for this genetic disorder, the sisters harbored compound heterozygous mutations in the insulin receptor gene associated with mild glucose intolerance. The cases highlight the diversity of clinical phenotypes associated with mutations of the insulin receptor gene.
Diabetes Res Clin Pract 2009 Mar
PMID:Two related cases of type A insulin resistance with compound heterozygous mutations of the insulin receptor gene. 1913 52

Friedreich ataxia (FRDA) is a rare autosomal recessive hereditary disorder that affects approximately 1 in 50,000 Caucasians. It is caused by hyperexpansion of GAA repeats in the first intron of the frataxin gene. Initial symptoms of FRDA usually appear around the beginning of the second decade of life. In addition to neuropathological disabilities such as ataxia, sensory loss, and muscle weakness, common signs are scoliosis, foot deformity, and hypertrophic cardiomyopathy. Approximately 10 % of patients with FRDA develop diabetes. The neuronopathy in the dorsal root ganglia, accompanied by the loss of peripheral sensory nerve fibres and the degeneration of posterior columns of the spinal cord, is a hallmark of the disease and is responsible for the typical combination of signs and symptoms specific to FRDA. Variation in neurophysiological abnormalities is correlated with the size of the GAA repeat expansion and likely accounts for individual variation in the progression of FRDA. Despite a range of disease severity, most patients will lose their ability to walk, stand, or sit without support within 10 to 15 years of disease onset. In addition to a review of the clinicopathological features of FRDA, a discussion of recent advances in our understanding of the underlying molecular mechanisms is provided.
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PMID:Friedreich ataxia: the clinical picture. 1928 44

Wolfram syndrome 1 (WFS1, OMIM 222300), a rare genetic disorder characterized by optic nerve atrophy, deafness, diabetes insipidus and diabetes mellitus, is caused by mutations of WFS1, encoding WFS1/wolframin. Non-syndromic WFS1 variants are associated with the risk of diabetes mellitus due to altered function of wolframin in pancreatic islet cells, expanding the importance of wolframin. This study extends a previous report for the monkey retina, using immunohistochemistry to localize wolframin on cryostat and paraffin sections of human retina. In addition, the human retinal pigment epithelial (RPE) cell line termed ARPE-19 and retinas from both pigmented and albino mice were studied to assess wolframin localization. In the human retina, wolframin was expressed in retinal ganglion cells, optic axons and the proximal optic nerve. Wolframin expression in the human retinal pigment epithelium (RPE) was confirmed with intense cytoplasmic labeling in ARPE-19 cells. Strong labeling of the RPE was also found in the albino mouse retina. Cryostat sections of the mouse retina showed a more extended pattern of wolframin labeling, including the inner nuclear layer (INL) and photoreceptor inner segments, confirming the recent report of Kawano et al. [Kawano, J., Tanizawa, Y., Shinoda, K., 2008. Wolfram syndrome 1 (Wfs1) gene expression in the normal mouse visual system. J. Comp. Neurol. 510, 1-23]. Absence of these cells in the human specimens despite the use of human-specific antibodies to wolframin may be related to delayed fixation. Loss of wolframin function in RGCs and the unmyelinated portion of retinal axons could explain optic nerve atrophy in Wolfram Syndrome 1.
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PMID:Expression of the diabetes risk gene wolframin (WFS1) in the human retina. 1952 51

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition characterized by progressive heterotopic ossification, increasing disability, and cumulative immobility. Thiazolidinediones, introduced in 1999 for the treatment of diabetes, enhance bone marrow adipogenesis at the expense of new bone formation, and this might be exploited for the treatment of FOP. A 48-year-old woman with severe FOP characterized by continuous flares that she was partially controlling only with high prednisone doses was given rosiglitazone (initially 4 mg and then 8 mg daily) for 14 months. No new flare-ups were observed during rosiglitazone therapy as compared to the five episodes observed during the previous year while on 20 to 25 mg prednisone daily. The steroid dose could be lowered progressively to 5 mg/day, the skin became softer, and the articular mobility improved impressively. This case report seems to suggest that rosiglitazone therapy, possibly in association with small doses of prednisone, is associated with important clinical improvements in patients with FOP.
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PMID:Rosiglitazone therapy is associated with major clinical improvements in a patient with fibrodysplasia ossificans progressiva. 1992 38

Hereditary hemochromatosis (HH) is a genetic condition that can lead to unregulated absorption of iron from the gut with resultant iron overload. The most common form of HH is caused by mutations in the HFE gene, with most cases of HH presenting in patients who are homozygous for the Cys282Tyr mutation. The prevalence of HFE gene mutations in persons of Northern European ancestry is fairly high (0.3-0.7% homozygous and 9-14% heterozygous for the Cys282Tyr mutation), but the penetrance of the disease is considered fairly low and is quite variable. While routine screening of the general population is not recommended, a targeted approach to screening in symptomatic patients and in those with a family member with iron overload is warranted. Untreated, iron overload can lead to considerable morbidity including liver cirrhosis, arthritis and diabetes mellitus, and increased mortality. The pathophysiology of diabetes mellitus in HH is thought to be due primarily to defects in the early insulin response to glucose. An Hfe(-/-) mouse model of HH has demonstrated defects in beta-cell function and beta-cell apoptosis that may be mediated by increased oxidative stress. Fortunately, these defects seem to be reversible if phlebotomy treatment is initiated before the development of cirrhosis or diabetes mellitus in patients. Further research into the long-term effects of treatment on prevention of diabetes mellitus in HH is needed.
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PMID:Hereditary hemochromatosis and diabetes mellitus: implications for clinical practice. 2001 Sep 68


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