Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In models of type 1 diabetes, cytokines induce pancreatic beta-cell death by apoptosis. This process seems to be facilitated by a reduction in the amount of the islet-brain 1/JNK interacting protein 1 (IB1/JIP1), a JNK-scaffold with an anti-apoptotic effect. A point mutation S59N at the N terminus of the scaffold, which segregates in diabetic patients, has the functional consequence of sensitizing cells to apoptotic stimuli. Neither the mechanisms leading to IB1/JIP1 down-regulation by cytokines nor the mechanisms leading to the decreased capacity of the S59N mutation to protect cells from apoptosis are understood. Here, we show that IB1/JIP1 stability is modulated by intracellular calcium. The effect of calcium depends upon JNK activation, which primes the scaffold for ubiquitination-mediated degradation via the proteasome machinery. Furthermore, we observe that the S59N mutation decreases IB1/JIP1 stability by sensitizing IB1/JIP1 to calcium- and proteasome-dependent degradation. These data indicate that calcium influx initiated by cytokines mediates ubiquitination and degradation of IB1/JIP1 and may, therefore, provide a link between calcium influx and JNK-mediated apoptosis in pancreatic beta-cells.
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PMID:Calcium- and proteasome-dependent degradation of the JNK scaffold protein islet-brain 1. 1450 25

Failure of insulin producing pancreatic beta-cells is a common characteristic of type 1 (insulin-dependent) and type 2 (insulin non-dependent) diabetes mellitus. Accumulating evidence suggests that programmed cell death (apoptosis) is the main form of beta-cell death in these disorders. The beta-cell is particularly sensitive to apoptotic stimuli due to the inherent features of the specialized beta-cell phenotype. In type 1 diabetes anti-beta-cell autoimmune reactivity delivers the apoptotic signals in the form of inflammatory mediators or T-cell effectors. In type 2 diabetes, the metabolic derangement is associated with production of inflammatory mediators in insulin-sensitive tissues leading elevated levels of circulating inflammatory mediators such as IL-6 and TNF. Further glucose has been suggested to induce beta-cell apoptosis via the induction of beta-cell synthesis of IL-1 which via autocrine action may elicit signalling cascades analogous to those seen in beta-cell destruction in type 1 diabetes. Considering the apparent importance of IL-1-beta signalling in beta-cell failure in both type 1 and type 2 diabetes, we here review the modulatory effect exerted on IL-1signalling by cellular characteristics related to the specialized beta-cell phenotype. We conclude that beta-cell differentiation signals (Pdx-1), glucose metabolism, calcium handling as well as regulation of naturally occurring inhibitors of cytokine signalling contribute to sensitize the beta-cell to apoptotic stimuli. We hypothesize that immunological stimuli in type 1 diabetes and metabolic/inflammatory signals in type 2 diabetes converge on common signalling pathways leading to beta-cell failure and destruction in these two diseases.
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PMID:Apoptotic signal transduction pathways in diabetes. 1455 18

The death of insulin-secreting beta-cells that causes type I diabetes mellitus (DM) occurs in part by apoptosis, and apoptosis also contributes to progressive beta-cell dysfunction in type II DM. Recent reports indicate that ER stress-induced apoptosis contributes to beta-cell loss in diabetes. Agents that deplete ER calcium levels induce beta-cell apoptosis by a process that is independent of increases in [Ca(2+)](i). Here we report that the SERCA inhibitor thapsigargin induces apoptosis in INS-1 insulinoma cells and that this is inhibited by a bromoenol lactone (BEL) inhibitor of group VIA calcium-independent phospholipase A(2) (iPLA(2)beta). Overexpression of iPLA(2)beta amplifies thapsigargin-induced apoptosis of INS-1 cells, and this is also suppressed by BEL. The magnitude of thapsigargin-induced INS-1 cell apoptosis correlates with the level of iPLA(2)beta expression in various cell lines, and apoptosis is associated with stimulation of iPLA(2)beta activity, perinuclear accumulation of iPLA(2)beta protein and activity, and caspase-3-catalyzed cleavage of full-length 84 kDa iPLA(2)beta to a 62 kDa product that associates with nuclei. Thapsigargin also induces ceramide accumulation in INS-1 cells, and this response is amplified in cells that overexpress iPLA(2)beta. These findings indicate that iPLA(2)beta participates in ER stress-induced apoptosis, a pathway that promotes beta-cell death in diabetes.
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PMID:Apoptosis of insulin-secreting cells induced by endoplasmic reticulum stress is amplified by overexpression of group VIA calcium-independent phospholipase A2 (iPLA2 beta) and suppressed by inhibition of iPLA2 beta. 1474 35

The influence of duration of diabetes and metabolic control on phalangeal quantitative ultrasound (QUS) was evaluated in a group of children and adolescents with type 1 diabetes. Eighty-six patients (mean age 11.9 years; mean duration 4.3 years) were studied. Daily calcium intake was assessed by means of a questionnaire. Amplitude-dependent speed of sound (AD-SoS) was measured at the phalanxes of the non-dominant hand and expressed as a z-score. Linear and multivariate correlations with duration of diabetes and, short term and long term metabolic control were sought. AD-SoS z-score was -0.43+/-1.4 (95% CI, -0.73; -0.13). Nine subjects had values below -2S.D. Daily calcium intake was 1042+/-456 mg/day; 47 subjects (54.6%) were below the recommended levels. A negative correlation was found between AD-SoS z-score and duration (r, -0.33, P=0.002) or metabolic control (HbA1c-last year r, -0.32, P=0.002; HbA1c-whole duration, r, -0.40; P=0.003). Negative AD-SoS z-scores depended significantly and directly on duration and quality of metabolic control, even when controlled for calcium intake. In conclusion, the architectural organization of bone was impaired in 10.5% patients. Duration of diabetes and poor metabolic control were the main determinants affecting AD-SoS. QUS may be a useful tool in the screening of bone disturbance in young patients with diabetes. Optimization of metabolic control is required to prevent osteoporosis.
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PMID:Quantitative ultrasound of proximal phalanxes in patients with type 1 diabetes mellitus. 1512 2

Studies on skeletal involvement in patients with diabetes mellitus have generated conflicting results, largely because of the pathogenetic complexity of the condition. Several mechanisms may contribute to skeletal damage, including the increased urinary excretion coupled with the lower intestinal absorption of calcium, the inappropriate homeostatic response in terms of parathyroid hormone secretion, and also the complex alteration of vitamin D regulation. Decreased or increased insulin and IGF-1 concentrations and the effects of the accumulation of glycation endproducts on the bone tissue could also play a role. A possible genetic predisposition is also currently under investigation. Finally, the role of fat tissue in type 1 and type 2 diabetes and that of diabetic complications also deserve note. As far as bone mass is concerned, in adult patients with type 1 diabetes a moderately reduced bone mineral density has been shown in both axial and appendicular skeleton. On the contrary, patients with type 2 diabetes seem to have higher bone mineral density in respect to healthy control subjects, especially when overweight women are considered. No clear relationship between bone mass measurements and biochemical parameters of mineral metabolism has been shown in the different types of diabetes. Cohort studies recently carried out on large samples indicate that diabetic patients (with both type 1 and type 2 disease) have a higher risk for fracture, in particular for hip fracture, the most dangerous osteoporotic complication. This seems to be dependent both on qualitative and quantitative alterations of the bone, as well as on extra-skeletal factors due to the neuropathic and microangiopathic complications of the disease.
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PMID:Skeletal involvement in patients with diabetes mellitus. 1513 50

New results present C-peptide as a biologically active peptide hormone in its own right. Although C-peptide is formed from proinsulin and cosecreted with insulin, it is a separate entity with biochemical and physiological characteristics that differ from those of insulin. There is direct evidence of stereospecific binding of C-peptide to a cell surface receptor, which is different from those for insulin and other related hormones. The C-peptide binding site is most likely a G-protein-coupled receptor. The association constant for C-peptide binding is approximately 3 x 10(9) M(-1). Saturation of the binding occurs already at a concentration of about 1 nM, which explains why C-peptide effects are not observed in healthy subjects. Binding of C-peptide results in activation of Ca2+ and MAPK-dependent pathways and stimulation of Na+,K(+)-ATPase and eNOS activities. The latter 2 enzymes are both deficient in several tissues in type 1 diabetes. There is some evidence that C-peptide, and insulin may interact synergistically on the insulin signaling pathway. Clinical evidence suggests that replacement of C-peptide, together with regular insulin therapy, may be beneficial in patients with type 1 diabetes and serve to retard or prevent the development of long-term complications.
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PMID:Molecular and cellular effects of C-peptide--new perspectives on an old peptide. 1519 68

Although it was originally proposed that the major role of calbindin is to facilitate the vitamin D dependent movement of calcium through the cytosolic compartment of the intestinal or renal cell, we found that calbindin also has a major role in different cell types in protecting against apoptotic cell death. Calbindin, which buffers calcium, can inhibit apoptosis induced by different proapoptotic stimuli. Expression of calbindin-D(28k) in neural cell suppressed the proapoptotic actions of presenilin-1, which is causally linked to familial Alzheimer's disease, by preventing calcium mediated mitochondrial damage and the subsequent release of cytochrome c. Calbindin, by buffering intracellular calcium can also protect HEK 293 kidney cells from parathyroid hormone induced apoptosis that was found to be mediated by a phospholipase C dependent increase in intracellular calcium. In addition, cytokine mediated destruction of pancreatic beta cells can be prevented by calbindin. Induction by cytokines of nitric oxide, peroxynitrite and lipid hydroperoxide production was significantly decreased in calbindin expressing beta cells. Thus, calbindin-D(28k), by inhibiting free radical formation, can protect islet beta cells from autoimmune destruction in type 1 diabetes. Calbindin-D(28k) can also protect against apoptosis in bone cells. Calbindin was found to block apoptosis in osteocytic and osteoblastic cells. Our findings suggest that calbindin is capable of directly inhibiting the activity of caspase-3, a common downstream effector of multiple apoptotic signaling pathways, and that this inhibition results in an inhibition of tumor necrosis factor (TNFalpha) and glucocorticoid induced apoptosis in bone cells. Thus, while part of calbindin's protective effect may result from buffering rises in intracellular calcium, other mechanisms of action, such as inhibition of caspase activity, also play a significant role in the prevention of apoptosis by calbindin-D(28k). These findings have implications for the prevention of degeneration in different cell types and therefore could prove important for the therapeutic intervention of many diseases, including diabetes and osteoporosis.
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PMID:Biological actions and mechanism of action of calbindin in the process of apoptosis. 1522 9

While it is generally agreed that apoptosis of pancreatic beta-cells is the most important and final step in the progression of type 1 diabetes without which clinical diabetes does not develop, it has not been elucidated which molecule(s) are the real culprit(s) in type 1 diabetes. Perforin, FasL, TNFalpha, IL-1, IFNgamma, and NO have been claimed as the effector molecules; however, they, as a single agent, might explain only part of beta-cell death in type 1 diabetes. While FasL was initially considered as a strong candidate for the most important death effector, following experiments cast doubt on such a hypothesis. Combinations or synergism between IFNgamma and TNFalpha or IL-1beta are being revisited as the death effectors, and molecular mechanism explaining such a synergism was addressed in several recent papers. The role of NF-kappaB for pancreatic beta-cell death in type 1 diabetes is also controversial. While NF-kappaB plays anti-apoptotic roles in most other death models, its role in type 1 diabetes might be different probably due to the involvement of multiple cytokines at different stages of the disease progression and the peculiarity of pancreatic beta-cells. Recent papers also suggested a role for Ca2+ in cytokine-mediated pancreatic beta-cell death. Such participation of Ca2+ in beta-cell death appears to have a close relevance to the mitochondrial events or ER stress that constitutes an important part of cell death machinery recently identified.
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PMID:Death effectors of beta-cell apoptosis in type 1 diabetes. 1546 23

Since Albright first proposed the concept of "diabetic osteopenia", many studies have investigated the levels of bone mineral density (BMD) and the risk of osteoporosis in type 1 and type 2 diabetes. The presence of osteoporosis in type 1 diabetes seems to be a reliable evidence. On the other hand, there is still some controversy about the risk of osteoporosis in type 2 diabetes probably due to different pathogenesis, clinical stage and environmental factors. Although details of the pathogenic mechanisms are not fully understood, low insulin secretion, insulin resistance, hyperglycemia, adipocytokines and other diabetic complications including diabetic triopathy may determine changes in diabetic bone metabolism. Recent findings suggest that several drugs for life style-related disease such as statins, beta blockers and thiazolidinediones may have a potential role to promote bone formation other than their own therapeutic effects.
Clin Calcium 2004 Feb
PMID:[Diabetes and osteoporosis]. 1557 81

Most humans depend on sun exposure to satisfy their requirements for vitamin D. Solar ultraviolet B photons are absorbed by 7-dehydrocholesterol in the skin, leading to its transformation to previtamin D3, which is rapidly converted to vitamin D3. Season, latitude, time of day, skin pigmentation, aging, sunscreen use, and glass all influence the cutaneous production of vitamin D3. Once formed, vitamin D3 is metabolized in the liver to 25-hydroxyvitamin D3 and then in the kidney to its biologically active form, 1,25-dihydroxyvitamin D3. Vitamin D deficiency is an unrecognized epidemic among both children and adults in the United States. Vitamin D deficiency not only causes rickets among children but also precipitates and exacerbates osteoporosis among adults and causes the painful bone disease osteomalacia. Vitamin D deficiency has been associated with increased risks of deadly cancers, cardiovascular disease, multiple sclerosis, rheumatoid arthritis, and type 1 diabetes mellitus. Maintaining blood concentrations of 25-hydroxyvitamin D above 80 nmol/L (approximately 30 ng/mL) not only is important for maximizing intestinal calcium absorption but also may be important for providing the extrarenal 1alpha-hydroxylase that is present in most tissues to produce 1,25-dihydroxyvitamin D3. Although chronic excessive exposure to sunlight increases the risk of nonmelanoma skin cancer, the avoidance of all direct sun exposure increases the risk of vitamin D deficiency, which can have serious consequences. Monitoring serum 25-hydroxyvitamin D concentrations yearly should help reveal vitamin D deficiencies. Sensible sun exposure (usually 5-10 min of exposure of the arms and legs or the hands, arms, and face, 2 or 3 times per week) and increased dietary and supplemental vitamin D intakes are reasonable approaches to guarantee vitamin D sufficiency.
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PMID:Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. 1558 88


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