We examined the effect of three months of rosiglitazone treatment (4 mg b.i.d.) on whole-body insulin sensitivity and in vivo peripheral adipocyte insulin sensitivity as assessed by glycerol release in microdialysis from subcutaneous fat during a two-step (20 and 120 mU ⅐ m ؊2 ⅐ min ؊1 ) hyperinsulinemic-euglycemic clamp in nine type 2 diabetic subjects. In addition, the effects of rosiglitazone on liver and muscle triglyceride content were assessed by 1 H-nuclear magnetic resonance spectroscopy. Rosiglitazone treatment resulted in a 68% (P < 0.002) and a 20% (P < 0.016) improvement in insulinstimulated glucose metabolism during the low-and highdosage؊insulin clamps, respectively, which was associated with ϳ40% reductions in plasma fatty acid concentration (P < 0.05) and hepatic triglyceride content (P < 0.05). These changes were associated with a 39% increase in extramyocellular lipid content (P < 0.05) and a 52% increase in the sensitivity of peripheral adipocytes to the inhibitory effects of insulin on lipolysis (P ؍ 0.04). In conclusion, these results support the hypothesis that thiazolidinediones enhance insulin sensitivity in patients with type 2 diabetes by promoting increased insulin sensitivity in peripheral adipocytes, which results in lower plasma fatty acid concentrations and a redistribution of intracellular lipid from insulin responsive organs into peripheral adipocytes. Diabetes 51: 797-802, 2002
IntroductionInsulin resistance is a primary factor in the development of type 2 diabetes, and recent studies have implicated fatty acid activation of a serine/threonine kinase cascade in the pathogenesis of insulin resistance (1-7). Recently Yuan et al. hypothesized that IKKβ is a key downstream mediator in this process and demonstrated that high doses of salicylates, which inhibit IKKβ activity (8), reversed hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling (9). Evidence that these effects were mediated by salicylate inhibition of IKKβ activity, as opposed to inhibition of cyclooxygenases, was obtained by demonstrating that heterozygous deletion of IKKβ protected mice against the development of insulin resistance during high-fat feeding (9) or lipid infusion (10).However, the effects of aspirin in patients with type 2 diabetes are less clear. While early studies suggested a salutary effect of aspirin on glucose metabolism in diabetic patients (11-16), more recent clinical trials have demonstrated a detrimental effect of aspirin therapy on insulin sensitivity (17)(18)(19). Important differences between these studies included lower aspirin dosages (<3 g/d) and therapeutic duration (a few days) in the more recent studies than in the earlier studies (6-9 g/d for 1-3 weeks). In view of the recent rodent data demonstrating a potentially important role of IKKβ in mediating insulin resistance and the ability of high-dose salicylate to inhibit IKKβ activity, we decided to examine this hypothesis in patients with type 2 diabetes. We measured basal and insulin-stimulated rates of whole-body glucose metabolism before and after high-dose aspirin therapy (∼7 g/d) using hyperinsulinemic-euglycemic clamps in combination with indirect calorimetry and [6,6-2 H 2 ]glucose turnover measurements. In addition, mixed-meal tolerance testing was done before, during, and after the aspirin treatment. MethodsStudy subjects. Nine subjects with type 2 diabetes (six men and three women, age 48 ± 4, weight 108 ± 7 kg, body surface area 2.2 ± 0.1 m 2 , body mass index 37 ± 3 kg/m 2 ) were studied before and after 2 weeks of treatment with aspirin. All the patients were initially screened to rule out any other systemic disease and any biochemical evidence of abnormal renal or hepatic functions. Patients Recent studies have implicated fatty acid-dependent activation of the serine kinase IKKβ, which plays a key role in tissue inflammation, in the pathogenesis of insulin resistance. High doses of salicylates have recently been shown to inhibit IKKβ activity and might therefore ameliorate insulin resistance and improve glucose tolerance in patients with type 2 diabetes. To test this hypothesis, we studied nine type 2 diabetic subjects before and after 2 weeks of treatment with aspirin (∼7 g/d). Subjects underwent mixed-meal tolerance tests and hyperinsulinemic-euglycemic clamps with [6,6-2 H 2 ]glucose to assess glucose turnover before and after treatment. High-dose aspirin treatment resulted in a ∼...
IntroductionInsulin resistance is a primary factor in the development of type 2 diabetes, and recent studies have implicated fatty acid activation of a serine/threonine kinase cascade in the pathogenesis of insulin resistance (1-7). Recently Yuan et al. hypothesized that IKKβ is a key downstream mediator in this process and demonstrated that high doses of salicylates, which inhibit IKKβ activity (8), reversed hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling (9). Evidence that these effects were mediated by salicylate inhibition of IKKβ activity, as opposed to inhibition of cyclooxygenases, was obtained by demonstrating that heterozygous deletion of IKKβ protected mice against the development of insulin resistance during high-fat feeding (9) or lipid infusion (10).However, the effects of aspirin in patients with type 2 diabetes are less clear. While early studies suggested a salutary effect of aspirin on glucose metabolism in diabetic patients (11-16), more recent clinical trials have demonstrated a detrimental effect of aspirin therapy on insulin sensitivity (17)(18)(19). Important differences between these studies included lower aspirin dosages (<3 g/d) and therapeutic duration (a few days) in the more recent studies than in the earlier studies (6-9 g/d for 1-3 weeks). In view of the recent rodent data demonstrating a potentially important role of IKKβ in mediating insulin resistance and the ability of high-dose salicylate to inhibit IKKβ activity, we decided to examine this hypothesis in patients with type 2 diabetes. We measured basal and insulin-stimulated rates of whole-body glucose metabolism before and after high-dose aspirin therapy (∼7 g/d) using hyperinsulinemic-euglycemic clamps in combination with indirect calorimetry and [6,6-2 H 2 ]glucose turnover measurements. In addition, mixed-meal tolerance testing was done before, during, and after the aspirin treatment. MethodsStudy subjects. Nine subjects with type 2 diabetes (six men and three women, age 48 ± 4, weight 108 ± 7 kg, body surface area 2.2 ± 0.1 m 2 , body mass index 37 ± 3 kg/m 2 ) were studied before and after 2 weeks of treatment with aspirin. All the patients were initially screened to rule out any other systemic disease and any biochemical evidence of abnormal renal or hepatic functions. Patients Recent studies have implicated fatty acid-dependent activation of the serine kinase IKKβ, which plays a key role in tissue inflammation, in the pathogenesis of insulin resistance. High doses of salicylates have recently been shown to inhibit IKKβ activity and might therefore ameliorate insulin resistance and improve glucose tolerance in patients with type 2 diabetes. To test this hypothesis, we studied nine type 2 diabetic subjects before and after 2 weeks of treatment with aspirin (∼7 g/d). Subjects underwent mixed-meal tolerance tests and hyperinsulinemic-euglycemic clamps with [6,6-2 H 2 ]glucose to assess glucose turnover before and after treatment. High-dose aspirin treatment resulted in a ∼...
IntroductionInsulin resistance is a primary factor in the development of type 2 diabetes, and recent studies have implicated fatty acid activation of a serine/threonine kinase cascade in the pathogenesis of insulin resistance (1-7). Recently Yuan et al. hypothesized that IKKβ is a key downstream mediator in this process and demonstrated that high doses of salicylates, which inhibit IKKβ activity (8), reversed hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling (9). Evidence that these effects were mediated by salicylate inhibition of IKKβ activity, as opposed to inhibition of cyclooxygenases, was obtained by demonstrating that heterozygous deletion of IKKβ protected mice against the development of insulin resistance during high-fat feeding (9) or lipid infusion (10).However, the effects of aspirin in patients with type 2 diabetes are less clear. While early studies suggested a salutary effect of aspirin on glucose metabolism in diabetic patients (11-16), more recent clinical trials have demonstrated a detrimental effect of aspirin therapy on insulin sensitivity (17)(18)(19). Important differences between these studies included lower aspirin dosages (<3 g/d) and therapeutic duration (a few days) in the more recent studies than in the earlier studies (6-9 g/d for 1-3 weeks). In view of the recent rodent data demonstrating a potentially important role of IKKβ in mediating insulin resistance and the ability of high-dose salicylate to inhibit IKKβ activity, we decided to examine this hypothesis in patients with type 2 diabetes. We measured basal and insulin-stimulated rates of whole-body glucose metabolism before and after high-dose aspirin therapy (∼7 g/d) using hyperinsulinemic-euglycemic clamps in combination with indirect calorimetry and [6,6-2 H 2 ]glucose turnover measurements. In addition, mixed-meal tolerance testing was done before, during, and after the aspirin treatment. MethodsStudy subjects. Nine subjects with type 2 diabetes (six men and three women, age 48 ± 4, weight 108 ± 7 kg, body surface area 2.2 ± 0.1 m 2 , body mass index 37 ± 3 kg/m 2 ) were studied before and after 2 weeks of treatment with aspirin. All the patients were initially screened to rule out any other systemic disease and any biochemical evidence of abnormal renal or hepatic functions. Patients Recent studies have implicated fatty acid-dependent activation of the serine kinase IKKβ, which plays a key role in tissue inflammation, in the pathogenesis of insulin resistance. High doses of salicylates have recently been shown to inhibit IKKβ activity and might therefore ameliorate insulin resistance and improve glucose tolerance in patients with type 2 diabetes. To test this hypothesis, we studied nine type 2 diabetic subjects before and after 2 weeks of treatment with aspirin (∼7 g/d). Subjects underwent mixed-meal tolerance tests and hyperinsulinemic-euglycemic clamps with [6,6-2 H 2 ]glucose to assess glucose turnover before and after treatment. High-dose aspirin treatment resulted in a ∼...
The incidence of thyroid involvement by metastatic disease from distant organs ranges from an average of 3.1% in surgical series to 5.3% in autopsy series. However, the metastasis of one tumor into another (traditionally referred to as 'tumor-to-tumor metastasis') is distinctly uncommon. Typically, they are identified as new manifestations or necropsy findings of a known, pre-existing donor tumor. Herein is described the case of a 59-year-old woman whose thyroid nodule (a follicular adenoma) was resected and found to contain foci of a well-differentiated adenocarcinoma with a morphologic and immunohistochemical profile consistent with origination from the lower gastrointestinal tract. Subsequent diagnostic work-up revealed a sigmoid colon tumor with metastases to the liver. This is, to the authors' knowledge, the first reported example of a colon adenocarcinoma whose initial clinical manifestation was a metastasis to a thyroid neoplasm and only the third reported example of a colonic adenocarcinoma metastatic to a thyroid tumor. In a review of previously reported examples of tumor-to-tumor metastases involving a thyroid neoplasm as the recipient, the following features were present in the majority: (i) multifocality of the metastatic tumor aggregates; (ii) a total lack of, or only minimal amounts of reaction (desmoplastic, inflammatory or myxoid) of the recipient tumor to the metastatic deposits; and (iii) retention of the histopathologic characteristics of the donor tumor in the metastatic deposits. In general, strikingly divergent morphologic features in an otherwise typical thyroid neoplasm should elicit a differential diagnosis that takes into consideration the possibility of metastasis.
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