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)

This randomized, double-blind study was undertaken to compare the efficacy and tolerability of policosanol (10 mg/day) and lovastatin (20 mg/day) in patients with hypercholesterolemia and noninsulin dependent diabetes mellitus. After 6 weeks on a lipid lowering diet, 53 patients were randomized to receive either policosanol or lovastatin tablets that were taken o.i.d. for 12 weeks under double-blind conditions. Both groups were similar at randomization. Policosanol significantly (p < 0.001) lowered low-density lipoprotein (LDL)-cholesterol (20.4%), total cholesterol (14.2%) and the ratio of LDL-cholesterol to high-density lipoprotein (HDL)-cholesterol (23.7%). Lovastatin significantly (p < 0.01) lowered LDL-cholesterol (16.8%), total cholesterol (14.0%) and the ratio (p < 0.05) of LDL-cholesterol to HDL-cholesterol (14.9%). Triglyceride levels did not significantly change after therapy. Policosanol, but not lovastatin, significantly increased (p < 0.01) levels of HDL-cholesterol (7.5%). Comparison between groups showed that changes in HDL-cholesterol induced by policosanol were significantly greater (p < 0.01) than those induced by lovastatin. Both treatments were safe and well tolerated. Lovastatin moderately but significantly (p < 0.05) increased levels of aspartate aminotransferase, creatine phosphokinase and alkaline phosphatase. Adverse reactions were more frequent in the lovastatin group (p < 0.01) than in the policosanol group. In conclusion, policosanol administered at 10 mg/day produces more advantageous changes in HDL-cholesterol and has a better safety and tolerability profile than lovastatin 20 mg/day.
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PMID:Comparative study of the efficacy and tolerability of policosanol and lovastatin in patients with hypercholesterolemia and noninsulin dependent diabetes mellitus. 1093 29

One strategy to treat the insulin resistance that is central to type II diabetes mellitus may be to maintain insulin receptors (IR) in the active (tyrosine phosphorylated) form. Because protein tyrosine phosphatase 1B (PTP1B) binds and subsequently dephosphorylates IR, inhibitors of PTP1B-IR binding are potential insulin 'sensitizers.' A Scintillation Proximity Assay (SPA) was developed to characterize and quantitate PTP1B-IR binding. Human IR were solubilized and captured on wheat germ agglutinin (WGA)-coated SPA beads. Subsequent binding of human, catalytically inactive [35S] PTP1B Cys(215)/Ser (PTP1B(C215S)) to the lectin-anchored IR results in scintillation from the SPA beads that can be quantitated. Binding of PTP1B to IR was pH- and divalent cation-sensitive. Ca(2+) and Mn(2+), but not Mg(2+), dramatically attenuated the loss of PTP1B-IR binding observed when pH was raised from 6.2 to 7.8. PTP1B binding to IR from insulin-stimulated cells was much greater than to IR from unstimulated cells and was inhibited by either an antiphosphotyrosine antibody or treatment of IR with alkaline phosphatase, suggesting that tyrosine phosphorylation of IR is required for PTP1B binding. Phosphopeptides modeled after various IR phosphotyrosine domains each only partially inhibited PTP1B-IR binding, indicating that multiple domains of IR are likely involved in binding PTP1B. However, competitive displacement of [35S]PTP1B(C215S) by PTP1B(C215S) fitted best to a single binding site with a K(d) in the range 100-1000 nM, depending upon pH and divalent cations. PNU-200898, a potent and selective inhibitor of PTP1B whose orientation in the active site of PTP1B has been solved, competitively inhibited catalysis and PTP1B-IR binding with equal potency. The results of this novel assay for PTP1B-IR binding suggest that PTP1B binds preferentially to tyrosine phosphorylated IR through its active site and that binding may be susceptible to therapeutic disruption by small molecules.
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PMID:Analysis of in vitro interactions of protein tyrosine phosphatase 1B with insulin receptors. 1122 82

Both high morbidity and potentiation of systemic complications emphasise significance of diabetes mellitus and hypertension co-incidence. The aim of the study was to analyse the influence of hypertension accompanied with type 2 diabetes mellitus on calcium phosphorus and magnesium metabolism. The study was performed in standard low-calcium diet conditions on the group of 49 patients with type 2 diabetes mellitus (among them 27 had hypertension), 14 patients with essential hypertension and 20 healthy persons. Both serum and urine concentration of creatinine, calcium, phosphorus, hydroxyproline, hydroxylysine and uric acid were analysed. Oral calcium load test was done. Serum alkaline phosphatase activity and oxalic acid urine excretion were also estimated. There were no significant differences between diabetic patients with and without hypertension as far as calcium, phosphorus or magnesium metabolism were concerned.
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PMID:[Bone complications in diabetic subjects with good metabolic control and without any long-term complications--certain problems. Part III: The influence of hypertension and type 2 diabetes mellitus co-incidence of calcium, phosphorus and magnesium metabolism]. 1176 86

Troglitazone maleate (Rezulin) has been associated with severe hepatotoxicity, which led to its withdrawal from the U.S. market in March 2000. Rosiglitazone maleate (Avandia) is being marketed as a safe alternative in the treatment of type 2 diabetes mellitus. We report a case of severe thiazolidinedione-induced cholestatic hepatitis in a 56-year-old female patient at a university hospital who was given rosiglitazone, 8 mg/day, after she developed milder hepatotoxicity while taking troglitazone. Rosiglitazone was discontinued, and the patient was treated with prednisone, azathioprine, and ursodiol. Clinical evaluation and liver biopsy were performed and liver function tests were monitored. After being switched from troglitazone to rosiglitazone the patient developed a severe cholestatic hepatitis with marked jaundice and moderate increases in serum alkaline phosphatase and gamma-glutamyltranspeptidase but only mild increases in serum aminotransferases. Discontinuation of rosiglitazone and treatment with prednisone, azathioprine, and ursodiol led to improvement, albeit with residual injury, dropout of intrahepatic bile ducts, and persisting elevations of serum alkaline phosphatase. Rosiglitazone is not always a safe alternative in patients who have had hepatotoxicity to troglitazone. It is important to monitor the serum alkaline phosphatase in addition to the serum aminotransferases in patients taking thiazolidinediones.
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PMID:Severe cholestatic hepatitis caused by thiazolidinediones: risks associated with substituting rosiglitazone for troglitazone. 1214 28

Type 2 diabetes mellitus is a complex metabolic disorder with adverse cardiovascular risk. The role of micronutrients has not yet been well clarified in this condition, especially in India.THE OBJECTIVES OF THIS STUDY WERE TO: (1) evaluate chromium status in Indian subjects with type 2 diabetes mellitus, (2) assess the effect of chromium picolinate (200 &mgr;g trivalent chromium twice daily) administration on glycaemic control and lipid profile in these subjects and (3) comment on the possible mechanism of any beneficial effect noted above.Fifty subjects were studied in a double blind, placebo-controlled, crossover fashion, with each treatment arm (chromium/placebo) lasting 12 weeks and 4 weeks' wash-off period in between. 50 healthy age- and sex-matched volunteers served as controls. Serum chromium level appeared to be higher in the general population in our country compared to western countries (36.5-59.5 nmol/L as compared to 2.3-40.3 nmol/L) However, the local diabetics were found to have a lower serum chromium level than the healthy controls (32.3 nmol/L against 44.7 nmol/L; p < 0.0001) and a mean increase of 3.5 nmol/L was noted after 12 weeks of chromium supplementation that was, expectedly, not seen in the placebo phase (p < 0.0001).Significant improvement in glycaemic control was noted in the chromium-treated group (DeltaFasting serum glucose = 0.44 mmol/L, p < 0.001; DeltaPost-prandial serum glucose = 1.97 mmol/L, p < 0.001; Deltaglycated hemoglobin = 0.01; p = 0.04, in comparison to placebo) This was accompanied by a significant greater fall in fasting serum insulin in the chromium-treated group, p < 0.05.The change in lipid parameters (total serum cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides) did not show significant difference between the chromium and placebo groups.Clinically significant hematological, renal or hepatic toxicity were excluded by routine hemogram, serum urea, creatinine, alanine amino transferase (ALT) and alkaline phosphatase estimations.In conclusion, chromium supplementation seems to improve glycaemic control in type 2 diabetic patients, which appears to be due to an increase in insulin action rather than stimulation of insulin secretion.
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PMID:Role of chromium supplementation in Indians with type 2 diabetes mellitus. 1255 67

Insulin is the key hormone that controls glucose homeostasis. Dysregulation of insulin function causes diabetes mellitus. Among the two major forms of diabetes, type 2 diabetes accounts for over 90% of the affected population. The incidence of type 2 diabetes is highly related to obesity. To find novel proteins potentially involved in obesity-related insulin resistance and type 2 diabetes, a functional expression screen was performed to search for genes that negatively regulate insulin signaling. Specifically, a reporter system comprised of the PEPCK promoter upstream of alkaline phosphatase was used in a hepatocyte cell-based assay to screen an expression cDNA library for genes that reverse insulin-induced repression of PEPCK transcription. The cDNA library used in this study was derived from the white adipose tissue of ob/ob mice, which are highly insulin-resistant. The mitogen-activated dual specificity protein kinase phosphatase 4 (MKP-4) was identified as a candidate gene in this screen. Here we show that MKP-4 is expressed in insulin-responsive tissues and that the expression levels are up-regulated in obese insulin-resistant rodent models. Heterologous expression of MKP-4 in preadipocytes significantly blocked insulin-induced adipogenesis, and overexpression of MKP-4 in adipocytes inhibited insulin-stimulated glucose uptake. Our data suggest that MKP-4 negatively regulates insulin signaling and, consequently, may contribute to the pathogenesis of insulin resistance.
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PMID:Dual specificity mitogen-activated protein (MAP) kinase phosphatase-4 plays a potential role in insulin resistance. 1277 78

We report two cases of monostotic Paget's disease which were effectively treated with bisphosphonate. Case 1 was a 60-year-old female. Medical examination revealed high alkaline phosphatase (ALP) levels making her visit our clinic. Hematological examination showed high levels of ALP isozyme 3 and bone metabolism markers, and bone scintigraphy demonstrated strong accumulation of 99mTc on the skull. With the diagnosis of monostotic Paget's disease of the skull, treatment with bisphosphonate (etidronate) was started. The response to etidronate was good and after 12 weeks of treatment, the ALP levels decreased to about 26% of the levels before treatment, without the appearance of any symptoms or lesion development. One year and three months later, ALP increased again, and etidronate administration was resumed. However, four years after the diagnosis of the disease, etidronate became ineffective and oral administration of alendronate, a stronger bisphosphonate, was started at 5 mg/day. The patient responded favorably to the bisphosphonate and is still under observation. Case 2 was a 71-year-old female. High ALP levels were found during the follow-up of type 2 diabetes, and the case was diagnosed as monostotic Paget's disease of the pelvis based on bone metabolism markers and bone scintigraphy. Etidronate treatment at 200 mg/day resulted in the improvement of bone metabolism markers and bone scintigraphy findings. When she died of colon cancer twelve months later, with no marked progress of the Paget's disease of bone observed clinically.
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PMID:Two cases of monostotic Paget's disease: effects of bisphosphonate. 1459 11

Retrospective and uncontrolled studies suggest that the lipid-lowering statin class of drugs has either no or beneficial effects on bone density and may reduce fracture risk. We have examined the effects of atorvastatin on serum and plasma markers of bone turnover in 25 patients (age 56 +/- 8 years) with type 2 diabetes (duration: 4.7 +/- 5.0 years, 16 female, 2 insulin-treated, 4 diet alone, and 19 on oral hypoglycemic agents) and baseline hypercholesterolemia (cholesterol 6.6 +/- 0.8 mmol/l) in a double-blind, placebo-controlled, crossover study of 12 weeks of placebo/40 mg of atorvastatin with an 8-week wash-out period. Atorvastatin resulted in a fall in total cholesterol of 2.3 +/- 0.9 mmol/l. There were no effects of active or placebo therapy on total alkaline phosphatase, bone-specific alkaline phosphatase, osteocalcin, or beta C-telopeptide of type 1 collagen (beta-CTX). We conclude that atorvastatin (40 mg/day) has no significant effect on bone turnover in man.
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PMID:The effect of atorvastatin on markers of bone turnover in patients with type 2 diabetes. 1533 14

Thiazolidinediones (TZDs) increase peripheral tissue insulin sensitivity in patients with type 2 diabetes mellitus by activating the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma). In bone marrow stromal cell cultures and in vivo, activation of PPARgamma by high doses (20 mg/kg/day) of TZDs has been reported to alter stem cell differentiation by promoting commitment of progenitor cells to the adipocytic lineage while inhibiting osteoblastogenesis. Here, we have examined the in vivo effects of low-dose rosiglitazone (3 mg/kg/day) on bone, administered to mice by gavage for 90 days. Rosiglitazone-treated mice had increased weight when compared with controls, with no significant alterations in serum levels of glucose, calcium or parathyroid hormone (PTH). Bone mineral density (BMD) at the lumbar vertebrae (L1-L4), ilium/sacrum, and total body was diminished by rosiglitazone treatment. Histologically, bone was characterized by decreased trabecular bone volume and increased marrow space with no significant change in bone marrow adipocity. Decreased osteoblast number and activity due to increased apoptotic death of osteoblasts and osteocytes was apparent while osteoclast parameters and serum levels of osteocalcin, alkaline phosphatase activity, and leptin were unaltered by rosiglitazone treatment. Therefore, the imbalance in bone remodeling that follows rosiglitazone administration arises from increased apoptotic death of osteogenic cells and diminished bone formation leading to the observed decrease in trabecular bone volume and BMD. These novel in vivo effects of TZDs on bone are of clinical relevance as patients with type 2 diabetes mellitus and other insulin resistant states treated with these agents may potentially be at increased risk of osteoporosis.
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PMID:Rosiglitazone impacts negatively on bone by promoting osteoblast/osteocyte apoptosis. 1552 88

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear transcription factor that comprises the primary molecular target for thiazolidinedione (TZD) insulin-sensitizing drugs. Whilst expressed in many tissues in humans, its abundant expression in adipose tissue is believed to be the focal point through which TZDs regulate genes involved in glucose and lipid metabolism and via which these agents ultimately improve the hyperglycemia of type 2 diabetes. However, TZDs exhibit many additional properties, not least an array of effects which suggest a broad attack on the inflammatory process. Thus, TZDs have been shown to reduce plasma levels of the chemokine, monocyte chemotactic protein-1 (MCP-1), the anti-fibrinolytic protein, plasminogen activator inhibitor-1 (PAI-1), the endothelial cell adhesion molecules, e-selectin and inter-cellular adhesion molecule-1 (ICAM-1), the leucocyte-activating molecule, CD40L, and the tissue-remodeling enzyme, matrix metalloproteinase-9 (MMP-9). Further tangible evidence of a reduction by TZDs of systemic inflammation in patients with the classical metabolic syndrome stems from falls in the white blood cell count, P-selectin-positive platelets and in the acute-phase inflammatory proteins, C-reactive protein, serum amyloid A and fibrinogen. At the tissue level, TZDs improve vascular endothelial function, and reduce the rate of progression of intimal-medial thickening of the carotid artery and the microalbuminuria of type 2 diabetes. Further, TZDs have been shown to be efficacious in inflammatory diseases as wide-ranging as psoriasis, ulcerative colitis and non-alcoholic steatohepatitis (NASH). In the case of the latter, a broad spectrum of TZD-related properties is visible. Here, these drugs improve insulin sensitivity for glucose metabolism, reduce hyperinsulinemia, hepatic steatosis, inflammation and fibrosis, and lower the circulating levels of liver transaminases (ALT, AST), alkaline phosphatase and gamma glutamyl transferase. These effects in humans are also well-supported by investigative animal and in vitro studies. The ameliorative effects on liver fibrosis are of particular interest since they suggest that TZDs are able to activate a program of corrective tissue-remodeling. The basis for this action may be partly an ability to inhibit matrix protein secretion by hepatic stellate cells. An analogous action has also been seen in kidney mesangial cells. In conclusion, TZDs are important new drugs, presently indicated for the treatment of type 2 diabetes but with a spectrum of properties which suggests their potential for treating a number of degenerative inflammatory diseases, including NASH. However, full-scale, long-term clinical trials are needed with TZDs to test their potential to treat NASH, not least because of the (hepatotoxic) legacy of the prototype TZD, troglitazone, but also in view of the escalating burden of liver disease which is accompanying the increasing global prevalence of clinical obesity and type 2 diabetes.
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PMID:Thiazolidinediones: Pleiotropic drugs with potent anti-inflammatory properties for tissue protection. 1619 19


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