Effects of pioglitazone on bone in postmenopausal women with impaired fasting glucose or impaired glucose tolerance: a randomized, double-blind, placebo-controlled study.

Context: Meta-analyses of clinical studies have suggested an increased incidence of peripheral fractures in postmenopausal women with type 2 diabetes mellitus taking pioglitazone. The mechanism behind this apparent increase is unknown.

Objective: The objective of the study was to examine the effects of pioglitazone on bone mineral density (BMD) and turnover.

Observational follow-up of the PROactive study: a 6-year update.

Aims: The PROactive study investigated pioglitazone for secondary prevention of macrovascular events in type 2 diabetes mellitus. Pioglitazone showed a 10% (non-significant) relative risk (RR) reduction for the primary composite endpoint and a significant 16% reduction for the main secondary endpoint (death, myocardial infarction, stroke) after a mean 34.5 months.

High-density lipoprotein-cholesterol and not HbA1c was directly related to cardiovascular outcome in PROactive.

Aim: In PROactive, pioglitazone reduced the incidence of death, myocardial infarction and stroke, and significantly improved HbA1c, systolic blood pressure (SBP), triglycerides and high-density lipoprotein (HDL)-cholesterol relative to placebo. As these glycaemic and lipid parameters are major cardiovascular (CV) risk factors, we assessed their separate contribution to the reduced incidence of CV outcomes.

Methods: Patients (n = 5238) with type 2 diabetes and macrovascular disease were randomized to 45 mg pioglitazone or placebo.

Effects of pioglitazone and metformin fixed-dose combination therapy on cardiovascular risk markers of inflammation and lipid profile compared with pioglitazone and metformin monotherapy in patients with type 2 diabetes.

. Type 2 diabetes mellitus (T2DM) treatment should not increase cardiovascular (CV) risk and at best could provide benefit beyond lowering glucose. Pioglitazone has demonstrated a favorable CV profile relative to other oral antidiabetic drugs (OADs) in outcome and observational studies.

Pioglitazone and the risk of cardiovascular events in patients with Type 2 diabetes receiving concomitant treatment with nitrates, renin-angiotensin system blockers, or insulin: results from the PROactive study (PROactive 20).

Background: Patients with Type 2 diabetes mellitus (T2DM) are often treated with multiple glucose-lowering and cardiovascular agents. The concomitant use of nitrates, renin-angiotensin system (RAS) blockers, or insulin has been linked to a potential increase in myocardial ischemic risk with rosiglitazone. The PROactive database provides an opportunity to investigate the effects of these medications on the potential macrovascular benefits reported with pioglitazone.

Efficacy and safety of pioglitazone/metformin fixed-dose combination therapy compared with pioglitazone and metformin monotherapy in treating patients with T2DM.

Background: Studies have shown that many patients with type 2 diabetes do not achieve optimal glycemic control, and progression of diabetes over time requires more than one pharmacotherapy to achieve glycemic goal.

Objective: To examine the efficacy and safety of the fixed-dose combination (FDC) of pioglitazone 15 mg and metformin 850 mg versus its individual components in a twice-daily regimen over 24 weeks of treatment in type 2 diabetes patients who were currently not receiving antidiabetes therapy.

Methods: This was a double-blind, randomized, parallel-group, controlled study.

Long-term lipid effects of pioglitazone by baseline anti-hyperglycemia medication therapy and statin use from the PROactive experience (PROactive 14).

Studies have shown that pioglitazone treatment in patients with type 2 diabetes mellitus can improve parameters of diabetic dyslipidemia. The aim of this study was to examine the effect of pioglitazone on triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels in patients from the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) to determine whether pioglitazone-induced lipid effects were altered by different baseline antihyperglycemia medication or statin use. PROactive was a long-term, randomized, double-blind, cardiovascular outcomes study in patients with type 2 diabetes at high cardiovascular risk who had pioglitazone or placebo added to existing treatment.

The molecular basis of salt adaptation in Methanosarcina mazei Gö1.

The study on the molecular basis of salt adaptation and its regulation in archaea is still in its infancy, but genomics and functional genome analyses combined with classical biochemistry shed light on the processes conferring salt adaptation in the methanogenic archaeon Methanosarcina mazei Gö1. In this article, we will review discoveries made within the last years that will culminate in the description of the overall cellular response of M. mazei Gö1 to elevated salinities.

The salt-induced ABC transporter Ota of the methanogenic archaeon Methanosarcina mazei Gö1 is a glycine betaine transporter.

The genes encoding the three subunits of the primary ABC transporter Ota of the methanogenic archaeon Methanosarcina mazei Gö1 were cloned in an expression vector (pBAD24) and transformed into the glycine betaine transport-negative mutant Escherichia coli MKH13. Ota was produced as demonstrated by Western blotting. Uptake studies revealed that Ota catalyzed the transport of glycine betaine in E.

Differential regulation of Ota and Otb, two primary glycine betaine transporters in the methanogenic archaeon methanosarcina mazei Gö1.

Methanogenic archaea accumulate glycine betaine in response to hypersalinity, but the regulation of proteins involved, their mechanism of activation and regulation of the corresponding genes are largely unknown. Methanosarcina mazei differs from most other methanoarchaea in having two gene clusters both encoding a potential glycine betaine transporter, Ota and Otb. Western blot as well as quantitative real-time PCR revealed that Otb is not regulated by osmolarity.

Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08).

Objective: PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) enrolled patients with type 2 diabetes and preexisting cardiovascular disease. These patients were at high risk for heart failure, so any therapeutic benefit could potentially be offset by risk of associated heart failure mortality. We analyzed the heart failure cases to assess the effects of treatment on morbidity and mortality after reports of serious heart failure.

Study of an alternate glyoxylate cycle for acetate assimilation by Rhodobacter sphaeroides.

Organisms, which grow on organic substrates that are metabolized via acetyl-CoA, are faced with the problem to form all cell constituents from this C(2)-unit. The problem was solved by the seminal work of Kornberg and is known as the glyoxylate cycle. However, many bacteria are known to not contain isocitrate lyase, the key enzyme of this pathway.

Effects of pioglitazone on lipid and lipoprotein profiles in patients with type 2 diabetes and dyslipidaemia after treatment conversion from rosiglitazone while continuing stable statin therapy.

The aim of this study was to evaluate changes in lipid profiles in patients with type 2 diabetes after treatment conversion from rosiglitazone to pioglitazone while maintaining stable statin and other lipid-altering therapies. A total of 305 patients were enrolled in this open-label study. Patients had been taking stable dosages of rosiglitazone and statins for > 90 days.

Vascular effects of TZDs: new implications.

The incidence of diabetes, now affecting more than 170 million individuals is growing rapidly. Type 2 diabetes, which accounts for 90% of all diabetes cases, is associated with increased cardiovascular morbidity and mortality. Thiazolidinediones (TZDs), used for the treatment of patients with type 2 diabetes improve insulin sensitivity and endothelial dysfunction and exert beneficial effects on the lipid profile by activating the peroxisome proliferator-activated receptor gamma (PPAR-gamma).

Stress response by solute accumulation in archaea.

The accumulation of organic solutes is a prerequisite for osmotic adjustment of all organisms. Archaea synthesize unusual solutes such as beta-amino acids, Nepsilon-acetyl-beta-lysine, mannosylglycerate and di-myo-inositol phosphate but, as in other cells, uptake of solutes such as glycine betaine is preferred over de novo synthesis. Study of the molecular basis of osmoadaptation and its regulation in archaea is still in its infancy, but genomics and functional genome analyses combined with classical biochemistry shed light on the processes that confer osmoadaptation in archaea.

Reducing cardiovascular risk in diabetes. Which factors to modify first?

Up to 80% of diabetic patients die of macrovascular complications, including CAD, stroke, and peripheral vascular disease. Because of the growing numbers of diabetic patients and the increased mortality after their first cardiovascular event, it is critical to identify and treat risk factors early and aggressively in these patients. Numerous studies in patients with type 2 diabetes have shown the benefits of aggressive treatment of blood pressure and lipids to levels that 10 years ago would have seemed abnormally low.

L-fucose reduces collagen and noncollagen protein production in cultured cerebral microvessel endothelial cells.

L-fucose is a monosaccharide which is present in low concentrations in normal serum but is increased in diabetes, cancer, and inflammatory diseases. The contribution that abnormal L-fucose levels make to the progression of these disorders is unknown. In a previous study we showed that increased L-fucose concentration reduced proliferation and proteoglycan production by cultured cerebral microvessel endothelial cells.

Regulation of growth factor mRNA levels in the eyes of diabetic rats.

The underlying etiology of diabetic microvascular disease remains unknown. To examine the potential contribution of basic fibroblast growth factor (bFGF), which is an angiogenic factor, and insulin-like growth factor-I (IGF-I) to the development of diabetic microvascular disease, bFGF and IGF-I mRNA levels were measured in tissues of control, diabetic, and insulin-treated diabetic rats. Diabetes was induced in rats by intravenous injection of streptozotocin (STZ) 65 mg/kg, and the rats were maintained for 21 days.

Correlation between decreased collagen production in diabetic animals and in cells exposed to diabetic serum: response to insulin.

Collagen production has been shown to be decreased in costal cartilage from nondiabetic animals after incubation with diabetic rat serum. Since collagen was decreased to a similar degree in tissues from diabetic animals, we questioned whether altered collagen production in vivo could be related to altered production induced in vitro. Collagen and noncollagen protein production in articular cartilage from diabetic animals (production in vivo) was compared to protein production in dermal fibroblasts from non-diabetic rats exposed to serum from the same diabetic rats (production in vitro).

Tissue-specific regulation of basic fibroblast growth factor mRNA levels by diabetes.

Because basic fibroblast growth factor (bFGF) is recognized as an angiogenic factor and diabetes is characterized by multiple vascular complications, including diabetic microangiopathy, we examined the regulation of tissue bFGF mRNA levels by diabetes. Diabetes was induced in male Sprague-Dawley rats by injection of 125 mg/kg body wt i.v.

Inhibition of collagen production by diabetic rat serum: response to insulin and insulin-like growth factor-I added in vitro.

Diabetes mellitus is associated with a generalized defect in connective tissue metabolism. Since collagen is the major protein of connective tissues, we used collagen as a probe to examine the role of factors in diabetic rat serum (DRS) in the etiology of these defects. Serum and skin fibroblasts were isolated from nondiabetic rats, and serum was taken from rats 48 h after injection of 200 mg/kg streptozotocin.

Collagen production in fasted and food-restricted rats: response to duration and severity of food deprivation.

Malnutrition is associated with defects in connective tissue metabolism such as altered growth and wound healing. Because collagen is the major protein in most tissues, we determined the threshold for induction of altered collagen production by partial food restriction in rats. Groups of animals were fasted 2 or 4 d or were fed 20-100% of a predetermined food intake for 4 to 8 d.

Phenytoin-induced agranulocytosis: a nonimmunologic idiosyncratic reaction?

Agranulocytosis is a rare side effect of phenytoin treatment. We describe the case of an elderly man who developed agranulocytosis 2 weeks following initiation of phenytoin treatment, on no cytotoxic drugs or any other medications except decadron. The white blood cell count was 300/mm3 with absent granulocytes.