Troglitazone prevents insulin dependent diabetes in the non-obese diabetic mouse

Troglitazone has recently been introduced in the treatment of Type 2 diabetes. In addition to its anti-diabetic effects it acts as a perixosome proliferator activated receptor-gamma (PPAR-γ) agonist and has anti-inflammatory properties by inhibiting macrophage tumour necrosis factor-alpha (TNF-α) secretion. It also inhibits the production of endothelial selectin (e-selectin). Troglitazone also reduces interleukin-1α induced nitric oxide production in pancreatic beta-cells, which may be relevant in preventing nitric oxide mediated damage to these cells in the Type 1 diabetes process. We tested troglitazone in the spontaneous model of autoimmune diabetes, the non-obese diabetic (NOD) mouse, to determine its effect on the disease process. When administered by gavage from weaning at a dose of 400 mg/kg body weight (n=32), troglitazone reduced the incidence of diabetes by 16 weeks compared to controls (n=32) in a pattern that was maintained up to the conclusion of the experiment at 31 weeks of age (p<0.05). Insulitis was unaltered (index=1.05±0.71 vs. 1.13±0.82, treated vs. controls, p=0.78). The study was repeated using troglitazone in the diet of NOD mice (n=24) to give a dose of approximately 200 mg/kg body weight in order to provide a more consistent level of troglitazone during the time course of the experiment. There was a reduction of diabetes incidence in this group but it did not reach significance. Insulin levels were reduced in gavage treated mice although such reduction did not reach significance (p<0.07). We conclude that, in view of its effect on this model of autoimmune diabetes and because of its known function as an insulin sensitiser, troglitazone might be considered for potential use in those patients with Type 1 masquerading as Type 2 diabetes. Copyright (C) 1998 Elsevier Science B.V

The effect of metformin on liver blood flow in vivo in normal subjects and patients with non insulin dependent diabetes

We previously reported that metformin improves insulin-mediated glucose liver metabolism in patients with non insulin dependent diabetes (NIDDM). It is not clear whether this is a direct effect of metformin on liver metabolism or mediated by other mechanisms such as increased liver blood flow. In this respect it has recently been reported that metformin increases hepatic blood flow (HBF) in diabetic rats. The aim of this study was to evaluate whether the administration of metformin is associated with modifications in HBF in humans. Patients affected by NIDDM (n = 11) and normal subjects (n = 6) were studied. In the first protocol HBF was investigated in six overweight (BMI 27 +/- 2 Kg/m(2)) NIDDM patients and six normal subjects (age and BMI matched) already on metformin treatment before and 2 h after the administration of 500 mg metformin. In the second protocol HBF was investigated in obese (BMI 32 +/- 1 Kg/m(2)) NIDDM patients (n = 5) in good metabolic control before and after 15 days of metformin at the dose of 1 g daily. HBF was measured by intravenous injection of 3 mCi Tc-99m-phytate. In both protocols no significant changes in HBF were observed following metformin administration either in NIDDM patients or normal subjects. No significant differences were observed in HBF between diabetic patients and normal subjects. These data indicate that metformin has no effect on HBF in man. The previously reported improvement of insulin mediated liver metabolism induced by metformin is likely to be a consequence of the direct effect of the drug at hepatocyte level which is independent of HBF modifications

Myocardial perfusion imaging in patients with unprotected left main disease

The management of patients with unprotected left main (LM) coronary artery disease remains challenging, with recent data casting a shadow of doubt on the safety of percutaneous coronary intervention. We aimed at describing the features of patients undergoing myocardial perfusion imaging subsequently found to have LM disease

Assessment of the fate of myocardial necrosis by serial myocardial perfusion imaging

BACKGROUND: Myocardial necrosis after myocardial infarction (MI) is common; extent and severity are however variable. The pattern is recognized by myocardial perfusion imaging (MPI) as fixed perfusion defects (FPD). The fate of such FPD is not well appraised. This study addressed this important issue in a large number of patients undergoing serial MPI in relation to type of intervening therapy. METHODS: Patients with prior MI or MPI-evidence of myocardial necrosis undergoing serial MPI without intervening acute coronary syndromes were included. The fate of necrosis by MPI on per-patient and per-region analysis was analyzed, factoring also the impact of intervening coronary revascularization (CR). RESULTS: A total of 3691 patients with 25,837 regions were identified, including 1413 (38.3%) subjects with 3358 (13.0%) regions exhibiting necrosis. Serial MPI after 29±21 months confirmed the persistent presence of myocardial necrosis FPD in the vast majority of patients and regions (86%); the consistency was even higher in the presence of moderate or severe necrosis (99%). Neither type nor site of CR significantly impacted on the presence and extent of myocardial necrosis at multivariable analysis. CONCLUSIONS: The finding of myocardial necrosis by MPI remains highly consistent over time, and is not significantly altered by CR

Impact of coronary revascularization on the clinical and scintigraphic outlook of patients with myocardial ischemia

Aims The impact of coronary revascularization on outcomes and ischemic burden among patients with objective proof of ischemia is not yet established. We appraised the impact of revascularization on outcomes and residual ischemia in patients with objective evidence of ischemia at myocardial perfusion scintigraphy (MPS).Methods We queried our database for stable patients with myocardial ischemia at MPS, excluding those with prior myocardial infarction, systolic dysfunction, or cardiomyopathy. The impact of revascularization (defined as revascularization as first follow-up event) on outcomes and changes in myocardial ischemia at repeat MPS was appraised with propensity-matched analyses.Results From 6195 patients, propensity matching yielded 1262 pairs of patients undergoing revascularization versus not undergoing revascularization. After 35.2 +/- 23.9 months, revascularization was associated with lower risks of cardiac death [2 (0.2%) versus 10 (0.8%) in those not revascularized, P = 0.038] and of the composite of cardiac death or myocardial infarction [17 (1.3%) versus 37 (2.9%), P = 0.007]. In addition, revascularization was associated with a higher rate of improvement in ischemia degree after 28.1 +/- 20.7 months of follow-up (P<0.001), with 257 (69.3%) patients with moderate or severe ischemia at baseline MPS improving after revascularization versus 136 (42.0%) in the nonrevascularization group. Conversely, revascularization did not prove impactful on follow-up MPS in patients with only minimal or mild ischemia at baseline MPS (P<0.001).Conclusion In a large series of patients with objective evidence of myocardial ischemia at MPS, especially when moderate or severe, revascularization was associated with a better clinical prognosis and a lower ischemic burden at repeat MPS

Temporal trends in the prevalence, severity, and localization of myocardial ischemia and necrosis at myocardial perfusion imaging after myocardial infarction

The definition, presentation, and management of myocardial infarction (MI) have changed substantially in the last decade. Whether these changes have impacted on the presence, severity, and localization of necrosis at myocardial perfusion imaging (MPI) has not been appraised to date. Subjects undergoing MPI and reporting a history of clinical MI were shortlisted. We focused on the presence, severity, and localization of necrosis at MPI with a retrospective single-center analysis. A total of 10,476 patients were included, distinguishing 5 groups according to the period in which myocardial perfusion scintigraphy had been performed (2004 to 2005, 2006 to 2007, 2008 to 2009, 2010 to 2011, 2012 to 2013). Trend analysis showed over time a significant worsening in baseline features (e.g., age, diabetes mellitus, and Q waves at electrocardiogram), whereas medical therapy and revascularization were offered with increasing frequency. Over the years, there was also a lower prevalence of normal MPI (from 16.8% to 13.6%) and ischemic MPI (from 35.6% to 32.8%), and a higher prevalence of ischemic and necrotic MPI (from 12.0% to 12.7%) or solely necrotic MPI (from 35.7% to 40.9%, p <0.001). Yet the prevalence of severe ischemia decreased over time from 11.4% to 2.0%, with a similar trend for moderate ischemia (from 15.9% to 11.8%, p <0.001). Similarly sobering results were wound for the prevalence of severe necrosis (from 19.8% to 8.2%) and moderate necrosis (from 8.5% to 7.8%, p = 0.028). These trends were largely confirmed at regional level and after propensity score matching. In conclusion, the outlook of stable patients with previous MI has substantially improved in the last decade, with a decrease in the severity of residual myocardial ischemia and necrosis, despite an apparent worsening in baseline features

Prognostic accuracy of myocardial perfusion imaging in octogenarians

BACKGROUND: Myocardial perfusion imaging (MPI) has an established role in the work-up of coronary artery disease (CAD), but its comparative accuracy is debated in elderly patients. We examined a large administrative database to appraise the performance of MPI in octogenarians. METHODS: Our institutional database was queried for patients undergoing MPI without recent coronary revascularization or myocardial infarction (MI). We compared baseline, procedural, diagnostic, and prognostic features in patients aged < 80 vs ≥ 80 years with bivariate and propensity-adjusted analyses. RESULTS: From 13,254 patients, 12,737 (96.1%) were < 80 years old and 517 (3.9%) ≥ 80 years. Octogenarians were less likely to undergo exercise testing, had more severe and extensive myocardial ischemia (all P < 0.001), whereas CAD was more prevalent and diffuse in them (P = 0.012), and major adverse cardiac events more common during follow-up (P = 0.009). Diagnostic accuracy of MPI was similar or higher in octogenarians than in younger patients (e.g., sensitivity for three-vessel disease 92% in octogenarians vs 91% in younger patients), as was prognostic accuracy. Using propensity-matched analyses, MPI again yielded satisfactory prognostic accuracy in octogenarians. CONCLUSIONS: Use of MPI in octogenarians is associated with similar or better prognostic accuracy than in younger subjects

Impact of specific coronary lesions on regional ischemia at single photon emission computed tomography

Prior studies using stress myocardial perfusion imaging (MPI), which examined the association between obstructive epicardial coronary disease and presence of myocardial ischemia did not provide a detailed assessment on a regional level. We examined this relationship in a large population of patients in whom the coronary anatomy was defined by invasive coronary angiography