OBJECTIVE-To investigate the relationship between fasting glucose levels, insulin resistance, and cognitive impairment in old age. Diabetes is associated with cognitive impairment in older people.... Show moreOBJECTIVE-To investigate the relationship between fasting glucose levels, insulin resistance, and cognitive impairment in old age. Diabetes is associated with cognitive impairment in older people. However, the link between elevated fasting glucose levels and insulin resistance in nondiabetic individuals, and the risk of cognitive impairment is unclear. RESEARCH DESIGN AND METHODS-We analyzed data from, in total, 8,447 participants in two independent prospective studies: the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), 5,019 participants, aged 69-84 years, and the Rotterdam Study, 3,428 participants, aged 61-97 years. Fasting glucose levels were assessed at baseline in both studies; fasting insulin levels were assessed in the Rotterdam Study only. Cognitive function was assessed in both studies at baseline and during follow-up. RESULTS-Subjects with diabetes had impaired cognitive function at baseline. In contrast, in people without a history of diabetes, there was no clear association between baseline fasting glucose levels and executive function and memory, nor was there a consistent relationship between elevated baseline fasting glucose levels and the rate of cognitive decline in either cohort. Insulin resistance (homeostasis model assessment index) was also unrelated to cognitive function and decline. CONCLUSIONS-Elevated fasting glucose levels and insulin resistance are not associated with worse cognitive function in older people without a history of diabetes. These data suggest either that there is a threshold for effects of dysglycemia on cognitive function or that factors other than hyperglycemia contribute to cognitive impairment in individuals with frank diabetes. Diabetes 59:1601-1607, 2010 Show less
Objectives The aim of this study was to evaluate the efficacy and safety of mipomersen in hypercholesterolemic subjects taking stable statin therapy. Background Mipomersen is an apolipoprotein (apo... Show moreObjectives The aim of this study was to evaluate the efficacy and safety of mipomersen in hypercholesterolemic subjects taking stable statin therapy. Background Mipomersen is an apolipoprotein (apo) B synthesis inhibitor that has demonstrated significant reductions in apo B and low-density lipoprotein (LDL) cholesterol in Phase 1 clinical trials in healthy volunteers. Methods A randomized, placebo-controlled, dose-escalation Phase 2 study was designed to evaluate the effects of mipomersen in hypercholesterolemic subjects taking stable statin therapy. Seventy-four subjects were enrolled sequentially into 1 of 6 dose cohorts at a 4:1 (active/placebo) ratio. Subjects received 7 doses of 30 to 400 mg over 5 weeks in the first 5 cohorts and 15 doses of 200 mg over 13 weeks in the sixth cohort. Pre-specified end points included percentage change from baseline in apo B and LDL cholesterol. Safety was assessed with laboratory test results and by the incidence and severity of adverse events. Results The apo B and LDL cholesterol were reduced by 19% to 54% and 21% to 52%, respectively, at doses of 100 mg/week mipomersen and higher in the 5-week treatment cohorts. Efficacy seemed to increase upon treatment for 13 weeks at a dose of 200 mg/week. Injection site reactions (mild to moderate erythema [90%]) and hepatic transaminase increases (17%) were the most common adverse events, leading to discontinuation in 2 subjects and 1 subject, respectively. In the 13-week treatment cohort, 5 of 10 subjects (50%) had elevations >= 3x the upper limit of normal, 4 of which persisted on 2 consecutive occasions. Conclusions Mipomersen might hold promise for treatment of patients not reaching target LDL cholesterol levels on stable statin therapy. Further studies are needed to address the mechanisms and clinical relevance of transaminase changes after mipomersen administration. (Dose-Escalating Safety Study in Subjects on Stable Statin Therapy; NCT00231569) (J Am Coll Cardiol 2010;55:1611-8) (C) 2010 by the American College of Cardiology Foundation Show less
Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting... Show moreLevels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes. Show less
