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Arterial Effects of Canakinumab in Patients With Atherosclerosis and Type 2 Diabetes or Glucose Intolerance.
Choudhury, RP, Birks, JS, Mani, V, Biasiolli, L, Robson, MD, L'Allier, PL, Gingras, MA, Alie, N, McLaughlin, MA, Basson, CT, et al
Journal of the American College of Cardiology. 2016;(16):1769-1780
Abstract
BACKGROUND Evidence suggests that interleukin (IL)-1β is important in the pathogenesis of atherosclerosis and its complications and that inhibiting IL-1β may favorably affect vascular disease progression. OBJECTIVES The goal of this study was to evaluate the effects of IL-1β inhibition with canakinumab versus placebo on arterial structure and function, determined by magnetic resonance imaging. METHODS Patients (N = 189) with atherosclerotic disease and either type 2 diabetes mellitus or impaired glucose tolerance were randomized to receive placebo (n = 94) or canakinumab 150 mg monthly (n = 95) for 12 months. They underwent magnetic resonance imaging of the carotid arteries and aorta. RESULTS There were no statistically significant differences between canakinumab compared with placebo in the primary efficacy and safety endpoints. There was no statistically significant change in mean carotid wall area and no effect on aortic distensibility, measured at 3 separate anatomic sites. The change in mean carotid artery wall area was -3.37 mm2 after 12 months with canakinumab versus placebo. High-sensitivity C-reactive protein was significantly reduced by canakinumab compared with placebo at 3 months (geometric mean ratio [GMR]: 0.568; 95% confidence interval [CI]: 0.436 to 0.740; p < 0.0001) and 12 months (GMR: 0.56; 95% CI: 0.414 to 0.758; p = 0.0002). Lipoprotein(a) levels were reduced by canakinumab compared with placebo (-4.30 mg/dl [range: -8.5 to -0.55 mg/dl]; p = 0.025] at 12 months), but triglyceride levels increased (GMR: 1.20; 95% CI: 1.046 to 1.380; p = 0.01). In these patients with type 2 diabetes mellitus or impaired glucose tolerance, canakinumab had no effect compared with placebo on any of the measures assessed by using a standard oral glucose tolerance test. CONCLUSIONS There were no statistically significant effects of canakinumab on measures of vascular structure or function. Canakinumab reduced markers of inflammation (high-sensitivity C-reactive protein and interleukin-6), and there were modest increases in levels of total cholesterol and triglycerides. (Safety & Effectiveness on Vascular Structure and Function of ACZ885 in Atherosclerosis and Either T2DM or IGT Patients; NCT00995930).
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Higher magnesium intake reduces risk of impaired glucose and insulin metabolism and progression from prediabetes to diabetes in middle-aged americans.
Hruby, A, Meigs, JB, O'Donnell, CJ, Jacques, PF, McKeown, NM
Diabetes care. 2014;(2):419-27
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Abstract
OBJECTIVE To assess 7-year associations between magnesium intake and incident prediabetes and/or insulin resistance (IR), and progression from these states to type 2 diabetes. RESEARCH DESIGN AND METHODS In 2,582 community-dwelling participants 26-81 years old at baseline, magnesium intake and risk of incident "metabolic impairment," defined as impaired fasting glucose (FG) (≥5.6 to <7.0 mmol/L), impaired glucose tolerance (2-h postload glucose ≥7.8 to <11.1 mmol/L), IR, or hyperinsulinemia (≥90th percentile of homeostasis model assessment of IR or fasting insulin, respectively), was estimated among those with normal baseline status, and risk of incident diabetes was estimated among those with baseline metabolic impairment. In participants without incident diabetes, we examined magnesium intake in relation to 7-year changes in fasting and postload glucose and insulin, IR, and insulin sensitivity. RESULTS After adjusting for age, sex, and energy intake, compared with those with the lowest magnesium intake, those with the highest intake had 37% lower risk of incident metabolic impairment (P trend = 0.02), and in those with baseline metabolic impairment, higher intake was associated with 32% lower risk of incident diabetes (P trend = 0.05). In the combined population, the risk in those with the highest intake was 53% (P trend = 0.0004) of those with the lowest intake. Adjusting for risk factors and dietary fiber attenuated associations in the baseline normal population but did not substantially affect associations in the metabolically impaired. Higher magnesium intake tended to associate with lower follow-up FG and IR, but not fasting insulin, postload values, or insulin sensitivity. CONCLUSIONS Magnesium intake may be particularly beneficial in offsetting risk of developing diabetes among those at high risk. Magnesium's long-term associations with non-steady-state (dynamic) measures deserve further research.
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Effect of insulin resistance improvement due to lifestyle intervention on overweight perimenopausal Japanese women: a preliminary study.
Chihara, H, Kawase, R, Otsubo, Y, Hiraizumi, Y, Takeshita, T
Journal of Nippon Medical School = Nippon Ika Daigaku zasshi. 2008;(1):15-22
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OBJECTIVE We hypothesized that body composition and biomarkers of menopausal obesity would be affected by administration of a nutrition and exercise regimen. To test this hypothesis, an interventional study was performed in which perimenopausal subjects increased their daily level of physical activity and decreased their daily caloric intake for a period of 12 weeks. METHOD Nine patients with a chief complaint of obesity and menopausal disorders were enrolled in this study. We prescribed that the subjects engage in the daily physical activity of walking more than 10,000 steps, which is equivalent to 150 to 400 kcal per day, and reduce their daily nutritional intake by 200 kcal. Daily physical activity was measured with a computerized accelerometer, and nutrition intake was measured using food frequency questionnaires. Body composition was measured via biophysical impedance analysis. Biochemical examinations were performed before and after the study. As an assessment of glucose tolerance, homeostasis model assessment-insulin resistance (HOMA-IR) values were measured. RESULTS There were no significant changes in weight, body mass index, or body composition after 12 weeks. However, daily physical activity related to energy consumption was slightly but not significantly increased. Six of the nine subjects (66.7%) had abnormal baseline HOMA-IR values (mean 7.0 +/- 2.6; normal upper limit = 1.5) and demonstrated decreases in HOMA-IR values, with an average of 5.2 +/- 2.3 (P <0.05), after 12 weeks of study. CONCLUSION Our mild intervention on daily physical activity and nutrition changed HOMA-IR values, an assessment of impaired glucose tolerance. These results suggest that longitudinal mild intervention on daily physical activity and nutrition could change insulin sensitivity even without weight reduction.
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Elevated plasma nonesterified fatty acids are associated with deterioration of acute insulin response in IGT but not NGT.
Stefan, N, Stumvoll, M, Bogardus, C, Tataranni, PA
American journal of physiology. Endocrinology and metabolism. 2003;(6):E1156-61
Abstract
High concentrations of nonesterified fatty acids (NEFA) are a risk factor for developing type 2 diabetes in Pima Indians. In vitro and in vivo, chronic elevation of NEFA decreases glucose-stimulated insulin secretion. We hypothesized that high fasting plasma NEFA would increase the risk of type 2 diabetes by inducing a worsening of glucose-stimulated insulin secretion in Pima Indians. To test this hypothesis, fasting plasma NEFA concentrations, body composition, insulin action (M), acute insulin response (AIR, 25-g IVGTT), and glucose tolerance (75-g OGTT) were measured in 151 Pima Indians [107 normal glucose tolerant (NGT), 44 impaired glucose tolerant (IGT)] at the initial visit. These subjects, participants in ongoing studies of the pathogenesis of obesity and type 2 diabetes, had follow-up measurements of body composition, glucose tolerance, M, and AIR. In NGT individuals, cross-sectionally, high fasting plasma NEFA concentrations at the initial visit were negatively associated with AIR after adjustment for age, sex, percent body fat, and M (P = 0.03). Longitudinally, high fasting plasma NEFA concentrations at the initial visit were not associated with change in AIR. In individuals with IGT, cross-sectionally, high fasting plasma NEFA concentrations at the initial visit were not associated with AIR. Longitudinally, high fasting plasma NEFA concentrations at the initial visit were associated with a decrease in AIR before (P < 0.0001) and after adjustment for sex, age at follow-up, time of follow-up, change in percent body fat and insulin sensitivity, and AIR at the initial visit (P = 0.0006). In conclusion, findings in people with NGT indicate that fasting plasma NEFA concentrations are not a primary etiologic factor for beta-cell failure. However, in subjects who have progressed to a state of IGT, chronically elevated NEFA seem to have a deleterious effect on insulin-secretory capacity.