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Brain Insulin Action in the Control of Metabolism in Humans
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
The mixture of different nutrients in a meal triggers several physiological reactions in the periphery and the CNS. Hence, a more standardized way to study insulin action is the oral glucose tolerance test (oGTT), which is strongly implemented in the clinical routine. After oral ingestion of a 75 g glucose solution, blood glucose rises and several endocrine factors, including insulin, are released into the circulation. Peripheral insulin sensitivity can be assessed from this test e.g. by the oGTT-derived Matsuda insulin sensitivity index (39) and insulin secretion can be estimated e.g. by the oral Disposition Index (40). Insulin secretion can also be stimulated by an iv glucose bolus during an iv glucose tolerance test (ivGTT) (41) or by hyperglycemic glucose clamps (42). While the intravenous route of glucose administration is not physiological, it has the advantage of stimulating insulin release without major effects on several other endocrine systems that are activated after oral food or glucose intake, such as incretins, which also act in the brain (43). For both tests, several indices are available to assess peripheral insulin sensitivity and insulin secretion.
L-Arginine and Omega-3 Fatty Acids in Adjuvant Treatment for Type 2 Diabetes and Chronic Kidney Disease
Published in Robert Fried, Richard M. Carlton, Flaxseed, 2023
Robert Fried, Richard M. Carlton
Increasing Omega-3 Index was significantly correlated with higher insulin sensitivity, higher disposition index and lower CRP concentrations. Masuda Index insulin sensitivity scores were 43% (significantly) higher in HOI than in LOI men. Similarly, HOI men had a disposition index that was 70% (significantly) higher and fasting insulin concentrations 25% (significantly) lower. HOI men displayed significantly lower nocturnal systolic blood pressure and significantly greater systolic blood pressure dip. Men in the HOI group also had significantly lower concentrations of CRP (41% lower) and significantly lower concentrations of free fatty acids (21% lower).
Lifestyle Medicine and the Management of Prediabetes
Published in James M. Rippe, Lifestyle Medicine, 2019
Karla I. Galaviz, Lisa Staimez, Lawrence S. Phillips, Mary Beth Weber
In the Tübingen Lifestyle Intervention Program (TULIP), participants with prediabetes underwent nine months of lifestyle modification intervention that included up to ten sessions of dietary counseling from a dietitian and advice to perform at least three hours of moderate-intensity sports per week. Authors identified participants with a high-risk phenotype at baseline-consisting of low disposition index or low insulin sensitivity plus nonalcoholic fatty liver disease-and participants with a low-risk phenotype consisting of all other traits. Overall, 67% of individuals with the low-risk phenotype, compared with only 31% of those with the high-risk phenotype, reached NGR status at the end of the intervention. Low-risk participants were four times more likely to reach NGR than high-risk participants.70 See Table 29.1.
Designing phase II clinical trials in Friedreich ataxia
Published in Expert Opinion on Emerging Drugs, 2021
A0001 is an analogue of Coenzyme Q10 and Idebenone with superior bioavailability, and is thus hypothesized to improve mitochondrial function in FRDA. Thirty-one FRDA patients were enrolled in a phase II, double-blind, randomized, placebo-controlled trial [21]. 10 patients received 510 mg per day, 11 patients received 750 mg per day, and 10 patients received placebo, all via oral administration for 28 days. The primary outcome measure was disposition index, a measure of diabetic tendency. While no significant change was seen in disposition index, significant improvement in FARS (Friedreich’s ataxia rating scale, a quantitative neurological exam) scores at both doses was seen compared to placebo group. A0001 was well tolerated in patients in this study with only mild adverse events reported.
Emerging therapies in Friedreich’s Ataxia
Published in Expert Review of Neurotherapeutics, 2020
Theresa A. Zesiewicz, Joshua Hancock, Shaila D. Ghanekar, Sheng-Han Kuo, Carlos A. Dohse, Joshua Vega
EPI-743 (alpha-tocotrienol quinone, or Vatiquinone), is a catalytic, potent antioxidant and para-benzoquinone that was originally studied as a treatment of Leber’s Hereditary Optic Neuropathy (LHON) [28]. EPI-743’s original analog A0001 (α-tocopheryl quinone or EPI-A0001) was previously tested in a 4-week, placebo-controlled trial of 31 FRDA patients [29]. The study assessed the potential benefits of A0001 in glucose metabolism and neurological function; the primary outcome was the Disposition Index, a measure of glucose tolerance to indicate diabetic tendencies, and the secondary outcome was the FARS. Each of the 31 FRDA patients was randomized to one of three treatment arms: low-dose A0001 (510 mg), high-dose A0001 (750 mg), and placebo. At the study endpoint, there were no significant differences in the Disposition Index. Conversely, patients treated with A0001 noted significant improvements in the FARS-Neuro scores (4.9-point improvement in the low-dose A0001 group and a 6.1-point improvement in the high dose group (p < 0.01) compared to placebo. Furthermore, A0001 was safe and tolerable, as drug-related adverse events were minimal, and drug-related severe adverse events did not occur [29]. Promising results from this clinical trial of short length led to a subsequent more extensive study with EPI-743.
Melatonin receptor 1B gene rs10830963 polymorphism, depressive symptoms and glycaemic traits
Published in Annals of Medicine, 2018
Kadri Haljas, Jari Lahti, Tiinamaija Tuomi, Bo Isomaa, Johan G. Eriksson, Leif Groop, Katri Räikkönen
Homeostatic model assessment for Insulin Resistance (HOMA-IR) [24], HOMA2-IR using online HOMA calculator (https://www.dtu.ox.ac.uk/homacalculator/) and Insulin Sensitivity Index (ISI) [25] were used as indices of insulin resistance [26]. Disposition Index (DI) [27] and Corrected Insulin Response (CIR) [26] were used as indices of insulin secretion. The following formulas were used to calculate these indices: HOMA-IR = Fasting insulin [mU/l]×fasting glucose [mmol/l]/22.5; ISI =10000/√ (fasting glucose [mmol/l]×fasting insulin [mU/l]) × (mean OGTT glucose [mmol/l]×mean OGTT insulin [mU/l]); CIR = (100 × insulin [mU/l] at 30 min)/((glucose [mmol/l] at 30 min) × (glucose [mmol/l] at 30 min–3.89 mmol/l)); DI = CIR × ISI. Area Under the Curve (AUC) for insulin and glucose were calculated as follows: AUC insulin =15 × fasting insulin [mU/l] + 15 × insulin [mU/l] at 30 min +45 × insulin [mU/l] at 30 min +45 × insulin [mU/l] at 120 min; AUC glucose = 15 × fasting glucose +15 × glucose [mmol/l] at 30 min +45 × glucose [mmol/l] at 30 min +45 × glucose [mmol/l] at 120 min.