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Predictors of the Acute Postprandial Response to Breaking Up Prolonged Sitting.
Henson, J, Edwardson, CL, Celis-Morales, CA, Davies, MJ, Dunstan, DW, Esliger, DW, Gill, JMR, Kazi, A, Khunti, K, King, J, et al
Medicine and science in sports and exercise. 2020;(6):1385-1393
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Abstract
PURPOSE To identify predictors of favorable changes to postprandial insulin and glucose levels in response to interrupting prolonged sitting time with standing or light-intensity physical activity. METHODS Data were combined from four similarly designed randomized acute cross-over trials (n = 129; body mass index [BMI] range, 19.6-44.6 kg·m; South Asian = 31.0%; dysglycemia = 27.1%). Treatments included: prolonged sitting (6.5 h) or prolonged sitting broken-up with either standing or light-intensity physical activity (5 min every 30 min). Time-averaged postprandial responses for insulin and glucose were calculated for each treatment (mean ± 95% confidence interval). Mutually adjusted interaction terms were used to examine whether anthropometric (BMI), demographic (age, sex, ethnicity [white European vs South Asian]) and a cardiometabolic variable (Homeostatic Model Assessment of Insulin Resistance)-modified responses. RESULTS Postprandial insulin and glucose were reduced when individuals interrupted prolonged sitting with bouts of light physical activity, but not with standing. Reductions in time-averaged postprandial insulin were more pronounced if individuals were South Asian compared with white European (-18.9 mU·L [-23.5%] vs -8.2 mU·L [-9.3%]), female compared with male (-15.0 mU·L [-21.2%] vs -12.1 mU·L [-17.6%]) or had a BMI ≥27.2 kg·m (-20.9 mU·L [-22.9%] vs -8.7 mU·L [-18.2%]). Similarly, being female (-0.4 mmol·L [-0.6 mmol·L, -0.2 mmol·L], -6.8% vs -0.1 mmol·L [-0.3 mmol·L, 1 mmol·L], -1.7%) or having a BMI ≥27.2 kg·m (-0.4 mmol·L [-0.6 mmol·L, -0.2 mmol·L], -6.7% vs -0.2 mmol·L [-0.4 mmol·L, 0.0 mmol·L], -3.4%) modified the postprandial glucose response. No significant interactions were found for Homeostatic Model Assessment of Insulin Resistance or age. CONCLUSIONS Being female, South Asian, or having a higher BMI, all predicted greater reductions in postprandial insulin, whereas being female and having a higher BMI predicted greater reductions in postprandial glucose when sitting was interrupted with light physical activity. These results could help to guide personalized interventions in high-risk participants for whom breaking prolonged sitting time with light activity may yield the greatest therapeutic potential.
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Understanding Metabolic Memory: A Tale of Two Studies.
Miller, RG, Orchard, TJ
Diabetes. 2020;(3):291-299
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The results of the Diabetes Control and Complications Trial (DCCT) have given rise to much encouragement in the battle to stave off the complications of type 1 diabetes, showing dramatic declines in the development of severe retinopathy, nephropathy, and neuropathy in those treated intensively compared with conventional therapy. Particularly encouraging has been the continuing difference between the two groups despite both having similar HbA1c (∼8%) since the end of DCCT, when 96% of participants entered the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. This continuing relative benefit has been termed "metabolic memory," which implies altered metabolic regulation. Based on evidence from both the Epidemiology of Diabetes Complications (EDC) prospective cohort study of childhood-onset type 1 diabetes and DCCT/EDIC, we show that the metabolic memory effect can be largely explained by lower cumulative glycemic exposure in the intensive therapy group, and, on average, the development of complications increases with greater glycemic exposure, irrespective of whether this results from a high exposure for a short time or a lower exposure for a longer time. Thus, there is no need for a concept like "metabolic memory" to explain these observations. Potential mechanisms explaining the cumulative glycemic effect are also briefly discussed.
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Determination of amyloid core regions of insulin analogues fibrils.
Surin, AK, Grishin, SY, Galzitskaya, OV
Prion. 2020;(1):149-162
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UNLABELLED A rapid-acting insulin lispro and long-acting insulin glargine are commonly used for the treatment of diabetes. Clinical cases have described the formation of injectable amyloidosis with these insulin analogues, but their amyloid core regions of fibrils were unknown. To reveal these regions, we have analysed the hydrolyzates of insulin fibrils and its analogues using high-performance liquid chromatography and mass spectrometry methods and found that insulin and its analogues have almost identical amyloid core regions that intersect with the predicted amyloidogenic regions. The obtained results can be used to create new insulin analogues with a low ability to form fibrils. ABBREVIATIONS a.a., amino acid residues; HPLC-MS, high-performance liquid chromatography/mass spectrometry; m/z, mass-to-charge ratio; TEM, transmission electron microscopy.
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Incretin hormones, insulin, glucagon and advanced glycation end products in relation to cognitive function in older people with and without diabetes, a population-based study.
Dybjer, E, Engström, G, Helmer, C, Nägga, K, Rorsman, P, Nilsson, PM
Diabetic medicine : a journal of the British Diabetic Association. 2020;(7):1157-1166
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AIM: The aim of this observational study was to investigate relationships between physiological levels of glucometabolic biomarkers and cognitive test results in a population-based setting. METHODS Cross-sectional data were obtained from the Swedish population-based Malmö Diet and Cancer Study Re-examination 2007-2012 comprising 3001 older people (mean age 72 years). Through oral glucose tolerance testing (OGTT), fasting and post-load levels of serum insulin, plasma glucagon, serum glucose-dependent insulinotropic peptide (GIP) and plasma glucagon-like peptide-1 (GLP-1) were measured. Insulin resistance and insulin sensitivity levels were calculated. In 454 participants, advanced glycation end products (AGEs) were estimated through skin autofluorescence. Associations between biomarkers and two cognitive tests, the Mini-Mental State Examination (MMSE) and A Quick Test of Cognitive Speed (AQT) respectively, were explored in multiple regression analyses. RESULTS Positive associations following adjustments for known prognostic factors were found between MMSE scores and insulin sensitivity (B = 0.822, P = 0.004), 2-h plasma glucagon (B = 0.596, P = 0.026), 2-h serum GIP (B = 0.581, P = 0.040) and 2-h plasma GLP-1 (B = 0.585, P = 0.038), whereas negative associations were found between MMSE scores and insulin resistance (B = -0.734, P = 0.006), fasting plasma GLP-1 (B = -0.544, P = 0.033) and AGEs (B = -1.459, P = 0.030) were found. CONCLUSIONS Higher levels of insulin sensitivity, GIP and GLP-1 were associated with better cognitive outcomes, but AGEs were associated with worse outcomes, supporting evidence from preclinical studies. Glucagon was linked to better outcomes, which could possibly reflect neuroprotective properties similar to the related biomarker GLP-1 which has similar intracellular properties. Longitudinal and interventional studies are needed to further evaluate neuromodulating effects of these biomarkers. Abstract presented at the European Association for the Study of Diabetes (EASD) 2019, Barcelona, Spain.
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GLP-1 and insulin regulation of skeletal and cardiac muscle microvascular perfusion in type 2 diabetes.
Love, KM, Liu, J, Regensteiner, JG, Reusch, JEB, Liu, Z
Journal of diabetes. 2020;(7):488-498
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Muscle microvasculature critically regulates skeletal and cardiac muscle health and function. It provides endothelial surface area for substrate exchange between the plasma compartment and the muscle interstitium. Insulin fine-tunes muscle microvascular perfusion to regulate its own action in muscle and oxygen and nutrient supplies to muscle. Specifically, insulin increases muscle microvascular perfusion, which results in increased delivery of insulin to the capillaries that bathe the muscle cells and then facilitate its own transendothelial transport to reach the muscle interstitium. In type 2 diabetes, muscle microvascular responses to insulin are blunted and there is capillary rarefaction. Both loss of capillary density and decreased insulin-mediated capillary recruitment contribute to a decreased endothelial surface area available for substrate exchange. Vasculature expresses abundant glucagon-like peptide 1 (GLP-1) receptors. GLP-1, in addition to its well-characterized glycemic actions, improves endothelial function, increases muscle microvascular perfusion, and stimulates angiogenesis. Importantly, these actions are preserved in the insulin resistant states. Thus, treatment of insulin resistant patients with GLP-1 receptor agonists may improve skeletal and cardiac muscle microvascular perfusion and increase muscle capillarization, leading to improved delivery of oxygen, nutrients, and hormones such as insulin to the myocytes. These actions of GLP-1 impact skeletal and cardiac muscle function and systems biology such as functional exercise capacity. Preclinical studies and clinical trials involving the use of GLP-1 receptor agonists have shown salutary cardiovascular effects and improved cardiovascular outcomes in type 2 diabetes mellitus. Future studies should further examine the different roles of GLP-1 in cardiac as well as skeletal muscle function.
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Utilization of anthropometric parameters as a novel tool for detection of insulin resistance.
Chao, YP, Kao, TW, Chang, YW, Peng, TC, Chen, WL, Wu, LW
Clinical nutrition (Edinburgh, Scotland). 2020;(8):2571-2579
Abstract
BACKGROUND Anthropometric parameters have been widely applied in evaluating muscle mass, insulin resistance (IR), and cardiometabolic diseases. Arm circumference (AC) and calf circumference (CC) are used as informative markers for sarcopenia. However, few studies concern the correlation between AC, CC and IR. The aim of the present survey is to investigate the relationship between AC, CC and homeostatic model assessment of insulin resistance (HOMA-IR). METHODS This cross-sectional observational study included 11,527 participants aged 40-85 years from the National Health and Nutrition Examination Survey (NHANES), 1999 to 2006. We divided the participants into male and female groups. Each group was then divided into four subgroups depending on their AC and CC levels. RESULTS After adjustment for multiple covariates, we observed a significant negative correlation between the CC and HOMA-IR. This study showed a significant positive correlation between the AC and HOMA-IR after multiple adjustments. Subjects in the highest CC quartiles tended to have the lowest HOMA-IR in both male and female group (P for trend <0.001 in all models). CONCLUSIONS CC may be a novel tool to guide public health policy and clinical predictor of IR in middle-aged and older people.
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Influence of Metabolic Parameters and Treatment Method on OCT Angiography Results in Children with Type 1 Diabetes.
Wysocka-Mincewicz, M, Baszyńska-Wilk, M, Gołębiewska, J, Olechowski, A, Byczyńska, A, Hautz, W, Szalecki, M
Journal of diabetes research. 2020;:4742952
Abstract
AIM: To evaluate the influence of metabolic parameters and the treatment method in children with type 1 diabetes (T1D) on the optical coherence tomography angiography (OCTA) results as early markers of diabetic retinopathy (DR). Material and Methods. This prospective study enrolled 175 consecutive children with T1D. OCTA was performed using AngioVue (Avanti, Optovue). Whole superficial capillary vessel density (wsVD), fovea superficial vessel density (fsVD), parafovea superficial vessel density (psVD), whole deep vessel density (wdVD), fovea deep vessel density (fdVD), parafovea deep vessel density (pdVD), foveal thickness (FT), parafoveal thickness (PFT), and foveal avascular zone (FAZ) in superficial plexus were evaluated and analyzed in relation to individual characteristics, i.e., sex, weight, height, body mass index (BMI), and metabolic factors: current and mean value of glycated hemoglobin A1c (HbA1c). Furthermore, the analysis concerned the diabetes duration, age at the T1D onset, and type of treatment-multiple daily insulin injections (MDI) or continuous subcutaneous insulin infusion (CSII). RESULTS In the study group, we did not identify any patient with DR in fundus ophthalmoscopy. Age at the onset of diabetes correlated negatively with FAZ (r = -0.17, p < 0.05). The higher level of HbA1c corresponded to a decrease of wsVD (r = -0.13, p < 0.05). We found significantly lower fsVD (32.25 ± .1 vs. 33.98 ± .1, p < 0.01), wdVD (57.87 ± .1 vs. 58.64 ± .9, p < 0.01), and pdVD (60.60 ± .2 vs. 61.49 ± .1, p < 0.01) and larger FAZ area (0.25 ± .1 vs. 0.23 ± .1, p < 0.05) in the CSII vs. MDI group. CONCLUSION The metabolic parameters, age of the onset of diabetes, and treatment method affected the OCTA results in children with T1D. Further studies and observation of these young patients are needed to determine if these findings are important for early detection of DR or predictive of future DR severity.
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Effects of Evening-Only Low-Carbohydrate Meal on Healthy Volunteers.
Yaegashi, A, Suzuki, J
Journal of nutritional science and vitaminology. 2020;(3):229-236
Abstract
We performed a pre/post-interventional study with participants as self-controls to evaluate the effects of consuming an evening-only low-carbohydrate meal (LCM) at 1800 h on biochemical measures of glucose and lipid metabolism. Study participants comprised 14 healthy men (age range, 20-29 y) who, consumed standard test meals (STMs) or LCM at 1800 h. Blood samples were collected at fasting, and at 60-, 120-, and 240 min after the start of the meals. The 60-min postprandial levels and the area under the curve (AUC) 0-120 min for plasma glucose were significantly lower after the LCM than after the STMs. The 60- and 120-min postprandial levels and the AUC 0-240 min for plasma insulin were significantly lower after the LCM than after the STMs (p<0.01). Postprandial triglyceride (TG) levels at 120- and 240 min and the AUC 0-240 min were significantly higher after the LCM than after the STMs (p<0.05, p<0.01, and p<0.05, respectively). The interleukin-6 levels were significantly higher 240 min after the STMs than before the meals (p<0.05), but not after the LCM. In these healthy volunteers, consuming an LCM at 1800 h suppressed postprandial hyperglycemia and insulin secretion; however, postprandial TG increased. Consuming an LCM at 1800 h was beneficial as it inhibited elevation of blood glucose; however, it may also increase the risk of arteriosclerosis through increasing TG levels.
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Effects of liraglutide and empagliflozin added to insulin therapy in patients with type 2 diabetes: A randomized controlled study.
Nakaguchi, H, Kondo, Y, Kyohara, M, Konishi, H, Oiwa, K, Terauchi, Y
Journal of diabetes investigation. 2020;(6):1542-1550
Abstract
AIMS/INTRODUCTION Liraglutide and empagliflozin suppress cardiovascular events. However, reports on their long-term combined use with insulin therapy or direct comparisons of these drugs are limited. MATERIALS AND METHODS This open-label, parallel-group, randomized controlled trial compared the effects of liraglutide and empagliflozin combined with insulin therapy in type 2 diabetes patients. Adult type 2 diabetes outpatients undergoing stable insulin therapy with glycated hemoglobin levels of 7.0-9.5% were enrolled. Participants received 0.9 mg/day liraglutide or 10 mg/day empagliflozin for 24 weeks. The primary end-point was the change in glycated hemoglobin levels from week 0 to 24. Body composition was assessed by dual-energy X-ray absorptiometry. RESULTS A total of 64 insulin-treated patients were randomized to receive liraglutide or empagliflozin. We analyzed 61 patients (30 liraglutide and 31 empagliflozin) who could be followed up. Liraglutide induced greater changes in glycated hemoglobin and glycated albumin than empagliflozin (glycated hemoglobin -1.24 ± 0.15% vs -0.35 ± 0.11%, P < 0.0001; glycated albumin -4.4 ± 0.6% vs -2.4 ± 0.5%, P < 0.01). Bodyweight (-1.3 ± 0.4 kg vs -1.5 ± 0.3 kg, P = 0.69) or body fat mass/lean tissue mass; urinary albumin excretion (median -5.3 mg/g-creatinine [interquartile range -60.6, 9.9 mg/g-creatinine] vs -12.9 mg/g-creatinine [interquartile range -70.8, -2.0 mg/g-creatinine], P = 0.23); and frequency of hypoglycemia did not differ significantly between the groups over a period of 24 weeks. There were no cases of study discontinuation owing to adverse effects. CONCLUSIONS Liraglutide addition to ongoing insulin therapy more effectively reduced glycated hemoglobin and glycated albumin levels than empagliflozin in patients with inadequately controlled type 2 diabetes.
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Role of insulin, adenosine, and adipokine receptors in the foetoplacental vascular dysfunction in gestational diabetes mellitus.
Subiabre, M, Villalobos-Labra, R, Silva, L, Fuentes, G, Toledo, F, Sobrevia, L
Biochimica et biophysica acta. Molecular basis of disease. 2020;(2):165370
Abstract
Gestational diabetes mellitus (GDM) is a disease of pregnancy associated with maternal and foetal hyperglycaemia and altered foetoplacental vascular function. Human foetoplacental microvascular and macrovascular endothelium from GDM pregnancy show increased maximal l-arginine transport capacity via the human cationic amino acid transporter 1 (hCAT-1) isoform and nitric oxide (NO) synthesis by the endothelial NO synthase (eNOS). These alterations are paralleled by lower maximal transport activity of the endogenous nucleoside adenosine via the human equilibrative nucleoside transporter 1 (hENT1) and activation of adenosine receptors. A causal relationship has been described for adenosine-activation of A2A adenosine receptors, hCAT-1, and eNOS activity (i.e. the Adenosine/l-Arginine/Nitric Oxide, ALANO, signalling pathway). Insulin restores these alterations in GDM via activation of insulin receptor A (IR-A) form in the macrovascular but IR-A and IR-B forms in the microcirculation of the human placenta. Adipokines are secreted from adipocytes influencing the foetoplacental metabolic and vascular function. Various adipokines are dysregulated in GDM, with adiponectin and leptin playing major roles. Abnormal plasma concentration of these adipokines and the activation or their receptors are involved in the pathophysiology of GDM. However, involvement of adipokines, adenosine, and insulin receptors and membrane transporters in the aetiology of this disease of pregnancy is unknown. This review focuses on the pathophysiology of insulin and adenosine receptors and l-arginine and adenosine membranes transporters giving an overview of the key adipokines leptin and adiponectin in the foetoplacental vasculature in GDM. This article is part of a Special Issue entitled: Membrane Transporters and Receptors in Pregnancy Metabolic Complications edited by Luis Sobrevia.