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Closed-loop insulin delivery in adults with type 1 diabetes in real-life conditions: a 12-week multicentre, open-label randomised controlled crossover trial.
Benhamou, PY, Franc, S, Reznik, Y, Thivolet, C, Schaepelynck, P, Renard, E, Guerci, B, Chaillous, L, Lukas-Croisier, C, Jeandidier, N, et al
The Lancet. Digital health. 2019;(1):e17-e25
Abstract
BACKGROUND Closed-loop insulin delivery systems are expected to become a standard treatment for patients with type 1 diabetes. We aimed to assess whether the Diabeloop Generation 1 (DBLG1) hybrid closed-loop artificial pancreas system improved glucose control compared with sensor-assisted pump therapy. METHODS In this multicentre, open-label, randomised, crossover trial, we recruited adults (aged ≥18 years) with at least a 2 year history of type 1 diabetes, who had been treated with external insulin pump therapy for at least 6 months, had glycated haemoglobin (HbA1c) of 10% or less (86 mmol/mol), and preserved hypoglycaemia awareness. After a 2-week run-in period, patients were randomly assigned (1:1) with a web-based system in randomly permuted blocks of two, to receive insulin via the hybrid closed-loop system (DBLG1; using a machine-learning-based algorithm) or sensor-assisted pump therapy over 12 weeks of free living, followed by an 8-week washout period and then the other intervention for 12 weeks. The primary outcome was the proportion of time that the sensor glucose concentration was within the target range (3·9-10·0 mmol/L) during the 12 week study period. Efficacy analyses were done in the modified intention-to-treat population, which included all randomly assigned patients who completed both 12 week treatment periods. Safety analyses were done in all patients who were exposed to either of the two treatments at least once during the study. This trial is registered with ClinicalTrials.gov, number NCT02987556. FINDINGS Between March 3, 2017, and June 19, 2017, 71 patients were screened, and 68 eligible patients were randomly assigned to the DBLG1 group (n=33) or the sensor-assisted pump therapy group (n=35), of whom five dropped out in the washout period (n=1 pregnancy; n=4 withdrew consent). 63 patients completed both 12 week treatment periods and were included in the modified intention-to-treat analysis. The proportion of time that the glucose concentration was within the target range was significantly higher in the DBLG1 group (68·5% [SD 9·4] than the sensor-assisted pump group (59·4% [10·2]; mean difference 9·2% [95% CI 6·4 to 11·9]; p<0·0001). Five severe hypoglycaemic episodes occurred in the DBLG1 group and three episodes occurred in the sensor-assisted pump therapy group, which were associated with hardware malfunctions or human error. INTERPRETATION The DBLG1 system improves glucose control compared with sensor-assisted insulin pumps. This finding supports the use of closed-loop technology combined with appropriate health care organisation in adults with type 1 diabetes. FUNDING French Innovation Fund, Diabeloop.
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Dietary Insulin Load and Cancer Recurrence and Survival in Patients With Stage III Colon Cancer: Findings From CALGB 89803 (Alliance).
Morales-Oyarvide, V, Yuan, C, Babic, A, Zhang, S, Niedzwiecki, D, Brand-Miller, JC, Sampson-Kent, L, Ye, X, Li, Y, Saltz, LB, et al
Journal of the National Cancer Institute. 2019;(2):170-179
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Abstract
BACKGROUND Evidence suggests that diets inducing postprandial hyperinsulinemia may be associated with increased cancer-related mortality. The goal of this study was to assess the influence of postdiagnosis dietary insulin load and dietary insulin index on outcomes of stage III colon cancer patients. METHODS We conducted a prospective observational study of 1023 patients with resected stage III colon cancer enrolled in an adjuvant chemotherapy trial who reported dietary intake halfway through and six months after chemotherapy. We evaluated the association of dietary insulin load and dietary insulin index with cancer recurrence and survival using Cox proportional hazards regression adjusted for potential confounders; statistical tests were two-sided. RESULTS High dietary insulin load had a statistically significant association with worse disease-free survival (DFS), comparing the highest vs lowest quintile (adjusted hazard ratio [HR] = 2.77, 95% confidence interval [CI] = 1.90 to 4.02, Ptrend < .001). High dietary insulin index was also associated with worse DFS (highest vs lowest quintile, HR = 1.75, 95% CI = 1.22 to 2.51, Ptrend= .01). The association between higher dietary insulin load and worse DFS differed by body mass index and was strongest among patients with obesity (HR = 3.66, 95% CI = 1.88 to 7.12, Pinteraction = .04). The influence of dietary insulin load on cancer outcomes did not differ by mutation status of KRAS, BRAF, PIK3CA, TP53, or microsatellite instability. CONCLUSIONS Patients with resected stage III colon cancer who consumed a high-insulinogenic diet were at increased risk of recurrence and mortality. These findings support the importance of dietary management following resection of colon cancer, and future research into underlying mechanisms of action is warranted.
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Modest changes to glycemic regulation are sufficient to maintain glucose fluxes in healthy young men following overfeeding with a habitual macronutrient composition.
Morrison, DJ, Kowalski, GM, Bruce, CR, Wadley, GD
American journal of physiology. Endocrinology and metabolism. 2019;(6):E1061-E1070
Abstract
Currently, it is unclear whether short-term overfeeding in healthy people significantly affects postprandial glucose regulation, as most human overfeeding studies have utilized induced experimental conditions such as the euglycemic-hyperinsulinemic clamp technique to assess glucoregulation. The aim of this study was to quantify glucose fluxes [rates of meal glucose appearance (Ra), disposal (Rd), and endogenous glucose production (EGP)] in response to 5 and 28 days of overfeeding (+45% energy) while maintaining habitual macronutrient composition (31.0 ± 1.9% fat, 48.6 ± 2.2% carbohydrate, 16.7 ± 1.4% protein) in healthy, lean young men. Meal tolerance testing was combined with the triple-stable isotope glucose tracer approach. Visceral adipose volume increased by ~15% with 5 days of overfeeding, while there was no further change at 28 days. In contrast, body mass (+1.6 kg) and fat mass (+1.3 kg) were significantly increased only after 28 days of overfeeding. Fasting EGP, Rd, and insulin were increased at 5 but unchanged after 28 days. Postprandial glucose and insulin responses were unaltered by 5 days of overfeeding but were modestly increased after 28 days (P < 0.05). However, meal Ra and glucose Rd were significantly increased after both 5 and 28 days of overfeeding (P < 0.05). Despite this, overfeeding did not lead to alterations to postprandial EGP suppression. Thus, in contrast to findings from euglycemic-hyperinsulinemic clamp studies, chronic overfeeding did not affect the ability to suppress EGP or stimulate Rd under postprandial conditions. Rather, glucose flux was appropriately maintained following 28 days of overfeeding through modest increases in postprandial glycemia and insulinemia.
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The Effect of Conjugated Linoleic Acid Supplementation on Body Composition, Serum Insulin and Leptin in Obese Adults.
Esmaeili Shahmirzadi, F, Ghavamzadeh, S, Zamani, T
Archives of Iranian medicine. 2019;(5):255-261
Abstract
BACKGROUND Studies have reported contradictory findings regarding the effect of a mixture of 2 conjugated linoleic acid (CLA) isomers on body weight and some serum indices. This study aims to investigate the effect of daily supplementation of these 2 isomers on body composition and serum leptin and insulin levels in obese adults. METHODS This randomized, double-blind clinical trial was performed on 54 adults with class I obesity. The subjects were randomly assigned into 2 groups of 27 and were followed for 3 months so that a total of 3000 mg of CLA supplement and placebo were administered in 3 daily doses in the intervention and control groups, respectively. Body composition indices as well as fasting serum levels of insulin and leptin were also measured. The paired t-test was used for evaluating within-group effects from baseline. The independent t-test was used to compare between-group differences for variables with normal distribution. RESULTS Although body weight and body mass index (BMI) were not significantly decreased during intervention in groups, but the body fat mass (BFM) (P=0.034), body fat percentage (P=0.022) and trunk fat (P=0.027) decreased significantly during intervention with CLA. The fasting plasma sugar (P=0.042) and Homeostatic model assessment for insulin resistance (HOMA/IR) (P=0.044) in the intervention group declined during 12 weeks of intervention. Serum leptin was associated with a significant decrease during the intervention period (P=0.039). CONCLUSION CLA supplementation could reduce body fat and serum leptin. Hence, it could be taken into account as a factor for weight loss but not to control or prevent diabetes.
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Glycemic profile assessment during betamethasone administration in women with gestational diabetes mellitus.
Kakoulidis, I, Ilias, I, Linardi, A, Milionis, C, Michou, A, Koukkou, E
Diabetes & metabolic syndrome. 2019;(1):214-215
Abstract
AIM: Betamethasone's effect on glucose homeostasis in the presence of gestational diabetes has not been adequately investigated. MATERIALS-METHODS We assessed the glycemic profile of 99 women with gestational diabetes (52 on insulin, 47 on medical nutrition therapy) who were given betamethasone during hospitalization for at risk pregnancies. RESULTS In insulin-treated women the increase in total daily insulin dose significantly linked to betamethasone dose (p = 0.014). In women on diet, the need for insulin was positively related to betamethasone dose, age and gestational age >34th week (all p < 0.05). CONCLUSION Parsimonious betamethasone use might still be beneficial with a milder effect on glycemia.
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Urinary glucose excretion after dapagliflozin treatment: An exposure-response modelling comparison between Japanese and non-Japanese patients diagnosed with type 1 diabetes mellitus.
Sokolov, V, Yakovleva, T, Ueda, S, Parkinson, J, Boulton, DW, Penland, RC, Tang, W
Diabetes, obesity & metabolism. 2019;(4):829-836
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Abstract
AIMS: To assess the dapagliflozin exposure-response relationship in Japanese and non-Japanese patients with type 1 diabetes mellitus (T1DM) and investigate if a dose adjustment is required in Japanese patients. MATERIALS AND METHODS Data from two clinical studies were used to develop a non-linear mixed effects model describing the relationship between dapagliflozin exposure (area under the concentration curve) and response (24-hour urinary glucose excretion [UGE]) in Japanese and non-Japanese patients with T1DM. The effects of patient-level characteristics (covariates; identified using a stepwise procedure) on response was also assessed. Simulations were performed using median-normalized covariate values. RESULTS Data from 84 patients were included. Average self-monitored blood glucose (SMBG) at day 7, change from baseline in total insulin dose at day 7, and baseline estimated glomerular filtration rate (eGFR) all had a significant effect on 24-hours UGE, with SMBG being the most influential. Dapagliflozin systemic exposure for matching doses and baseline eGFR was similar between Japanese and non-Japanese patients; however, higher SMBG and a greater reduction in total insulin dose was observed in the Japanese population. When the significant covariates were included, the model fit the data well for both populations, and accurately predicted exposure-response in the Japanese and non-Japanese populations, in agreement with the observed data. CONCLUSIONS There was no difference in dapagliflozin exposure-response in Japanese and non-Japanese patients with T1DM once differences in renal function, glycaemic control and insulin dose reductions between studies were considered. Therefore, no dose adjustment is recommended in Japanese patients with T1DM.
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Continuous Subcutaneous Insulin Infusion in Adult Type 1 Diabetes Mellitus Patients: Results from a Public Health System.
Moreno-Fernandez, J, Gomez, FJ, Pinés, P, González, J, López, J, López, LM, Blanco, B, Roa, C, Herranz, S, Muñoz-Rodríguez, JR
Diabetes technology & therapeutics. 2019;(8):440-447
Abstract
Aims: To analyze prevalence and clinical effect of continuous subcutaneous insulin infusion (CSII) in adult type 1 diabetes mellitus (T1DM) patients in a public health system real-world scenario. Materials and Methods: All adult T1DM patients on CSII being followed at Castilla-La Mancha Health Public Service were included. Primary efficacy outcome was the change in HbA1c during the follow-up. Secondary efficacy outcomes included evaluation of the following variables: insulin pump indications, diabetes complication rates, insulin and pump use, continuous glucose monitoring use, patients achieving an HbA1c decrease ≥6 mmol/mol (0.5%) with or without severe hypoglycemia, and discontinuations. Direct patient data were typed through the web-based Spanish national registry on CSII therapy by nine diabetologists from eight different health care areas. Results: A total of 7% of T1DM adult patients were treated with insulin pumps in our region, with a regional prevalence of 18.7 CSII patients/100,000 inhabitants. Three hundred thirteen patients were analyzed with a mean age of 34.1 ± 11.0 years and T1DM duration of 16.6 ± 9.7 years. Mean duration of CSII therapy was 6.2 ± 4.0 years. Data completion was 91.2%. Main indications for treatment were high glucose variability (36%) and suboptimal glycemic control (32%). Mean duration of CSII therapy was 6.2 ± 4.0 years. Sensor-augment pump therapy was used by 26% of the patients. Glycated hemoglobin decreased to -5 mmol/mol (95% CI -6 to -3 mmol/mol; P < 0.001) during the follow-up (Mean difference in change -0.4%, 95% CI -0.5 to -0.2; P < 0.001). Percentage of patients with severe hypoglycemia decreased from 32% to 13% (P < 0.001). Frequent nonsevere hypoglycemia, severe hypoglycemia, and diabetic ketoacidosis were less frequent among patients using higher number of daily basal rates at the study end. The rate of CSII interruption was 3.8%. Conclusions: Prevalence of CSII therapy in our region remains under 10% of adult T1DM patients, although CSII treatment was associated with a sustained improvement in glycemic control.
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Effects of palm oil consumption on biomarkers of glucose metabolism: A systematic review.
Zulkiply, SH, Balasubramaniam, V, Abu Bakar, NA, Abd Rashed, A, Ismail, SR
PloS one. 2019;(8):e0220877
Abstract
INTRODUCTION Vegetable oil is an important source of fatty acids, and as palm oil being the highest consumed vegetable oil in many countries, its high saturated fatty acid content has led many concerns on cardiometabolic health. Dietary fatty acids has also been linked to affect glucose metabolism and insulin sensitivity. This systematic review is aimed at critically evaluating the available evidence on the association of palm oil with the biomarkers of glucose metabolism as compared to other vegetable oils. METHODS We systemically searched PubMed, CENTRAL and Scopus up to June 2018. We searched for published interventional studies on biomarkers of glucose metabolism (defined as fasting glucose, fasting insulin, HOMA, 2-hour post prandial glucose and HbA1C) that compared palm oil- or palm olein-rich diets with other edible vegetable oils (such as olive oil, canola oil and soybean oil). Two reviewers independently extracted data and assessed study risks of bias. Mean differences of outcomes were pooled for the meta-analysis. RESULTS We identified 1921 potentially eligible articles with only eight included studies. Seven randomised cross-over trials and one parallel trial were included. Study population were among young to middle-aged, healthy, non-diabetic, and normal weight participants. Intervention duration ranged from three to seven weeks, and fat substitution ranged from 15% to 20% energy. There were insignificant differences in fasting glucose when compared to partially hydrogenated soybean oil [-0.15mmol/L (-0.46,0.16) P = 0.33, I2 = 48%], soybean oil [0.05mmol/L (-0.09,0.18) P = 0.49, I2 = 0%] and olive oil [0.04mmol/L (-0.09,0.17) P = 0.76, I2 = 0%]. Insignificant effects were also seen on fasting insulin when compared to partially hydrogenated soybean oil [1.72pmol/L (-11.39,14.84) P = 0.80, I2 = 12%] and olive oil diet [-0.14pmol/L (-4.87,4.59) P = 0.95, I2 = 0%]. CONCLUSION Current evidence on the effects of palm oil consumption on biomarkers of glucose metabolism is poor and limited to only healthy participants. We conclude that little or no additional benefit will be obtained by replacing palm oil with other oils rich in mono or polyunsaturated fatty acids for changes in glucose metabolism.
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Genome-Wide Association Study on the Early-Phase Insulin Response to a Liquid Mixed Meal: Results From the NEO Study.
Li-Gao, R, Carlotti, F, de Mutsert, R, van Hylckama Vlieg, A, de Koning, EJP, Jukema, JW, Rosendaal, FR, Willems van Dijk, K, Mook-Kanamori, DO
Diabetes. 2019;(12):2327-2336
Abstract
Early-phase insulin secretion is a determinant of postprandial glucose homeostasis. In this study, we aimed to identify novel genetic variants associated with the early-phase insulin response to a liquid mixed meal by a genome-wide association study using a discovery and replication design embedded in the Netherlands Epidemiology of Obesity (NEO) study. The early-phase insulin response was defined as the difference between the natural logarithm-transformed insulin concentrations of the postprandial state at 30 min after a meal challenge and the fasting state (Δinsulin). After Bonferroni correction, rs505922 (β: -6.5% [minor allele frequency (MAF) 0.32, P = 3.3 × 10-8]) located in the ABO gene reached genome-wide significant level (P < 5 × 10-8) and was also replicated successfully (β: -7.8% [MAF 0.32, P = 7.2 × 10-5]). The function of the ABO gene was assessed using in vitro shRNA-mediated knockdown of gene expression in the murine pancreatic β-cell line MIN6. Knocking down the ABO gene led to decreased insulin secretion in the murine pancreatic β-cell line. These data indicate that the previously identified elevated risk of type 2 diabetes for carriers of the ABO rs505922:C allele may be caused by decreased early-phase insulin secretion.
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Individual and diabetes presentation characteristics associated with partial remission status in children and adults evaluated up to 12 months following diagnosis of type 1 diabetes: An ADDRESS-2 (After Diagnosis Diabetes Research Support System-2) study analysis.
Humphreys, A, Bravis, V, Kaur, A, Walkey, HC, Godsland, IF, Misra, S, Johnston, DG, Oliver, NS
Diabetes research and clinical practice. 2019;:107789
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Abstract
AIMS: People with recently-diagnosed type 1 diabetes mellitus (T1D) may undergo a transient period of glycaemic control with less exogenous insulin. Identification of predictors of this 'remission' could inform a better understanding of glycaemic control. METHODS Participants in the ADDRESS-2 study were included who had 1 or 2 assessments of remission status (coincident insulin dose and HbA1c measurement, with remission defined by ≤0.4 units insulin/kg-body-weight/day with HbA1c < 53 mmol/mol). Demographic and clinical presentation characteristics were compared according to remission status and predictors of remission were explored by logistic regression analysis. RESULTS 1470 first and 469 second assessments of remission status were recorded within 12 months of diagnosis of T1D. Step increases in the probability of remission were identified at age-at-diagnosis 20 years and 3 months after diagnosis (both p < 0.001). Among those aged < 20 years, remission was associated with male gender (p = 0.02), no ketoacidosis (p = 0.02) and fewer than 2 symptoms at presentation (p = 0.004). None of these characteristics predicted remission in those aged ≥ 20 years. In the subgroup with two assessments, transition to remission was independently associated with first remission assessment in months 1-2 post-diagnosis (p = 0.01), with age-at-diagnosis ≥ 20 years (p = 0.01) and, in those aged < 20 years, with an early HbA1c of <57 mmol/mol. Adiposity, ethnicity, autoantibody status and other autoimmune disease were unrelated to remission. CONCLUSIONS For those diagnosed before 20 years of age, males, ketoacidosis-free, with fewer symptoms and low early HbA1c were more likely to experience remission, but remission was most likely in anyone aged ≥ 20 at diagnosis.