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Effects of Vitamin D Supplementation on Insulin Sensitivity and Secretion in Prediabetes.
Rasouli, N, Brodsky, IG, Chatterjee, R, Kim, SH, Pratley, RE, Staten, MA, Pittas, AG, ,
The Journal of clinical endocrinology and metabolism. 2022;(1):230-240
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CONTEXT Vitamin D regulates glucose homeostasis pathways, but effects of vitamin D supplementation on β-cell function remain unclear. OBJECTIVE To investigate the effects of vitamin D3 supplementation on insulin sensitivity and β-cell function. METHODS This is a prespecified secondary analysis of the Vitamin D and Type 2 Diabetes study. Overweight/obese adults at high risk for type 2 diabetes (prediabetes) were randomly treated with vitamin D3 4000 IU or matching placebo daily for 24 months. MAIN OUTCOME Disposition index (DI), as an estimate of β-cell function, was calculated as the product of Homeostasis Model Assessment 2 indices derived from C-peptide values (HOMA2%Scpep) and C-peptide response during the first 30 minutes of a 75-g oral glucose tolerance test (OGTT). RESULTS Mean age was 60.5 ± 9.8 years and body mass index was 31.9 ± 4.4 kg/m2. Mean serum 25(OH)D level increased from 27.9 ± 10.3 ng/mL at baseline to 54.9 ng/mL at 2 years in the vitamin D group and was unchanged (28.5 ± 10.0 ng/mL) in the placebo group. The baseline DI predicted incident diabetes independent of the intervention. In the entire cohort, there were no significant differences in changes in DI, HOMA2%Scpep, or C-peptide response between the 2 groups. Among participants with baseline 25(OH)D level <12 ng/mL, the mean percent differences for DI between the vitamin D and placebo groups was 8.5 (95% CI, 0.2-16.8). CONCLUSIONS Supplementation with vitamin D3 for 24 months did not improve an OGTT-derived index of β-cell function in people with prediabetes not selected based on baseline vitamin D status; however, there was benefit among those with very low baseline vitamin D status.
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Gastrointestinal Hormones and β-Cell Function After Gastric Bypass and Sleeve Gastrectomy: A Randomized Controlled Trial (Oseberg).
Fatima, F, Hjelmesæth, J, Birkeland, KI, Gulseth, HL, Hertel, JK, Svanevik, M, Sandbu, R, Småstuen, MC, Hartmann, B, Holst, JJ, et al
The Journal of clinical endocrinology and metabolism. 2022;(2):e756-e766
Abstract
CONTEXT Whether Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) differentially affect postprandial gastrointestinal hormones and β-cell function in type 2 diabetes remains unclear. OBJECTIVE We aimed to compare gastrointestinal hormones and β-cell function, assessed by an oral glucose tolerance test (OGTT) 5 weeks and 1 year after surgery, hypothesizing higher glucagon-like peptide-1 (GLP-1) levels and greater β-cell response to glucose after RYGB than after SG. METHODS This study was a randomized, triple-blind, single-center trial at a tertiary care center in Norway. The primary outcomes were diabetes remission and IVGTT-derived β-cell function. Participants with obesity and type 2 diabetes were allocated (1:1) to RYGB or SG. We measured gastrointestinal hormone profiles and insulin secretion as β-cell glucose sensitivity (β-GS) derived from 180-minute OGTTs. RESULTS Participants were 106 patients (67% women), mean (SD) age 48 (10) years. Diabetes remission rates at 1 year were higher after RYGB than after SG (77% vs 48%; P = 0.002). Incremental area under the curve (iAUC0-180) GLP-1 and β-GS increased more after RYGB than after SG, with 1-year between-group difference 1173 pmol/L*min (95% CI, 569-1776; P = 0.0010) and 0.45 pmol/kg/min/mmol (95% CI, 0.15-0.75; P = 0.0032), respectively. After surgery, fasting and postprandial ghrelin levels were higher and decremental AUC0-180 ghrelin, iAUC0-180 glucose-dependent insulinotropic polypeptide, and iAUC0-60 glucagon were greater after RYGB than after SG. Diabetes remission at 1 year was associated with higher β-GS and higher GLP-1 secretion. CONCLUSION RYGB was associated with greater improvement in β-cell function and higher postprandial GLP-1 levels than SG.
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Islet Function and Insulin Sensitivity in Latent Autoimmune Diabetes in Adults Taking Sitagliptin: A Randomized Trial.
Yang, L, Liang, H, Liu, X, Wang, X, Cheng, Y, Zhao, Y, Liu, L, Huang, G, Wang, X, Zhou, Z
The Journal of clinical endocrinology and metabolism. 2021;(4):e1529-e1541
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CONTEXT The long-term effects of dipeptidyl peptidase-4 inhibitors on β-cell function and insulin sensitivity in latent autoimmune diabetes in adults (LADA) are unclear. OBJECTIVE To investigate the effects of sitagliptin on β-cell function and insulin sensitivity in LADA patients receiving insulin. DESIGN AND SETTING A randomized controlled trial at the Second Xiangya Hospital. METHODS Fifty-one patients with LADA were randomized to sitagliptin + insulin (SITA) group or insulin alone (CONT) group for 24 months. MAIN OUTCOME MEASURES Fasting C-peptide (FCP), 2-hour postprandial C-peptide (2hCP) during mixed-meal tolerance test, △CP (2hCP - FCP), and updated homeostatic model assessment of β-cell function (HOMA2-B) were determined every 6 months. In 12 subjects, hyperglycemic clamp and hyperinsulinemic euglycemic clamp (HEC) tests were further conducted at 12-month intervals. RESULTS During the 24-month follow-up, there were no significant changes in β-cell function in the SITA group, whereas the levels of 2hCP and △CP in the CONT group were reduced at 24 months. Meanwhile, the changes in HOMA2-B from baseline were larger in the SITA group than in the CONT group. At 24 months, first-phase insulin secretion was improved in the SITA group by hyperglycemia clamp, which was higher than in the CONT group (P < .001), while glucose metabolized (M), insulin sensitivity index, and M over logarithmical insulin ratio in HEC were increased in the SITA group (all P < .01 vs baseline), which were higher than in the CONT group. CONCLUSION Compared with insulin intervention alone, sitagliptin plus insulin treatment appeared to maintain β-cell function and improve insulin sensitivity in LADA to some extent.
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Pancreatic β-Cell Function Is Associated with Augmented Counterregulation to In-Exercise Hypoglycemia in Type 1 Diabetes.
McCarthy, O, Pitt, J, Eckstein, ML, Moser, O, Bain, SC, Bracken, RM
Medicine and science in sports and exercise. 2021;(7):1326-1333
Abstract
PURPOSE This study aimed to investigate the influence of residual β-cell function on counterregulatory hormonal responses to hypoglycemia during acute physical exercise in people with type 1 diabetes (T1D). A secondary aim was to explore relationships between biomarkers of pancreatic β-cell function and indices of glycemia following acute exercise including the nocturnal period. METHODS This study involved an exploratory, secondary analysis of data from individuals with T1D who partook in a four-peroid, randomized, cross-over trial involving a bout of evening exercise followed by an overnight stay in a clinical laboratory facility. Participants were split into two groups: (i) a stimulated C-peptide level of ≥30 pmol⋅L-1 (low-level secretors [LLS], n = 6) or (ii) <30 pmol⋅L-1 (microsecretors [MS], n = 10). Pancreatic hormones (C-peptide, proinsulin, and glucagon), catecholamines (epinephrine [EPI] and norepinephrine [NE]), and metabolic biomarkers (blood glucose, blood lactate, and β-hydroxybutyrate) were measured at rest, during exercise with and without a hypoglycemic (blood glucose ≤3.9 mmol⋅L-1) episode, and throughout a 13-h postexercise period. Interstitial glucose monitoring was used to assess indices of glycemic variability. RESULTS During in-exercise hypoglycemia, LLS presented with greater sympathoadrenal (EPI and NE P ≤ 0.05) and ketone (P < 0.01) concentrations. Glucagon remained similar (P = 0.09). Over exercise, LLS experienced larger drops in C-peptide and proinsulin (both P < 0.01) as well as greater increases in EPI (P < 0.01) and β-hydroxybutyrate (P = 0.03). LLS spent less time in the interstitial-derived hypoglycemic range acutely postexercise and had lower glucose variability throughout the nocturnal period. CONCLUSION Higher residual β-cell function was associated with greater sympathoadrenal and ketonic responses to exercise-induced hypoglycemia as well as improved glycemia leading into and throughout the nocturnal hours. Even a minimal amount of residual β-cell function confers a beneficial effect on glycemic outcomes during and after exercise in people with T1D.
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Effect of linagliptin on glucose metabolism and pancreatic beta cell function in patients with persistent prediabetes after metformin and lifestyle.
Alvarez-Canales, MFL, Salazar-López, SS, Farfán-Vázquez, D, Martínez-López, YE, González-Mena, JN, Jiménez-Ceja, LM, Vargas-Ortiz, K, Evia-Viscarra, ML, Montes de Oca-Loyola, ML, Folli, F, et al
Scientific reports. 2021;(1):8750
Abstract
The goal of the study was to evaluate the effect of adding linagliptin to metformin and lifestyle on glucose levels and pancreatic β-cell function in patients with persistent impaired glucose tolerance (IGT) after 12 months of metformin and lifestyle. A single center parallel double-blind randomized clinical trial with 6 months of follow-up was performed in patients with persistent IGT after 12 months of treatment with metformin and lifestyle; patients were randomized to continue with metformin 850 mg twice daily (M group, n = 12) or linagliptin/metformin 2.5/850 mg twice daily (LM group, n = 19). Anthropometric measurements were obtained by standard methods and by bioelectrical impedance; glucose was measured by dry chemistry, insulin by chemiluminescence, and pancreatic β-cell function was calculated with the disposition index using glucose and insulin values during oral glucose tolerance test (OGTT) and adjusting by insulin sensitivity. The main outcomes were glucose levels during OGTT and pancreatic β-cell function. Patients in the LM group had a reduction in weight (-1.7 ± 0.6, p < 0.05) and body mass index (BMI, -0.67 ± 0.2, p < 0.05). Glucose levels significantly improved in LM group with a greater reduction in the area under the glucose curve during OGTT (AUCGluc0_120min) as compared to the M group (-4425 ± 871 vs -1116 ± 1104 mg/dl/120 min, p < 0.001). Pancreatic β-cell function measured with the disposition index, improved only in LM group (2.3 ± 0.23 vs 1.7 ± 0.27, p 0.001); these improvements persisted after controlling for OGTT glucose levels. The differences in pancreatic β-cell function persisted also after pairing groups for basal AUCGluc0_120min. The addition of linagliptin to patients with persistent IGT after 12 months of treatment with metformin and lifestyle, improved glucose levels during OGTT and pancreatic β-cell function after 6 months of treatment.Trial registration: Clinicaltrials.gov with the ID number NCT04088461.
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Small changes in glucose variability induced by low and high glycemic index diets are not associated with changes in β-cell function in adults with pre-diabetes.
Utzschneider, KM, Johnson, TN, Breymeyer, KL, Bettcher, L, Raftery, D, Newton, KM, Neuhouser, ML
Journal of diabetes and its complications. 2020;(8):107586
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Oscillating glucose levels can increase oxidative stress and may contribute to β-cell dysfunction. We tested the hypothesis that increased glycemic variability contributes to β-cell dysfunction by experimentally altering glucose variability with controlled diets varying in glycemic index (GI). Fifty-two adults with prediabetes received a 2-week moderate GI (GI = 55-58) control diet followed by randomization to a four-week low GI (LGI: GI < 35) or high GI (HGI HI > 70) diet. Those on the HGI diet were randomized to placebo or the antioxidant N-acetylcysteine (NAC). Participants underwent blinded CGMS, fasting oxidative stress markers and an intravenous glucose tolerance test to estimate β-cell function (disposition index: DI). On the control diet, DI was inversely correlated with SD glucose (r = -0.314, p = 0.03), but neither DI nor glucose variability were associated with oxidative stress markers. The LGI diet decreased SD glucose (Control 0.96 ± 0.08 vs. LGI 0.79 ± 0.06, p = 0.02) while the HGI diet increased it (Control 0.88 ± 0.06 vs. HGI 1.06 ± 0.07, p = 0.03). Neither DI nor oxidative stress markers changed after the LGI or HGI diets. NAC had no effect on DI, glucose variability or oxidative stress markers. We conclude small changes in glucose variability induced by dietary GI in adults with pre-diabetes are unlikely to contribute to β-cell dysfunction.
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Adding vitamin D3 to the dipeptidyl peptidase-4 inhibitor saxagliptin has the potential to protect β-cell function in LADA patients: A 1-year pilot study.
Zhang, Z, Yan, X, Wu, C, Pei, X, Li, X, Wang, X, Niu, X, Jiang, H, Zeng, X, Zhou, Z
Diabetes/metabolism research and reviews. 2020;(5):e3298
Abstract
AIMS: This trial was conducted to explore the protective effect on β-cell function of adding vitamin D3 to DPP-4 inhibitors to treat patients with latent autoimmune diabetes in adults (LADA). METHODS 60 LADA patients were randomized to group A (n = 21) - conventional therapy with metformin (1-1.7 g/day) and/or insulin treatment; group B (n = 20) - saxagliptin (5 mg/day) plus conventional therapy; and group C (n = 19) - vitamin D3 (2000 IU/day) plus saxagliptin and conventional therapy for 12 months. Fasting and 2-hour postprandial blood samples were collected to measure blood glucose, glycosylated hemoglobin and C-peptide levels at baseline and after 3, 6 and 12 months of treatment. RESULTS During the 12 months of follow-up, the levels of fasting C-peptide (FCP), 2-hour postprandial C-peptide (PCP) and the C-peptide index (CPI, serum C-peptide-to-plasma glucose level ratio) were maintained in group C. In contrast to those in group A and group B, FCP levels decreased significantly in group B, and CPI levels declined significantly in group A during the 1-year treatment (P < .05). Additionally, the levels of GADA titers in group C significantly decreased compared with those at baseline (P < .05), but no significant differences in GADA titers levels were detected in group A and group B. No significant differences were found among the three groups in the levels of FCP, PCP, the CPI or GADA titers. CONCLUSIONS The data suggested that adding 2000 IU/day vitamin D3 to saxagliptin might preserve β-cell function in patients with LADA.
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Effect of vitamin D3 supplementation on insulin resistance and β-cell function in prediabetes: a double-blind, randomized, placebo-controlled trial.
Wallace, HJ, Holmes, L, Ennis, CN, Cardwell, CR, Woodside, JV, Young, IS, Bell, PM, Hunter, SJ, McKinley, MC
The American journal of clinical nutrition. 2019;(5):1138-1147
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BACKGROUND Observational studies have suggested an inverse association between low serum 25-hydroxyvitamin D [25(OH)D] concentrations and development of type 2 diabetes. High-quality trials are required to test the hypothesis that vitamin D is a direct contributor to type 2 diabetes pathogenesis. OBJECTIVE The purpose of this double-blind randomized placebo-controlled trial was to investigate the effect of vitamin D3 supplementation on insulin resistance (IR) and β-cell function in people with prediabetes and suboptimal vitamin D status (<50 nmol/L). METHODS Sixty-six individuals were randomly assigned to receive 3000 IU (75 µg) vitamin D3 or placebo daily for 26 wk. Compliance was monitored by pill count and change in serum 25(OH)D concentration using LC-MS. The primary endpoint was between-group difference in change in IR assessed using a 2-step euglycemic-hyperinsulinemic clamp combined with infusion of tritiated glucose. An oral-glucose-tolerance test was performed pre- and postintervention to calculate indices of β-cell function. Between-group comparisons were made using ANCOVA. RESULTS In total, 64 participants completed the study. Baseline serum 25(OH)D concentrations in the vitamin D3 and placebo group were 30.7 and 30.0 nmol/L, with status increasing by 70.5 nmol/L and 5.3 nmol/L, respectively (between-group difference in vitamin D: 65.8 nmol/L; 95% CI: 54.2, 77.3 nmol/L; P < 0.01), after supplementation. There was no difference between groups in measures of whole-body, peripheral, or hepatic IR or in any measure of glycemic control or β-cell function. CONCLUSION This study employed a robust assessment of IR and β-cell function and targeted a high-risk population with low 25(OH)D status at baseline and found that vitamin D3 supplementation had no effect on insulin action in people with prediabetes.This trial was registered on clinicaltrials.gov as NCT01889810.
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Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes.
Cusi, K, Bril, F, Barb, D, Polidori, D, Sha, S, Ghosh, A, Farrell, K, Sunny, NE, Kalavalapalli, S, Pettus, J, et al
Diabetes, obesity & metabolism. 2019;(4):812-821
Abstract
AIM: To evaluate the impact of the sodium glucose co-transporter 2 inhibitor canagliflozin on intrahepatic triglyceride (IHTG) accumulation and its relationship to changes in body weight and glucose metabolism. MATERIALS AND METHODS In this double-blind, parallel-group, placebo-controlled, 24-week trial subjects with inadequately controlled type 2 diabetes mellitus (T2DM; HbA1c = 7.7% ± 0.7%) from two centres were randomly assigned (1:1) to canagliflozin 300 mg or placebo. We measured IHTG by proton-magnetic resonance spectroscopy (primary outcome), hepatic/muscle/adipose tissue insulin sensitivity during a 2-step euglycaemic insulin clamp, and beta-cell function during a mixed meal tolerance test. Analyses were per protocol. RESULTS Between 8 September 2014-13 June 2016, 56 patients were enrolled. Canagliflozin reduced HbA1c (placebo-subtracted change: -0.71% [-1.08; -0.33]) and body weight (-3.4% [-5.4; -1.4]; both P ≤ 0.001). A numerically larger absolute decrease in IHTG occurred with canagliflozin (-4.6% [-6.4; -2.7]) versus placebo (-2.4% [-4.2; -0.6]; P = 0.09). In patients with non-alcoholic fatty liver disease (n = 37), the decrease in IHTG was -6.9% (-9.5; -4.2) versus -3.8% (-6.3; -1.3; P = 0.05), and strongly correlated with the magnitude of weight loss (r = 0.69, P < 0.001). Body weight loss ≥5% with a ≥30% relative reduction in IHTG occurred more often with canagliflozin (38% vs. 7%, P = 0.009). Hepatic insulin sensitivity improved with canagliflozin (P < 0.01), but not muscle or adipose tissue insulin sensitivity. Beta-cell glucose sensitivity, insulin clearance, and disposition index improved more with canagliflozin (P < 0.05). CONCLUSIONS Canagliflozin improves hepatic insulin sensitivity and insulin secretion and clearance in patients with T2DM. IHTG decreases in proportion to the magnitude of body weight loss, which tended to be greater and occur more often with canagliflozin.
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Selenium supplementation and insulin resistance in a randomized, clinical trial.
Jacobs, ET, Lance, P, Mandarino, LJ, Ellis, NA, Chow, HS, Foote, J, Martinez, JA, Hsu, CP, Batai, K, Saboda, K, et al
BMJ open diabetes research & care. 2019;(1):e000613
Abstract
OBJECTIVE While controversial, observational and randomized clinical trial data implicate the micronutrient selenium (Se) in the development of type 2 diabetes (T2D). The aim of this study was to test the hypothesis that Se supplementation adversely affects pancreatic β-cell function and insulin sensitivity. RESEARCH DESIGN AND METHODS In a subset of 400 individuals participating in a randomized, placebo-controlled trial of Se at 200 µg/day for colorectal adenomatous polyps, fasting plasma glucose and insulin were measured before randomization and within 6 months of completing intervention. Change in the homeostasis model assessment-β cell function (HOMA2-%β) and insulin sensitivity (HOMA2-%S) were compared between arms. A subgroup of 175 (79 Se and 96 placebo) participants underwent a modified oral glucose tolerance test (mOGTT) at the end of intervention and change in glucose values was assessed. RESULTS No statistically significant differences were observed for changes in HOMA2-%β or HOMA2-%S between those who received Se compared with placebo. After a mean of 2.9 years on study, mean HOMA2-%β values were 3.1±24.0 and 3.1±29.8 for the Se and placebo groups, respectively (p=0.99). For HOMA2-%S, the values were -0.5±223.2 and 80.9±1530.9 for the Se and placebo groups, respectively (p=1.00). Stratification by sex or age did not reveal any statistically significant effects on insulin sensitivity by treatment group. For mOGTT, mean baseline fasting blood glucose concentrations were significantly higher among participants in the placebo group compared with the Se group (96.6±14.6 and 92.3±12.0, respectively; p=0.04), a trend which remained through the 20 min assessment. CONCLUSIONS These findings do not support a significant adverse effect of daily Se supplementation with 200 µg/day of selenized yeast on β-cell function or insulin sensitivity as an explanation for previously reported associations between Se and T2D. Further clarification of longer term effects of Se is needed. CLINICAL TRIAL REGISTRY NIH Clinical Trials.gov number NCT00078897.