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Long-term glycemic variability and the risk of mortality in diabetic patients receiving peritoneal dialysis.
Afghahi, H, Nasic, S, Peters, B, Rydell, H, Hadimeri, H, Svensson, J
PloS one. 2022;(1):e0262880
Abstract
BACKGROUND The large amount of glucose in the dialysate used in peritoneal dialysis (PD) likely affects the glycemic control. The aim of this study was to investigate the association between HbA1c variability, as a measure of long-term glycemic variability, and the risk of all-cause mortality in diabetic patients with PD. METHODS 325 patients with diabetes and ESRD were followed (2008-2018) in the Swedish Renal Registry. Patients were separated in seven groups according to level of HbA1c variability. The group with the lowest variability was denoted the reference. The ratio of the standard deviation (SD) to the mean of HbA1c, HbA1c (SD)/HbA1c (mean), i.e. the coefficient of variation (CV), was defined as HbA1c variability. Hazard ratios (HR) and 95% confidence intervals (CI) were examined using Cox regression analyses. RESULTS During follow-up, 170 (52%) deaths occurred. The highest mortality was among patients with the second highest HbA1c variability, CV≥2.83 [n = 44 of which 68% patients died]. In the multivariate analyses where lowest HbA1c variability (CV≤0.51) was used as the reference group, HbA1c CV 2.83-4.60 (HR 3.15, 95% CI 1.78-5.55; p<0.001) and CV> 4.6 (HR 2.48, 95% CI 1.21-5.11; p = 0.014) were associated with increased risk of death. CONCLUSION The high risk of all-cause mortality in patients with diabetes and PD increased significantly with elevated HbA1c variability, as measure of long-term glycemic control. This indicates that stable glycemia is associated with an improvement of survival; whereas more severe glycemic fluctuations, possibly caused by radical changes in dialysis regimes or peritonitis, are associated with a higher risk of mortality in diabetic patients with PD.
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Alternative pre-analytic sample handling techniques for glucose measurement in the absence of fluoride tubes in low resource settings.
Nakanga, WP, Balungi, P, Niwaha, AJ, Shields, BM, Hughes, P, Andrews, RC, Mc Donald, TJ, Nyirenda, MJ, Hattersley, AT
PloS one. 2022;(2):e0264432
Abstract
INTRODUCTION Sodium fluoride (NaF) tubes are the recommended tubes for glucose measurements, but these are expensive, have limited number of uses, and are not always available in low resource settings. Alternative sample handling techniques are thus needed. We compared glucose stability in samples collected in various tubes exposed to different pre-analytical conditions in Uganda. METHODS Random (non-fasted) blood samples were drawn from nine healthy participants into NaF, Ethylenediaminetetraacetic acid (EDTA), and plain serum tubes. The samples were kept un-centrifuged or centrifuged with plasma or serum pipetted into aliquots, placed in cool box with ice or at room temperature and were stored in a permanent freezer after 0, 2, 6, 12 and 24 hours post blood draw before glucose analysis. RESULTS Rapid decline in glucose concentrations was observed when compared to baseline in serum (declined to 64%) and EDTA-plasma (declined to 77%) after 6 hours when samples were un-centrifuged at room temperature whilst NaF-plasma was stable after 24 hours in the same condition. Un-centrifuged EDTA-plasma kept on ice was stable for up to 6 hours but serum was not stable (degraded to 92%) in the same conditions. Early centrifugation prevented glucose decline even at room temperature regardless of the primary tube used with serum, EDTA-plasma and NaF-plasma after 24 hours. CONCLUSION In low resource settings we recommend use of EDTA tubes placed in cool box with ice and analysed within 6 hours as an alternative to NaF tubes. Alternatively, immediate separation of blood with manual hand centrifuges will allow any tube to be used even in remote settings with no electricity.
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Predictors of type 2 diabetes remission in the Diabetes Remission Clinical Trial (DiRECT).
Thom, G, Messow, CM, Leslie, WS, Barnes, AC, Brosnahan, N, McCombie, L, Al-Mrabeh, A, Zhyzhneuskaya, S, Welsh, P, Sattar, N, et al
Diabetic medicine : a journal of the British Diabetic Association. 2021;(8):e14395
Abstract
AIM: To identify predictors of type 2 diabetes remission in the intervention arm of DiRECT (Diabetes Remission Clinical Trial). METHODS Participants were aged 20-65 years, with type 2 diabetes duration of <6 years and BMI 27-45 kg/m2 , and were not receiving insulin. Weight loss was initiated by total diet replacement (825-853 kcal/day, 3-5 months, shakes/soups), and weight loss maintenance support was provided for 2 years. Remissions (HbA1c <48 mmol/mol [<6.5%], without antidiabetes medications) in the intervention group (n = 149, mean age 53 years, BMI 35 kg/m2 ) were achieved by 68/149 participants (46%) at 12 months and by 53/149 participants (36%) at 24 months. Potential predictors were examined by logistic regression analyses, with adjustments for weight loss and effects independent of weight loss. RESULTS Baseline predictors of remission at 12 and 24 months included being prescribed fewer antidiabetes medications, having lower triglyceride and gamma-glutamyl transferase levels, and reporting better quality of life with less anxiety/depression. Lower baseline HbA1c was a predictor at 12 months, and older age and male sex were predictors at 24 months. Being prescribed antidepressants predicted non-remission. Some, but not all effects were explained by weight loss. Weight loss was the strongest predictor of remission at 12 months (adjusted odds ratio per kg weight loss 1.24, 95% CI 1.14, 1.34; P < 0.0001) and 24 months (adjusted odds ratio 1.23, 95% CI 1.13, 1.35; P <0.0001). Weight loss in kilograms and percentage weight loss were equally good predictors. Early weight loss and higher programme attendance predicted more remissions. Baseline BMI, fasting insulin, fasting C-peptide and diabetes duration did not predict remission. CONCLUSIONS Other than weight loss, most predictors were modest, and not sufficient to identify subgroups for which remission was not a worthwhile target.
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Risk Factors for Intraoperative Hypoglycemia in Children: A Multicenter Retrospective Cohort Study.
Riegger, LQ, Leis, AM, Golmirzaie, KH, Malviya, S
Anesthesia and analgesia. 2021;(4):1075-1083
Abstract
BACKGROUND Intraoperative hypoglycemia can result in devastating neurologic injury if not promptly diagnosed and treated. Few studies have defined risk factors for intraoperative hypoglycemia. The authors sought to characterize children with intraoperative hypoglycemia and determine independent risk factors in a multicenter cohort. METHODS This retrospective multicenter study included all patients <18 years undergoing an anesthetic from January 1, 2012, to December 31, 2016, at 12 institutions participating in the Multicenter Perioperative Outcomes Group (MPOG). The primary outcome was blood glucose <60 mg/dL (3.3 mmol/L). Data collected included patient characteristics, comorbidities, and intraoperative factors. A multivariable logistic regression model was used to identify independent predictors of intraoperative hypoglycemia. RESULTS Blood glucose was measured in 26,142 of 394,231 (6.6%) cases. Of these, 1017 (3.9%) had a glucose <60 mg/dL (3.3 mmol/L). Independent predictors for intraoperative hypoglycemia identified were age <30 days (estimated adjusted odds ratio [AOR] vs ≥5 years 4.2; 95% confidence interval [CI], 3.4-5.3), age 30 days to <5 years (estimated AOR vs ≥5 years 2.7; 95% CI, 2.3-3.2), weight for age <5th percentile (estimated AOR, 1.6; 95% CI, 1.4-1.9), American Society of Anesthesiologists (ASA) status ≥III (estimated AOR, 1.3; 95% CI, 1.1-1.6), presence of a gastric or jejunal tube (estimated AOR, 1.3; 95% CI, 1.1-1.6), poor feeding (estimated AOR, 1.5; 95% CI, 1.2-1.7), and abdominal surgery (estimated AOR, 1.4; 95% CI, 1.1-1.7). Eighty percent of hypoglycemia occurred in children <5 years of age and in children <20 kg. CONCLUSIONS Young age, weight for age <5th percentile, ASA status ≥III, having a gastric or jejunal tube, poor feeding, and abdominal surgery were risk factors for intraoperative hypoglycemia in children. Monitoring of blood glucose is recommended in these subsets of children.
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Maternal Metabolites Associated With Gestational Diabetes Mellitus and a Postpartum Disorder of Glucose Metabolism.
Liu, Y, Kuang, A, Bain, JR, Muehlbauer, MJ, Ilkayeva, OR, Lowe, LP, Metzger, BE, Newgard, CB, Scholtens, DM, Lowe, WL
The Journal of clinical endocrinology and metabolism. 2021;(11):3283-3294
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Abstract
CONTEXT Gestational diabetes is associated with a long-term risk of developing a disorder of glucose metabolism. However, neither the metabolic changes characteristic of gestational diabetes in a large, multi-ancestry cohort nor the ability of metabolic changes during pregnancy, beyond glucose levels, to identify women at high risk for progression to a disorder of glucose metabolism has been examined. OBJECTIVE This work aims to identify circulating metabolites present at approximately 28 weeks' gestation associated with gestational diabetes mellitus (GDM) and development of a disorder of glucose metabolism 10 to 14 years later. METHODS Conventional clinical and targeted metabolomics analyses were performed on fasting and 1-hour serum samples following a 75-g glucose load at approximately 28 weeks' gestation from 2290 women who participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Postpartum metabolic traits included fasting and 2-hour plasma glucose following a 75-g glucose load, insulin resistance estimated by the homeostasis model assessment of insulin resistance, and disorders of glucose metabolism (prediabetes and type 2 diabetes) during the HAPO Follow-Up Study. RESULTS Per-metabolite analyses identified numerous metabolites, ranging from amino acids and carbohydrates to fatty acids and lipids, before and 1-hour after a glucose load that were associated with GDM as well as development of a disorder of glucose metabolism and metabolic traits 10 to 14 years post partum. A core group of fasting and 1-hour metabolites mediated, in part, the relationship between GDM and postpartum disorders of glucose metabolism, with the fasting and 1-hour metabolites accounting for 15.7% (7.1%-30.8%) and 35.4% (14.3%-101.0%) of the total effect size, respectively. For prediction of a postpartum disorder of glucose metabolism, the addition of circulating fasting or 1-hour metabolites at approximately 28 weeks' gestation showed little improvement in prediction performance compared to clinical factors alone. CONCLUSION The results demonstrate an association of multiple metabolites with GDM and postpartum metabolic traits and begin to define the underlying pathophysiology of the transition from GDM to a postpartum disorder of glucose metabolism.
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Effects of Vitamin D Supplementation on Cardiovascular and Glycemic Biomarkers.
Miao, J, Bachmann, KN, Huang, S, Su, YR, Dusek, J, Newton-Cheh, C, Arora, P, Wang, TJ
Journal of the American Heart Association. 2021;(10):e017727
Abstract
Background Experimental and observational studies have suggested a link between vitamin D and cardiovascular and metabolic disease, but this has not been confirmed in randomized controlled trials. We sought to determine whether vitamin D supplementation reduces biomarkers of insulin resistance, inflammation, neurohormonal activation, and lipids. Methods and Results This was a prespecified, secondary analysis of the DAYLIGHT (Vitamin D Therapy in Individuals at High Risk of Hypertension) randomized controlled trial. We measured circulating homeostatic model assessment of insulin resistance, hs-CRP (high-sensitivity C-reactive protein), N-terminal pro-B-type natriuretic peptide, renin, aldosterone, and lipids at baseline and at 6 months in 289 individuals with low vitamin D status (25-hydroxyvitamin-D [25-OH-D] ≤25 ng/mL) receiving low-dose (400 IU/d) versus high-dose (4000 IU/d) vitamin D3 for 6 months. A meta-analysis of randomized controlled trials reporting biomarker changes after vitamin D supplementation was then performed. Levels of 25-OH-D increased in the high-dose relative to the low-dose vitamin D group (+15.5 versus +4.6 ng/mL, P<0.001). Changes in biomarkers of glycemia, inflammation, and neurohormonal activation did not differ by dose. Lipids did not differ between groups, other than triglycerides, which increased in the high-dose compared with the low-dose group (+11.3 versus -6.2 mg/dL, P<0.001). The meta-analysis showed potential modest decreases in homeostatic model assessment of insulin resistance and hs-CRP, but no changes in low-density lipoprotein, after vitamin D supplementation compared with control groups. Conclusions In the DAYLIGHT randomized controlled trial, high-dose vitamin D supplementation did not improve biomarkers of glycemia, inflammation, neurohormonal activation, or lipids. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01240512.
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Prediabetes is associated with proteinuria development but not with glomerular filtration rate decline: A longitudinal observational study.
Furukawa, M, Onoue, T, Kato, K, Wada, T, Shinohara, Y, Kinoshita, F, Goto, M, Arima, H, Tsushita, K
Diabetic medicine : a journal of the British Diabetic Association. 2021;(8):e14607
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AIMS: Diabetes is recognized as the leading cause of chronic kidney disease (CKD); however, the association of prediabetes with CKD remains unclear, in particular, the independent effect of prediabetes on proteinuria or estimated glomerular filtration rate (eGFR) has not been evaluated. This study aimed to investigate the associations of prediabetes with the proteinuria development and with eGFR decline separately in the Japanese general population without CKD. METHODS Participants who underwent health check-ups in 2014 and had adequate data after 2 years were retrospectively analysed. A total of 405,487 participants without CKD (eGFR, ≥60 ml min-1 1.73 m-2 , with negative or trace urinary protein) at baseline were categorized according to fasting plasma glucose as having diabetes (≥126 mg/dl [7.0 mmol/l]), prediabetes (100-125 mg/dl [5.6-6.9 mmol/l]) or normal glucose level (˂100 mg/dl [5.6 mmol/l]). Logistic regression analysis was used to analyse the effects of prediabetes (vs. normal glucose level) on the proteinuria development (urinary protein of ≥1+) and eGFR decline (˂60 ml min-1 1.73 m-2 ) after 2 years. RESULTS After 2 years, 7037 participants (1.7%) developed proteinuria alone, 19,015 (4.7%) presented eGFR decline alone and 636 (0.2%) showed both proteinuria and eGFR decline. Compared to normal glucose level and adjusting for prognostic factors, prediabetes was independently associated with the proteinuria development (odds ratio [OR] 1.233; 95% confidence interval [CI] 1.170-1.301], whereas prediabetes was not associated with eGFR decline (OR 0.981; 95% CI 0.947-1.017). CONCLUSIONS Prediabetes is associated with the proteinuria development but not with eGFR decline in the general population.
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In children and young people with type 1 diabetes using Pump therapy, an additional 40% of the insulin dose for a high-fat, high-protein breakfast improves postprandial glycaemic excursions: A cross-over trial.
Smith, TA, Smart, CE, Fuery, MEJ, Howley, PP, Knight, BA, Harris, M, King, BR
Diabetic medicine : a journal of the British Diabetic Association. 2021;(7):e14511
Abstract
AIM: To determine the insulin requirement for a high-fat, high-protein breakfast to optimise postprandial glycaemic excursions in children and young people with type 1 diabetes using insulin pumps. METHODS In all, 27 participants aged 10-23 years, BMI <95th percentile (2-18 years) or BMI <30 kg/m2 (19-25 years) and HbA1c ≤64 mmol/mol (≤8.0%) consumed a high-fat, high-protein breakfast (carbohydrate: 30 g, fat: 40 g and protein: 50 g) for 4 days. In this cross-over trial, insulin was administered, based on the insulin-to-carbohydrate ratio (ICR) of 100% (control), 120%, 140% and 160%, in an order defined by a randomisation sequence and delivered in a combination bolus, 60% ¼ hr pre-meal and 40% over 3 hr. Postprandial sensor glucose was assessed for 6 hr. RESULTS Comparing 100% ICR, 140% ICR and 160% ICR resulted in significantly lower 6-hr areas under the glucose curves: mean (95%CI) (822 mmol/L.min [605,1039] and 567 [350,784] vs 1249 [1042,1457], p ≤ 0.001) and peak glucose excursions (4.0 mmol/L [3.0,4.9] and 2.7 [1.7,3.6] vs 6.0 [5.0,6.9],p < 0.001). Rates of hypoglycaemia for 100%-160% ICR were 7.7%, 7.7%, 12% and 19% respectively (p ≥ 0.139). With increasing insulin dose, a step-wise reduction in mean glucose excursion was observed from 1 to 6 hr (p = 0.008). CONCLUSIONS Incrementally increasing the insulin dose for a high-fat, high-protein breakfast resulted in a predictable, dose-dependent reduction in postprandial glycaemia: 140% ICR improved postprandial glycaemic excursions without a statistically significant increase in hypoglycaemia. These findings support a safe, practical method for insulin adjustment for high-fat, high-protein meals that can be readily implemented in practice to improve postprandial glycaemia.
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Impact of endogenous insulin secretion on the improvement of glucose variability in Japanese patients with type 2 diabetes treated with canagliflozin plus teneligliptin.
Miya, A, Nakamura, A, Cho, KY, Kawata, S, Nomoto, H, Nagai, S, Sugawara, H, Taneda, S, Tsuchida, K, Omori, K, et al
Journal of diabetes investigation. 2021;(8):1395-1399
Abstract
AIMS/INTRODUCTION To identify the effect of combination therapy with a dipeptidyl peptidase-4 inhibitor and a sodium-glucose cotransporter 2 inhibitor compared with switching from a dipeptidyl peptidase-4 inhibitor to a sodium-glucose cotransporter 2 inhibitor on improving the glucose variability in patients with or without impaired endogenous insulin secretion. MATERIALS AND METHODS A secondary analysis regarding the relationship between endogenous insulin secretion and the change in mean amplitude of glycemic excursions (ΔMAGE) was carried out in a multicenter, prospective, randomized, parallel-group comparison trial that enrolled patients with type 2 diabetes who had been taking teneligliptin and were treated by switching to canagliflozin (SWITCH) or adding canagliflozin (COMB). Participants were categorized into the following four subgroups: SWITCH or COMB and high or low fasting C-peptide (CPR) divided at baseline by the median. RESULTS ΔMAGE in the COMB group was greatly improved independent of a high or low CPR (-29.2 ± 28.3 vs -20.0 ± 24.6, respectively; P = 0.60). However, ΔMAGE was not ameliorated in the low CPR SWITCH group, and the ΔMAGE was significantly smaller than that in the high CPR COMB group (P < 0.01). CONCLUSIONS COMB would be a better protocol rather than switching teneligliptin to canagliflozin to improve daily glucose variability in patients with impaired endogenous insulin secretion.
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Insulin resistance in type 1 diabetes managed with metformin (INTIMET): Study protocol of a double-blind placebo-controlled, randomised trial.
Snaith, JR, Samocha-Bonet, D, Evans, J, Liu, Z, Kowalski, G, Bruce, C, Holmes-Walker, DJ, Greenfield, JR
Diabetic medicine : a journal of the British Diabetic Association. 2021;(9):e14564
Abstract
BACKGROUND Insulin resistance is an under-recognised metabolic defect and cardiovascular risk factor in Type 1 diabetes. Whether metformin improves hepatic, muscle or adipose tissue insulin sensitivity has not been studied in adults with Type 1 diabetes. We initiated the INTIMET study (INsulin resistance in Type 1 diabetes managed with METformin), a double-blind randomised, placebo-controlled trial to measure the effect of metformin on tissue-specific insulin resistance in adults with Type 1 diabetes. METHODS We will study 40 adults aged 20-55 years with Type 1 diabetes (HbA1c ≤ 80 mmol/mol [9.5%], fasting C-peptide <0.3 nmol/L) and 20 age-, gender- and body mass index (BMI)-matched controls. Insulin sensitivity will be determined by the two-step hyperinsulinaemic-euglycaemic clamp method with deuterated glucose to document liver, muscle and adipose insulin sensitivity. Subjects with Type 1 diabetes will be randomised to metformin extended-release 1500 mg daily or matched placebo for 26 weeks. The primary outcome is change in hepatic insulin sensitivity, assessed by change in basal rate of appearance (Ra) of glucose and suppression of endogenous glucose production (EGP) during the low-dose stage of the clamp. CONCLUSION The INTIMET study is the first clinical trial to quantify the impact of metformin on liver, muscle and adipose insulin resistance in adults with Type 1 diabetes. This study may identify factors that predict an individual's response to metformin in Type 1 diabetes. TRIAL REGISTRATION ACTRN12619001440112.