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The impact of botanical fermented foods on metabolic syndrome and type 2 diabetes: a systematic review of randomised controlled trials.
Chan, M, Larsen, N, Baxter, H, Jespersen, L, Ekinci, EI, Howell, K
Nutrition research reviews. 2023;:1-20
Abstract
Our systematic review assessed the impact of botanical fermented food (BFF) consumption on glucose, lipid, anthropometric, inflammatory and gut microbiota parameters, in adults with metabolic syndrome (MetS), MetS components or type 2 diabetes mellitus (T2DM). Embase, MEDLINE, Cochrane CENTRAL and Google Scholar were searched with no language limits, from inception to 31 August 2022, for eligible randomised controlled trials (RCTs). Two independent reviewers screened 6873 abstracts and extracted relevant data. Risk of bias (ROB) was assessed using the Cochrane Collaboration's ROB2 tool. The final review included twenty-six RCTs, with thirty-one reports published between 2001 and 2022. Significant (p < 0·05) within-group and between-group changes in cardiometabolic outcome means were reported in twenty-three and nineteen studies, respectively. Gut microbiota composition was assessed in four studies, with two finding significant between-group differences. No significant difference between groups of any measured outcomes was observed in five studies. There were fourteen studies at low ROB; ten were of some concern; and two were at high ROB. In 73% of included studies, BFF consumption by participants with obesity, MetS or T2DM led to significant between-group improvements in discrete cardiometabolic outcomes, including fasting blood glucose, lipid profile, blood pressure, waist circumference, body fat percentage and C-reactive protein. BFF consumption increased the abundance of beneficial gut bacteria, such as Bifidobacterium and LAB, whilst reducing potential pathogens such as Bacteroides. To determine the clinical significance of BFFs as therapeutic dietary adjuncts, their safety, tolerability and affordability must be balanced with the limited power and magnitude of these preliminary findings.
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Body mass index is inversely associated with capillary ketones at the time of colonoscopy: Implications for SGLT2i use.
Hamblin, PS, Wong, R, Ekinci, EI, Sztal-Mazer, S, Balachandran, S, Frydman, A, Hanrahan, TP, Hu, R, Ket, SN, Moss, A, et al
Clinical endocrinology. 2022;(4):549-557
Abstract
OBJECTIVE Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been associated with diabetic ketoacidosis at the time of colonoscopy. This study aimed to identify factors associated with ketone concentrations in SGLT2i-treated type 2 diabetes compared with non-SGLT2i-treated diabetes, and those with impaired fasting glycaemia (IFG) and normoglycaemia. DESIGN Cross-sectional, multicentre, observational study June-December 2020 in four Australian tertiary hospitals. PARTICIPANTS Capillary glucose and ketones were measured in people undergoing colonoscopy: 37 SGLT2i-treated and 105 non-SGLT2i-treated type 2 diabetes, 65 IFG and 151 normoglycaemia. MEASUREMENTS Body mass index (BMI), age, glucose, fasting duration and where relevant, HbA1c and time since last SGLT2i dose. RESULTS In SGLT2i-treated diabetes, BMI (ρ = -0.43 [95% confidence interval: -0.67, -0.11]) and duration since last SGLT2i dose (ρ = -0.33 [-0.60, 0.00]) correlated negatively with increasing ketones, but there was no correlation with fasting duration. In non-SGLT2i-treated diabetes, BMI correlated negatively (ρ = -0.24 [-0.42, -0.05]) and fasting duration positively (ρ = 0.26 [0.07, 0.43]) with ketones. In IFG participants, only fasting duration correlated with ketones (ρ = 0.28 [0.03, 0.49]). In normoglycaemic participants, there were negative correlations with BMI (ρ = -0.20 [-0.35, -0.04]) and fasting glucose (ρ = -0.31 [-0.45, -0.15]) and positive correlations with fasting duration (ρ = 0.20 [0.04, 0.35]) and age (ρ = 0.19 [0.03, 0.34]). Multiple regression analysis of the entire cohort showed BMI, age and fasting glucose remained independently associated with ketones, but in SGLT2i-treated participants only BMI remained independently associated. CONCLUSIONS In SGLT2i-treated diabetes, lower BMI was a novel risk factor for higher ketones precolonoscopy. Pending larger confirmatory studies, extra vigilance for ketoacidosis is warranted in these people.
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Complications of Diabetes and Metrics of Glycemic Management Derived From Continuous Glucose Monitoring.
Yapanis, M, James, S, Craig, ME, O'Neal, D, Ekinci, EI
The Journal of clinical endocrinology and metabolism. 2022;(6):e2221-e2236
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Abstract
CONTEXT Although glycated hemoglobin A1c is currently the best parameter used clinically to assess risk for the development of diabetes complications, it does not provide insight into short-term fluctuations in glucose levels. This review summarizes the relationship between continuous glucose monitoring (CGM)-derived metrics of glycemic variability and diabetes-related complications. EVIDENCE ACQUISITION PubMed and Embase databases were searched from January 1, 2010 to August 22, 2020, using the terms type 1 diabetes, type 2 diabetes, diabetes-related microvascular and macrovascular complications, and measures of glycaemic variability. Exclusion criteria were studies that did not use CGM and studies involving participants who were not diabetic, acutely unwell (post stroke, post surgery), pregnant, or using insulin pumps. EVIDENCE SYNTHESIS A total of 1636 records were identified, and 1602 were excluded, leaving 34 publications in the final review. Of the 20 852 total participants, 663 had type 1 diabetes (T1D) and 19 909 had type 2 diabetes (T2D). Glycemic variability and low time in range (TIR) showed associations with all studied microvascular and macrovascular complications of diabetes. Notably, higher TIR was associated with reduced risk of albuminuria, retinopathy, cardiovascular disease mortality, all-cause mortality, and abnormal carotid intima-media thickness. Peripheral neuropathy was predominantly associated with standard deviation of blood glucose levels (SD) and mean amplitude of glycemic excursions (MAGE). CONCLUSION The evidence supports the association between diabetes complications and CGM-derived measures of intraday glycemic variability. TIR emerged as the most consistent measure, supporting its emerging role in clinical practice. More longitudinal studies and trials are required to confirm these associations, particularly for T1D, for which there are limited data.
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The comparative epidemiology and outcomes of hospitalized patients treated with SGLT2 or DPP4 inhibitors.
Huang, W, Whitelaw, J, Kishore, K, Neto, AS, Holmes, NE, Marhoon, N, Bellomo, R, Ekinci, EI
Journal of diabetes and its complications. 2021;(12):108052
Abstract
OBJECTIVE To compare the outcomes of sodium glucose linked cotransporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase 4 inhibitors (DPP4i) in hospitalized patients. RESEARCH DESIGN AND METHODS Electronic medical records-based cohort study. Identification of patients with type 2 diabetes and treatment with SGLT2i (n = 466) or DPP4i (n = 1541). Outcomes compared between those who received SGLT2i and those who received DPP4i. The primary outcome: adjusted percentage of blood glycemia within 4-10 mmol/L. RESULTS After adjustment, SGLT2i use had a statistically equivalent percentage of glycemia within range (coefficient: 4.55, 95% CI -3.23 to 12.32, p = 0.25) or <4 mmol/L (coefficient -0.17, 95% CI -0.71 to 3.72, p = 0.54). There were no significant differences in hospital length of stay (p = 0.22), complications, (p = 0.11) or mortality (p = 0.57). When measured, ketone levels were higher in the SGLT2i group on admission, but lower on days 3, 4 and 5 (p < 0.001 for interaction). Bicarbonate levels were not statistically different between groups. Finally, 54% of patients whose SGLT2i was ceased during admission, were discharged home without it. CONCLUSION Among inpatients with type 2 diabetes, SGLT2i use was associated with equivalent within-target glycaemia and no significant increase in hypoglycemia, ketonemia, or lower bicarbonate levels. These hypothesis-generating findings support further investigation of SGLT2i therapy in inpatients.
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An overview of COVID-19 in people with diabetes: Pathophysiology and considerations in the inpatient setting.
Fleming, N, Sacks, LJ, Pham, CT, Neoh, SL, Ekinci, EI
Diabetic medicine : a journal of the British Diabetic Association. 2021;(3):e14509
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INTRODUCTION The coronavirus disease (COVID-19) pandemic has continued to have a devastating impact on health worldwide. There has been a rapid evolution of evidence, establishing an increased risk of morbidity and mortality associated with diabetes and concurrent COVID-19. The objective of this review is to explore the current evidence for inpatient assessment and management of diabetes during the COVID-19 pandemic and highlight areas requiring further exploration. METHODS A literature search of databases was conducted to November 2020 using variations on keywords SARS-CoV-2, COVID-19, SARS, MERS and diabetes. Information relating to the impact of diabetes on severity of COVID-19 infection, the impact of COVID-19 infection on diabetes management and diabetes-related complications was integrated to create a narrative review. DISCUSSION People with diabetes and COVID-19 are at an increased risk of morbidity and mortality. It is important that people with both known and previously unrecognised diabetes and COVID-19 be promptly identified and assessed during acute illness, with close monitoring for clinical deterioration or complications. People with diabetes may require titration or alteration of their glycaemic management due to the potential for worse outcomes with hyperglycaemia and COVID-19 infection. Comprehensive discharge planning is vital to optimise ongoing glycaemic management. CONCLUSION Further understanding of the risk of adverse outcomes and optimisation of glycaemic management for people with diabetes during COVID-19 is required to improve outcomes. Increased glucose and ketone monitoring, substitution of insulin for some oral anti-hyperglycaemic medications and careful monitoring for complications of diabetes such as diabetic ketoacidosis should be considered.
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Gut microbiome, prebiotics, intestinal permeability and diabetes complications.
Snelson, M, de Pasquale, C, Ekinci, EI, Coughlan, MT
Best practice & research. Clinical endocrinology & metabolism. 2021;(3):101507
Abstract
Diabetes is a metabolic condition. The composition of the gut microbiota is altered in diabetes with reduced levels of short chain fatty acids (SCFA) producers, notably butyrate. Butyrate is associated with a number of beneficial effects including promoting the integrity of the gastrointestinal barrier. Diabetes may lead to an increase in the permeability of the gut barrier, which is thought to contribute to systemic inflammation and worsen the microvascular complications of diabetes. Prebiotics, non-digestible carbohydrates, are fermented by the colonic microbiota leading to the production of a range of metabolites including SCFAs. Thus, prebiotics represent a dietary approach to increase levels of microbially produced SCFAs and improve intestinal permeability in diabetes. Whether prebiotics can lead to a reduction in the risk of developing diabetes complications in individuals with type 2 diabetes needs to be explored.
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Performance of 4 Creatinine-based Equations in Assessing Glomerular Filtration Rate in Adults with Diabetes.
Zafari, N, Lotfaliany, M, O'Keefe, GJ, Kishore, K, Torkamani, N, MacIsaac, RJ, Churilov, L, Ekinci, EI
The Journal of clinical endocrinology and metabolism. 2021;(1):e61-e73
Abstract
AIMS: To evaluate diagnostic performance of glomerular filtration rate (GFR) estimated by modification of diet in renal disease (MDRD), chronic kidney disease epidemiology collaboration (CKD-EPI), full age spectrum (FAS), and revised Lund-Malmö (r-LM) equations in adults with diabetes. METHODS Individuals were included in this cross-sectional study if they had at least 1 measurement of technetium-99m diethylenetriamine-pentaacetic acid (99mTc-DTPA) GFR (mGFR) and serum creatinine (1487 patients with 2703 measures). GFR calculated by estimation equations was compared with mGFR. Diagnostic performance was assessed using concordance correlation coefficient (CCC), bias, precision, accuracy, reduced major axis regression (RMAR), and Bland-Altman plot. Analysis was repeated in subgroups based on sex, diabetes type, Hemoglobin A1C, and GFR level. RESULTS Of all patients, 1189 (86%) had type 2 diabetes. Mean mGFR, MDRD, CKD-EPI, FAS, and revised Lund-Malmö eGFR were 66, 72, 74, 71, and 67 mL/min/1.73m2, respectively. Overall, the r-LM had the highest CCC (0.83), lowest bias (-1.4 mL/min/1.73 m2), highest precision (16.2 mL/min/1.73 m2), and highest accuracy (P10 = 39%). The RMAR (slope, intercept) in r-LM, FAS, MDRD, and CKD-EPI was 1.18, -13.35; 0.97, -2.9; 1, -6.4, and 1.04, -11.3, respectively. The Bland-Altman plot showed that r-LM had the lowest mean difference and the narrowest 95% limit of agreement (-1.0, 54.1 mL/min/1.73 m2), while mean difference was more than 5-fold higher in FAS, MDRD, and CKD-EPI (-5.2, -6.3, and -8.2, respectively). CONCLUSIONS In adults with diabetes the revised Lund-Malmö performs better than MDRD, CKD-EPI, and FAS in calculating point estimates of GFR.
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Advances in type 2 diabetes therapy: a focus on cardiovascular and renal outcomes.
Libianto, R, Davis, TM, Ekinci, EI
The Medical journal of Australia. 2020;(3):133-139
Abstract
Treatment options for type 2 diabetes have expanded. While metformin remains the first line treatment in most cases, choices for second line treatment now extend beyond sulfonylureas and include the sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP1) receptor agonists, and dipeptidyl peptidase 4 (DPP4) inhibitors. SGLT2 inhibitors are recommended for people with atherosclerotic cardiovascular disease, heart failure or kidney disease. Diabetic ketoacidosis is an uncommon but important side effect; its occurrence can be minimised with appropriate patient education and management, especially during perioperative periods and times of illness. GLP1 receptor agonists are recommended for people with atherosclerotic cardiovascular disease. Gastrointestinal side effects are common but are less prominent with the longer acting agents and can be minimised with slow titration of the shorter acting agents. DPP4 inhibitors are generally well tolerated, but alogliptin and saxagliptin should be used with caution in people with risk factors for heart failure. To optimise the management of type 2 diabetes, clinicians need to be aware of the pharmacological characteristics of each class of blood glucose-lowering medications and of the effect on cardiovascular health and renal function, balanced by potential adverse effects. Medications that have cardiovascular or renal benefits should be prescribed for patients with these comorbidities, and this is reflected in recent international guidelines.
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Effect of angiotensin II receptor blocker and salt supplementation on short-term blood pressure variability in type 2 diabetes.
Chen, AX, Moran, JL, Libianto, R, Baqar, S, O'Callaghan, C, MacIsaac, RJ, Jerums, G, Ekinci, EI
Journal of human hypertension. 2020;(2):143-150
Abstract
High blood pressure variability (BPV) has been associated with increased cardiovascular (CV) risk. The effect of dietary salt and renin-angiotensin-aldosterone system (RAAS) activity on short-term BPV in type 2 diabetes mellitus (T2DM) is not well characterised. We aimed to determine the effect of dietary salt (sodium chloride, NaCl) supplementation on 24-h mean arterial BPV (24hBPV) during angiotensin II receptor blocker (telmisartan) use and to evaluate the effects of age, sex, plasma renin activity (PRA) and serum aldosterone on 24hBPV. In a randomised, double-blind, crossover study, patients with T2DM (n = 28), treated with telmisartan received NaCl (100 mmol/24 h) or placebo capsules during 2 weeks of telmisartan. Following a 6-week washout, the protocol was repeated in reverse. 24hBPV was evaluated as a co-efficient of variation [CV (%) = mean/standard deviation] × 100). Twenty-four hour urinary sodium excretion, ambulatory BP and biochemical tests were performed at each phase. Results were analysed using a linear mixed model to generate predicted values for 24hBPV. Predicted 24hBPV was higher with telmisartan vs baseline (p = 0.01), with a trend towards reduced 24hBPV with salt (p = 0.052). Predicted 24hBPV was lower in females (p = 0.017), increasing age (p = 0.001) and increasing PRA (p = 0.011). In patients with T2DM, predicted 24hBPV increased from baseline with telmisartan, but there was no additional increase in predicted 24hBPV with salt supplementation. This suggests that in the short-term, salt supplementation has no apparent deleterious effects on 24hBPV. Long-term studies are required to evaluate the effect of 24hBPV on CV outcomes in patients with T2DM.
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Effect of Salt Supplementation on Sympathetic Activity and Endothelial Function in Salt-Sensitive Type 2 Diabetes.
Baqar, S, Kong, YW, Chen, AX, O'Callaghan, C, MacIsaac, RJ, Bouterakos, M, Lambert, GW, Jerums, G, Lambert, EE, Ekinci, EI
The Journal of clinical endocrinology and metabolism. 2020;(4)
Abstract
CONTEXT Lower sodium intake is paradoxically associated with higher mortality in type 2 diabetes (T2D). OBJECTIVE To determine whether sympathetic nervous system (SNS) activation and endothelial dysfunction contribute to these observations, we examined the effect of salt supplementation on these systems in people with T2D with habitual low sodium. We hypothesized that salt supplementation would lower SNS activity and improve endothelial function compared to placebo. DESIGN We conducted a randomized, double-blinded, placebo-controlled crossover trial. SETTING The study took place in a tertiary referral diabetes outpatient clinic. PARTICIPANTS Twenty-two people with T2D with habitual low sodium intake (24-hour urine sodium <150 mmol/24h) were included. INTERVENTION Salt supplementation (100 mmol NaCl/24h) or placebo for 3 weeks was administered. MAIN OUTCOME MEASURES The primary outcome of SNS activity and endothelial function was assessed as follows: Microneurography assessed muscle sympathetic nerve activity (MSNA), pulse amplitude tonometry assessed endothelial function via reactive hyperemic index (RHI), and arterial stiffness was assessed via augmentation index (AI). Secondary outcomes included cardiac baroreflex, serum aldosterone, ambulatory blood pressure monitoring (ABPM), heart rate variability (HRV), and salt sensitivity. RESULTS Compared to placebo, salt supplementation increased MSNA (burst frequency P = .047, burst incidence P = .016); however, RHI (P = .24), AI (P = .201), ABPM (systolic P = .09, diastolic P = .14), and HRV were unaffected. Salt supplementation improved baroreflex (slope P = .026) and lowered aldosterone (P = .004), and in salt-resistant individuals there was a trend toward improved RHI (P = .07). CONCLUSIONS In people with T2D and low habitual sodium intake, salt supplementation increased SNS activity without altering endothelial function or blood pressure but improved baroreflex function, a predictor of cardiac mortality. Salt-resistant individuals trended toward improved endothelial function with salt supplementation.