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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.

ObjectiveTo assess whether botanical fermented food (BFF) consumption has an impact on cardiometabolic biomarkers or gut microbiota in adults with obesity, metabolic syndrome (MetS) or type 2 diabetes mellitus (T2DM).DesignSystematic reviewData sourcesEmbase, MEDLINE, Cochrane CENTRAL and Google Scholar were searched with no language limits, from inception to August 31, 2022.Eligibility criteriaRandomised controlled trials (RCTs) investigating the effects of BFFs on glucose, lipid, anthropometric, inflammatory and gut microbial parameters, in participants with obesity, MetS or T2DM.Data extraction and synthesisTwo independent reviewers screened 6873 abstracts and extracted relevant data. Risk of bias (ROB) was assessed using the Cochrane Collaboration’s ROB2 tool. A qualitative, narrative synthesis was produced.ResultsThe final review included 26 RCTs, with 31 reports published between 2001 and 2022. Significant (pConclusionIn 73% of included studies, BFF consumption by participants with obesity, MetS or T2DM led to significant between-group improvements in 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 asBifidobacteriumand LAB, whilst reducing potential pathogens likeBacteroides. 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.EthicsEthical approval was not required as primary data was not collected.PROSPERO registration numberCRD42018117766STRENGTHS AND LIMITATIONS OF THIS STUDYTo the best of our knowledge, this is the first systematic review assessing RCTs of BFFs on metabolic, inflammatory, anthropometric and gut microbiota parameters in adults with obesity, T2DM, MetS or its components.Our search strategy adhered to the Cochrane review methodology and the PRISMA statement requirements.To ensure cultural inclusion and comprehensive up-to-date findings, our search started from inception to 31 August 2022, and had no language limits.ROB2, the most recent version of the Cochrane risk-of-bias tool, was used to assess the risk of bias in five domains covering the design, conduct and reporting of the included RCTs.Due to significant heterogeneity of BFF types, dosage, length of intervention and target populations, meta-analysis could not be conducted.

Sodium glucose co-transporter-2 inhibitors (SGLT-2i) are a relatively new class of oral glucose lowering agents that improve glycaemic control and also provide significant cardiac and renal benefits. However, SGLT-2i use is associated with a small but significant increased risk of diabetic ketoacidosis (DKA) especially during periods of reduced oral intake such as following dental procedures, bowel preparation for colonoscopy, surgery and concurrent illness. In contrast with typical DKA, in many cases of SGLT2i-associated DKA, the blood glucose is normal or only slightly elevated, giving rise to the term euglycaemic DKA (euDKA). Patients with euDKA often present with non-specific symptoms. Moreover, their normal or only mildly elevated blood glucose levels might lead to delayed diagnosis and treatment and hence potentially life-threatening complications. Not only should patients taking an SGLT-2i be informed about the risk of euDKA, and be provided with SGLT-2i sick day management education, but clinicians should also be alert to this diagnosis.

Context The increasing burden of diabetic kidney disease (DKD) has led to the discovery of novel therapies. Objective This review aims to summarize the results of recent clinical trials that test the efficacy of potential therapies for DKD. Methods A systematized narrative review was performed utilizing the PubMed, Embase (Ovid), CINAHL, and Cochrane databases (January 2010 to January 2021). The included trials assessed the efficacy of specific medications using renal endpoints in adult participants with type 1 or 2 diabetes. Results Fifty-three trials were identified. Large, multinational, and high-powered trials investigating sodium-glucose cotransporter 2 (SGLT2) inhibitors demonstrated improved renal outcomes, even in patients with established DKD. Trials examining incretin-related therapies also showed some improvement in renal outcomes. Additionally, mineralocorticoid receptor antagonists exhibited potential with multiple improved renal outcomes in large trials, including those involving participants with established DKD. Atrasentan, baricitinib, ASP8232, PF-04634817, CCX140-B, atorvastatin, fenofibrate, probucol, doxycycline, vitamin D, omega-3 fatty acids, silymarin, turmeric, total glucosides of paeony, and tripterygium wilfordii Hook F extract were all associated with some improved renal endpoints but need further exploration. While bardoxolone methyl was associated with a decrease in albuminuria, high rates of cardiovascular adverse effects curtailed further exploration into this agent. Selonsertib, allopurinol, praliciguat, palosuran, benfotiamine, and diacerein were not associated with improved renal outcomes. Conclusion Trials have yielded promising results in the search for new therapies to manage DKD. SGLT2 inhibitors and incretin-related therapies have demonstrated benefit and were associated with improved cardiovascular outcomes. Mineralocorticoid receptor antagonists are another class of agents with increasing evidence of benefits.

Aims Pre-diabetes is a common condition that affects about 16.4% of Australian adults. Hyperglycaemia is a strong risk factor for the development of stroke. Metformin XR is an approved medication to treat type 2 diabetes in Australia but not pre-diabetes. Additionally, whether it is tolerated following a stroke is unclear. In this pilot study, we aimed to assess the feasibility of Metformin XR in people with stroke and pre-diabetes. Methods In this PROBE design trial, people who had recent stroke (within 3 months) with pre-diabetes were randomized to either the active arm (n = 13) receiving usual care plus Metformin XR (500 mg daily increased to a total daily dose of 1500 mg) or the control group receiving only usual care (n = 13). At baseline & after four months of intervention, clinical and biomedical characteristics, cardiovascular risk factors and medication data were recorded. At one month and 2.5 months into the study, compliance rate and side effects were determined. Results This trial showed that it is feasible to recruit, retain and monitor participants. However, the compliance rate was low. Adherence to metformin XR was 52% (IQR:42% to 61%) based on the remaining tablets in the container after 4 months of intervention. None of the reported side effects were deemed to be related to the study treatment and no significant differences were observed between the metformin XR and the control group. Conclusion Treatment with Metformin XR in participants admitted with stroke and with pre-diabetes is feasible and safe. Strategies are needed to improve adherence in future trials.

BACKGROUND & AIMS: Sarcopenia is prevalent in post acute inpatient rehabilitation. An easy to administer screening test may improve identification of sarcopenia in this population, which may promote its early detection and treatment. THE AIMS OF THIS STUDY WERE: a) To investigate clinical utility of SARC-F as a European Working Group on Sarcopenia in Older People2 (EWGSOP2) recommended tool for sarcopenia case finding in post acute inpatient rehabilitation. b) To develop an easy and pragmatic screening test for sarcopenia in healthcare settings with limited ability to measure the patients' muscle mass for confirmation of the sarcopenia diagnosis. METHODS: This cross-sectional study with prospective data collection recruited patients admitted to a general inpatient rehabilitation unit in a metropolitan tertiary referral hospital in Australia. Participant's true sarcopenia status was ascertained, as per EWGSOP2, from their grip strength and muscle mass. Two SARC-F questionnaires were administered, for participants' current and, by recall, premorbid status. To develop GripBMI screening tool, BMI test positivity cut off was established on training sample and validated in conjunction with the established grip strength cut off on validation sample using area under the Receiver Operating Curve (ROC) analysis. RESULTS: True prevalence of sarcopenia in 277 participants (median age 64 years (IQR 53-72), 52% male) was 14% (95%CI 11%-19%). Screening utility of SARC-F positive status at the time of admission for sarcopenia had ROC of 0.50, and of premorbid SARC-F positive status had ROC of 0.51. Out of 42 participants positive on the GripBMI screen, 33 had sarcopenia, and out of 235 participants negative on the GripBMI screen, 7 participants had sarcopenia, resulting in GripBMI ROC area 0.89, sensitivity 83%, specificity 96%, positive predictive value 79%, negative predictive value 97%, diagnostic odds ratio 119 (95% CI 42-338). CONCLUSIONS: The GripBMI screening tool uses the combination of EWGSOP2 recommended low grip strength cut offs and Body Mass Index of less than 25 as a positive screening test for sarcopenia. It may assist in promoting early detection and management of sarcopenia in post acute inpatient rehabilitation.

Renal echo planar diffusion tensor imaging (DTI) has clinical potential but suffers from geometric distortion. We evaluated feasibility of reversed gradient distortion correction in 10 diabetic patients and 6 volunteers. Renal area, apparent diffusion coefficient, fractional anisotropy, and tensor eigenvalues were measured on uncorrected and distortion-corrected DTI. Corrected DTI correlated better than uncorrected DTI (r = 0.904 vs 0.840, P = 0.002) with reference anatomic T2-weighted imaging, with no significant difference in DTI metrics.

BACKGROUND: Understanding the risk factors and pregnancy outcomes in women affected by Type 1 and Type 2 diabetes is important for pre-pregnancy counselling. AIM: To explore differences in pregnancy outcomes between women with Type 1 and Type 2 diabetes, and healthy controls, and to examine the relationships between potential adverse risk factors and pregnancy outcomes in this cohort of women. METHODS: This is a 10-year retrospective study of women with Type 1 diabetes (n = 92), Type 2 diabetes (n = 106) and healthy women without diabetes (controls) (n = 119) from a tertiary obstetric centre. Clinical and biochemical characteristics of women with Type 1 and Type 2 diabetes were determined and related to major obstetric outcomes using univariate analysis. RESULTS: Women with pre-existing diabetes had higher adverse pregnancy outcomes (preeclampsia, emergency caesarean section, preterm birth

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.

Hypoglycemia is a major barrier impeding glycemic control in persons with type 2 diabetes mellitus and creates a substantial burden on the healthcare system. Certain populations that require special attention, such as older adults and individuals with renal impairment, a longer duration of diabetes or those who have experienced prior hypoglycemia, may be at a higher risk of hypoglycemia, particularly with insulin treatment. Second-generation basal insulin analogues (insulin glargine 300 U/mL and degludec) have demonstrated reductions in hypoglycemia compared with insulin glargine 100 U/mL although evidence of this benefit across specific populations is less clear. In this review we summarize the literature with respect to the efficacy and safety data for second-generation basal insulin analogues in adults with type 2 diabetes mellitus who are at risk of hypoglycemia or who require special attention. Randomized controlled trials, meta-analyses and real-world evidence demonstrate that the use of second-generation basal insulin analogues is associated with less hypoglycemia compared with insulin glargine 100 U/mL without compromising glycated hemoglobin control. A reduced risk of hypoglycemia with second-generation basal insulin analogues was evident in older adults and in individuals with obesity, renal impairment, a history of cardiovascular disease or a long duration of insulin use. Further studies are needed in other populations, including those with more severe renal impairment or hepatic dysfunction, the hospitalized population and those with cognitive impairment. Overall, less hypoglycemia associated with second-generation basal insulin analogues may help reduce barriers for insulin use, improve adherence and offset the costs of hypoglycemia-related healthcare resource utilization.

Background The effect of bariatric surgery on ‘emotional eating’ (EE) in people with obesity is unclear. This systematic review and meta‐analysis aimed to examine changes in self‐reported emotional eating behaviour after bariatric surgery. Methods Fifteen electronic databases were searched from inception to August 2019. Included studies encompassed patients undergoing primary bariatric surgery, quantitatively assessed EE, and reported EE scores before and after surgery in the same participants. Studies were excluded if they were not in English or available in full text. The systematic review and meta‐analysis were conducted according to the PRISMA guidelines. Random‐effects models were used for quantitative analysis. Study quality was assessed using the National Heart, Lung, and Blood Institute quality assessment tool for before–after (pre–post) studies with no control group. Results Some 23 studies containing 6749 participants were included in the qualitative synthesis, with follow‐up of from 2 weeks to 48 months. EE scores decreased to 12 months after surgery. Results were mixed beyond 12 months. Quantitative synthesis of 17 studies (2811 participants) found that EE scores decreased by a standardized mean difference of 1·09 (95 per cent c.i. 0·76 to 1·42) 4–18 months after surgery, indicating a large effect size. Conclusion Bariatric surgery may mitigate the tendency to eat in response to emotions in the short to medium term., In this meta‐analysis involving 17 studies, self‐reported emotional eating scores decreased significantly by a standardized mean difference of 1·09 (95 per cent c.i. 0·76 to 1·42) at 4–18 months after bariatric surgery. This raises the possibility of a mitigating effect of bariatric surgery on emotional eating in the short to medium term. Little evidence of an effect beyond 12 months

Background: Central homeostatic regulation of fat stores is attenuated during pregnancy, to allow for adequate fat deposition to support fetal development and lactation. What factors particular to pregnancy facilitate fat accumulation, and why gestational weight gain (GWG) is so variable, are not clear. The aim of this cross-sectional study was to examine the associations between GWG and circulating hormones with known effects on appetite and growth. Methods: Women without obesity (body mass index, BMI

Introduction Sodium glucose cotransporter 2 inhibitors (SGLT2i) have emerged as an important class of blood glucose–lowering medications, due to cardiovascular, metabolic, and renal benefits. However, there is a small but significant risk of diabetic ketoacidosis (DKA) associated with their use. Methods A literature search was conducted in Ovid MEDLINE and Embase to July 2019 using variants on the key search terms sodium-glucose cotransporter 2, diabetic ketoacidosis, and type 2 diabetes. A broad spectrum of evidence was incorporated to facilitate a comprehensive narrative review. Further sources were identified through hand searching of reference lists. Discussion Although cardiovascular outcome trials demonstrated mixed evidence of SGLT2i associated DKA, increasing evidence from case reports and cohort studies has identified an increased risk. SGLT2i use is associated with a ketotic state caused by an increased glucagon:insulin ratio and stimulated by factors including stress-induced hormonal changes, insufficient insulin, decreased glucose, increased ketone resorption, and hypovolemia. Atypical presentations of DKA with lower-than-expected blood glucose levels are possible with SGLT2i use, so clinical and biochemical monitoring is vital for early identification and management. DKA risk is particularly increased with precipitating factors, therefore optimization of risk factors is vital. Recommendations for perioperative and sick day management of patients taking SGLT2i have been suggested based on available evidence. Conclusion SGLT2i are an excellent class of drug in the physician’s toolkit for managing type 2 diabetes. However, both clinicians and patients must be aware of the potential for DKA and the need for increased monitoring, both clinically and biochemically, when potential precipitating factors are present. In acutely unwell patients, these medications should be withheld to reduce the risk of DKA.

A relationship between diabetes, glucose and COVID-19 outcomes has been reported in international cohorts. This study aimed to assess the relationship between diabetes, hyperglycaemia and patient outcomes in those hospitalised with COVID-19 during the first year of the Victorian pandemic prior to novel variants and vaccinations.Retrospective cohort study from March to November 2020 across five public health services in Melbourne, Australia.All consecutive adult patients admitted to acute wards of participating institutions during the study period with a diagnosis of COVID-19, comprising a large proportion of patients from residential care facilities and following dexamethasone becoming standard-of-care. Admissions in patients without known diabetes and without inpatient glucose testing were excluded.The DINGO COVID-19 cohort comprised 840 admissions. In 438 admissions (52%), there was no known diabetes or in-hospital hyperglycaemia, in 298 (35%) patients had known diabetes, and in 104 (12%) patients had hyperglycaemia without known diabetes. ICU admission was more common in those with diabetes (20%) and hyperglycaemia without diabetes (49%) than those with neither (11%, P 0.001 for all comparisons). Mortality was higher in those with diabetes (24%) than those without diabetes or hyperglycaemia (16%, P = 0.02) but no difference between those with in-hospital hyperglycaemia and either of the other groups. On multivariable analysis, hyperglycaemia was associated with increased ICU admission (adjusted odds ratio (aOR) 6.7, 95% confidence interval (95% CI) 4.0-12, P 0.001) and longer length of stay (aOR 173, 95% CI 11-2793, P 0.001), while diabetes was associated with reduced ICU admission (aOR 0.55, 95% CI 0.33-0.94, P = 0.03). Neither diabetes nor hyperglycaemia was independently associated with in-hospital mortality.During the first year of the COVID-19 pandemic, in-hospital hyperglycaemia and known diabetes were not associated with in-hospital mortality, contrasting with published international experiences. This likely mainly relates to hyperglycaemia indicating receipt of mortality-reducing dexamethasone therapy. These differences in published experiences underscore the importance of understanding population and clinical treatment factors affecting glycaemia and COVID-19 morbidity within both local and global contexts.

Diabetic kidney disease is expected to increase rapidly over the coming decades with rising prevalence of diabetes worldwide. Current measures of kidney function based on albuminuria and estimated glomerular filtration rate do not accurately stratify and predict individuals at risk of declining kidney function in diabetes. As a result, recent attention has turned towards identifying and assessing the utility of biomarkers in diabetic kidney disease. This review explores the current literature on biomarkers of inflammation and kidney injury focussing on studies of single or multiple biomarkers between January 2014 and February 2020. Multiple serum and urine biomarkers of inflammation and kidney injury have demonstrated significant association with the development and progression of diabetic kidney disease. Of the inflammatory biomarkers, tumour necrosis factor receptor-1 and -2 were frequently studied and appear to hold most promise as markers of diabetic kidney disease. With regards to kidney injury biomarkers, studies have largely targeted markers of tubular injury of which kidney injury molecule-1, beta-2-microglobulin and neutrophil gelatinase-associated lipocalin emerged as potential candidates. Finally, the use of a small panel of selective biomarkers appears to perform just as well as a panel of multiple biomarkers for predicting kidney function decline.

A recent case series of diabetic ketoacidosis (DKA) associated with colonoscopy in sodium–glucose cotransporter 2 inhibitor (SGLT2i)-treated diabetes (1) prompted a clinical alert update to include colonoscopy (2). That update advised colonoscopy cancellation when capillary ketone concentrations are >1.0 mmol/L (if blood gas analysis is unavailable) when SGLT2i have not been withheld for 72 h. However, those guidelines were formulated in the absence of data regarding the normal range for capillary ketone concentrations at the time of colonoscopy. Unnecessary colonoscopy cancellation carries risks, including delays in possible cancer detection, and psychological consequences, whereas a ketone cutoff that is too high increases the risk of DKA. To define a ketone concentration that may serve as an empirical determinant of the need for further investigation, we now report a nondiabetic reference interval for capillary ketone concentrations at the time of colonoscopy from a multicenter observational study conducted between June and December 2020 at four tertiary health services (Alfred, Austin, Eastern, and Western Health) in Melbourne, Australia. Multisite approval was granted by the Alfred Human Research Ethics Committee. Inclusion criteria for the reference population were community-dwelling, normoglycemic adults undergoing colonoscopy. Exclusion criteria were a history of diabetes, pancreatitis, pancreatic cancer, pancreatic surgery, hemochromatosis, cystic fibrosis, starvation ketosis (defined as fasting >72 h), pregnancy, or the discovery during recruitment of a fasting capillary glucose >5.5 mmol/L (100 mg/dL). Participants with type 2 diabetes were also recruited to compare capillary ketone concentrations with the reference interval population. Except for physician-adjudicated …

Despite the high prevalence of diabetes in older people, there is limited information on optimal methods to support their diabetes management, including how to incorporate technology. This article reports on the results of semi-structured interviews with 41 adult participants with type 2 diabetes (mean age 74 ± 7 years) on their perspectives of a new model of care (the Older People With Type 2 Diabetes–Individualising Management With a Specialised Community Team [OPTIMISE] program) for older people with type 2 diabetes. The OPTIMISE program involved telemedicine consultations, home visits by a credentialed diabetes educator, and intermittent flash glucose monitoring. Human connection and relationships were key to the positive perspectives expressed by participants in this program that used technology to enhance the care of older people in their homes.

Diabetic kidney disease (DKD) is a highly prevalent complication of diabetes and the leading cause of end‐stage kidney disease. Inflammation is recognized as an important driver of progression of DKD. Activation of the immune response promotes a pro‐inflammatory milieu and subsequently renal fibrosis, and a progressive loss of renal function. Although the role of the innate immune system in diabetic renal disease has been well characterized, the potential contribution of the adaptive immune system remains poorly defined. Emerging evidence in experimental models of DKD indicates an increase in the number of T cells in the circulation and in the kidney cortex, that in turn triggers secretion of inflammatory mediators such as interferon‐γ and tumor necrosis factor‐α, and activation of cells in innate immune response. In human studies, the number of T cells residing in the interstitial region of the kidney correlates with the degree of albuminuria in people with type 2 diabetes. Here, we review the role of the adaptive immune system, and associated cytokines, in the development of DKD. Furthermore, the potential therapeutic benefits of targeting the adaptive immune system as a means of preventing the progression of DKD are discussed.

Aim: To report the first study of temelimab, a monoclonal antibody neutralizing the pathogenic human endogenous retrovirus type W envelope, in patients with type 1 diabetes (T1D). Materials and Methods: This double-blind, placebo-controlled, randomized clinical trial recruited adult patients with T1D within 4 years postdiagnosis and remaining C-peptide secretion. Sixty-four patients were randomized (2:1) to monthly temelimab 6 mg/kg or placebo during 24 weeks, followed by a 24-week, open-label extension, during which all patients received temelimab. The primary objective was the safety and tolerability of temelimab. The secondary objective was to assess the pharmacodynamics response such as C-peptide levels, insulin use, HbA1c, hypoglycaemia and autoantibodies. Results: Temelimab was well tolerated without any group difference in the frequency or severity of adverse events. Concerning exploratory endpoints, there was no difference in the levels of C-peptide, insulin use or HbA1c between treatment groups at weeks 24 and 48. The frequency of hypoglycaemia events was reduced with temelimab (P = 0.0004) at week 24 and the level of anti-insulin antibodies was lower with temelimab (P < 0.01); the other autoantibodies did not differ between groups. Conclusions: Temelimab appeared safe in patients with T1D. Pharmacodynamics signals (hypoglycaemia and anti-insulin antibodies) under temelimab were observed. Markers of β-cell functions were not modified by treatment. These results need to be further explored in younger patients with T1D with earlier disease onset.

The relationship between serial changes in soluble tumor necrosis factor receptor type 1 (TNFR1) levels and an early decline in estimated glomerular filtration rate (eGFR) decline remains to be defined. We found that in patients with an early decline in renal function (n = 30), soluble TNFR1 values increased (2,595 ± 683 vs 3,596 ± 1,203 pg/mL, P

There is ongoing debate surrounding the complex relationship between dietary sodium intake and cardiovascular morbidity and mortality. The existing literature consists largely of observational studies that have demonstrated positive, negative, U-/J-shaped or unclear associations between sodium intake and cardiovascular outcomes. Our group and others have previously demonstrated an inverse relationship between dietary sodium intake and cardiovascular outcomes in people with type 2 diabetes. Increased activity of the renin-angiotensin-aldosterone system and sympathetic nervous system is postulated to contribute to these paradoxical findings through endothelial dysfunction, a precursor to the development of cardiovascular disease. Microvesicles are submicron (0.1 – 1.0μm) vesicles that form during cellular activation, injury or death with endothelial microvesicles being recognized markers of endothelial dysfunction. They are pathologically elevated in a variety of vascular-related conditions including type 2 diabetes. Lower habitual sodium intake in type 2 diabetes has been associated with higher pro-coagulant platelet microvesicles levels but not with endothelial microvesicles. Research utilizing endothelial microvesicles to evaluate the mechanistic relationship between dietary sodium intake and adverse cardiovascular outcomes in type 2 diabetes remains scarce.

The sequelae of diabetes include microvascular complications such as diabetic kidney disease (DKD), which involves glucose-mediated renal injury associated with a disruption in mitochondrial metabolic agility, inflammation, and fibrosis. We explored the role of the innate immune complement component C5a, a potent mediator of inflammation, in the pathogenesis of DKD in clinical and experimental diabetes. Marked systemic elevation in C5a activity was demonstrated in patients with diabetes; conventional renoprotective agents did not therapeutically target this elevation. C5a and its receptor (C5aR1) were upregulated early in the disease process and prior to manifest kidney injury in several diverse rodent models of diabetes. Genetic deletion of C5aR1 in mice conferred protection against diabetes-induced renal injury. Transcriptomic profiling of kidney revealed diabetes-induced downregulation of pathways involved in mitochondrial fatty acid metabolism. Interrogation of the lipidomics signature revealed abnormal cardiolipin remodeling in diabetic kidneys, a cardinal sign of disrupted mitochondrial architecture and bioenergetics. In vivo delivery of an orally active inhibitor of C5aR1 (PMX53) reversed the phenotypic changes and normalized the renal mitochondrial fatty acid profile, cardiolipin remodeling, and citric acid cycle intermediates. In vitro exposure of human renal proximal tubular epithelial cells to C5a led to altered mitochondrial respiratory function and reactive oxygen species generation. These experiments provide evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD by disrupting mitochondrial agility, thereby establishing a new immunometabolic signaling pathway in DKD.

■Metformin is recommended as first-line therapy for type 2 diabetes because of its safety, low cost and potential cardiovascular benefits. ■The use of metformin was previously restricted in people with chronic kidney disease (CKD) - a condition that commonly coexists with diabetes - due to concerns over drug accumulation and metformin-associated lactic acidosis. ■There are limited data from observational studies and small randomised controlled trials to suggest that metformin, independent of its antihyperglycaemic effects, may be associated with lower risk of myocardial infarction, stroke and all-cause mortality in people with type 2 diabetes and CKD. ■Research into the risk of metformin-associated lactic acidosis in CKD has previously been limited and conflicting, resulting in significant variation across international guidelines on the safe prescribing and dosing of metformin at different stages of renal impairment. ■Present-day large scale cohort studies now provide supporting evidence for the safe use of metformin in mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-60 mL/min/1.73m2 ). However, prescribing metformin in people with severe renal impairment (eGFR

Gestational diabetes mellitus (GDM) and large for gestational age (LGA) offspring are two common pregnancy complications. Connections also exist between the two conditions, including mutual maternal risk factors for the conditions and an increased prevalence of LGA offspring amongst pregnancies affected by GDM. Thus, it is important to elucidate potential shared underlying mechanisms of both LGA and GDM. One potential mechanistic link relates to macronutrient metabolism. Indeed, derangement of carbohydrate and lipid metabolism is present in GDM, and maternal biomarkers of glucose and lipid control are associated with LGA neonates in such pregnancies. The aim of this paper is therefore to reflect on the existing nutritional guidelines for GDM in light of our understanding of the pathophysiological mechanisms of GDM and LGA offspring. Lifestyle modification is first line treatment for GDM, and while there is some promise that nutritional interventions may favourably impact outcomes, there is a lack of definitive evidence that changing the macronutrient composition of the diet reduces the incidence of either GDM or LGA offspring. The quality of the available evidence is a major issue, and rigorous trials are needed to inform evidence-based treatment guidelines.

Aims Using routine HbA1c measurement to determine the prevalence of diabetes mellitus (known and previously unrecognized) and their hospital outcomes among hematology and oncology inpatients. Methods This was a prospective, observational study. Routine automated HbA1c testing was performed in all hematology and oncology inpatients aged ≥54 years at a tertiary hospital, July 2013-January 2015. The outcome measures were: (i) prevalence of known and previously unrecognized diabetes, and (ii) hospital outcomes: length-of-stay (LOS), intensive-care-unit (ICU) admission, 30-day/18-month readmission, and 18-month mortality. Results Over the 18-month study period, 1076 inpatients aged ≥54 years were admitted to hematology (n = 298) and oncology (n = 778) units: 21% had known diabetes and 7% had previously unrecognized diabetes. Patients with known diabetes had a longer LOS (IRR: 1.18, 95%CI: 1.02–1.37, p = 0.03), compared to those without diabetes, adjusting for age, hemoglobin level, estimated-glomerular-filtration-rate, admission specialty unit, Charlson’s comorbidity index score, and glucocorticoid exposure. No significant differences were observed in ICU admission, 30-day/18-month readmission, and 18-month mortality among patients with known, previously unrecognized and no diabetes (p ≥ 0.05). Conclusions Approximately one in five hematology or oncology inpatients aged ≥54 years had known diabetes, and one in fourteen had previously unrecognized diabetes. Those with known diabetes had a longer hospital stay. Routine HbA1c measurement is can be useful for identifying previously unrecognized diabetes, particularly among patients with high glucocorticoid exposure. Further study is required to determine cost-effectiveness in screening for unrecognized diabetes and optimal management of these patients.

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.

AIMS To compare levels of renal hypoxia measured by Blood Oxygen Level Dependent (BOLD) magnetic resonance imaging (MRI) with measured transverse relaxation rate (R2*) and renal structural changes including apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in patients with type 1 diabetes and healthy controls. METHODS Cohort study comparing MRI metrics in type 1 diabetes (n = 32, GFR 105 (77, 120) ml/min.1.73m2) and controls (n = 10). Renal function and selected inflammatory renal biomarkers were also measured. RESULTS For BOLD, we found reduced cortical [14.7 (13.7,15.8) (1/s) vs 15.7 (15.1,16.6) (1/s), p

To compare the outcomes of sodium glucose linked cotransporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase 4 inhibitors (DPP4i) in hospitalized patients.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.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) or4 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.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.

Background: Reliable insulin delivery is critical in the management of type 1 diabetes. Limitations of insulin pump therapy (IPT) are the maximum cannula life of three days, and a reported failure rate of 15-25% prior to this, which may impact glycemia and quality of life. Objective: We aimed to determine the feasibility of a prototype cannula for an extended wear infusion set. Materials and Methods: CapBio’s SteadiFlow technology (Capillary Biomedical, Irvine, CA, USA) consists of a cannula with a soft outer polymer reinforced by an internal metal coil to prevent kinking and three additional side ports to reduce the risk of cannula blockages. Adults with type 1 diabetes using IPT participated in a study with three study periods. For each period a new infusion set was inserted for an intended wear of 7 days. During Period 1 saline was infused via the investigational set through an additional insulin pump. During Periods 2 and 3 insulin lispro was delivered via the investigational set connected to the participant’s own insulin pump. Results are expressed as mean (SD). Results: Twenty participants (Medtronic 640G [n=11]; 670G [n=3]; Tandem t-slim X2 [n=6]) with type 1 diabetes (age 44Y [14]; HbA1c 7.3% [0.6]/56mmol/mol [6]; female 50%) were studied. The 7-day survival rates of the prototype cannula set were 19/20 (95%) for period one and 36/41(88%) for periods two and three combined. No serious adverse events were reported. Mild infusion site reactions occurred in 7 participants. Hyperglycemia was reported as an adverse event in 7 participants resulting in premature cannula removal in 4 cases (occurring, respectively, on Days 1, 2, 5, and 6 during Weeks 2 or 3). Infusion site infection caused the 5th premature removal (on Day 3). Post-removal, no kinked cannulas were observed. Conclusions: These study results confirm the feasibility of the extended-life investigational cannula. Larger, randomised studies are required to confirm these preliminary observations. Disclosure D. N. O’neal: Advisory Panel; Self; Abbott Diabetes, Medtronic, Sanofi, Research Support; Self; Dexcom, Inc., GlySens Incorporated, Medtronic, Pacific Diabetes Technologies. N. Venkatesh: None. K. Brown: None. E. I. Ekinci: None. S. Fourlanos: Advisory Panel; Self; Pfizer Foundation, Speaker’s Bureau; Self; AstraZeneca, Eli Lilly and Company. J. R. Kastner: None. R. Macisaac: Advisory Panel; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Servier Laboratories, Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Novo Nordisk. D. B. Muchmore: Consultant; Self; Capillary Biomedical, Inc., Diasome Pharmaceuticals, Inc., Zucara Therapeutics Inc., Stock/Shareholder; Self; Capillary Biomedical, Inc., Diasome Pharmaceuticals, Inc.