Expresser phenotype determines ABO(H) blood group antigen loading on platelets and von Willebrand factor.

ABO blood group is associated with cardiovascular disease, with significantly lower risk in blood group O individuals. ABO(H) blood group determinants are expressed on different glycoproteins on platelet surfaces. In addition, ABO(H) structures are also present on VWF glycans. These ABO(H) carbohydrates influence both platelet and VWF function. Previous studies have reported that approximately 5-10% of normal blood donors express abnormally high or low levels of A or B blood group antigens on their platelet surfaces (high expresser phenotype, HXP or low expresser phenotype, LXP respectively). In this study, the biological effects of the ABO Expresser phenotype were investigated. ABO(H) expression on platelets and plasma VWF was studied in a series of 541 healthy blood donors. Overall, 5.6% of our study cohort were classified as HXP, whilst 4.4% satisfied criteria for LXP. We demonstrate that genotype at the ABO blood group locus plays a critical role in modulating the platelet HXP phenotype. In particular, A1A1 genotype is a major determinant of ABO high-expresser trait. Our data further show that ABH loading on VWF is also affected by ABO expresser phenotype. Consequently, A antigen expression on VWF was significantly elevated in HXP individuals and moderately reduced in LXP subjects (P < 0.05). Collectively, these findings suggest that ABO expresser phenotype influences primary hemostasis though several different pathways. Further studies will be required to define whether inter-individual variations in ABO(H) expression on platelets and/or VWF (particularly HXP and LXP) impact upon risk for cardiovascular disease.

Checkpoint Inhibitor-Associated Autoimmune Diabetes Is Distinct From Type 1 Diabetes.

CONTEXT: Checkpoint inhibitor-associated autoimmune diabetes mellitus (CIADM) is a rare illness, and little is known about its incidence, clinical features, or pathogenesis. CASE SERIES DESCRIPTION: Consecutive patients from a single quaternary melanoma center who developed new-onset insulin-requiring diabetes after commencing anti-programmed cell death-1 (PD-1) immunotherapy were studied to describe CIADM characteristics. Ten (1.9%) of 538 patients with metastatic melanoma treated with anti-PD-1-based immunotherapy from March 2015 to March 2018 developed CIADM. Nine patients had no history of diabetes, and one had pre-existing type 2 diabetes mellitus. Median time from immunotherapy start to CIADM diagnosis was 25 weeks [interquartile range (IQR), 17.5 to 34.5 weeks]. All patients had normal serum C-peptide shortly before CIADM onset and an inappropriately low level when measured soon after. At CIADM diagnosis, median hemoglobin A1c was 7.6% (IQR, 7.15% to 9.75%), median glucose level was 32.5 mmol/L (IQR, 21.6 to 36.7 mmol/L), and median C-peptide concentration was 0.35 nmol/L (IQR, 0.10 to 0.49 mmol/L). Type 1 diabetes (T1D)-associated autoantibodies (DAAs) were present in two patients (both of whom had anti-glutamic acid decarboxylase antibody); all were negative for insulin-associated protein 2, insulin, and ZnT8. Three patients were heterozygous for an HLA class II T1D-risk haplotype; two additional patients also carried protective haplotypes for T1D. All patients continued immunotherapy; eight (80%) had complete or partial oncological response, and all patients required ongoing insulin therapy. CONCLUSION: CIADM is characterized by sudden permanent ß-cell failure occurring after immunotherapy. It is distinct from T1D, usually lacks DAA or T1D-associated HLA-risk haplotypes, and is associated with difficult glycemic control from the onset. As such, CIADM represents a new model of auto-inflammatory ß-cell failure.

HbA1c variability in adults with type 1 diabetes on continuous subcutaneous insulin infusion (CSII) therapy compared to multiple daily injection (MDI) treatment.

OBJECTIVE: To determine if continuous subcutaneous insulin infusion (CSII) therapy is associated with lower glycated haemoglobin (HbA1c) variability (long-term glycaemic variability; GV) relative to multiple daily injection (MDI) treatment in adults with type 1 diabetes mellitus (T1DM). DESIGN: Retrospective audit. SETTING AND PARTICIPANTS: Clinic records from 506 adults with T1DM from two tertiary Australian hospitals. OUTCOME MEASURES: Long-term GV was assessed by HbA1c SD and coefficient of variation (CV) in adults on established MDI or CSII therapy, and in a subset changing from MDI to CSII. RESULTS: Adults (n=506, (164 CSII), 50% women, mean±SD age 38.0±15.3 years, 17.0±13.7 years diabetes, mean HbA1c 7.8%±1.2% (62±13 mmol/mol) on CSII, 8.0%±1.5% (64±16 mmol/mol) on MDI) were followed for 4.1±3.6 years. CSII use was associated with lower GV (HbA1c SD: CSII vs MDI 0.5%±0.41% (6±6 mmol/mol) vs 0.7%±0.7% (9±8 mmol/mol)) and CV: CSII vs MDI 6.7%±4.6% (10±10 mmol/mol) vs 9.3%±7.3% (14±13 mmol/mol), both p<0.001. Fifty-six adults (73% female, age 36±13 years, 16±13 years diabetes, HbA1c 7.8%±0.8% (62±9 mmol/mol)) transitioned from MDI to CSII. Mean HbA1c fell by 0.4%. GV from 1 year post-CSII commencement decreased significantly, HbA1c SD pre-CSII versus post-CSII 0.7%±0.5% (8±5 mmol/mol) vs 0.4%±0.4% (5±4 mmol/mol); p<0.001, and HbA1c CV 9.2%±5.5% (13±8 mmol/mol) vs 6.1%±3.9% (9±5 mmol/mol); p<0.001. CONCLUSIONS: In clinical practice with T1DM adults relative to MDI, CSII therapy is associated with lower HbA1c GV.

Large-for-Gestational-Age Neonates in Type 1 Diabetes and Pregnancy: Contribution of Factors Beyond Hyperglycemia.

Despite significant reductions in serious adverse perinatal outcomes for women with type 1 diabetes in pregnancy, the opposite effect has been observed for fetal overgrowth and associated complications, such as neonatal hypoglycemia, shoulder dystocia, and admission to the neonatal intensive care unit. In addition, infants born large for gestational age (LGA) have an increased lifetime risk of obesity, diabetes, and chronic disease. Although exposure to hyperglycemia plays an important role, women who seemingly achieve adequate glycemic control in pregnancy continue to experience a greater risk of excess fetal growth, leading to LGA neonates and macrosomia. We review potential contributors to excess fetal growth in pregnancies complicated by type 1 diabetes. In addition to hyperglycemia, we explore the role of glycemic variability, prepregnancy overweight and obesity, gestational weight gain, and maternal lipid levels. Greater understanding of the stimuli that drive excess fetal growth could lead to targeted management strategies in pregnant women with type 1 diabetes, potentially reducing the incidence of LGA neonates and the inherent risk of acute and long-term complications.

Role of DOTATATE-PET/CT in preoperative assessment of phaeochromocytoma and paragangliomas.

CONTEXT: Diagnosis of paragangliomas (PGL) and phaeochromocytomas (PC) can be challenging particularly if the tumour is small. Detection of metastatic disease is important for comprehensive management of malignant PC/PGL. Somatostatin receptor imaging (SRI) agents have high sensitivity for these tumours, particularly the DOTA family of radiopharmaceuticals labelled with 68 Gallium. OBJECTIVE: To describe the utility of SRI in primary assessment (ie before surgery) for PC/PGL and whether measures of maximum standardized uptake (SUVmax) could be used to distinguish between adrenal adenomas and PCs. DESIGN: Retrospective analysis of patients with PC and PGL between 2012 and 2017. PATIENTS: Somatostatin receptor imaging (SRI) was performed for suspected PC (n = 46) or PGL (n = 27) of which 36 were during primary assessment and 37 during secondary assessment (follow-up after surgery). For comparison of adrenal SUVmax, scans from 30 patients without suspected PC/PGL (20 with normal adrenals; 10 with incidental adenomas) were evaluated. MEASUREMENTS: Baseline description, sensitivity, specificity, Youden's index. RESULTS: Sensitivity of DOTATATE-PET was 88% for PC and 100% for PGL. False-negative scans were seen in 2/10 PCs < 28 mm and in 1/14 PCs > 28 mm which had features of cystic degeneration. SUVmax of PCs and PGLs was more than double compared to adrenal adenomas (P > .001). CONCLUSION: Somatostatin receptor imaging (SRI) has high sensitivity in primary assessment for PC and PGL. We recommend that SRI should be performed as part of primary assessment in all suspected PGLs (due to higher risk of multifocal lesions) and in PCs suspected to be associated with hereditary syndromes or metastases.

Utility of the Hospital Admission Risk Programme diabetes risk calculator in identifying patients with type 2 diabetes at risk of unplanned hospital presentations.

BACKGROUND: Prevention of hospitalisation is an important aspect of type 2 diabetes (T2D) management. AIMS: We retrospectively determined the utility of the Hospital Admission Risk Programme (HARP) diabetes risk calculator (HARP tool) in identifying patients with T2D more likely to have unplanned hospital presentations. METHODS: The HARP tool includes a clinical assessment score (Part A) and a psychosocial and self-management impact score (Part B), and categorises patients into low, medium, high or urgent risk of acute hospitalisation. It was completed for T2D patients attending Royal North Shore Hospital, Sydney, in 2013. RESULTS: Within the cohort of 278 patients (age 65.3 ± 10.5 years; 62.9% male; diabetes duration 10.7 ± 6.6 years), 67.3% were classified as low risk, 32.7% as medium risk and none as high or urgent risk. Following adjustment for confounders, a medium HARP score was associated with a 3.1-fold increased risk of unplanned hospital presentations in the subsequent 12 months (95% confidence interval: 1.35-7.31; P = 0.008). Part A scores were significantly higher for patients that presented to hospital compared to those that did not (14.2 ± 6.8 vs 11.4 ± 5.5; P = 0.034), whereas there was no difference in Part B scores (P = 0.860). CONCLUSIONS: In patients with low and medium HARP scores, clinical features were more predictive of hospital presentations than certain psychosocial or self-management factors in the present cohort. Further studies are required to characterise unplanned hospitalisation in patients with higher HARP scores, or whether additional psychosocial assessments could improve the tool's predictability.

Suboptimal behaviour and knowledge regarding overnight glycaemia in adults with type 1 diabetes is common.

BACKGROUND: In people with type 1 diabetes (T1D), nocturnal hypoglycaemia (NH) can be slept through and can cause seizures, arrhythmias and death. Hypoglycaemia avoidance can induce hyperglycaemia and ketosis. Patient behaviour impacts clinical outcomes and may be changed by education. AIM: To develop and utilise a survey to evaluate patient self-management of overnight glycaemia in adults with T1D. METHODS: Adults with T1D attending two Australian tertiary referral diabetes clinics completed a survey about their diabetes self-management and glycaemic control, including responses to hypothetical pre-bed blood glucose (BG) levels (4-20 mmol/L). Statistical analyses included t-tests, Chi square tests and ANOVA with significance considered at P < 0.05. RESULTS: There were 205 participants (103 females), with a mean (SD) age of 41 (17) years, T1D duration of 20 (16) years, HbA1c of 7.8(1.4)%, (61.3(8.2) mmol/mol), 38% on insulin pump therapy (CSII) and 36% with impaired hypoglycaemia awareness (IHA). Mean (SD) number of BG tests/day was 5.4 (2.7). Patients set higher BG target levels at bedtime and overnight: 7.5(1.4) and 7.1(1.3) mmol/L, respectively, compared to daytime (6.9(1.0); P < 0.0001 and P = 0.002 respectively). Only 36% of participants reported treating nocturnal hypoglycaemia (NH) with the recommended refined, then complex, carbohydrate. Only 28% of patients made safe choices in all bedtime BG scenarios, with higher rates for CSII users, P = 0.0005. Further education was desired by 32% of respondents, with higher rates in those with (44%) versus without IHA (25%), P = 0.006. CONCLUSIONS: Many adults with T1D have suboptimal knowledge and behaviour regarding overnight BG self-management. A survey, piloted herein, may facilitate the identification of patients who could benefit from further education.

Outcomes for Women with Gestational Diabetes Treated with Metformin: A Retrospective, Case-Control Study.

Metformin is increasingly being used a therapeutic option for the management of gestational diabetes mellitus (GDM). The aim of this study was to compare the maternal characteristics and perinatal outcomes of women with GDM treated with metformin (with or without supplemental insulin) with those receiving other management approaches. A retrospective, case-control study was carried out and 83 women taking metformin were matched 1:1 with women receiving insulin or diet and lifestyle modification alone. Women managed with diet and lifestyle modification had a significantly lower fasting plasma glucose (p < 0.001) and HbA1c (p < 0.01) at diagnosis of GDM. Furthermore, women managed with metformin had a higher early pregnancy body mass index (BMI) compared to those receiving insulin or diet and lifestyle modification (p < 0.001). There was no difference in mode of delivery, birth weight or incidence of large- or small-for-gestational-age neonates between groups. Women receiving glucose lowering therapies had a higher rate of neonatal hypoglycaemia (p < 0.05). The incidence of other adverse perinatal outcomes was similar between groups. Despite their greater BMI, women with metformin-treated GDM did not have an increased risk of adverse perinatal outcomes. Metformin is a useful alternative to insulin in the management of GDM.

Identification of Patients With Diabetes Who Benefit Most From a Health Coaching Program in Chronic Disease Management, Sydney, Australia, 2013.

INTRODUCTION: Chronic disease management programs (CDMPs) that include health coaching can facilitate and coordinate diabetes management. The aim of this study was to assess changes in patients' general knowledge of diabetes, self-reported health status, diabetes distress, body mass index (BMI), and glycemic control after enrollment in a face-to-face CDMP group health coaching session (with telephone follow-up) compared with participation in telephone-only health coaching, during a 12-month period. METHODS: Patients with diabetes were enrolled in a health coaching program at Royal North Shore Hospital, Sydney, Australia, in 2013. Questionnaires were administered at baseline and at 3, 6, and 12 months, and the results were compared with baseline. Glycemic control, measured with glycated hemoglobin A1c (HbA1c) and BMI, were measured at baseline and 12 months. RESULTS: Overall, 238 patients attended a face-to-face CDMP session with telephone follow-up (n = 178) or participated in telephone-only health coaching (n = 60). We found no change in BMI in either group; however, HbA1c levels in patients with baseline above the current recommended target (>7%) decreased significantly from 8.5% (standard deviation [SD], 1.0%) to 7.9% (SD, 1.0%) (P = .03). Patients with the lowest self-reported health status at baseline improved from 4.4 (SD, 0.5) to 3.7 (SD, 0.9) (P = .001). Diabetes knowledge improved in all patients (24.4 [SD, 2.4] to 25.2 [SD, 2.4]; P < .001), and diabetes distress decreased among those with the highest levels of distress at baseline (3.0 [SD, 0.4] vs 3.8 [SD, 0.6]; P = .003). CONCLUSION: Diabetes health coaching programs can improve glycemic control and reduce diabetes distress in patients with high levels of these at baseline.

The renal consequences of maternal obesity in offspring are overwhelmed by postnatal high fat diet.

AIMS/HYPOTHESIS: Developmental programming induced by maternal obesity influences the development of chronic disease in offspring. In the present study, we aimed to determine whether maternal obesity exaggerates obesity-related kidney disease. METHODS: Female C57BL/6 mice were fed high-fat diet (HFD) for six weeks prior to mating, during gestation and lactation. Male offspring were weaned to normal chow or HFD. At postnatal Week 8, HFD-fed offspring were administered one dose streptozotocin (STZ, 100 mg/kg i.p.) or vehicle control. Metabolic parameters and renal functional and structural changes were observed at postnatal Week 32. RESULTS: HFD-fed offspring had increased adiposity, glucose intolerance and hyperlipidaemia, associated with increased albuminuria and serum creatinine levels. Their kidneys displayed structural changes with increased levels of fibrotic, inflammatory and oxidative stress markers. STZ administration did not potentiate the renal effects of HFD. Though maternal obesity had a sustained effect on serum creatinine and oxidative stress markers in lean offspring, the renal consequences of maternal obesity were overwhelmed by the powerful effect of diet-induced obesity. CONCLUSION: Maternal obesity portends significant risks for metabolic and renal health in adult offspring. However, diet-induced obesity is an overwhelming and potent stimulus for the development of CKD that is not potentiated by maternal obesity.

Impact of obesity and epicardial fat on early left atrial dysfunction assessed by cardiac MRI strain analysis.

BACKGROUND: Diastolic dysfunction is a major cause of morbidity in obese individuals. We aimed to assess the ability of magnetic resonance imaging (MRI) derived left atrial (LA) strain to detect early diastolic dysfunction in individuals with obesity and type 2 diabetes, and to explore the association between cardiac adipose tissue and LA function. METHODS: Twenty patients with obesity and T2D (55 ± 8 years) and nineteen healthy controls (48 ± 13 years) were imaged using cine steady state free precession and 2-point Dixon cardiovascular magnetic resonance. LA function was quantified using a feature tracking technique with definition of phasic longitudinal strain and strain rates, as well as radial motion fraction and radial velocities. RESULTS: Systolic left ventricular size and function were similar between the obesity and type 2 diabetes and control groups by MRI. All patients except four had normal diastolic assessment by echocardiography. In contrast, measures of LA function using magnetic resonance feature tracking were uniformly altered in the obesity and type 2 diabetes group only. Although there was no significant difference in intra-myocardial fat fraction, Dixon 3D epicardial fat volume(EFV) was significantly elevated in the obesity and type 2 diabetes versus control group (135 ± 31 vs. 90 ± 30 mL/m2, p < 0.001). There were significant correlations between LA functional indices and both BMI and EFV (p ≤ 0.007). CONCLUSIONS: LA MRI-strain may be a sensitive tool for the detection of early diastolic dysfunction in individuals with obesity and type 2 diabetes and correlated with BMI and epicardial fat supporting a possible association between adiposity and LA strain. Trials Registration Australian New Zealand Clinical Trials Registry No. ACTRN12613001069741.

Mouse Models of Diabetes, Obesity and Related Kidney Disease.

Multiple rodent models have been used to study diabetic kidney disease (DKD). The purpose of the present study was to compare models of diabetes and obesity-induced metabolic syndrome and determine differences in renal outcomes. C57BL/6 male mice were fed either normal chow or high fat diet (HFD). At postnatal week 8, chow-fed mice were randomly assigned to low-dose streptozotocin (STZ, 55 mg/kg/day, five consecutive days) or vehicle control, whereas HFD-fed mice were given either one high-dose of STZ (100 mg/kg) or vehicle control. Intraperitoneal glucose tolerance tests were performed at Week 14, 20 and 30. Urinary albumin to creatinine ratio (ACR) and serum creatinine were measured, and renal structure was assessed using Periodic Acid Schiff (PAS) staining at Week 32. Results showed that chow-fed mice exposed to five doses of STZ resembled type 1 diabetes mellitus with a lean phenotype, hyperglycaemia, microalbuminuria and increased serum creatinine levels. Their kidneys demonstrated moderate tubular injury with evidence of tubular dilatation and glycogenated nuclear inclusion bodies. HFD-fed mice resembled metabolic syndrome as they were obese with dyslipidaemia, insulin resistance, and significantly impaired glucose tolerance. One dose STZ, in addition to HFD, did not worsen metabolic features (including fasting glucose, non esterified fatty acid, and triglyceride levels). There were significant increases in urinary ACR and serum creatinine levels, and renal structural changes were predominantly related to interstitial vacuolation and tubular dilatation in HFD-fed mice.

Use of metformin earlier in pregnancy predicts supplemental insulin therapy in women with gestational diabetes.

The use of metformin in gestational diabetes is safe and effective, yet some women require additional insulin therapy to achieve glycaemic targets. We found a significant association between earlier gestational age at initiation of metformin therapy and the necessity for supplemental insulin in women treated with metformin during pregnancy.

Maternal Obesity Promotes Diabetic Nephropathy in Rodent Offspring.

Maternal obesity is known to increase the risk of obesity and diabetes in offspring. Though diabetes is a key risk factor for the development of chronic kidney disease (CKD), the relationship between maternal obesity and CKD has not been clearly defined. In this study, a mouse model of maternal obesity was employed to determine the impact of maternal obesity on development of diabetic nephropathy in offspring. Female C57BL/6 mice were fed high-fat diet (HFD) for six weeks prior to mating, during gestation and lactation. Male offspring were weaned to normal chow diet. At postnatal Week 8, offspring were randomly administered low dose streptozotocin (STZ, 55 mg/kg/day for five days) to induce diabetes. Assessment of renal damage took place at postnatal Week 32. We found that offspring of obese mothers had increased renal fibrosis, inflammation and oxidative stress. Importantly, offspring exposed to maternal obesity had increased susceptibility to renal damage when an additional insult, such as STZ-induced diabetes, was imposed. Specifically, renal inflammation and oxidative stress induced by diabetes was augmented by maternal obesity. Our findings suggest that developmental programming induced by maternal obesity has implications for renal health in offspring. Maternal obesity should be considered a risk factor for CKD.

Effect of GLP-1 Receptor Activation on Offspring Kidney Health in a Rat Model of Maternal Obesity.

Maternal obesity is associated with an increased risk of chronic disease in offspring, including type 2 diabetes (T2D). Exendin-4 (Exd-4) activates the glucagon like peptide-1 (GLP-1) receptor thereby decreasing serum glucose levels and body weight. In addition, Exd-4 has been shown to reduce renal and cardiac complications in experimental models of T2D. We hypothesized that treatment with Exd-4 would ameliorate the detrimental effects of maternal and diet-induced obesity on renal characteristics in offspring. Female Sprague-Dawley rats were fed either normal or high-fat diet (HFD) for 6 weeks prior to pregnancy, during pregnancy and lactation, and their offspring were weaned to normal or HFD. The offspring were randomized to Exd-4 or placebo from weaning and their kidneys harvested at Week 9. We found that the kidneys of offspring from obese mothers, regardless of postnatal diet, had significantly increased markers of inflammation, oxidative stress and fibrosis. Exd-4 ameliorated the negative renal effects of maternal obesity and in particular, reduced renal inflammation, oxidative stress and fibrosis. In conclusion, maternal obesity has persisting effects on renal structure in the offspring. GLP-1 analogues are potentially useful for protecting against the deleterious effects of maternal obesity on renal physiology in offspring.