Heterogeneity of beta-cell function in subjects with multiple islet autoantibodies in the TEDDY family prevention study - TEFA

Background Individuals with multiple islet autoantibodies are at increased risk for clinical type 1 diabetes and may proceed gradually from stage to stage complicating the recruitment to secondary prevention studies. We evaluated multiple islet autoantibody positive subjects before randomisation for a clinical trial 1 month apart for beta-cell function, glucose metabolism and continuous glucose monitoring (CGM). We hypothesized that the number and type of islet autoantibodies in combination with different measures of glucose metabolism including fasting glucose, HbA1c, oral glucose tolerance test (OGTT), intra venous glucose tolerance test (IvGTT) and CGM allows for more precise staging of autoimmune type 1 diabetes than the number of islet autoantibodies alone. Methods Subjects (n = 57) at 2–50 years of age, positive for two or more islet autoantibodies were assessed by fasting plasma insulin, glucose, HbA1c as well as First Phase Insulin Response (FPIR) in IvGTT, followed 1 month later by OGTT, and 1 week of CGM (n = 24). Results Autoantibodies against GAD65 (GADA; n = 52), ZnT8 (ZnT8A; n = 40), IA-2 (IA-2A; n = 38) and insulin (IAA; n = 28) were present in 9 different combinations of 2–4 autoantibodies. Fasting glucose and HbA1c did not differ between the two visits. The estimate of the linear relationship between log2-transformed FPIR as the outcome and log2-transformed area under the OGTT glucose curve (AUC) as the predictor, adjusting for age and sex was − 1.88 (− 2.71, − 1.05) p = 3.49 × 10–5. The direction of the estimates for all glucose metabolism measures was positive except for FPIR, which was negative. FPIR was associated with higher blood glucose. Both the median and the spread of the CGM glucose data were significantly associated with higher glucose values based on OGTT, higher HbA1c, and lower FPIR. There was no association between glucose metabolism, autoantibody number and type except that there was an indication that the presence of at least one of ZnT8(Q/R/W) A was associated with a lower log2-transformed FPIR (− 0.80 (− 1.58, − 0.02), p = 0.046). Conclusions The sole use of two or more islet autoantibodies as inclusion criterion for Stage 1 diabetes in prevention trials is unsatisfactory. Staging type 1 diabetes needs to take the heterogeneity in beta-cell function and glucose metabolism into account. Trial registration ClinicalTrials.gov identifier: NCT02605148, November 16, 2015

The relationship between neck circumference and gestational diabetes mellitus in Iranian women

Background The aim of the present study was to assess the relationship between neck circumference and gestational diabetes. Methods This prospective study was conducted on 372 Iranian pregnant women. The criteria set by the American Diabetes Association through 2 h was used to classify subjects with regard to their gestational diabetes. At the 14–16th weeks of pregnancy, the neck circumference was measured. The maternal and fetal outcomes were measured as well. Results The adjusted logistic regression revealed that neck circumference was a predictor for gestational diabetes mellitus (OR = 1.20; 95% CI = 1.06, 1.34; P = 0.002). The ROC analysis depicted that the cut-off for neck circumference in indicating gestational diabetes was 34.3 cm, with the sensitivity of 53% and the specificity of 66%. Conclusion The findings of the present study revealed that the neck circumference of ≥34.3 cm can be deemed as a predictor of gestational diabetes in the case of Iranian pregnant women.

Type 2 diabetes reversal with digital twin technology-enabled precision nutrition and staging of reversal: a retrospective cohort study

Background Type 2 diabetes reversal has been viewed in the literature primarily as a dichotomous event (reversed or not reversed), even though this viewpoint may not be optimal for clinicians or patients. This cohort study’s objectives were to define stages of type 2 diabetes reversal and measure changes in reversal stages before and after 90 days of digital twin-enabled precision nutrition therapy. Methods This study defines seven stages of diabetes reversal. The study is a retrospective pre/post comparison of changes in reversal stage, hemoglobin A1c (HbA1c), weight, body mass index (BMI), and other metrics measured before and after precision nutrition therapy. Reversal stages were defined as Stage 0: HbA1c < 5.7% without medication for > 1 year, Stage 1: HbA1c < 5.7% without medication for < 1 year, Stage 2: HbA1c < 6.5% without medication, Stage 3: estimated HbA1c (eA1c) between 5.7 and 6.4% without medication, Stage 4: estimated HbA1c (eA1c) between 5.7 and 6.4% with metformin monotherapy, Stage 5: dual oral therapy, Stage 6: > = 3 medications. Results Reversal stage information was available for 463 patients at baseline and 90 days. At baseline, the proportions of patients in each reversal stage were Stages 1 and 2: 0%, Stage 3: 1%, Stage 4: 8%, Stage 5: 6%, and Stage 6: 85%. After 90 days, the proportions in each reversal stage were Stage 1: 2%, Stage 2: 9%, Stage 3: 32%, Stage 4: 39%, Stage 5: 7%, and Stage 6: 11%, indicating significant progress. Reversal stage progression rates varied by patient subgroup. Conclusions Type 2 diabetes patients reached differing reversal stages during 90 days of precision nutrition therapy. Use of reversal stages may benefit patients during therapy. Trial registration This was a retrospective study that was approved by the Medisys Clinisearch Ethical Review Board (without registration number) in 2019.

Serial urinary neutrophil gelatinase associated lipocalin in pediatric diabetic ketoacidosis with acute kidney injury

Background Acute kidney injury (AKI) due to Diabetic Ketoacidosis (DKA) is rather common. Novel biomarkers to diagnose AKI are being increasingly used in different settings. The use of urinary Neutrophil Gelatinase-Associated Lipocalin (uNGAL) in predicting persistent AKI in pediatric DKA cases is still not thoroughly investigated. Methods This was a secondary analysis of Saline versus Plasma-Lyte in Ketoacidosis (SPinK) trial data; 66 children (> 1 month-12 years) with DKA, defined by the International Society for Pediatric and Adolescent Diabetes (ISPAD), were analyzed. Children with cerebral edema, chronic kidney disease and those who received pre-referral fluids and/or insulin were excluded. uNGAL and urine NGAL-creatinine ratio (uNCR) at 0 and 24 h were measured in all. Persistent AKI was defined as a composite outcome of continuance of AKI defined by the Kidney Disease Improving Global Outcomes (KDIGO) stage 2 or 3 beyond 48 h from AKI onset, progression of AKI from either KDIGO stage 0 or 1 to a worse stage, need of renal replacement therapy or death. Main outcomes Thirty-five (53%) children had AKI at admission; 32 (91.4%) resolved within 48 h. uNGAL was significantly higher in the AKI group at admission [79.8 ± 27.2 vs 54.6 ± 22.0, p = 0.0002] and at 24 h [61.4 ± 28.3 vs 20.2 ± 14.5, p = 0.0003]. Similar trend was observed with uNCR at admission [6.7 ± 3.7 vs 4.1 ± 2.6, p = 0.002] and at 24 h [6.3 ± 2.5 vs 1.2 ± 1.0, p = 0.01]. Furthermore, uNGAL at admission showed a moderate positive linear correlation with serum creatinine. Additionally, elevated uNGAL at 0 and 24 h correlated with corresponding KDIGO stages. Admission uNGAL >88 ng/ml and uNCR of >11.3 ng/mg had a sensitivity of 66% and 67%, specificity of 76% and 95%, and Area under the receiver operating characteristic curve (AUC) of 0.78 and 0.89 respectively for predicting persistent AKI at 48 h. Conclusions Majority of AKI resolved with fluid therapy. While uNGAL and uNCR both correlated with serum creatinine and AKI stages, serial uNCR was a better predictor of persistent AKI than uNGAL alone. However, feasibility of routine uNGAL measurement to predict persistent AKI in DKA needs further elucidation. Trial registration This was a secondary analysis of the data of SPinK trial [CTRI/2018/05/014042 (ctri.nic.in)].

The diagnostic indicators of gestational diabetes mellitus from second trimester to birth: a systematic review

Background Gestational diabetes mellitus (GDM) is glucose intolerance first recognised during pregnancy. Both modalities and thresholds of the GDM diagnostic test, the Oral Glucose Tolerance Test (OGTT), have varied widely over time and among countries. Additionally, OGTT limitations include inconsistency, poor patient tolerability, and questionable diagnostic reliability. Many biological parameters have been reported to be modified by GDM and could potentially be used as diagnostic indicators. This study aimed to 1) systematically explore biomarkers reported in the literature as differentiating GDM from healthy pregnancies 2) screen those indicators assessed against OGTT to propose OGTT alternatives. Main body A systematic review of GDM diagnostic indicators was performed according to PRISMA guidelines (PROSPERO registration CRD42020145499). Inclusion criteria were full-text, comprehensible English-language articles published January 2009-January 2021, where a biomarker (from blood, ultrasound, amniotic fluid, placenta) was compared between GDM and normal glucose tolerance (NGT) women from the second trimester onward to immediately postpartum. GDM diagnostic method had to be clearly specified, and the number of patients per study higher than 30 in total or 15 per group. Results were synthesised by biomarkers. Results Of 13,133 studies identified in initial screening, 174 studies (135,801 participants) were included. One hundred and twenty-nine studies described blood analytes, one amniotic fluid analytes, 27 ultrasound features, 17 post-natal features. Among the biomarkers evaluated in exploratory studies, Adiponectin, AFABP, Betatrophin, CRP, Cystatin-C, Delta-Neutrophil Index, GGT, TNF-A were those demonstrating statistically and clinically significant differences in substantial cohorts of patients (> 500). Regarding biomarkers assessed versus OGTT (i.e. potential OGTT alternatives) most promising were Leptin > 48.5 ng/ml, Ficolin3/adiponectin ratio ≥ 1.06, Chemerin/FABP > 0.71, and Ultrasound Gestational Diabetes Score > 4. These all demonstrated sensitivity and specificity > 80% in adequate sample sizes (> / = 100). Conclusions Numerous biomarkers may differentiate GDM from normoglycaemic pregnancy. Given the limitations of the OGTT and the lack of a gold standard for GDM diagnosis, advanced phase studies are needed to triangulate the most promising biomarkers. Further studies are also recommended to assess the sensitivity and specificity of promising biomarkers not yet assessed against OGTT. Trial registration PROSPERO registration number CRD42020145499.

Risk factors for diabetic foot ulcers in metreleptin naïve patients with lipodystrophy

Aim Patients with lipodystrophy are at high risk for chronic complications of diabetes. Recently, we have reported 18 diabetic foot ulcer episodes in 9 subjects with lipodystrophy. This current study aims to determine risk factors associated with foot ulcer development in this rare disease population. Methods Ninety metreleptin naïve patients with diabetes registered in our national lipodystrophy database were included in this observational retrospective cohort study (9 with and 81 without foot ulcers). Results Patients with lipodystrophy developing foot ulcers had longer diabetes duration (p = 0.007), longer time since lipodystrophy diagnosis (p = 0.008), and higher HbA1c levels (p = 0.041). Insulin use was more prevalent (p = 0.003). The time from diagnosis of diabetes to first foot ulcer was shorter for patients with generalized lipodystrophy compared to partial lipodystrophy (p = 0.036). Retinopathy (p < 0.001), neuropathy (p < 0.001), peripheral artery disease (p = 0.001), and kidney failure (p = 0.003) were more commonly detected in patients with foot ulcers. Patients with foot ulcers tended to have lower leptin levels (p = 0.052). Multiple logistic regression estimated significant associations between foot ulcers and generalized lipodystrophy (OR: 40.81, 95% CI: 3.31–503.93, p = 0.004), long-term diabetes (≥ 15 years; OR: 27.07, 95% CI: 2.97–246.39, p = 0.003), and decreased eGFR (OR: 13.35, 95% CI: 1.96–90.67, p = 0.008). Conclusions Our study identified several clinical factors associated with foot ulceration among patients with lipodystrophy and diabetes. Preventive measures and effective treatment of metabolic consequences of lipodystrophy are essential to prevent the occurrence of foot ulcers in these high-risk individuals.

Gonadotropin releasing hormone analogue treatment of central precocious puberty is not associated with altered prevalence of polycystic ovary syndrome: a single center cohort study

Background There is conflicting evidence regarding an association between gonadotropin releasing hormone analogue (GnRHa) therapy and polycystic ovary syndrome (PCOS). This study aimed to compare the prevalence of endocrine disorders, primarily PCOS, between women who had been treated with GnRHa for central precocious puberty (CPP) and those who were not treated. Methods This was a retrospective cohort study, including women diagnosed with central precocious puberty between 1989 and 2011 in a university affiliated tertiary medical center. Data collected included demographic data, medical background, clinical presentation at diagnosis and duration of treatment (zero for non-treated). Gynecologic and endocrine long-term outcomes were compared by treatment group. Results Fifty-one women were included in the study, 27/51 had been treated with gonadotropin releasing hormone analogue (GnRHa). Overall prevalence of PCOS was 19.6%. No statistically significant difference in prevalence of PCOS was demonstrated between the treated and non-treated groups. Similarly, overall prevalence of either clinical or laboratory hyper-androgenism, was 29.4% and 33.3%, for the treatment and non-treatment groups respectively (p = non-significant). Conclusions GnRHa treatment for precocious puberty is not associated with increased risk of polycystic ovary syndrome.

Safety, tolerability, pharmacokinetics and pharmacodynamics of single oral doses of BI 187004, an inhibitor of 11beta-hydroxysteroid dehydrogenase-1, in healthy male volunteers with overweight or obesity

Background The study characterizes safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single rising doses of the 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD1) inhibitor BI 187004 in healthy men with overweight or obesity. Methods This was a randomized, double-blind, parallel group, placebo-controlled study with administration of 2.5–360 mg BI 187004 or placebo once daily as single dose in 72 healthy male volunteers with overweight or obesity. Assessments included 11beta-HSD1 inhibition in the liver (assessed indirectly by urinary tetrahydrocortisol/tetrahydrocortisone ratio) and in subcutaneous adipose tissue ex vivo and determination of hypothalamus–pituitary–adrenal axis hormones. Results BI 187004 was well tolerated and safe in all tested dose groups. The incidence of drug-related adverse events was 16.7% (n = 9) for all 9 BI 187004 dose groups and 5.9% (n = 1) for placebo. All treatment groups were similar concerning kind and intensity of adverse events. No clinically relevant deviations in clinical laboratory or ECG parameters were reported. Exposure of BI 187004 increased non-proportionally over the entire dose range tested. The geometric mean apparent terminal half-life decreased from 33.5 h (5 mg) to 14.5 h (160 mg) remaining stable up to 360 mg. Renal excretion of BI 187004 was low (3–5%). Urinary tetrahydrocortisol/tetrahydrocortisone ratio decreased, indicating liver 11beta-HSD1 inhibition. Median inhibition of 11beta-HSD1 in subcutaneous adipose tissue biopsies following single dosing ranged from 86.8% (10 mg) to 99.5% (360 mg) after 10 h and from 59.4% (10 mg) to 98.6% (360 mg) after 24 h. Conclusions BI 187004 as single dose was safe and well tolerated and is suitable for once daily dosing. There was significant, sustained 11beta-HSD1 inhibition in liver and adipose tissue. Trial registration ClinicalTrials.gov, NCT01587417, registered on 26-Apr-2012.

Recurrent DKA results in high societal costs – a retrospective study identifying social predictors of recurrence for potential future intervention

Aims Diabetic ketoacidosis (DKA) is an emergency with high morbidity and mortality. This study examined patient factors associated with hospitalization for recurrent DKA. Methods Characteristics of 265 subjects admitted for DKA at Hennepin County Medical Center between January 2017 and January 2019 were retrospectively analyzed. Differences between subjects with a single admission versus multiple were reviewed. Results Forty-eight out of 265 patients had recurrent DKA. Risk factors included African American race (adjusted odds ratio (aOR) versus white non-Hispanic = 4.6, 95% CI 1.8–13, p = 0.001) or other race/ethnicity (aOR = 8.6, 2.9–28, p < 0.0001), younger age (aOR 37-52y versus 18-36y = 0.48, 0.19–1.16, p = 0.10; aOR 53-99y versus 18-36y = 0.37, 0.12–0.99, p = 0.05), type 1 diabetes mellitus (aOR = 2.4, 1.1–5.5, p = 0.04), ever homeless (aOR = 2.5, 1.1–5.4, p = 0.03), and drug abuse (aOR = 3.2, 1.3–7.8, p = 0.009). DKA cost a median of $29,981 per admission. Conclusions Recurrent DKA is costly, and social determinants are strong predictors of recurrence. This study highlights the need for targeted preventative care programs.

Determinants of diabetic retinopathy in Tikur Anbessa Hospital, Ethiopia: a case–control study

Background Diabetic retinopathy is the most frequent complication of Diabetes Mellitus and remains the leading cause of preventable blindness. However, there are limited studies on the determinants of diabetic retinopathy in the study area as well in Ethiopia. Hence, this study aimed to assess the determinants of diabetic retinopathy among diabetic patients at Tikur Anbessa Hospital. Methods An institution-based unmatched case–control study design was conducted at Tikur Anbessa Hospital from May 11 to June 26, 2020. Diabetic patients who developed retinopathy within 2 years were cases in the study. Patients who were free of retinopathy were controls in this study. Data were collected using a pretested interviewer-administered questionnaire, Topcon retinal examination, and a record review. The collected data were entered into Epi Data version 3.1 software, and analyzed using SPSS version 25. Binary logistic regression analysis was used to assess the determinants of diabetic retinopathy. Results A total of 282 patients (142 cases and 140 controls) were included in the study. The mean age (± Standard deviation) for the cases and the controls were 50.6 (SD: ± 18.7) and 44.9 (SD: ± 17.65) respectively. Patients who had a glucometer at home (AOR = 0.048; 95% CI: 0.005–0.492), exercise adherence (AOR = 0.075; 95% CI: 0.007–0.84), diabetes duration < 5 years (AOR = 0.005; 95% CI: 0.00–0.10) and 5–10 years (AOR = 0.041; 95% CI: 0.003–0.57), health information on diabetic complications (AOR = 0.002; 95% CI: 0.00–0.042) and appointments every month (AOR = 0.004; 95% CI: 0.00–0.073) and every 3 months (AOR = 0.022; 95% CI: 0.002–0.23) were less likely to develop diabetic retinopathy. Participants who had poor glycemic control (AOR = 19.9; 95% CI: 2.34–168.69), systolic hypertension (AOR = 23.4; 95% CI: 2.56–215.36) and nephropathy (AOR = 17.85; 95% CI: 2.01–158.1), had a higher risk of developing diabetic retinopathy. Conclusions Patients who had a glucometer at home, exercise adherence, diabetes duration < 10 years, health information on diabetic complications, and frequent follow-up had a preventive role. However, poor glycemic control, systolic hypertension, and nephropathy increase the risk of diabetic retinopathy. A concerted effort should be made to improve the health status of patients with Diabetes Mellitus, with particular emphasis on lifestyle modification practices to prevent diabetic retinopathy.