The impact of vildagliptin as an add-on therapy on matrix metalloproteinase-14 levels, liver stiffness and subclinical atherosclerosis in adolescents with type 1 diabetes and non-alcoholic steatohepatitis: A randomized controlled trial.

AIM: Many patients with type 1 diabetes mellitus (T1DM) met the histological criteria for non-alcoholic steatohepatitis (NASH), which leads to cardiovascular disease morbidity and mortality. Matrix metalloproteinase-14 (MMP-14) is involved in cardiovascular disease and atherosclerosis. OBJECTIVES: To assess the impact of oral dipeptidyl peptidase-4 inhibitor, vildagliptin, as adjunctive therapy on NASH in adolescents with T1DM and its effect on glycaemic control, MMP-14 levels and carotid intima media thickness (CIMT). METHODS: Sixty adolescents with T1DM and NASH were randomly assigned to receive oral vildagliptin (50 mg once daily) for 6 months or not. Glycated haemoglobin, lipid profile, hepatic steatosis index, triglyceride glucose (TyG) index and MMP-14 levels were assessed. Transient elastography with controlled attenuation parameter (CAP) was performed together with measuring CIMT. RESULTS: By transient elastography, 12 (20%) patients with T1DM with NASH had elevated liver stiffness ≥7 kPa (F2 stage or higher). Baseline MMP-14 was positively correlated to insulin dose (p = 0.016), triglycerides and TyG index, CIMT, liver stiffness and CAP levels among the studied patients (p < 0.001 for all). After 6 months, patients with T1DM on vildagliptin therapy had significantly lower glycated haemoglobin, lipid profile, hepatic steatosis index and TyG index, as well as MMP-14 (p < 0.001). CIMT, liver stiffness and CAP were significantly decreased post-therapy compared with baseline levels and compared with the control group (p < 0.001). Vildagliptin was safe and well-tolerated. CONCLUSIONS: Administration of vildagliptin for adolescents with T1DM and NASH improved glycaemic control, dyslipidaemia and MMP-14 levels and decreased liver stiffness and CIMT; hence, reducing subclinical atherosclerosis and disease progression.

Clinical practice recommendations for management of Diabetes Mellitus in Arab region: An expert consensus statement from Arab Diabetes Forum (ADF).

Prevalence of diabetes in Arab region has significantly increased, resulting in a significant economic burden on healthcare systems. This surge can be attributed to obesity, rapid urbanization, changing dietary habits, and sedentary lifestyles. The Arab Diabetes Forum (ADF) has established localized recommendations to tackle the region's rising diabetes prevalence. The recommendations, which incorporate worldwide best practices, seek to enhance the quality of treatment for people with diabetes by raising knowledge and adherence among healthcare providers. The guidelines include comprehensive recommendations for screening, diagnosing, and treating type 1 and type 2 diabetes in children and adults for better overall health results.

Heterozygous missense variant in GLI2 impairs human endocrine pancreas development.

Missense variants are the most common type of coding genetic variants. Their functional assessment is fundamental for defining any implication in human diseases and may also uncover genes that are essential for human organ development. Here, we apply CRISPR-Cas9 gene editing on human iPSCs to study a heterozygous missense variant in GLI2 identified in two siblings with early-onset and insulin-dependent diabetes of unknown cause. GLI2 is a primary mediator of the Hedgehog pathway, which regulates pancreatic ß-cell development in mice. However, neither mutations in GLI2 nor Hedgehog dysregulation have been reported as cause or predisposition to diabetes. We establish and study a set of isogenic iPSC lines harbouring the missense variant for their ability to differentiate into pancreatic ß-like cells. Interestingly, iPSCs carrying the missense variant show altered GLI2 transcriptional activity and impaired differentiation of pancreatic progenitors into endocrine cells. RNASeq and network analyses unveil a crosstalk between Hedgehog and WNT pathways, with the dysregulation of non-canonical WNT signaling in pancreatic progenitors carrying the GLI2 missense variant. Collectively, our findings underscore an essential role for GLI2 in human endocrine development and identify a gene variant that may lead to diabetes.

Mitigating iftar-related glycemic excursions in adolescents and young adults with type 1 diabetes on MiniMed™ 780G advanced hybrid closed loop system: a randomized clinical trial for adjunctive oral vildagliptin therapy during Ramadan fasting.

BACKGROUND: Ramadan Iftar meal typically causes glucose excursions. Dipeptidyl peptidase-4 inhibitors increase glucagon-like peptide-1 and thus, decrease blood glucose levels with low risk of hypoglycemia. AIM: To investigate the efficacy and safety of vildagliptin as an add-on therapy on glucose excursions of Iftar Ramadan meals among adolescents and young adults with type 1 diabetes mellitus (T1DM) using advanced hybrid closed-loop (AHCL) treatment. METHODS: Fifty T1DM patients on MiniMed™ 780G AHCL were randomly assigned either to receive vildagliptin (50 mg tablet) with iftar meal during Ramadan month or not. All participants received pre-meal insulin bolus based on insulin-to-carbohydrate ratio (ICR) for each meal constitution. RESULTS: Vildagliptin offered blunting of post-meal glucose surges (mean difference - 30.3 mg/dL [- 1.7 mmol/L] versus - 2.9 mg/dL [- 0.2 mmol/L] in control group; p < 0.001) together with concomitant exceptional euglycemia with time in range (TIR) significantly increased at end of Ramadan in intervention group from 77.8 ± 9.6% to 84.7 ± 8.3% (p = 0.016) and time above range (180-250 mg/dL) decreased from 13.6 ± 5.1% to 9.7 ± 3.6% (p = 0.003) without increasing hypoglycemia. A significant reduction was observed in automated daily correction boluses and total bolus dose by 23.9% and 16.3% (p = 0.015 and p < 0.023, respectively) with less aggressive ICR settings within intervention group at end of Ramadan. Coefficient of variation was improved from 37.0 ± 9.4% to 31.8 ± 7.1%; p = 0.035). No severe hypoglycemia or diabetic ketoacidosis were reported. CONCLUSION: Adjunctive vildagliptin treatment mitigated postprandial hyperglycemia compared with pre-meal bolus alone. Vildagliptin significantly increased TIR while reducing glycemic variability without compromising safety. Trial registration This trial was registered under ClinicalTrials.gov Identifier no. NCT06021119.

Lessons Learned From COVID-19 Lockdown: An ASPED/MENA Study on Lifestyle Changes and Quality of Life During Ramadan Fasting in Children and Adolescents Living With Type 1 Diabetes.

Background: Lockdown was a unique experience that affected many aspects of life, particularly during the challenge of Ramadan fasting (RF). Studying this can increase understanding of the effects of lifestyle changes on quality of life (QoL) for children with type 1 diabetes (T1D) during RF. Methods: A cross-sectional study that assessed the effect of lockdown on lifestyle and QoL on fasting children living with T1D during Ramadan in the Middle East and North Africa region (2020-2021). We compared the child (self) and parent (proxy) reports using PEDQoL v3.0 disease specific questionnaire during lockdown and non-lockdown periods, and assessed correlations with lifestyle changes using regression and gap analyses. Results: A total of 998 reports from 499 children with T1D aged 8 to 18 years (study = 276, control = 223), and their parents during RF in lockdown and non-lockdown periods. Fathers were more involved in their children's care during lockdown (P = .019). Patients had better compliance with treatment (P = .002), a reversed sleep pattern (P = .033), increased food intake (P ⩽ .001), and less exercise (P < .001). Children and parents perceived better QoL during lockdown (P ⩽.001) with no differences between their reports in "Diabetes Symptoms", "Treatment Adherence," and "Communication" domains. Self and proxy reports were different in all domains during non-lockdown (P = <.001-.009). In gap analysis, although not statistically significant, the gap was approximated between children's and parents' perceptions in all domains during lockdown. Conclusion: COVID-19 lockdown had a positive impact on QoL of children living with T1D during RF, possibly due to lifestyle changes and superior psychosocial family dynamics.

MiniMed 780G™ advanced hybrid closed-loop system performance in Egyptian patients with type 1 diabetes across different age groups: evidence from real-world users.

BACKGROUND: Advanced hybrid closed loop (AHCL) system provides both automated basal rate and correction boluses to keep glycemic values in a target range. OBJECTIVES: To evaluate the real-world performance of the MiniMed™ 780G system among different age groups of Egyptian patients with type 1diabetes. METHODS: One-hundred seven AHCL system users aged from 3 to 71 years were enrolled. Data uploaded by patients were aggregated and analyzed. The mean glucose management indicator (GMI), percentage of time spent within glycemic ranges (TIR), time below range (TBR) and time above range (TAR) were determined. RESULTS: Six months after initiating Auto Mode, patients spent a mean of 85.31 ± 22.04% of the time in Auto Mode (SmartGuard) and achieved a mean GMI of 6.95 ± 0.58% compared with 7.9 ± 2.1% before AHCL initiation (p < 0.001). TIR 70-180 mg/dL was increased post-AHCL initiation from 63.48 ± 10.14% to 81.54 ± 8.43% (p < 0.001) while TAR 180-250 mg/dL, TAR > 250 mg/dL, TBR < 70 mg/dL and TBR < 54 mg/dL were significantly decreased (p < 0.001). After initiating AHCL, TIR was greater in children and adults compared with adolescents (82.29 ± 7.22% and 83.86 ± 9.24% versus 78.4 ± 7.34%, respectively; p < 0.05). The total daily dose of insulin was increased in all age groups primarily due to increased system-initiated insulin delivery including auto correction boluses and basal insulin. CONCLUSIONS: MiniMed™ 780G system users across different age groups achieved international consensus-recommended glycemic control with no serious adverse effects even in challenging age group as children and adolescents.

Omega-3 fatty acids supplementation improves early-stage diabetic nephropathy and subclinical atherosclerosis in pediatric patients with type 1 diabetes: A randomized controlled trial.

BACKGROUND: Numerous studies have evaluated the beneficial effects of omega-3 fatty acids on inflammatory, autoimmune and renal diseases. However, data about the effects of omega-3 fatty acids on diabetic kidney disease in type 1 diabetes mellitus (T1DM) are lacking. OBJECTIVES: This randomized-controlled trial assessed the effect of oral omega-3 supplementation on glycemic control, lipid profile, albuminuria level, kidney injury molecule-1 (KIM-1) and carotid intima media thickness (CIMT) in pediatric patients with T1DM and diabetic nephropathy. METHODS: Seventy T1DM patients and diabetic nephropathy were enrolled with a mean age 15.2 ± 1.96 years and median disease duration 7 years. Patients were randomly assigned into two groups; intervention group which received oral omega-3 fatty acids capsules (1 g daily). The other group received a matching placebo and served as a control group. Both groups were followed-up for 6 months with assessment of fasting blood glucose (FBG), HbA1c, fasting lipids, urinary albumin creatinine ratio (UACR), KIM-1 and CIMT. RESULTS: After 6 months, omega-3 fatty acids adjuvant therapy for the intervention group resulted in a significant decrease in FBG, HbA1c, triglycerides, total cholesterol, LDL-cholesterol, UACR, KIM-1 and CIMT, whereas, HDL-cholesterol was significantly higher post-therapy compared with baseline levels and compared with the control group (p < 0.05). Baseline KIM-1 levels were positively correlated to HbA1c, UACR and CIMT. Supplementation with omega-3 fatty acids was safe and well-tolerated. CONCLUSIONS: Omega-3 fatty acids as an adjuvant therapy in pediatric T1DM patients with diabetic nephropathy improved glycemic control, dyslipidemia and delayed disease progression and subclinical atherosclerosis among those patients. This trial was registered under ClinicalTrials.gov Identifier no. NCT05980026.

Insulin delivery patterns required to maintain postprandial euglycemia in type 1 diabetes following consumption of traditional Egyptian Ramadan Iftar meal using insulin pump therapy: A randomized crossover trial.

OBJECTIVES: During Ramadan, traditional Egyptian Iftar meals have large amounts of high-glycemic index carbohydrate and fat. The efficacy of different bolus regimens on optimizing post prandial glucose (PPG) excursion following this Iftar meal was assessed. METHODS: A randomized controlled trial evaluating 4-h PPG measured by continuous glucose-monitoring was conducted. A total of 25 youth with T1DM using insulin pumps were given the same Iftar meal (fat [45 g], protein [28 g], CHO [95 g]) on seven consecutive days. Insulin to carbohydrate ratio (ICR) was individualized, and all boluses were given upfront 20 min before Iftar. Participants were randomized to receive a standard bolus and six different split boluses delivered over 4 h in the following splits: dual wave (DW) 50/50; DW 50/50 with 20% increment (120% ICR); DW60/40; DW 60/40 with 20% increment; DW 70/30 and DW 70/30 with 20% increment. RESULTS: Standard bolus and split 70/30 with 20% increment resulted in significantly lower early glucose excursions (120 min) with mean excursions of less than 40 mg/dL (2.2 mmol/L) compared to other conditions (p < 0.01). The split 70/30 with 20% increment significantly optimized late PPG excursion (240 min) in comparison to standard bolus (p < 0.01), as well as resulting in a significantly lower post meal glucose area under the curve compared with all other conditions (p < 0.01), with no late hypoglycemia. CONCLUSION: To achieve physiologic PPG profile in traditional Iftar meal, a DW bolus with 20% increment given 20 min preprandial as split bolus 70/30 over 4 h, optimized both early and delayed PPG excursions.

Glycemic control during Ramadan fasting in adolescents and young adults with type 1 diabetes on MiniMed™ 780G advanced hybrid closed­loop system: A randomized controlled trial.

BACKGROUND: MiniMedTM 780G is the most advanced insulin pump system approved for the treatment of type 1 diabetes mellitus (T1DM). Hypoglycemic events are a serious complication associated with T1DM management during Ramadan fasting. AIM: This prospective study assessed the safety, effectiveness and optimization of advanced hybrid closed loop (AHCL) system on glycemic metrics and the level of hypoglycemia in T1DM patients who wished to fast Ramadan. METHODS: Forty-two T1DM patients (mean age 15.2 ± 3.4 years) using AHCL system were divided into two groups (each n = 21): intervention group who adjusted AHCL settings and control group who kept the same settings as before Ramadan. RESULTS: The most aggressive system settings among control group consisting of a 100 mg/dL glucose target, active insulin time of 2 h and bolus increment,maintained exceptional glycemia withtime in range reaching82.0 ± 10.2%, time above range >180 mg/dL of 12.1 ± 3.5% without an increase in hypoglycemia (time below range 3.0 ± 0.3%). All of which were non-significant in comparison to the intervention group. Overall time spent in closed loop (SmartGuard) by users averaged 98.7 ± 2.1% in Auto Mode and involved only 1.0 ± 0.7 exits per week indicating confidence in the system's performance. There were no severe hypoglycemic or diabetic ketoacidosis events during the study. CONCLUSIONS: MiniMed™ 780G AHCL system assist in safe fasting with minimal user input and allows for achievement of recommended glycemic targets in people with T1DM during Ramadan fasting. The system demonstrated reduction in hypoglycemia exposure without compromising safety.

Effect of metformin as an add-on therapy on neuregulin-4 levels and vascular-related complications in adolescents with type 1 diabetes: A randomized controlled trial.

BACKGROUND: Inflammation is closely associated with atherosclerosis and plays a crucial role in the development of cardiovascular disease. Metformin sensitizes body cells to insulin, which may cause a reduction of atherogenic lipid fractions. Low neuregulin-4 (Nrg-4) levels, an adipokine, are linked to obesity, insulin resistance, impaired glucose tolerance and type 2 diabetes. OBJECTIVES: We assessed the effect of oral supplementation with metformin on glycemic control, neuregulin-4 levels and carotid intima media thickness (CIMT) as a marker for subclinical atherosclerosis in adolescents with type 1 diabetes mellitus (T1DM) and microvascular complications. METHODS: This randomized placebo-controlled trial included 80 type 1 diabetic patients with microvascular complications who were randomly divided to receive either 24 weeks of metformin 500 mg/day or matching placebo. Fasting blood glucose (FBG), HbA1c, C-reactive protein (CRP), urinary albumin creatinine ratio (UACR), lipid profile, Nrg-4 and CIMT were assessed at baseline and study end. RESULTS: Both groups were well-matched as regards baseline clinical and laboratory data (p greater than 0.05). After 24-weeks, metformin therapy for the intervention group resulted in a significant decrease of HbA1c, CRP, UACR, total cholesterol and CIMT while Nrg-4 levels were increased compared with baseline levels (p < 0.001) and with placebo group(p < 0.001). Baseline Nrg-4 levels were negatively correlated to FBG, HbA1c, total cholesterol, CRP and CIMT. Metformin was well-tolerated. CONCLUSIONS: Oral metformin supplementation once daily for 24 weeks as an adjuvant therapy to intensive insulin in pediatric T1DM was safe and effective in improving glycemic control, dyslipidemia and Nrg-4 levels; hence, it decreased inflammation, microvascular complications and subclinical atherosclerosis.

The Challenges of Managing Pediatric Diabetes and Other Endocrine Disorders During the COVID-19 Pandemic: Results From an International Cross-Sectional Electronic Survey.

Background: Frequency, dimensions, management, and outcomes of the COVID-19 pandemic in children with endocrine disorders and diabetes were assessed. Methods: A cross-sectional electronic survey was distributed to the global network of endocrine societies. Respondents' professional and practice profiles, clinic sizes, their country of practice, and the impact of COVID-19 on endocrine diseases were investigated. Results: Respondents from 131 pediatric endocrine centers in 51 countries across all continents completed the survey. Routine check-ups and education were altered in most pediatric endocrine clinics. Over 20% of clinics experienced a shortage of critical medications or essential supplies. ICU treatment was required for patients with diabetes and COVID-19 in 21.2% of centers. In diabetes, 44% of respondents reported increased diabetic ketoacidosis episodes in newly diagnosed cases and 30% in established cases. Biopsychosocial and behavioral changes were explicitly reported to be occurring among pediatric patients with endocrine disorders. Conclusions: This large global survey conducted during the COVID-19 pandemic highlights that diabetes is more challenging to manage than any other pediatric endocrine disorder, with an increased risk of morbidity. Psychological distress due to COVID-19 needs to be recognized and addressed. The importance of close contact with healthcare professionals should be emphasized, and medical supplies should be readily available to all patients.

Ramadan fasting in people with type 1 diabetes during COVID-19 pandemic: The DaR Global survey.

OBJECTIVES: The DaR Global survey was conducted to determine the impact of the COVID-19 pandemic on the intentions to fast and the outcomes of fasting in <18 years versus ≥18 years age groups with type 1 diabetes mellitus (T1DM). METHODS: Muslim people with T1DM were surveyed in 13 countries between June and August 2020, shortly after the end of Ramadan (23rd April-23rd May 2020) using a simple questionnaire. RESULTS: 71.1% of muslims with T1DM fasted during Ramadan. Concerns about COVID-19 were higher in individuals ≥18 years (p = 0.002). The number of participants who decided not to fast plus those who received Ramadan-focused education were significantly higher in the ≥18-year group (p < 0.05). Hypoglycemia (60.7%) as well as hyperglycemia (44.8%) was major complications of fasting during Ramadan in both groups irrespective of age. CONCLUSION: COVID-19 pandemic had minor impact on the decision to fast Ramadan in T1DM cohort. This was higher in the age group of ≥18 years compared to those <18 years group. Only regional differences were noted for fasting attitude and behavior among T1DM groups. This survey highlights the need for Ramadan focused diabetes education to improve glucose control and prevent complications during fasting.

COVID-19 outbreak and pediatric diabetes: Perceptions of health care professionals worldwide.

BACKGROUND: Coronavirus diasease (COVID-19) is an infectious disease that started in Wuhan, China in late 2019 and later spread around the world. Diabetes has been recognized as a possible risk factor for COVID-19 complications. OBJECTIVE: International Society for Pediatric and Adolescent Diabetes (ISPAD) investigated perceptions, challenges and experience of health care professionals (HCP) taking care of children and young people with diabetes worldwide during COVID-19 pandemic. METHODS: From 21st April to 17th May 2020, during COVID-19 pandemic, a web-based survey was sent to ISPAD members and former participants of ISPAD conferences by email. RESULTS: Responders from 215 diabetes centers from 75 countries completed the survey. Majority were from UK (35; 16.3%), USA (20; 9.3%), and India (15; 7%). HCP were mostly pediatric endocrinologists (64%). During COVID-19 pandemic, 16.5% of responders continued face-to-face consultation while most changed to telephone (32%) or video (18%) consultations. 19% reported a shortage of medical supplies. 22% reported a delay in diagnosis of patients with new-onset diabetes, while 15% reported a higher incidence of DKA. 12% reported having one or more patients with COVID-19. Most of the 86 children and adolescents with diabetes and COVID-19 had only mild/moderate symptoms, while 5 required admission to an intensive care unit. No deaths were reported. CONCLUSIONS: This large global survey during COVID-19 pandemic showed that many HCP adapted to the pandemic by resorting to telemedicine. One fourth of HCP reported delays in diagnosis and an increased rate of DKA. The emergence of COVID-19 pandemic had an important impact on family's behavior that might have led to increase in diabetic ketoacidosis presentation.

Zinc supplementation improves glucose homeostasis in patients with ß-thalassemia major complicated with diabetes mellitus: A randomized controlled trial.

OBJECTIVES: The development of abnormal glucose tolerance in ß-thalassemia major (ß-TM) is associated with alterations in the oxidant-antioxidant status. Zinc is an antioxidant and an essential element for insulin synthesis, storage, and secretion. This randomized controlled trial assessed the effect of oral zinc supplementation on glucose homeostasis in pediatric ß-TM patients complicated with diabetes mellitus (DM). METHODS: Eighty patients were randomly assigned into two groups: an intervention group that received oral zinc in a dose of 40 mg/d for 12 wk and a placebo group. Hemolysis markers, serum ferritin, fasting blood glucose (FBG), fructosamine, fasting C-peptide, urinary albumin excretion (UAE), and serum zinc levels were assessed. Homeostasis model assessment insulin resistance index (HOMA-IR) was calculated. RESULTS: Baseline clinical and laboratory parameters were consistent among both groups. Baseline zinc levels were decreased in both groups compared with control values. After 12 wk, supplementation with zinc for the intervention group resulted in a significant decrease in lactate dehydrogenase, serum ferritin, FBG, fructosamine, HOMA-IR, and UAE, whereas fasting C-peptide was higher compared with baseline levels and with the placebo group (P < 0.05). Baseline serum zinc was negatively correlated to FBG (r = -0.534, P < 0.001) and fructosamine (r = -0.555, P < 0.001) but positively correlated to fasting C-peptide (r = 0.777, P = 0.002). CONCLUSIONS: Zinc supplementation as an adjuvant therapy in ß-TM patients with DM reduced iron burden, decreased hyperglycemia, increased insulin secretion, and improved glycemic control without any adverse effects.

Vitamin B complex supplementation as a homocysteine-lowering therapy for early stage diabetic nephropathy in pediatric patients with type 1 diabetes: A randomized controlled trial.

BACKGROUND: Homocysteine levels are elevated in patients with type 1 diabetes mellitus (T1DM) and could induce renal injury. B vitamins have an important role in preventing microvascular complications of diabetes. AIM: We performed a randomized-controlled trial of oral supplementation with vitamin B complex as an adjuvant therapy for nephropathy in pediatric T1DM patients and assessed its relation to homocysteine and cystatin C as a marker of nephropathy. METHODS: This trial included 80 T1DM patients with microalbuminuria, despite oral angiotensin-converting enzyme inhibitors, aged 12-18 years with at least 5 years disease duration and HbA1c ≤8.5%. Patients were randomly assigned into two groups; intervention group which received oral vitamin B complex (B1, B6 and B12) once daily and placebo group. Both groups were followed-up for 12 weeks with assessment of plasma homocysteine, HbA1c, urinary albumin excretion (UAE) and cystatin C. RESULTS: Both groups were well-matched in baseline clinical and laboratory parameters. Baseline homocysteine levels were elevated in both groups compared with reference control values. After 12 weeks, supplementation with vitamin B complex for the intervention group resulted in a significant decrease of homocysteine, fasting blood glucose, HbA1c, triglycerides, total cholesterol, UAE and cystatin C compared with baseline levels (p < 0.001) and with placebo group (p < 0.001). No adverse reactions were reported. Baseline cystatin C was negatively correlated to vitamin B12 (r = -0.77, p = 0.001). CONCLUSIONS: Vitamin B complex improved glycemic control and renal function through decreasing homocysteine and could be a safe and effective strategy for treatment of early stage nephropathy in pediatric T1DM. This trial was registered at ClinicalTrials.gov (NCT03594240).

Role of neopterin as a biochemical marker for peripheral neuropathy in pediatric patients with type 1 diabetes: Relation to nerve conduction studies.

BACKGROUND: Neopterin, a marker of inflammation and cellular immune response, is elevated in conditions of T-cell or macrophages activation. Diabetic peripheral neuropathy (DPN) is associated with inflammatory/immune processes and therefore, we hypothesized that neopterin could be used as a marker of neuropathy in type 1 diabetes mellitus (T1DM). AIM: To measure neopterin levels in children and adolescents with T1DM and assess its possible relation to DPN and nerve conduction studies (NCS). METHODS: Sixty patients aged ≤18 years and >5 years disease duration were subjected to neurological assessment by neuropathy disability score (NDS) and NCS for median, ulnar, posterior tibial and common peroneal nerves. Mean fasting blood glucose, lipid profile, HbA1c, high sensitivity C-reactive protein (hs-CRP) and serum neopterin levels were assessed. Patients were compared with 30 age- and sex-matched healthy controls. RESULTS: The frequency of DPN according to NDS was 40 (66.7%) patients out of 60 while NCS confirmed that only 30 of those 40 patients had this complication (i.e. 50% out of the total studied patients). Neopterin levels were significantly higher in patients with DPN than those without (median [IQR], 53.5 [35-60] nmol/L versus 17 [13-32] nmol/L) and healthy controls (5.0 [3.2-7.0] nmol/L) (p < 0.001). Significant positive correlations were found between neopterin levels and HbA1c (r = 0.560, p = 0.005), serum creatinine (r = 0.376, p = 0.003), total cholesterol (r = 0.405, p = 0.026) and hs-CRP (r = 0.425, p = 0.012) among patients with DPN. Neopterin levels were positively correlated to motor latency of tibial and common peroneal nerves as well as motor and sensory latencies of median and ulnar nerves. Logistic regression analysis revealed that neopterin was a significant independent variable related to DPN (Odds ratio, 2.976). Neopterin cutoff value 32 nmol/L could differentiate patients with and without DPN with 100% sensitivity and 96.7% specificity. CONCLUSIONS: Neopterin could be used as an early reliable serum biomarker for DPN in pediatric patients with T1DM.

The effect of 12 weeks carnosine supplementation on renal functional integrity and oxidative stress in pediatric patients with diabetic nephropathy: a randomized placebo-controlled trial.

BACKGROUND AND OBJECTIVES: Oxidative stress is a significant contributor to the pathogenesis of diabetic nephropathy. Carnosine is a natural radical oxygen species scavenger. We investigated the effect of carnosine as an adjuvant therapy on urinary albumin excretion (UAE), the tubular damage marker alpha 1-microglobulin (A1M), and oxidative stress in pediatric patients with type 1 diabetes and nephropathy. METHODS: This randomized placebo-controlled trial included 90 patients with diabetic nephropathy, despite oral angiotensin-converting enzyme inhibitors (ACE-Is), who were randomly assigned to receive either 12 weeks of carnosine 1 g/day (n = 45), or matching placebo (n = 45). Both groups were followed-up with assessment of hemoglobin A1c (HbA1c), UAE, A1M, total antioxidant capacity (TAC) and malondialdhyde (MDA). RESULTS: Baseline clinical and laboratory parameters were consistent between carnosine and placebo groups (P > .05). After 12 weeks, carnosine treatment resulted in significant decrease of HbA1c (8.2 ± 2.1% vs 7.4 ± 1.3%), UAE (91.7 vs 38.5 mg/g creatinine), A1M (16.5 ± 6.8 mg/L vs 9.3 ± 6.6 mg/L), MDA levels (25.5 ± 8.1 vs 18.2 ± 7.7 nmol/mL) while TAC levels were increased compared with baseline levels (P < .001) and compared with placebo (P < .001). No adverse reactions due to carnosine supplementation were reported. Baseline TAC was inversely correlated to HbA1c (r = -0.58, P = .04) and A1M (r = -0.682, P = .015) among carnosine group. CONCLUSIONS: Oral supplementation with L-Carnosine for 12 weeks resulted in a significant improvement of oxidative stress, glycemic control and renal function. Thus, carnosine could be a safe and effective strategy for treatment of pediatric patients with diabetic nephropathy.

An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence.

This paper represents an international collaboration of paediatric endocrine and other societies (listed in the Appendix) under the International Consortium of Paediatric Endocrinology (ICPE) aiming to improve worldwide care of adolescent girls with polycystic ovary syndrome (PCOS)1. The manuscript examines pathophysiology and guidelines for the diagnosis and management of PCOS during adolescence. The complex pathophysiology of PCOS involves the interaction of genetic and epigenetic changes, primary ovarian abnormalities, neuroendocrine alterations, and endocrine and metabolic modifiers such as anti-Müllerian hormone, hyperinsulinemia, insulin resistance, adiposity, and adiponectin levels. Appropriate diagnosis of adolescent PCOS should include adequate and careful evaluation of symptoms, such as hirsutism, severe acne, and menstrual irregularities 2 years beyond menarche, and elevated androgen levels. Polycystic ovarian morphology on ultrasound without hyperandrogenism or menstrual irregularities should not be used to diagnose adolescent PCOS. Hyperinsulinemia, insulin resistance, and obesity may be present in adolescents with PCOS, but are not considered to be diagnostic criteria. Treatment of adolescent PCOS should include lifestyle intervention, local therapies, and medications. Insulin sensitizers like metformin and oral contraceptive pills provide short-term benefits on PCOS symptoms. There are limited data on anti-androgens and combined therapies showing additive/synergistic actions for adolescents. Reproductive aspects and transition should be taken into account when managing adolescents.

Circulating angiopoietin-2 levels in children and adolescents with type 1 diabetes mellitus: relation to carotid and aortic intima-media thickness.

BACKGROUND: Angiopoietin-2 is a growth factor involved in the pathophysiology of vascular and inflammatory diseases such as arteriosclerosis. Carotid or aortic scans provide noninvasive screening tools for assessment of preclinical atherosclerosis in high-risk children. AIM: We assessed serum angiopoietin-2 in children and adolescents with type 1 diabetes mellitus as a potential marker for vascular complications in relation to glycemic control, inflammation and vascular structure. METHODS: Sixty patients with type 1 diabetes were divided into 2 groups according to the presence of micro-vascular complications and compared with 30 healthy controls. High-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c (HbA1c), urinary albumin/creatinine ratio, serum angiopoietin-2, carotid and aortic intima-media thickness (CIMT and AIMT) were measured. RESULTS: CIMT, AIMT and serum angiopoietin-2 levels were significantly increased in patients with and without micro-vascular complications compared with controls, and the highest levels were in patients with complications (p < 0.001). Angiopoietin-2 was higher in patients with microalbuminuria than normoalbuminuric group (p < 0.001). Fasting blood glucose, HbA1c, hs-CRP, CIMT and AIMT were independently related to angiopoietin-2 in multiple regression analysis. Disease duration, hyperglycemia, poor glycemic control, hypercholesterolemia, inflammation and angiopoietin-2 were independent factors contributing to atherosclerosis risk. CONCLUSION: The relation between angiopoietin-2 and assessed parameters of vascular structure in type 1 diabetes reflects a state of endothelial injury and highlights the role of disturbed angiogenesis and vascular inflammation in the occurrence of diabetic complications.

Serum apelin as a novel non-invasive marker for subclinical cardiopulmonary complications in children and adolescents with sickle cell disease.

BACKGROUND: Cardiovascular involvement represents a leading cause of mortality and morbidity in sickle cell disease (SCD). Apelin is a peptide involved in the regulation of cardiovascular function. AIM: To determine serum apelin among 40 children and adolescents with SCD compared with 40 healthy controls and assess its relation to markers of hemolysis, iron overload as well as cardiopulmonary complications. METHODS: SCD patients, in steady state and asymptomatic for heart disease, were studied stressing on hydroxyurea/chelation therapy, hematological profile, serum ferritin and apelin levels. Full echocardiographic study including assessment of biventricular systolic function and pulmonary artery pressure was done. RESULTS: Apelin levels were significantly lower in SCD patients compared with controls (P<0.001). Cardiopulmonary complications were encountered in 30% of patients. Apelin was significantly decreased among patients with cardiopulmonary disease (P=0.006) whether those at risk of pulmonary hypertension (P=0.018) or patients with heart disease (P=0.043). Hydroxyurea-treated patients had higher apelin levels than untreated ones (P=0.001). Apelin was negatively correlated to lactate dehydrogenase, indirect bilirubin, serum ferritin, end systolic diameter, tricuspid regurgitant jet velocity, right ventricle systolic pressure, pulmonary vascular resistance and tissue Doppler imaging S wave. Apelin cutoff value of 1650ng/L could significantly detect the presence of cardiopulmonary complications in SCD with 90.9% sensitivity and 72.4% specificity. CONCLUSION: Apelin is a promising marker for screening of SCD patients at risk of cardiopulmonary disease because it is altered during the early subclinical stage of cardiac affection. A combination of apelin and echocardiography provides a reliable method to assess cardiopulmonary affection in young SCD patients.