The effects of oral trehalose on glycaemia, inflammation, and quality of life in patients with type 2 diabetes: a pilot randomized controlled trial.

Introduction: Trehalose is a naturally occurring disaccharide of 2 glucose molecules, which has been suggested as a potential therapeutic agent to reduce blood glucose and ameliorate diabetes-related complications in type 2 diabetes (T2D). This study aimed to determine the efficacy of medium-term trehalose treatment in patients with T2D. Material and methods: A double-blind, randomized, placebo-controlled trial in 40 patients with T2D was undertaken; 20 ingested trehalose 3.3 g/day and 20 placebo (sucrose), for 3 months. Parameters of glycaemic indices, high-sensitivity C-reactive protein (CRP), mood status, and quality of life were measured. Results: CRP was significantly lower with trehalose treatment (-0.62 ±0.3 mg/l, p = 0.02); however, no differences in glycaemic indices of fasting blood glucose (FBG) (-7.1 ±10.7 mg/dl, p = 0.15), glycated hemoglobin (HbA1c) (-0.1 ±0.4%, p = 0.73), insulin (0.73 ±0.8 µU/ml, p = 0.39), or insulin resistance (HOMA-IR) (0.19 ±0.33, p = 0.56) were seen between groups after 12 weeks. Depression and stress scores were lower with trehalose compared to the placebo group (p = 0.02 and p = 0.05, respectively), whilst the quality-of-life score was higher with trehalose compared to placebo (p = 0.03) at the end of study. Between-group differences in these indices did not reach statistical significance (-2.36 ±1.20, -2.21 ±1.39 and 3.00 ±1.76 for depression, stress, and quality-of-life score, respectively) (p > 0.05). The pro-oxidant antioxidant balance (PAB) did not differ between groups (-4.6 ±12.8, p = 0.72). Conclusions: 12 weeks of treatment with 3.3 g/day of oral trehalose significantly improves CRP as a marker of inflammation, with potential favourable effects on quality of life, depression, and stress levels, but overall glycaemic control and pro-oxidant-antioxidant balance were unaltered during this time frame.

The Relationship Between Psoriasis, COVID-19 Infection and Vaccination During Treatment of Patients.

Since the outbreak of the COVID-19 pandemic in December 2019, scientists worldwide have been looking for a way to control this global threat. One of the most successful and practical solutions has been the development and worldwide distribution of the COVID-19 vaccines. However, in a small percentage of cases, vaccination can lead to de novo development or exacerbation of immune or inflammatory conditions such as psoriasis. Due to the immunomodulatory nature of this disease, people affected by psoriasis and other related skin conditions have been encouraged to receive COVID-19 vaccines, which are immunomodulatory by nature. As such, dermatological reactions are possible in these patients, and cases of onset, exacerbation or change in the type of psoriasis have been observed in patients administered with COVID-19 vaccines. Considering the rarity and minor nature of some of these cutaneous reactions to COVID-19 vaccination, there is a general consensus that the benefits of vaccination outweigh the potential risks of experiencing such side effects. Nevertheless, healthcare workers who administer vaccines should be made aware of the potential risks and advise recipients accordingly. Furthermore, we suggest careful monitoring for potentially deleterious autoimmune and hyperinflammatory responses using point-of-care biomarker monitoring.

Investigating Genetic Mutations in a Large Cohort of Iranian Patients with Congenital Hyperinsulinism

Objective: Congenital hyperinsulinism (CHI) is the most frequent cause of severe and persistent hypoglycaemia from birth. Understanding the pathophysiology and genetic defects behind hyperinsulinism and its complications provides clues to timely diagnosis and management. The aim of this study was to evaluate the underlying genetic aetiology of a specific Iranian pediatric cohort with CHI. Methods: A total of 44 unrelated children, 20 girls and 24 boys, with an initial diagnosis or history of CHI from all regions of Iran were recruited between 2016 and 2019. Targeted next generation sequencing (tNGS) was performed for the genes found in about half of CHI patients. Results: Mutations were identified in 24 cases (55%). Patients with a confirmed genetic cause were mainly diagnosed below age of one year old (p=0.01), had fewer other syndromic features, excluding seizure, (p=0.03), were less diazoxide responsive (p=0.04) and were more diazoxide unresponsive leading to pancreatectomy (p=0.007) compared to those with no identified mutations. Among 24 patients with identified genetic mutations, 17 (71%) had a mutation in ABCC8, 3 (12%) in KCNJ11, 3 (12%) in HADH, and 1 patient had a mutation in KMT2D. These included five novel mutations in ABCC8, KCNJ11, and KMT2D. Conclusion: This is the biggest genetic study of CHI in Iran. A high frequency of recessive forms of CHI, especially HADH mutations, in our study could be due to a high rate of consanguineous marriage. We recommend tNGS to screen for all the CHI genes.

Optimal Frequency to Screen Celiac Disease amongst Patients with Type 1 Diabetes Mellitus: A Multicenter Study.

AIMS: Celiac disease (CD) is frequent amongst patients with type 1 diabetes mellitus (T1DM). Since there is a disagreement on the optimal interval and frequency to perform screening tests for CD among diabetic patients, this study aimed to evaluate these issues amongst patients with T1DM. METHODS: This retrospective cohort study was conducted in seven referral diabetic centers in different cities of Iran from January 2020 to January 2021. Data belonging to 106 patients who were affected by both T1DM and CD was collected. The time interval between CD diagnosis and diabetes (IBCD), the age of diabetes onset, and any associated diseases, symptoms, and family history of T1DM and CD were recorded and analyzed. RESULTS: Results show that 45% of the patients with CD were diagnosed during the first year of diabetes onset; furthermore, 18% and 16% of the patients with CD were diagnosed in the second or third year after being diagnosed with diabetes. In addition, another 18% of patients with CD were diagnosed during the fourth till the eighth year after diabetes onset. Moreover, there was a negative relationship between the age of T1DM diagnosis and IBCD. Most participants were asymptomatic at the time of CD diagnosis. CONCLUSIONS: Screening tests to detect CD amongst patients with T1DM should continue for at least eight years after the initial T1DM diagnosis, especially those affected at a younger age.

Genotyping of ABCC8, KCNJ11, and HADH in Iranian Infants with Congenital Hyperinsulinism.

BACKGROUND: Congenital hyperinsulinism (CHI) is a heterogeneous disease with various underlying genetic causes. Among different genes considered effective in the development of CHI, ABCC8, KCNJ11, and HADH genes are among the important genes, especially in a population with a considerable rate of consanguineous marriage. Mutational analysis of these genes guides clinicians to better treatment and prediction of prognosis for this rare disease. The present study aimed to evaluate genetic variants in ABCC8, KCNJ11, and HADH genes as causative genes for CHI in the Iranian population. METHODS: The present case series took place in Mashhad, Iran, within 11 years. Every child who had a clinical phenotype and confirmatory biochemical tests of CHI enrolled in this study. Variants in ABCC8, KCNJ11, and HADH genes were analyzed by the polymerase chain reaction and sequencing in our patients. RESULTS: Among 20 pediatric patients, 16 of them had variants in ABCC8, KCNJ11, and HADH genes. The mean age of genetic diagnosis was 18.6 days. A homozygous missense (c.2041-21G > A) mutation in the ABCC8 gene was seen in three infants. Other common variants were frameshift variants (c.3438dup) in the ABCC8 gene and a missense variant (c.287-288delinsTG) in the KCNJ11 gene. Most of the variants in our population were still categorized as variants of unknown significance and only 7 pathogenic variants were present. CONCLUSION: Most variants were located in the ABCC8 gene in our population. Because most of the variants in our population are not previously reported, performing further functional studies is warranted.

Clinical Efficacy Evaluation of Sirolimus in Congenital Hyperinsulinism.

BACKGROUND: Congenital hyperinsulinism (CHI) is a rare and life-threatening genetic disorder. Sirolimus as a mammalian target of rapamycin inhibitor may be helpful in patients with CHI who do not respond well to other treatments including diazoxide and octreotide. However, the safety and efficacy of this therapy are still unclear. This study aimed to evaluate the potential therapeutic effects of sirolimus in CHI patients with mutations in the ABCC8 and KCNJ11 genes. METHODS: During the period of this follow-up study, every child with a confirmed diagnosis of unresponsive CHI underwent genetic evaluation. Among those who had positive genetic testing, six families agreed to participate in this study. The participants were evaluated for ABCC8, KCNJ11, or HNF4α gene mutations by polymerase chain reaction (PCR) sequencing. The participants who were unresponsive to diazoxide and octreotide therapy received 0.5 mg/m2/d of sirolimus, and the dose was gradually increased until a serum concentration of 5-15 ng/ml was achieved. Then, the participants were followed up for any possible complications. RESULTS: Among the study participants, only one neonate was completely free of hypoglycemia after one year of follow-up, whereas three others experienced a partial reduction in hypoglycemic episodes over six months. One neonate underwent pancreatectomy despite receiving sirolimus. The oldest participant with a mutation in the ABCC8 gene responded well to sirolimus therapy after surgery and remained asymptomatic for 18 months. CONCLUSION: This study suggested that sirolimus therapy needs further evaluation to determine which patients will benefit the most. The genetic basis of CHI may have possible implications for determining the patient's response.

Genetic variants of the phenylalanine hydroxylase gene in patients with phenylketonuria in the northeast of Iran.

Background Phenylketonuria (PKU) is a common metabolic disorder with great burden if left untreated or undiagnosed. Genetic variations in the phenylalanine hydroxylase (PAH) gene may be widely varied across different regions of a country. By knowing the most common mutations, diagnostic work-ups will be offered sooner and with lower costs for patients. The present study defines the most common genetic variations in the PAH gene in Khorasan province of Iran. Methods The present cross-sectional study took place in Khorasan province of Iran within a 6-year period starting from 2012 to 2018. Every patient who had been referred as suspicious PKU cases or referred for prenatal diagnosis was included in the present study. Results A total number of 122 individuals with a mean age of 26.22 years were enrolled in the present study. The most frequent genetic variations in the PAH gene were c.1066-11G > A and c.143 T > C. Exon 7 carried the most genetic variations compared to any single exon. Also, three patients had compound heterozygous status for c.727 C > T/c.1066-11 G > A in exon 7 and 11 of the PAH gene. Conclusions Mutations in the PAH gene are widely varied among different populations, and our results confirmed this fact. Determination of the most prevalent mutations and polymorphisms in each region will reduce the time and cost of diagnosing such preventable diseases and will therefore reduce the disease burden.

Niemann-Pick Diseases: The Largest Iranian Cohort with Genetic Analysis.

OBJECTIVES: Niemann-Pick diseases (NPD) is an autosomal recessive inherited lysosomal lipid storage disorder which occurs due to a defect in cellular cholesterol trafficking, leading to excess lipid accumulation in multiple organ systems such as the brain, lungs, spleen, and liver. SPMD1-associated disease includes classic infantile and visceral NPD type A and B respectively. Type C NPD is subacute or juvenile. MATERIALS & METHODS: During 2012-2016, the patients who had the clinical and biochemical signs and symptoms of different types of NPD, underwent genetic analysis. All patients were collected from five provinces in Iran (Razavi Khorasan, South Khorasan, Khozaestan, Isfahan and Tehran province). Sanger sequencing of the candidate genes for NPD was performed followed by bioinformatics analysis to confirm the types of NPD and to identify novel mutations. All patients underwent full clinical assessment. RESULTS: We present two cases with NPD type A, six cases with NPD type B, and 11 cases with type C with various enzymatic defects identified in these cases. Within these 19 patients, we present 9 previously reported mutations and 10 novel mutations causing NPD. CONCLUSION: This study is the largest Iranian study for NPD analysis ever. Our report demonstrates that NPD has a variable age of onset and can present early in life. We investigated the clinical and genetic manifestations of a large Iranian cohort. Understanding the variable presentation of NPD will allow for clinicians to have a high index of suspicion for the disease.

A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature.

Beta-ketothiolase deficiency is a rare autosomal recessive disorder characterized by an inborn error of isoleucine catabolism and affecting ketone body metabolism. Clinical features characterized by intermittent keto acidotic episodes are associated with clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients, with an onset during infancy or toddler-hood. A two months old girl presented to pediatric ward of Imam Reza Hospital in Mashhad City, Northwestern Iran in October 2016, with acute episode of fever and toxic encephalopathy with attack of vomiting, hypotonia, lethargy, tonic-clonic seizures and then a day in coma, few days after vaccination. After then similar episodes happened until 7 months age. Bio chemical tests that suggested diagnose of beta ketothiolase deficiency were attacks of ketoacidosis with urinary exertion of 2-methyl-3-hydroxybutyric acid 2-methyl aceto acetic acid tiglylglycine. In genetic assessment, we detected a novel homozygous mutation c.664A> C (p. Ser 222 Arg) in ACAT gene. This is the first report of beta ketothiolase deficiency confirmed by molecular analysis from Iran. We report on a homozygous variant in the ACAT1 gene and that is a novel mutation. We recommended carrier testing for all informative family members to recognize mutations in asymptomatic family members.

Peripheral Neuropathy in Children and Adolescents with Insulin-dependent Diabetes Mellitus.

OBJECTIVE: Type 1 diabetes mellitus (T1DM) is a chronic immune-mediated disease. Diabetic peripheral neuropathy (DPN) is an important microvascular complication of T1DM. One of the most important risk factors for the development of DPN is poor glycemic control. We evaluated the prevalence of DPN among T1DM patients and determined the association between DPN and glycated hemoglobin (HbA1c) level. MATERIALS & METHODS: The subjects were recruited prospectively upon initial evaluation at Imam Reza Hospital, Mashhad, Iran from Jan 2013 to Jan 2015. Patients with T1DM were selected based on the inclusion criteria (i.e., age of 6≤yr and absence of other co-morbidities). DPN was assessed through electrodiagnostic studies and neurological examinations, while diabetes control was evaluated by measuring the HbA1c level. RESULTS: Fifty patients with T1DM were enrolled in this study. The mean diabetes duration of patients was 8.38±3.79 yr (mean age16.68±6.68 yr). The mean HbA1c level was 8.6±2.1% in patients without DPN and 10.5±3 in those with DPN (P=0.016). Overall, 24% of the subjects were presented with DPN according to nerve conduction velocity study (NCV) findings. A positive correlation was found between NCV and clinical symptoms with signs (P<0.001, r=0.45 and P<0.001, r=0.644, respectively). Sensitivity and specificity of neurological examination for DPN diagnosis were 91.7% and 63.2%, respectively. Poor diabetes control is associated with DPN. Moreover, HbA1c level was used as an index for glycemic control over the past 3 months. CONCLUSION: Rigid blood glucose control and periodic neurological examinations were the best strategies to prevent DPN.