Objective To explore the relationship between time in range (TIR) derived from flash glucose monitoring system (FGM) and HbA1c in Chinese adults with type 1 diabetes mellitus (T1DM). Methods Adult T1DM patients attended outpatient department of Peking Union Medical College Hospital (PUMCH) between October 2018 to March 2019 were included. HbA1c and data of FGM were obtained at the same time. TIR was calculated, and the relationship between TIR and HbA1c was investigated by correlation and regression analysis. Results A total number of 77 patients who met the inclusion and exclusion criteria were included in the analysis. The average HbA1c was (7.5±1.3)%; TIR 62.0 (48.7, 67.8)% and CV (coefficient of variation) (39.7±8.1)%. TIR derived from FGM had a negative liner correlation with HbA1c (r=-0.645, P<0.001). The regression equation is:HbA1c=10.58-0.05×TIR. The HbA1c level decreased by 0.5% for every 10% increase in TIR. TIR was correlated with HbA1c negatively in both patients with stable glucose (CV<36%) and unstable glucose (CV ≥ 36%), but the correlation coefficient between TIR and HbA1c in stable glucose patients was higher. For a specific TIR, HbA1c was higher in stable glucose patients. Conclusions The FGM-derived TIR could be helpful in the glucose management of Chinese adult T1DM, while glucose variability should be taken into consideration in interpreting the relationship between TIR and HbA1c.

目的 评估蛋白尿阴性的成人1型糖尿病(type 1 diabetes mellitus,T1DM)患者肾小球滤过率(estimated glomerular filtration rate,eGFR),并探究影响eGFR的相关因素.方法 纳入2018年6月～2019年6月在北京协和医院门诊就诊的T1DM患者,收集人体测量学指标,检测血糖、血脂、肌酐、C肽等指标,计算eGFR,通过Pearson相关性分析、多元线性回归方法,探讨蛋白尿阴性的成人T1 DM患者eGFR的相关因素.结果 共纳入89例T1DM患者,10例蛋白尿阳性,79例蛋白尿阴性,蛋白尿阴性患者平均年龄为39.03±13.20岁,平均病程为9.89±9.21年,平均HbA1c为7.44％±1.32％,平均eGFR为111.61±13.43ml/(min·1.73m2),其中eGFR 60～ 90ml/(min·1.73m2)者5例(6.3％).Pearson相关性分析显示,年龄、病程、SBP、TC、2hCP均与eGFR相关,而HbA1c与蛋白尿阴性患者eGFR水平无关.多元线性回归分析发现年龄、病程是eGFR的独立危险因素.结论 蛋白尿阴性的中国成人T1DM中eGFR下降不罕见,对于年龄较大、病程较长者,即使尿蛋白阴性仍需密切监测肾功能.

To the Editor: Wolfram syndrome (WS, MIM 222300) is a rare autosomal recessive disorder caused by mutations in WFS1 or CISD2 (WFS2). Its prevalence is estimated to be one in 160,000 to 770,000.[1] Patients usually present with insulin-dependent diabetes mellitus (DM) at around 6 years old and then with optic atrophy (OA) at around 11 years old. Other symptoms, such as diabetes insipidus, sensorineural deafness, urinary tract abnormalities, and neuropsychiatric disorders, occur at older ages and affect a fraction of individuals. The expected age at death is approximately 30 to 40 years, mostly caused by respiratory failure. WS is inherited in an autosomal recessive manner, while some pathogenic mutations in the WFS1 gene are dominant, are associated with hearing impairment, OA, DM, and psychiatric problems, and cause Wolfram-like syndrome.[2] In the present report, we describe a case of WFS1-related spectrum disorder onset with non-insulin-dependent DM and OA in a Chinese patient. This patient had compound heterozygous mutations in the WFS1 gene, and a novel nonsense mutation, c.2217C>A, was found. A 19-year-old man was referred to our department with a 5-month history of DM and a 7-year history of progressive visual loss. Five months earlier, the patient presented to the local hospital with polydipsia, polyphagia, and polyuria and weight decreasing from 58 (1 year earlier) to 52 kg. His height was 173 cm. Fasting serum glucose was 14.4 mmol/L, and anti-glutamic acid decarboxylase, anti-islet cell antibodies, and anti-insulin autoantibodies were negative. He was diagnosed with type 2 DM and was treated with intensive insulin therapy (multiple daily insulin injections) for 1 month. Then, his therapy gradually changed to acarbose and 2 U recombinant insulin glargine at bedtime. Those symptoms resolved once the therapy was initiated. He came to our department for counseling on future management. We conducted a 2 h oral glucose tolerance test with a standard meal. His serum glucose, insulin, and C-peptide were 5.2 mmol/L, 2.95 μIU/mL (normal range: 5.2–17.2 μIU/mL), and 0.57 ng/mL (normal range: 0.8–4.2 ng/mL) at 0 h and were 3.2 mmol/L, 13.77 μIU/mL, and 2.68 ng/mL at 2 h, respectively. Hemoglobin A1c (HbA1c) was 5.7% and C-reactive protein was 0.19 mg/L. Urine albumin was negative. The patient has no siblings. His parents are non-consanguineous and have no signs or symptoms. His grandmother on his father's side was diagnosed with type 2 DM at 62 years of age. The patient was young and not obese. Suspecting that he had genetic diabetes such as maturity-onset diabetes of the young or recessive genetic syndromes, we performed whole-exome sequencing and patient consent forms were obtained. No diabetes-associated genetic defects were detected except for compound heterozygous mutations in the WFS1 gene. Sanger sequencing confirmed that the patient inherited a missense variant, c.1673G>A, from his father and a nonsense variant, c.2217C>A, from his mother [Figure 1]. Both parents carry one mutated allele and do not have hearing impairment, OA, or DM. Given the genetic testing results, we suggested that the patient receive optic nerve and hearing tests. His visual acuity was normal before 11 years of age and gradually decreased to 20/40 and 20/50 in each eye. Brain magnetic resonance imaging showed bilateral optic nerve atrophy. Audiometry demonstrated normal hearing. No signs of urological abnormalities or psychiatric disorders were observed. DM, OA and gene mutations confirmed the diagnosis of WFS1-related spectrum disorder.Figure 1: Sequencing of exon 8 of WFS1 (NM_006005.3). The patient inherited a missense variant c.1673G>A (p. Arg558His) from his father and a nonsense variant c.2217C>A (p. Tyr739*) from his mother.WS is a rare, neurodegenerative, progressive, autosomal recessive disease, and the diagnosis requires the coincidence of insulin-dependent DM and bilateral OA before the second decade.[1] Though the patient presented here was confirmed to have bilateral OA, his non-insulin-dependent DM is atypical for WS. The application of next-generation sequencing technology allowed rapid diagnosis and appropriate evaluations. Genetic analyses have identified more than 300 pathogenic variants in WFS1, and the severity of the disease varies with the mutation type. Efforts have been put into establishing genotype-phenotype correlation for better diagnosis and management.[3] Our patient's c.1673G>A mutation causes a substitution of arginine at residue 558 for histidine, and the c.2217C>A mutation generates p.Y739X, which has never been reported. A brother and sister with the same p.R558C mutation in compound heterozygosity with a p.E864X nonsense mutation were reported to have DM and OA in their teens without any signs of other problems.[4] According to the genetic test results, our patient is likely to have a mild form of WS. What is special about this patient is that his DM was diagnosed at an early stage and he had not progressed to insulin-dependent DM with good control of serum glucose. Certain dominant WFS1 mutations have been discovered to cause type 2 DM due to relative insulin insufficiency, but recessive mutations are almost always considered to cause insulin-dependent DM.[2,5] The patient's parents do not have DM, visual loss, or hearing problems. He maintained glucose control with diet and exercise and without medication for the next 3 months, and his HbA1c was 6.4% at the last follow-up. The prognosis of this patient remains to be further studied. This case can broaden our knowledge about WFS1 gene function in DM and its genotype-phenotype correlation. Declaration of patient consent The author certifies that they have obtained all appreciate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Conflicts of interest None.