Volume 11 · Issue 11 · 2019

Special type of diabetes refers to some diabetes mellitus with relatively clear pathogenesis. A clear diagnosis may directly affect the treatment and prognosis, especially in monogenic diabetes. However, in clinical diagnosis and treatment, the actual prevalence of diabetes mellitus is greatly underestimated due to the large overlap between its clinical manifestations and type 1 and type 2 diabetes mellitus. Misdiagnosis not only delays the condition, but also increases the economic burden on families and society. Therefore, strengthening the understanding of special types of diabetes is very important to improve the level of diabetes prevention and treatment. This article aims to further sort out some common clinical features and clues of special types of diabetes, and combined with the consensus update of the American Diabetes Society in recent years, to put forward specific suggestions for which patients need further genetic testing, aiming at assisting the majority of medical workers to discover those special types of diabetes hidden in type 1 diabetes and type 2 diabetes in clinical practice, and standardize their treatment.

With the progress of molecular biology and medical genetics, the pathogenic mechanism of single-gene diabetes has gradually become clear, and the molecular detection methods have become more abundant and diverse. The rapid development of second-generation sequencing technology has brought more patients the opportunity to receive genetic testing. It also provides more diagnostic basis for clinical practice. However, how to interpret the genetic variation data generated by second-generation sequencing is a huge challenge that affects the clinical use of genetic data. Therefore, we need to establish a standard for interpretation of variation data, so as to make the use of data more standardized and accurate, and ensure that the same genetic variation has the same evaluation results, so as to avoid the phenomenon of different conclusions for the same variation. The guidelines issued by the American Society of Medical Genetics and Genomics provide us with a good reference. According to the guidelines, we can interpret the second-generation sequencing data of patients, so that genetic variation can be well combined with clinical phenotype and provide a basis for clinical diagnosis.

Single-gene diabetes is a special type of diabetes caused by a single gene mutation. Most of its pathogenic genes are involved in the development and function of pancreatic islet β cells or the transmission of insulin signaling pathway. Adult-onset diabetes and neonatal diabetes in adolescents are the most common. The study found that multiple single-gene diabetes causative genes overlap with type 2 diabetes (T2DM) susceptibility genes, and their common variants significantly increase the risk of T2DM. In addition, the research and development of hypoglycemic drugs targeting monogenic diabetes-causing genes is progressing rapidly. In-depth research on monogenic diabetes is helpful to deepen the understanding of the pathogenesis, prognosis and drug development of T2DM.

Monogenic diabetes is a kind of diabetes with clear molecular etiology caused by a single gene defect, and most of them belong to special types of diabetes. Clinically, adolescents with adult-onset diabetes, neonatal diabetes, mitochondrial diabetes, and diabetic syndrome are often misdiagnosed, and their symptoms and medication are also different from common type 1 and type 2 diabetes. Genetic testing is the gold standard for single-gene diabetes diagnosis at present, but it is necessary to choose reasonably in detection methods to increase the weight of gene defects in diabetes classification and diagnosis and treatment, which is conducive to individualized accurate diagnosis and treatment.

To explore the clinical features, treatment and prognosis of pregnancy-associated fulminant type 1 diabetes mellitus (PF).

Patients admitted in Peking Union Medical College Hospital from January 2012 to December 2018 with the diagnose of PF were enrolled in the study. All the clinical data were collected and analyzed.

A total of 6 patients were enrolled with 1 case occurred in the first trimester, 3 cases occurred in the third trimester and 2 cases within 2 weeks after delivery. Four fetus survived and two resulted in stillbirth. Flu-like symptoms and gastrointestinal symptoms right before the onset were observed in 3 patients. Three patients were diagnosed as gestational diabetes mellitus and were found to be allergic to insulin regimes during the treatment of multiple insulin injections, two of them developed PF after insulin allergy. All patients were treated with multiple insulin injections, of which 5 patients manifested as robust blood glucose fluctuations and frequent hypoglycemia episodes. Insulin autoantibody was tested in 4 patients and all were positive, thus the diagnose of exogenous insulin antibody syndrome was probable.

PF has remarkably abrupt onset and could be lethal to both mothers and fetus.

To investigate the correlation between heteroplasmy level of the mitochondrial DNA A3243G mutation and the onset of mitochondria diabetes.

We performed a systematic review of mitochondrial DNA A3243G mutation using PubMed, Wiley online library, Wan fang data, CQVIP and CNKI. Selected cases were divided into two groups: affected group and unaffected maternal relatives group. Statistical analyses were performed using Box-plot, independent sample t test, cumulative frequency and binary logistic regression.

The heteroplasmy level of affected group was significantly higher than the unaffected maternal relatives group (35.49%±16.28% vs 8.38%±10.24%, t=11.31, P<0.001). Binary logistic regression was applied to build a forecasting model. The predicted probability of being affected was 0.079 at the mutation level of 4%.

The onset of mitochondria diabetes is positively associated with mitochondrial DNA A3243G mutation level. Forecasting model could be used to establish the cutoff value of mutation level.

To explore the clinical and genetic characteristics of neonatal diabetes mellitus (NDM) induced by insulin gene mutation.

A Chinese pedigree of permanent neonatal diabetes mellitus (PNDM) diagnosed in Peking Union Medical College Hospital in December 2017 was analyzed for the clinical characteristics and laboratory examinations. Sanger sequencing was performed to identify mutations in KCNJ11, ABCC8 and insulin gene in proband and her parents. Data of NDM induced by mutations in insulin gene were collected and analyzed.

A heterozygous mutation in insulin gene (NM_000207.2) located in exon 2 (c.265C>T; p.R89C) was identified in the proband. The mutation changes the structure of insulin molecule. Literature review found that there were altogether 12 pathogenic mutations in insulin gene which had been reported to result in NDM. All NDM caused by mutations in insulin gene were classified as PNDM. The onset age of PNDM with mutations in the insulin gene ranges widely, from several weeks to several years, usually with diabetic ketoacidosis or marked hyperglycemia, with very low or undetectable C-peptide values. The patients usually need to be treated with insulin once diagnosed.

There are PNDM pedigrees caused by insulin gene (R89C) heterozygous mutation in Chinese population. Genetic testing including channel genes (KCNJ11 and ABCC8) and insulin gene should be conducted in patients with suspected PNDM for early diagnosis and appropriate treatment.

To investigate olfactory functional network alterations and the association of odor-induced brain activation with cognitive and metabolic parameters in patients with type 2 diabetes.

Participants with normal cognition, including 51 patients with type 2 diabetes and 41 non-diabetic controls, were enrolled. Detailed neuropsychological assessment and computerized olfactory behavior tests evaluating olfactory threshold, odor identification and odor memory function were performed. Neural activation intensity in response to odor stimuli was assessed by functional magnetic resonance imaging (fMRI) for between group analysis. Independent sample t test and chi-square test were used for comparison between the two groups.

Compared with the control, patients with type 2 diabetes had significantly lower olfactory threshold score [(8.7±3.2) vs (11.0±2.5) points, P<0.01]. Reduced activation in the left hippocampus and parahippocampus in the olfactory network was revealed by fMRI. Within the diabetic patients group, negative association between 2 h C-peptide and the time spent in the executive function test (r=-0.434, P<0.01) and positive associations of 2 h C-peptide with the olfactory behavior test scores and the left parahippocampus activation were observed (r=0.379, 0.288, both P<0.05).

Functional alterations of the brain olfactory circuit is present before clinical measurable cognitive decrements in type 2 diabetes, and might constitute a potential marker of cognitive decline in diabetes.

The characteristics of dietary structure in overweight/obese type 2 diabetic patients were investigated for providing individualized medical nutrition therapy for diabetes mellitus.

A total of 103 out-patients (58 males, 45 females, ≥25 years) from the 900 Hospital of the Joint Logistics Team between January and June in 2017 were recruited and divided into 3 groups according to body mass index (BMI) : normal group (18.5<BMI<24.0 kg/m², n=31), overweight group (24.0≤BMI<28.0 kg/m², n=38) and obese group (BMI≥28.0 kg/m², n=34). 3×24 hours dietary records were collected by weighing method including height, weight and waist circumference measuring. Mean daily intakes of total calorie, energy supply ratio of three major nutrients, intake of three major nutrients and dietary fiber were calculated and analyzed by software of trophic analysis. One-way analysis of variance was used for comparison among multiple groups.

(1) Total calorie intake: the differences of total calorie intake among 3 groups were statistically significant (F=4.321, P<0.05); it was higher in the obese group than that in the normal group [(2 488±894) vs (2 094±346) kcal (1 kcal=4.18 kJ), P<0.05]; while there were no significant differences between the overweight group and the normal group or the obese group (bothP>0.05). (2) Energy supply ratio: there were no significant differences in energy supply ratio of carbohydrate, protein and fat among 3 groups (all P>0.05) . (3) Intake: differences were significant in the carbohydrate intake among 3 groups (F=6.755, P<0.05), intake in the obese group was higher than those in the normal group or the overweight group [(332±114) vs (265±52) vs (276±60) g, all P<0.05]. There was no significant difference between the normal and the overweight group (P>0.05). There were no significant differences in protein, fat and dietary fiber intake among 3 groups (all P>0.05).

Compared with normal weight patients with type 2 diabetics, obese type 2 diabetic patients have excessive daily energy intakes and excess energies, mainly due to excessive carbohydrate intake.

To explore the levels of cardiometabolic index (CMI) and its relationship with early phase β-cell function in overweight/obese polycystic ovary syndrome (PCOS) women.

Three hundred and eighty-two overweight and obese women from Nanjing Drum Tower Hospital between April, 2016 and September, 2017 were recruited and divided into body mass index matched simple overweight/obese group (n=75) and overweight/obese PCOS group (n=307). Data of weight, height, blood pressure, heart rate and related laboratory examinations at their first visit were collected, indexes of early phase β-cell function (AUCIns ₃₀/AUCGlu₃₀, DI₃₀, Ins₃₀/FINS) and CMI were calculated. Independent sample t test, analysis of variance and Pearson correlation coefficient were used for statistical analysis.

Compared with simple overweight/obese women, waist-hip ratio, serum insulin levels during oral glucose tolerance test (OGTT), CMI (1.86±0.69 vs 1.64±0.91) and AUCIns₃₀/AUCGlu₃₀ (1.08±0.24 vs 0.98±0.32) were significantly higher respectively (t=-5.631--2.522, P<0.05), while HDL-C, 1/HOMA-IR (0.20±0.13 vs 0.28±0.16), DI₃₀ (1.69±0.69 vs 1.88±0.72) and Ins₃₀/FINS (5.76±3.29 vs 6.79±3.90) were significantly lower respectively (t=1.938-4.974, P<0.05) in overweight/obese PCOS women. Indexes relating early phase insulin secretion were significantly lower in overweight/obese PCOS women with higher CMI levels than those in overweight/obese PCOS women with lower CMI levels (P<0.05). In addition, CMI was negatively correlated with lgDI₃₀ and Ins₃₀/FINS after adjusting age, BMI, blood pressure and heart rate (r=-0.167, -0.162, P=0.004, 0.006).

Compared with simple overweight/obese women, overweight/obese PCOS women have higher cardiovascular risk and impaired early phase insulin secretion function. Early phase β-cell function indexes were negatively correlated with cardiovascular metabolic risk in overweight/obese PCOS women.

To explore the effect of Nr2a1 on the pancreatic β cell apoptosis induced by palmitate acid (PA).

The plasmid overexpressing Nr2a1 was transfected into pancreatic β cell line Min6 cells with Lipofectin transfection. Min6 cells cultured in vitro were divided into Control, Vector, PA+Vector, and PA+Nr2a1. Real-time quantitative PCR and western blotting were performed to detect the expression of Nr2a1 in response to PA treatment. Using Hoechst 33258, the apoptotic rate of cells was determined by scoring the cells displaying pycnotic nucleus and/or fragmented nucleus. Caspase-3 activity was determined by western blotting and Caspase-3 activity assay. Moreover, the expression of peroxisome proliferative activated receptor gamma coactivator-1 alpha (PGC1α) was assessed by real-time quantitative PCR and western blotting. Further, we used RNAi to inhibit expression of PGC1α in order to investigate how PGC1α affects Min6 cells. Statistical analysis was performed by using independent-samples t test.

Compared with Vector group, apoptosis of Min6 cells was significantly induced (3.158±0.105 vs 1.000±0.096, t=-21.407, P<0.01) in response to PA, while expression of Nr2a1 was reduced at mRNA level (0.184±0.015 vs 1.000±0.069, t=16.386, P<0.01), and protein level (0.446±0.050 vs 1.000±0.097, t=7.179, P<0.01). Furthermore, PGC1α decreased at mRNA level (0.625±0.047 vs 1.000±0.090,t=5.242, P<0.05) and protein level (0.505±0.044 vs 1.000±0.027, t=13.499, P<0.01) respectively. Overexpression of Nr2a1 partially rescued PA induced apoptosis in Min6 cells. Compared with that of group PA+Vector, cleaved Caspase-3 abundance of group PA+Nr2a1 decreased (0.418±0.011 vs 1.000±0.007, t=63.739, P<0.01). Meanwhile, PGC1α increased at mRNA level (1.961±0.198 vs 1.000±0.072,t=-6.453, P<0.01) and protein level (2.203±0.157 vs 1.000±0.079, t=-9.688, P<0.01) respectively. Moreover, silencing PGC1α in Min6-Nr2a1 cells increased Cleaved caspase-3 abundance (1.371±0.100 vs 1.000±0.060,t=-4.514, P<0.05).

Min6 cells are protected by Nr2a1 from PA induced apoptosis, and there is potential synergy between Nr2a1 and its coactivator PGC1α in the anti-apoptosis progress.

Wolfram syndrome is a rare autosomal recessive hereditary disease, which usually manifests as multiple organ diseases such as early onset diabetes, diabetes insipidus, optic atrophy, neuropathic deafness, etc. Its causative genes are WFS1 gene and CISD2 gene. The proband was a 12-year-old male who developed diabetes, neuropathic bladder, optic atrophy, diabetes insipidus, bilateral hydronephrosis and ureteral abnormalities from the age of 4. His 8-year-old sister has also suffered from diabetes for 4 years and has not yet developed other systemic diseases. The younger brother was 4 years old, and the glucose tolerance results showed impaired glucose tolerance and no other systemic abnormalities. The results of genetic examination showed that the proband, his sibling sister and younger brother were homozygous for the insertion mutation of exon 8 of WFS1 gene, and all parents were heterozygous for the insertion mutation. The family of this case suggests that patients with insulin-dependent diabetes and optic atrophy should be alert to Wolfram syndrome for timely and correct diagnosis and treatment.

Continuous glucose monitoring (CGM) can provide researchers with more comprehensive and detailed glucose-related data, and it is increasingly widely used in clinical and basic research of diabetes. At present, there are two main CGM technologies applied to experimental animal models, including human CGM system applied to animal research and the emerging implantable blood glucose telemetry technology. The latter can monitor blood sugar for 6 to 8 weeks, with high accuracy, unrestricted animal activities, and can monitor body temperature and activity simultaneously, providing new ideas and research methods for the study of metabolic diseases such as diabetes, and will become one of the effective tools for studying hypoglycemic drugs.

Real-time continuous glucose monitoring (CGM) system and intermittent scanning CGM can monitor blood glucose in real time, show the real-time trend of blood glucose change, and give trend arrow information indicating the direction and rate of blood glucose change. Users can immediately judge the current blood sugar level and changing trend through the information given by the trend arrow data, and take corresponding measures to adjust it in time. From a practical point of view, this paper summarizes the interpretation methods of trend arrows in CGM at home and abroad in recent years, and provides suggestions for explaining trend arrows and subsequent insulin dose adjustment in combination with some models recommended by literature.