Volume 08 · Issue 06 · 2016

Diabetes mellitus is a class of metabolic diseases characterized by chronic hyperglycemia. At present, the classification is according to the pathogenesis of diabetes, which reflects the progress of human understanding of diabetes. We are not only able to diagnose type 1, type 2 diabetes and gestational diabetes, but also to detect specific types of diabetes through clinical manifestations and/or genetic testing. Molecular genetic diagnosis has entered the clinic of diabetes, and it has also linked precision medicine with diabetes. The understanding and diagnosis level of special types of diabetes have also made great progress in China, especially adult-onset diabetes (MODY) in adolescents, diabetes caused by mitochondrial gene mutation, permanent neonatal diabetes, and diabetes with extreme insulin resistance^[1,2,3]More and more special types of diabetes have been reported. This article will briefly review the classification and clinical problems of special types of diabetes.

According to the existing criteria (WHO, 1999), diabetes mellitus is classified into type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), gestational diabetes mellitus (GDM) and specific types of diabetes mellitus. With the deepening of understanding of the pathogenesis of diabetes mellitus, special types of diabetes, mainly monogenic diabetes, are attracting increasing attention^[1]。 Among them, adult-onset diabetes mellitus (MODY) and neonatal diabetes mellitus (NDM) in adolescents are the most common monogenic diabetes mellitus.

Adult-onset diabetes mellitus (MODY) in adolescents is caused by heterozygous mutations in various transcription factors that play an important role in the development and maturation of pancreatic islet beta cells and heterozygous mutations in glucokinase (GCK) or cholesteryl ester hydrolase (CEL) that lead to genetic defects in beta cell function. MODY is clinically characterized by autosomal dominance, early onset (usually diagnosed before 25 years of age), no association with autoimmunity or insulin resistance, and no complete loss of endogenous insulin secretion. In addition to the seven MODY genes named by the American Diabetes Association (ADA), six new disease-causing genes have been discovered in recent years, including those encoding ATP-sensitive potassium channels (K_ATPChannel), insulin gene and three transcription factor genes. About 80% of MODY individuals are currently misdiagnosed with either type 1 diabetes (T1DM) or type 2 diabetes (T2DM)^[1]。 Misdiagnosis leads to mistreatment, which delays the disease and aggravates the progression of diabetes. Therefore, it is important to correctly diagnose MODY and to identify MODY from T1DM and T2DM and to perform individualized or precision medicine when it is necessary to make decisions about a patient's treatment, predict their prognosis, and perform analysis and genetic counseling of family members at higher risk of developing the disease.

Mitochondrial gene tRNA^{Leu (UUR)}A3243G mutation (mt.3243A>G mutation) diabetes mellitus is one of the most common mitochondrial gene mutation diabetes mellitus^[1], belonging to a special type of diabetes caused by a single gene mutation^[2]The typical clinical characteristics are young onset, weight loss, progressive decline of pancreatic islet β cell secretion function, accompanied by hearing impairment, and maternal inheritance^[3]However, due to the cellular heterocytoplasm of mitochondrial DNA mutations, the clinical manifestations of the disease are obviously heterogeneous^[4]。 With the improvement of mutation screening and genetic diagnosis technology, it has become an urgent need for diabetes precision medicine to improve the multi-system accurate evaluation method of mt.3243A>G mutation diabetes.

To investigate the clinical and genetic characteristics of a Chinese pedigree with maturity onset diabetes of the young type 1(MODY 1).

A Chinese pedigree of MODY diagnosed in Peking Union Medical College Hospital in August 2015 was analyzed for the clinical features and laboratory data. Genomic DNA of related members in the pedigree were extracted. And Sanger sequencing was performed to identify mutations in hepatocyte nuclear factor (HNF)1α gene, HNF4α gene and glucokinase (GCK) gene in this pedigree.

A heterozygous mutation in HNF4α gene (NM_000457.4) located in the exon 8 (c.992G>A; p.R331H) was identified in two members of the pedigree(the proband and his mother). After the genetic diagnosis of the MODY 1, the proband was given a small dose of sulfonylurea instead of insulin for glucose-lowering therapy. As a result, the proband got a much more stable blood glucose.

There are MODY 1 pedigrees caused by HNF4α gene heterozygous mutations in Chinese population. A correct genetic diagnosis can significantly improve the treatment and blood control of the patients. MODY may co-exist with type 2 diabetes in a same pedigree, which is tend to be misdiagnosed, and should be paid more attention.

To explore the underlying pathogenic mechanism of lipodystrophic syndrome by analyzing the clinical manifestation and genetic information of a patient with lipodystrophy.

Clinical and laboratory data of a patient with lipodystrophy admitted to Peking Union Medical College Hospital in December 2015 were investigated. The quantification of adipose tissue was achieved by diffuse weight imaging. The levels of leptin and adiponectin were determined. Gene mutations related to congenital lipodystrophy were tested by Sanger sequencing.

Diffuse weight imaging showed atrophy of subcutaneous adipose tissue in multiple sites of the body. The levels of leptin and adiponectin were 0 and 3 mg/L respectively. Sanger sequencing result elicited LMNA mutation with c.1045C>T(p.349R> W).

The patient presents with classic lipodystrophic manifestation, including characteristic lipoatrophic appearance, insulin resistance and disorder of lipid metabolism and extremely low levels of leptin and adiponectin. The LMNA mutation and the low levels of leptin and adiponectin may contribute to the pathogenesis of lipodystrophic syndrome.

To investigate the impact of continuation or discontinuation of antibiotics on recurrence and clinical outcomes in patients with diabetic foot with varying severity of ischemia and infection when clinical signs have resolved.

Hospitalized patients with diabetic foot infection (DFI)were selected from March 2010 to August 2012. When the infectious symptoms disappeared after antibiotic treatment, the patients were divided into continuation group (group A) and discontinuation group (group B) with random number table. Recurrences of infection within 2 weeks and outcomes in 6 months were observed. Two sample t-test was used between group comparisons. Recurrent infection rates were analyzed using chi-square test. Relative risk analysis was applied to explore the correlation between recurrent infection and antibiotics usage and differences in clinical outcome between groups.

A total of 184 patients in group A(male/female: 131/53)and 191 patients in group B (male/female: 137/54)completed the follow-up periods. Among patients with mild infection, recurrence rate in group B was higher than that in group A in patients with severe ischemia(odds ratio(OR)=3.792, 95% confidence interval(CI) 1.090-13.185, P<0.05), but no differences were found between those with mild/moderate ischemia. Recurrence rate of infection in group B was higher than that in group A regardless of severity of ischemia (2.917 (1.078-7.889), 3.516 (1.375-8.994), all P<0.05)in patients with moderate/severe infection. No differences were found between the two groups in patients with sole neuropathy independent of infection severity. After follow-up of 6 months, no differences were found in clinical outcomes between the two groups. However, compared with group B, group A had higher healing rate (73.3% (74/101) vs 48.3%(42/87)), and lower amputation rate and death rate in patients with moderate/severe infection.

It is suggested to stop antibiotics in mild infection patients with mild/moderate ischemia or sole neuropathy after the clinical symptoms of infection have resolved. However, clinicians should consider to continue antibiotic therapy in moderate/severe infection and mild infection concomitant with severe ischemia.

To detect the levels of serum betatrophin in people with different glucose tolerance and to investigate the relationship between serum betatrophin levels and insulin secretion of pancreatic β cells as well as insulin resistance.

Forty seven patients with newly diagnosed type 2 diabetes mellitus (T2DM group), 27 patients with impaired glucose regulation (IGR group) and 36 individuals with normal glucose tolerance (NGT group) were recruited in the study from September 2014 to January 2015. All subjects underwent intravenous glucose tolerance test (IVGTT). Insulin levels during the first 10 min were measured and acute insulin response (AIR_3.5), 0-10 minutes insulin area under the curve (AUC) were evaluated. Homeostasis model assessments for insulin resistance (HOMA-IR) and for β-cell function (HOMA-β) were calculated. Meanwhile fasting serum betatrophin was determined by enzyme-linked immunosorbent assay(ELISA). The relationships between serum betatrophin, indexes mentioned above and metabolic parameters were analyzed. Comparisons among groups were performed by using analysis of variance (ANOVA). Pearson correlation analysis was used to determine simple bivariate relationships.

The levels of serum betatrophin were significantly higher in the T2DM group and IGR group than that in the NGT group (2.08 (1.08-2.89), 1.52 (0.54-2.55) and 0.76 (0.44-0.97) μg/L, respectively, F=16.142,P<0.01). The correlation analysis suggested that the serum betatrophin level in all participants was positively correlated with weight, body mass index, waist circumference, waist hip ratio, fasting plasma glucose, 2 h postprandial plasma glucose, glycated hemoglobin A_1c, fasting serum insulin, 2 h postprandial serum insulin, HOMA-IR and triglycerides(TG) (r=0.288-0.562, allP<0.05), and negatively related to the high-density lipoprotein-cholesterol (r=- 0.338,P<0.01). Stepwise multiple regression analysis showed that HOMA-IR and TG were independently related to serum betatrophin levels (β_HOMA-IR=0.438,P<0.001; β _TG=0.300,P=0.002).

Serum betatrophin level increases in patients with T2DM and IGR, and is closely related with glucolipid metabolism, but has no direct relation with first-phase of glucose-stimulated insulin secretion.

To assess the osteoporotic changes in diabetic rats and protective effects of genistein.

A total of 60 adult SD rats (four months old and weighted (200±20) g) were divided into three groups according to the random number table: normal control group(group CON), diabetic group (Group DM) and intervention group (Group Gen) (20 rats in each group). Rats in Group DM and Group Gen were injected with streptozotocin(STZ) at 60 mg/kg in the left lower abdominal cavity to establish STZ-induced diabetic model, which was considered valid if blood glucose was greater than or equal to 167 mmol/L after 72 hours. Group Gen received 30 mg·kg^-1·d^-1 of genistein, once a day. An equal volume of citrate buffer was given to Group CON, both were administered intraperitoneally. The immunohistochemical evaluation of the femoral head subchondral region and FⅧ factor were conducted in each group after 15 weeks. The microvessel density was measured with the ink perfusion. Vascular endothelial growth factor(VEGF) mRNA expression was measured and analyzed by the in situ hybridization. The date analysis was performed using LSD test.

(1) The trabecular bone in Group CON was thick and had complete osteoblasts area. The trabecular bone in Group DM was sparse and thin, the nucleus was pyknotic. The trabecular bone in Group Gen had arranged more closely. (2) Compared with the Group CON, the number of osteoblast (13.2±1.3 vs 22.4±2.5) decreased, microvascular relative area ((8.7±0.7)% vs (4.7±0.6)%) increased, FⅧ factor gray value of expression (137±5 vs 164±5) and the expression of VEGF mRNA (186±5 vs 213±4) decreased in Group DM. (3) Compared with Group DM; osteoporosis and pathological alterations of micrangium were improved in Group Gen. Osteoblasts (19.20±1.9) increased, microvascular unit area ((5.6±0.5)%) decreased, gray value of FⅧ factor (159±7)and the expression of VEGF mRNA (200±2)increased in Group Gen. Differences among these groups were statistically significant (F=39.191-58.815, respectively, all P<0.01).

Osteoporoic changes occur in the early stage of diabetes, and genistein has a protective effect on the microstructure.

To explore the effect of Zn-α2-glycoprotein(ZAG) on hepatic gene expression profiles in obese mice by using microarray technology.

The model of obese ICR mice induced by high fat diet (HFD) was established, and then the 21 mice models were divided into ZAG-treating group (ZAG group,n=8) and HFD group (n=13). Another 10 ICR mice were set as blank control (fed with standard food, SF group). Then the ZAG group were treated with ZAG expression plasmid injection and high fat diet; the HFD group were treated with negative saline injection and high fat diet; the SF group were treated with negative saline injection and standard food. Eight weeks later, the biochemical indexes of each group, such as the levels of blood glucose, blood lipids, fasting insulin and so on were checked. The gene expression profiles in liver, especially genes related to the glucolipid metabolism, were examined by the GeneChip microarray system, and the expression of glycogen synthase 2 (GYS2), peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1α) and suppressor of cytokine signaling 3 (SOCS3) were verified by quantitative real time polymerase chain reaction (qRT-PCR). Thet test was used when data were compared between two groups.

After 8-week of intervention, the body weight, white adipose tissue mass and fasting glucose level in ZAG group decreased by 14.5%, 57.17% and 35.5% respectively when compared with those in HFD group(F=7.948, 18.941, 4.327, all P<0.05). A total of 424 genes (299 increased, 125 decreased) expressed differentially in the two groups. Among them, six genes (enoyl-coenzyme A(Ehhadh), 3-ketoacyl-CoA thiolase 1(ACAA1), long-chain fatty-acid-coenzyme A ligase 1 (ACSL1), glucose-6-phosphate(G6P), PGC-1α and SOCS3) were found to be involved with glucose and lipid metabolism. Compared with those in the HFD group, the expression of PGC-1α and SOCS3 increased by 1.97 and 4.15 folds, while the expression of Ehhadh, ACAA1, ACSL1, G6P reduced to 0.35, 0.58, 0.52 and 0.33 folds, respectively. Quantitative real time PCR was used to confirm the results of partial genes, which was in accordance with the result of cDNA microarray analysis.

ZAG may significant improve the glucolipid metabolism in the obese mice. The beneficial action of ZAG may be associated with down-regulation of ACSL1 and G6P, up-regulation of PGC-1α and GYS2 expression in liver.

type B insulin resistance syndrome (TBIR) is a rare type of diabetes mellitus caused by the presence of specific insulin receptor antibodies in the circulation. Although the incidence of TBIR is extremely low, its mortality rate is high (>50%), and there is no standardized treatment protocol at present. This paper reports a case of TBIR with overlapping syndrome, which was treated with cyclophosphamide (CTX) and prednisone.

A 34-year-old woman was admitted to the hospital on 7 November 2012 due to "finding elevated blood sugar for 5 years and abnormal liver function for April". Five years ago, the patient's physical examination found that his blood glucose was significantly increased, and his fasting blood glucose was 20 mmol/L. He was hospitalized in our department and diagnosed with "type 2 diabetes". After discharge, he was given "insulin glargine 8 U subcutaneous injection before bed combined with metformin 0.5 g, 3 times/d" to control his blood glucose. Occasionally, blood glucose control was poor, and insulin glargine was gradually increased to 24 U. Four months ago, the outpatient review showed that serum alanine aminotransferase was 153 U/L and aspartate aminotransferase was 128 U/L. After intravenous infusion and oral "diammonium glycyrrhizinate" capsule for liver protection, there was no significant improvement. Reexamination of liver function 2 months ago showed alanine aminotransferase: 223 U/L, aspartate aminotransferase: 177 U/L, and glucose: 12.2 mmol/L, indicating aggravation of liver damage and poor blood sugar control, so he was admitted to the outpatient department. Previous history of "subclinical hypothyroidism" for 3 years, oral administration of "levothyroxine sodium 62.5 μ g, once/d"; "Cholecystectomy" 3 years ago; One year ago, he was diagnosed with polycystic ovary syndrome (PCOS) and underwent "bilateral mesangial cyst excision + bilateral ovarian perforation". Menstrual history: Menarche at the age of 14, 4 to 5 days, once every 28 to 30 days, last menstruation on October 7, 2012; Married but not pregnant. The mother suffered from "hypertension, type 2 diabetes".

Adult occult autoimmune diabetes mellitus (LADA) is a slow-progressing autoimmune diabetes mellitus with onset in adults. It belongs to a subtype of immune-mediated type 1 diabetes mellitus (T1DM), but its clinical characteristics are different from classical T1DM, and it is more intermediate between T1DM and type 2 diabetes mellitus (T2DM). Its early clinical manifestation is similar to T2DM, but it is characterized by slow autoimmune damage of islet cells, and the rate of islet function decline is 3 times that of T2DM^[1]。 Studies have shown that LADA accounts for 2% ~12% of newly diagnosed T2DM^[2], its main diagnostic criteria: diabetes diagnosis age ≥30 years; At least one islet autoantibody is positive in the body; Independence of insulin therapy within six months of diagnosis^[2]。

With the increase of age, the structure and function of human neuromuscular system undergo degenerative changes. In 1989, American scholar Rosenberg first named this skeletal muscle change after sarcopenia (hereinafter referred to as sarcopenia). Muscle mass and muscle function (muscle strength and mobility) are the two basic indicators for diagnosing sarcopenia. The evaluation of muscle mass includes CT, magnetic resonance imaging (MRI), dual energy X-ray (DEXA) and multi-frequency bioelectric impedance (BIA). In recent years, BIA technology has developed rapidly because of its simple operation, low time consumption, high repeatability and low price; Grip strength detector and pace detection are used to evaluate muscle strength and mobility respectively because of their low cost and high availability. The diagnostic criteria of the Asian Elderly Sarcopenia Working Group (AWGS) are presented inTable 1^[1]。

In 1986 Tervonen and Knuuttila suggested that diabetic patients were at risk of complications of periodontal disease^[1]Numerous studies have shown that diabetic patients have a higher risk of periodontal disease than non-diabetic patients^[2]whose level of glycemic control is associated with the severity of periodontal disease^[3]。 Statistics show that more than 3/4 of diabetic patients may be complicated with periodontal disease, and the high incidence of this periodontal disease has no obvious relationship with age, sex and oral hygiene status. This article reviews the pathogenesis, harm, prevention and treatment of diabetic periodontal disease.

Glucagon-like peptide 1 (GLP-1) receptor agonists (RA) are a new class of incretin-type hypoglycemic drugs that are administered by subcutaneous injection and can partially correct GLP-1 deficiency in patients with type 2 diabetes mellitus (T2DM), stimulate insulin secretion in a glucose concentration-dependent manner, reduce glucagon secretion, delay gastric emptying, increase satiety, and reduce food intake. These hypoglycemic drugs can improve fasting blood glucose (FPG) and postprandial blood glucose (PPG), and reduce glycosylated hemoglobin (HbA_1c) level. At the same time, because the hypoglycemic effect is dependent on blood sugar concentration, the risk of hypoglycemia is low. In addition, GLP-1RA can act on the central nervous system, suppress appetite, and be beneficial for weight loss.