Volume 06 · Issue 01 · 2014

The 2013 American Diabetes Society (ADA) Banting Award for Scientific Achievement was awarded to Professor Graeme Ian Bell, Professor of Medicine and Human Genetics and Director of the Diabetes Center at the University of Chicago, USA, in recognition of his outstanding contributions to the research of monogenic diabetes genetics. Professor Bell said: "Although genetics cannot cure diabetes, it can help lead to deeper and more reaching treatments for diabetes."

Neonatal diabetes mellitus^[1]It is a special type of diabetes caused by a single gene mutation. It usually refers to hyperglycemia within 6 months of birth. With the progress of molecular genetics research, in recent years, there are also reports that children with disease after 6 months of birth have been diagnosed with neonatal diabetes by genetic testing. According to the presence or absence of spontaneous remission in the course of the disease, it can be divided into transient neonatal diabetes mellitus (TNDM) and permanent neonatal diabetes mellitus (PNDM). About 45% of neonatal diabetes are TNDM, 45% are PNDM, and 10% occur as clinical syndromes or pancreatic agenesis^[2]。 The epidemiological data on neonatal diabetes are mainly from European and American countries, and the overall prevalence is about 1:160,000^[1]。 In 1986, the first case of neonatal diabetes was reported in China. As of 2010, there were 40 cases of neonatal diabetes related reports^[3]。

Adult-onset diabetes mellitus (MODY) in adolescents is a familial autosomal dominant type of diabetes mellitus. Typical cases usually develop before the age of 25 years, and are mainly related to primary insulin secretion defects. If the number of diabetes patients released by the latest epidemiological survey in China is 92.4 million to 119 million^[1,2]And the prevalence of MODY is 1% to 2%^[3]According to the calculation, the number of MODY in China has exceeded 1 million, which means that today, when MODY diagnosis and typing can only be determined through DNA testing, millions of Chinese MODY patients have not yet received individualized treatment depending on genetic diagnosis results, and their family relatives are also exposed to an increasing risk of diabetes because they don't get correct genetic information. Therefore, the situation of MODY prevention and control is very severe.

Since the first incretin drug in the world was launched in 2005, the research and clinical application of such drugs have developed rapidly. At present, two kinds of glucagon-like peptide 1 (GLP-1) receptor agonists and five kinds of dipeptidyl peptidase IV (DPP-4) inhibitors have been marketed in China. In order to facilitate users to comprehensively and quickly understand the basic knowledge of such drugs and the clinical research and application in China, the Diabetes Branch of Chinese Medical Association reached the following consensus.

To investigate the clinical characteristics, cause of disease on Chinese maturity-onset diabetes of the young type 2 (MODY2).

Four Chinese pedigrees of MODY2 diagnosed by Peking Union Medical College Hospital from February to August in 2013 were analyzed for their clinical features and laboratory data. Genomic DNA of related members in the pedigrees were extracted, followed by amplification with polymerase chain reaction. Then direct sequencing were performed to identify mutations in glucokinase (GCK) gene.

Totally 10 cases of diabetes and impaired glucose regulation (IGR) caused by GCK mutations were diagnosed in four pedigrees. Age at diagnosis for hyperglycemia was between 5.3 and 44.0 years. Health examination was the most common way to find hyperglycemia. All cases' plasma triglyceride were in the normal range or below the lower limit. Genetic testing for GCK gene found four mutations, two new heterozygous mutation c. 749G>A(R250H) and c. 781G>C(G261R), two previously reported mutation c. 127C>T(R43C) and c. 571C>T(R191W).

Clinical manifestations are various in Chinese MODY2 patients. GCK gene c. 749G>A mutation may be the cause of MODY2.

To determine the genetic basis of maturity-onset diabetes of the young in a Chinese pedigree.

A 32 years old female patient was noticed that there were two generations of the family with diabetes. The pathogenic gene in the proband was identified by target area capture deep sequencing, and then was verified and screened the genetic mutation in the proband and other family members by Sanger sequencing.

A new heterozygous frameshift mutation in hepatocyte nuclear factor-1α(HFN-1α) located in the exon 6 (c.1130-1131insC; p. V380Cfs*39) was identified. The mutation was co-segregated with diabetes.

A novel HNF-1α genetic mutation in a Chinese pedigree with MODY3 is found.

To investigate the contributions of preprandial and postprandial glucose to glycosylated hemoglobin A1c (HbA1c) levels and their correlations in type 2 diabetic patients treated with different drugs.

A total of 256 patients with type 2 diabetes (T2DM) with diabetes duration longer than one year and relative fixed treatments were enrolled, which includes 119 males and 137 females.Among them, the average age was (54±14) years, average diabetes duration was 4.5 years, average fasting glucose was 9.6 mmol/L, average HbA1c was 8.4%.The patients were divided into three groups: oral drug treatment group, basal insulin treatment group and premixed insulin treatment group.Each group was then subdivided according to HbA1c levels: <7% group, 7%≤&<8% group, 8%≤&<9% group, ≥9% group.The average of seven-point blood glucose from self-monitored blood glucose (SMBG) from three non-consecutive days was calculated and plotted on glucose-time graph.Meanwhile HbA1c was measured with immunoassay and the correlation between seven-point blood glucose and HbA1c levels was evaluated using Pearson's correlation analysis.On the glucose-time curse, a curve was drawn to connect the three points representing preprandial glucose and the one point representing bedtime glucose.The area between this curve and the horizontal line at 5.6 mmol/L was calculated as the preprandial glucose volume.Another curve (postprandial) was also drawn to connect the three points representing postprandial glucose and the area between preprandial curve and postprandial curve was calculated as postprandial glucose volume.The contribution of pre- and post-prandial glucose to HbA1c was determined by the ratio of pre- and post-prandial glucose volume over total glucose volume (pre- and post-prandial glucose volume together).

There were significant correlation between HbA1c levels and seven-point self-monitored blood glucose (r=0.38 to 0.76, all P<0.05), and the mean of all seven-point blood glucose had the highest correlation with HbA1c in all treatment groups (r≥0.71, P<0.05). The contribution of pre and post prandial glucose to HbA1c was 59%- 82%, 18%- 41% in oral drug treatment group, 60%- 82%, 18%- 40% in basal insulin treatment group and 38%- 66%, 34%- 62% in pre-mixed insulin treatment group.Tendency analysis showed that the relative contribution of preprandial hyperglycemia increased gradually with increasing values of HbA1c in diabetic patients treated with oral drug and basal insulin and premixed insulin(F=67.46, 168.51, 84.05, P<0.05), but the relative contribution of postprandial hyperglycemia showed a gradual decrease with increasing values of HbA1c.The relative contribution of preprandial hyperglycemia was lower in patients treated with basal insulin than treated with premixed insulin and oral antidiabetic drug(<7% group: 38% vs 66%, 8%≤&<9% group: 63% vs 77%, ≥9% group: 66% vs 82%,χ²=5.94, 5.88, 5.51, all P<0.05).

There are correlations between HbA1c levels and self-monitored blood glucose testing at various times of the day.Glycemic control and the form of treatment on T2DM patients change the relative contribution of preprandial versus postprandial glucose to HbA1C levels.

To evaluate the effects of intraperitoneal transplantation of encapsulated adult pit islets on blood glucose of diabetic mice.

Pancreata were digested with collagenase P using Ricordi chamber and purified with discontinued density gradient centrifugation and subsequently cultured.Islets were encapsulated using alginate-polylysine polymers.The quantity and purity of islets was determined by manual and counter machine after dithizone (DTZ) staining.Glucose stimulated insulin secretion test was performed to test the function of purified islets and encapsulated islets in vitro.BALB/c mice were intraperitoneal injected with streptozocin (STZ) 200 mg/kg body weight to induce type 1 diabetes model.Diabetic mice were randomly divided into 3 groups: encapsulated pig islet group, empty capsule group and saline control group.Encapsulated capsules (equivilent to 500 pig islets), empty caplules and normal saline were respectively transplanted into peritoneal cavity of three groups.The blood glucose of all the mice were regularly monitored before and after transplantation.

After purification of discontinued density gradient centrifugation, the mean purity of the islets was more than 90%.The viability of the islets was more than 90% by propidium iodide (PI) and fluorescein diacetate (FDA) staining.Glucose-stimulated insulin secretion (GSIS) of purified islet and encapsulated islet was more than 2.0 in vitro.In vivo, after transplantation, encapsulated pig islets group had a significantly improved survival and biochemical profile, compared to mice transplanted with empty capsule group and saline control group.Blood glucose of encapsulated pig islets group significantly reduced more than 60 days (<9.3 mmol/L), Duration time of normal blood glucose in encapsulated pig islets group was significantly longer, compared with empty capsules group and saline control group (F=13.587, P<0.05). The pathologic structure of encapsulated islets was normal, which of insulin staining was positive.

Encapsulated pig islet transplantation exerts good effects of reduction of blood glucose on diabetic mice and the capsules have good immuno-isolating function.

An animal model for type 2 diabetes mellitus(T2DM) was developed for studying improvment of anigotensinⅡ receptor blocker on insulin resistance(IR) and influence on insulin receptor substrate 1(IRS1)and Akt phosphorylation of phosphatidylinositol 3-kinase(PI3K)pathway and translocation of glucose transporter-4(GLUT4).

Twenty of 42 male SD rats were randomly fed with high-fat/high-sugar diet and treated with Streptozotozin for type 2 diabetic model and other 20 for normal control group fed with standard diet. Rats with FPG≥7.8 mmol/L accompanied by IR were considered as T2DM models. Rats were randomly divided into control group A, control treated group B, T2DM control group C and T2DM treated group D(n=10 in each group), rats in group B and D were treated with losartan.Six weeks later, blood samples were measured to calculate ISI( insulin-sensitivity index). Skeletal muscles were removed from hind legs and stored. Expressions of IRS1/P^tyr-IRS1, Akt/P^ser473-Akt and GLUT4 protein detected by Immunohistochemistry(IHC) and Western bloting.

(1) Models of T2DM rats were successfully induced. Compared with group A and B, expressions of P^tyr-IRS1, P^ser473-Akt in group C and D by IHC and expressions of P^tyr-IRS1 and membrane GLUT4 by Western bloting reduced significantly(P<0.05). (2)The value of FPG(mmol/L), FINS (μU/Ml) of T2DM rats decreased in Group D (18.8±4.1, 27±5)compared with group C(19.7±3.7, 27±6), while ISI increased(D group -6.18±0.08, C group -6.18±0.08,P<0.05), the expression of P^tyr-IRS1 increased(P<0.05)(IHC), expression of membrane GLUT4 and P^tyr-IRS1 increased(P<0.05)(Western bloting), there was no difference of P^ser473-Akt expression in both ways.

Losartan can increase the translocation of GLUT4 in muscle tissues to improve IR status of T2DM rats.

Insulin receptoropathies' main defect is at the level of insulin receptor, including insulin receptor autoimmune disease and insulin receptor genetic disorder, characterized with extreme insulin resistance and disordered glucose metabolism. Here we reported two cases of Insulin receptoropathies' clinical features, and reviewed the literatures. And the two forms of insulin receptoropathies typically present as follows: (1)extreme insulin resistance and heterogeneous glucose profile(especially paradoxical hypoglycaemia); (2) acanthosis nigricans, and hyperandrogenism in girls (hirsutism, oligo-/amenorrhoea and polycystic ovaries); (3) often presented with low level of triglyceride and serum leptin, elevated serum adiponectin ; (4) other autoimmune disorders are common in insulin receptor autoimmune disease.

Clinical data of one patient with Wolfram syndrome were collected and eight exons of WFS1 gene were screened in this patient by using polymerase chain reaction (PCR)-DNA direct sequencing.A thirty-four aged female patient complained deafness for 15 years before admitted on May 10, 2012.Seven years after deafness, she found she had thirst, polydipsia, polyphagia and polyuria and the glutamic acid decarboxylase antibody (GADA), anti-insulin antibody (IAA) were tested positive.She had impaired vision one year before admission and ophthalmic testing showed optic atrophy.Ultrasound revealed urinary tract injury.But this case didn't have diabetes insipidus at admission.Mutations of V333I and A611V, in the WFS1 gene were identified.The two homozygous mutation were in exon 8 of WFS1 gene in the patient.Wolfram syndrome usually presents type 1 diabetes as the first symptom.But the first symptom of this patient is deafness, which can easily lead to misdiagnosis.So if a patient have one of the symptoms of diabetes insipidus, type 1 diabetes, optic atrophy or deafness, wolfram syndrome should be considered.The mutation of WFS1 gene in this study is the first report of Wolfram syndrome with the mutation of V333I in the WFSl gene in a Chinese patient, but it needs to be confirmed by further research.

The 17th National Academic Conference of CDS (CDS2013 Annual Conference) sponsored by Chinese Medical Association and Diabetology Branch of Chinese Medical Association (CDS) was held at the Strait International Convention and Exhibition Center in Fuzhou, Fujian Province from November 20 to 23, 2013. This conference is the most important academic activity of CDS every year, and it is also the year-end climax of the academic activities of Chinese Medical Association. 6,438 registered representatives from 31 provinces, municipalities and autonomous regions in China attended the conference. In addition, more than 10 experts from Sweden, Britain, the United States, Italy, Israel and other countries were specially invited to attend the conference.

Recent Diabetes Guidelines^[1,2]All emphasize the treatment concept of "patient-centered" or "individualized management", that is, it is required to formulate corresponding blood sugar management strategies according to the characteristics of diabetic patients themselves, such as age, blood sugar control, weight, disease course, concomitant diseases, complications and history of hypoglycemia, so as to better improve the quality of life of patients and improve the prognosis of diseases. Basal insulin is an important part of the treatment plan of diabetic patients, especially for the management of fasting blood glucose. Currently commonly used basal insulins include low protamine zinc human insulin (NPH), insulin glargine and insulin detemir. In addition to effective glucose control by injection once a day, the advantages of small intra-individual variability, low risk of hypoglycemia and reduced weight gain enable insulin detemir to fully cover the diabetic population and meet the needs of individualized treatment to a greater extent.

Insulin therapy is a necessary treatment for achieving good glycemic control in patients with type 1 diabetes and type 2 diabetes who have failed oral medication^[1,2]。 However, due to the misunderstanding of diabetic patients about insulin therapy, lack of confidence in independent injection, worry about the occurrence of hypoglycemia, fear of injection pain and other reasons, the timing of starting insulin therapy is delayed, thus affecting the effect of insulin therapy^[3]。 At the same time, among the patients who are receiving insulin therapy, many patients have not achieved satisfactory results. The results of a cross-sectional study by the Diabetes Branch of the Chinese Medical Association showed that less than 30% of patients with insulin treatment achieved blood sugar control standards^[4]。 Previous studies have shown that poor treatment compliance of patients is the main obstacle to insulin therapy^[5,6]。 1/3 of patients have not received insulin on time for at least one day in the past month^[6]。 The majority of patients did not deliberately miss or fail to inject insulin on time^[7]。 Patients and medical staff surveyed said that in the process of insulin treatment, due to busy work, disrupted rhythm of life, irregular meals, mental stress and other reasons, patients generally forget to inject insulin easily, or are unsure whether they have injected insulin, or do not remember the last injected dose and other memory problems. Such problems seriously affect patients' compliance with insulin therapy, lead to poor blood sugar control, increase the risk of complications, bring heavy economic and psychological burden to diabetic patients, and bring challenges to diabetes management.

With the progress of urbanization and aging in China and the improvement of people's living standards, the field of diabetes treatment in China is facing severe challenges. Sitagliptin, as the first marketed dipeptidyl peptidase IV (DPP-4) inhibitor, can improve glycemic control in patients with type 2 diabetes by increasing active incretin levels. A large amount of evidence-based medical evidence accumulated in the seven years of marketing shows that sitagliptin has a similar hypoglycemic efficacy to existing hypoglycemic drugs. At the same time, it has a low risk of hypoglycemia, does not gain weight, has potential cardiovascular and microvascular clinical benefits, and meets the clinical needs of type 2 diabetes patients.

Reduced blood supply, neuropathy and weakened expression of growth factors seriously affect diabetic wound healing. The angiogenic neuropeptide secretoneurin has been shown on different animal models to improve tissue perfusion by increasing the number of blood vessels in the wound area. Topical secretoneurin gene therapy was validated on full-thickness injured wounds in db/db diabetic mice. Recent studies have found that secretoneurin gene therapy also improves left ventricular function in rat models of myocardial infarction, and the positive effect on cardiac function is mainly due to the increase in the number of capillaries in the border zone of infarcted tissue. Since damaged skin microvessels are one of the major risks of wound healing disorders in diabetic patients, it is hypothesized that topical secretoneurin gene therapy may have a positive effect on wound healing in a mouse model of type 2 diabetes.

As a serious complication of diabetes, diabetic foot brings great troubles to patients and their families, and seriously affects the quality of life of patients. It is of great clinical significance to investigate the influencing factors of health-related poor quality of life caused by diabetic foot ulcer and the relative importance of these factors.

I am interested in this article by Margolis et al. (Diabetes Care, 2013, 36:1961-1966.), but suspect that their conclusion is that "the effectiveness of hyperbaric oxygen (HBO) in the treatment of diabetic foot ulcers needs to be re-evaluated". First of all, statistical processing cannot change important issues in study design. The study used propensity score matching (PSM) to balance the observed variables between the treatment and control groups, thereby reducing bias. Factors affecting treatment group allocation were not included in the observation (e.g. economic profitability, physician propensity, lack of vascular surgical intervention, etc.), which is a controversial approach and may increase hidden bias.

The article by Margolis et al. (Diabetes Care, 2013, 36:1961-1966.) surprised me because many previous multicenter randomized controlled trials as well as separate experiments have shown that hyperbaric oxygen therapy (HBOT) is effective for diabetic foot ulcers. After reading through the article, I believe that the author of this article made a mistake in statistics so that the results were not credible, and the results did not confirm the correctness of the title.