Volume 07 · Issue 01 · 2015

A new year, a new start.

The mechanism of hypoglycemic agents is mainly based on two major pathophysiological alterations of type 2 diabetes mellitus (T2DM), namely impaired insulin secretion and insulin resistance, along with the possible presence of abnormal glucagon secretion. According to different mechanisms of action, oral hypoglycemic drugs are mainly divided into drugs that promote insulin secretion [such as sulfonylureas, glidenides and dipeptide kininase-IV (DPP-4) inhibitors] and other hypoglycemic drugs that do not promote insulin secretion [such as biguanides, thiazolidinediones (TZDs), alpha glycosidase inhibitors and sodium glucose cotransporter 2 (SGLT-2) inhibitors]. At present, the three most used drugs in China are metformin, sulfonylureas and alpha glycosidase inhibitors. Hypoglycemic drugs can prevent and treat microvascular complications of diabetes, but whether they are beneficial to prevent and treat macrovascular disease is still unclear. The following is an evaluation of several oral hypoglycemic drugs commonly used in China.

With the increasing variety of diabetes drugs, diabetic patients have more and more drug choices, and patients' treatment is more and more individualized. It is particularly gratifying that as the control rate of diabetes mellitus increases year by year, various complications show a significant downward trend^[1]。 However, due to the continuous increase in the prevalence of diabetes, the control rate of diabetes is far from ideal^[2]Therefore, it is necessary to further reveal the pathogenesis of diabetes and develop a series of hypoglycemic drugs with unique characteristics to meet the needs of different diabetic patients. This article mainly reviews the history of oral diabetes drug development, expounds the mechanism of action of hypoglycemic drugs, and emphasizes the new target hypoglycemic drugs that will be released soon.

Since Oskar Minkowski and others first discovered the relationship between pancreas and diabetes in 1889, the relationship between islet cells (islet of Langerhans) and diabetes has gradually become clear. In 1921, Frederick Banting, Charls Best, John Macleod and James Collip collaborated to purify bovine insulin, and in 1922, it successfully treated diabetic patients for the first time. The following year, Eli Lilly and Company began the quantitative production of high-purity bovine insulin and rapidly applied it to the treatment of diabetic patients worldwide. The rapid transformation of insulin from basic research to clinical application and the huge benefits it brings have always been a legend in medical history. In addition to Banting et al. winning the Nobel Prize in Physiology or Medicine in 1923, many landmark research discoveries in history are also related to insulin. For example, in 1958, British molecular biologist Frederick Sanger won the Nobel Prize in Chemistry for discovering the primary structure of insulin, and Rosalyn Sussman Yalow won the Nobel Prize in Physiology or Medicine in 1977 for developing radioimmunoassay to determine serum insulin. For more than 90 years, insulin has completely changed the quality of life of diabetic patients, especially those with type 1 diabetes (T1DM), and greatly prolonged the survival of patients.

Diabetes has become a major public health problem worldwide. Chronic complications of diabetes mellitus are the focus of diabetes prevention and control, and they are also important factors that affect the life expectancy and quality of life of patients. In recent years, people's understanding of the prevention and treatment of diabetes complications has improved, but the mechanism of diabetes is complex and related to many factors. Some diseases have similar mechanisms or "common soil" with diabetes. These diseases that occur at the same time or successively with diabetes have an impact on the treatment of diabetes and the treatment of complications, but they have not attracted enough attention from academic circles so far.

China's economy has developed rapidly in the past 30 years, but at the same time, the number of diabetes patients has increased rapidly. In the 1980s, the prevalence of diabetes in China was only 1.0%^[1]Increased to 5.5% in 2001^[2]Compared to 9.7% in 2008^[3]。 The reasons for this are sobering. In the prevention and treatment of diabetes, Chinese scholars have made arduous explorations and made their own contributions to the development of the international diabetes community.

In recent years, the contradiction between doctors and patients in China has become increasingly prominent. The reason is that the existing medical system has not formed a good hierarchical diagnosis and treatment system, and patients concentrate in large hospitals for treatment. Cumbersome registration, long waiting, short treatment, expensive medicine expenses, lack of doctor-patient communication, etc. are all direct causes of doctor-patient conflict. At present, the difficulty and complexity of implementing hierarchical diagnosis and treatment is the biggest challenge faced by China's medical reform (medical reform).

To understand whether independent relationships exist between elevated hepatic enzymes and insulin resistance, insulin secretion and type 2 diabetes in Chinese adult population.

Subjects in this study were participants in China National Diabetes and Metabolic Disorders Study, involving 16 035 residents aged ≥20 years (6 611 males and 9 424 females) from June 2007 to May 2008. All participants were measured for weight, height, waist circumference, oral glucose tolerance test, lipid profiles, and serum activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT). Indices for insulin resistance and insulin secretion were calculated. SUDAAN software was used to perform all weighted statistical analyses, with P<0.05 considered statistically significant.

The prevalence of pre-diabetes and diabetes increased with hepatic enzymes levels increasing (except diabetes not increasing with AST). The prevalence of diabetes from the lowest tertile to the highest tertile for ALT was 5.1%, 6.9% and 12.7%, respectively (P<0.001). With increasing of serum level of ALT and GGT from the lowest tertile to the highest tertile, the insulin resistance index tended to increase (1.3, 1.4 and 1.7,P<0.001) and the insulin sensitivity index tended to decrease (8.8, 7.9 and 6.7, all P trend<0.001). Hepatic enzymes were not related to indices for the insulin secretion. In separate logistic regression models adjusting for age, sex, alcohol consumption, BMI, and waist circumference, participants in the highest tertiles of ALT and GGT, but not AST, showed significantly higher odds ratio (OR) of pre-diabetes (1.69 (95%CI 1.27-2.26), 3.33 (2.00-5.53) for ALT and GGT, respectively) and diabetes (2.70 (1.87-3.90), 1.99 (1.05-3.77) for ALT and GGT, respectively) compared with those in the lowest tertiles.

Our findings indicate that markers of liver dysfunction, i.e ALT and GGT are independently associated with insulin resistance and presence of diabetes mellitus in Chinese population.

To investigate the prevalence of large genomic deletions and duplications in the hepatocyte nuclear factor 1β (HNF-1β) gene in patients presented with a clinical phenotype consistent with maturity onset diabetes of the young type 5 (MODY5) in Shanghai and nearby regions.

A total of 104 diabetic patients (74 males and 30 females, aged (65±14) years) with renal structural abnormalities and/or non-diabetic renal dysfunction were recruited from January 2003 to December 2006 inpatient database of Shanghai Diabetes Institute. Three patients carrying HNF-1β gene mutations were excluded from the study. One hundred and one patients without mutations were screened for large genomic deletions and duplications in the HNF-1β gene by multiplex ligation-dependent probe amplification (MLPA).

A heterozygous whole HNF-1β gene deletion was found in one patient who had renal cysts, renal dysplasia, uterus didelphys and pancreatic atrophy.

The prevalence of large genomic deletions in the HNF-1β gene in patients presented with a clinical phenotype consistent with MODY5 in shanghai and nearby regions is about 1%. Carriers of point mutations and the carrier of large genomic deletion have similar clinical features.

To evaluate the placebo effect of hypoglycemic treatment in Chinese type 2 diabetes patients.

The MEDLINE, EMBASE, CENTRAL databases were searched and qualified studies were included. All the studies were double blind, placebo-controlled randomized trials in Chinese type 2 diabetes patients; patients age≥18 years; duration of follow-up study ≥12 weeks with the efficacy evaluated by changes in glycated hemoglobin A_1c (HbA_1c) or fasting plasma glucose (FPG) from baseline in groups. References were collected until Dec. 2013. All statistical analyses were performed with the Review Manager statistical software package (Version 5.1). The Meta-analysis was performed by computing the weighted mean difference (WMD) for change from baseline to study endpoint.

Totally 14 qualified studies were included. In terms of HbA_1c change, treatment with placebo led to a significant HbA_1c reduction from baseline (WMD,-0.33%;95%CI: -0.41% to -0.25%). In terms of FPG, treatment with placebo led to a non-significant reduction from baseline (WMD, -0.04 mmol/L; 95%CI:-0.40 to 0.32 mmol/L). In terms of postprandial glucose (PPG), treatment with placebo led to a non-significant change from baseline (WMD, -0.32 mmol/L; 95%CI:-0.87 to 0.22 mmol/L). Moreover, treatment with placebo led to a non-significant weight change from baseline (WMD,-0.44 kg; 95%CI:-0.94 to 0.05 kg).

This Meta-analysis provided comprehensive clinical evidence on the placebo effect of hypoglycemic treatment in Chinese type 2 diabetes patients. Treatment with placebo led to a significant HbA_1c reduction from baseline of 0.33%, but non-significant FPG, PPG or weight reduction from baseline.

To explore the impact of initial dynamic blood glucose on the prognosis of critically ill patients in intensive care unit (ICU) in the first 24 hours.

Totally 104 critically ill patients were selected from March 2012 to March 2013. The dynamic blood glucose was monitored and acute physiology and chronic health evaluation (APACHE Ⅱ) scores were collected in the first 24 hours in ICU. Four subgroups were further divided by the results of hypoglycemia time windows, hyperglycemia time windows, euglycemia time windows and APACHE Ⅱ scores[G1 (P₀-P₂₅), G2 (P₂₅-P₅₀), G3 (P₅₀-P₇₅), G4 (P₇₅-P₁₀₀)]. Variance and Chi-square test were used to analyze and compare the changes of APACHE Ⅱ scores and rate of mortality.

The APACHE Ⅱ scores in death group (32.5±7.6) was significantly higher than that in survival group (19.9±6.5), the hypoglycemia time windows (2.29 (0-7.68) h) and hyperglycemia time windows (14.3 (3.36-24.00) h) in death group were significantly longer than those in the survival group (0.41 (0-2.88), 3.8 (0-12.96) h), and the euglycemia time windows (7.41 (0.24-17.52) h) in death group was significantly shorter than that in the survival group (19.79 (11.28-24.00) h,t=5.65, Z=-2.01,-3.01,-3.95, all P<0.05). Hyperglycemia time windows were positively correlated with APACHE Ⅱ scores, meanwhile, euglycemia time windows were found to be negatively correlated with APACHE Ⅱ scores (F=18.71, 32.20, both P<0.01). There was no significant difference in APACHE Ⅱ scores between patients developed hypoglycemia and did not (t=-1.3, P>0.05).

The euglycemia time windows is positively correlated with the prognosis of patients in ICU, and hyperglycemia time windows is negatively correlated with the prognosis of the patients. The initial dynamic blood glucose time window plays an important role in predicting the progress and prognosis of severe disease.

To explore the characteristics of β cell function in different glucose tolerance and the influence of body fat.

Cross sectional cluster random sampling investigation of the resident between 20-74 yrs in Urumuqi, north and south of Xinjiang Provience from March 2009 to March 2011. All the subjects used the standard 75 g oral glucose tolerance test (OGTT) and insulin releasing to define their β cell function. Normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG+IGT and type 2 diabetes mellitus (T2DM) were defined according to the WHO 1999 criteria.

(1) Compared with NGT group, HOMA-β (130±92, 90±79, 66±55, 68±47, 71±46; t=3.19-4.88, allP<0.01), AUC_ins/gluc30 (13±9, 12±7, 11±9, 10±7, 8±6; t=2.51-3.24, all P<0.01), AUC_ins/gluc120 (5.0±4.0, 4.6±4.2, 4.0±3.7, 3.9±2.9, 3.7±2.9; t=2.62-4.46, all P<0.01), DI₃₀ (10.1±5.6, 7.0±4.3, 5.2±3.9, 3.6±3.1, 2.2±2.1; t=2.76-3.64, all P<0.01) and DI₁₂₀ (3.1±3.0, 2.8±2.1, 1.8±1.5, 1.3±0.9, 1.2±1.0; t=2.71-9.22, all P< 0.01) were significantly decreased in IFG, IGT and T2DM groups. (2) Compared with NGT group, AUC_ins/gluc120 were increased with the increase of BMI (5.3±2.3, 6.2±2.3, 4.7±2.1, 4.1±2.0; t=-4.48--2.07, all P<0.05) in NGT, IFG, IGT and T2DM groups. (3) Multiple logistic regression analysis indicate that BMI is the related risk factor of HOMA-β (P=0.01) and AUC_ins/gluc120 (P<0.01).

With the progression of type 2 diabetes, the β cell function and its compromise with insulin resistance will decreased gradually. Body fat could have some influences on β cell function in different glucose tolerance state.

Adult-onset diabetes mellitus (MODY) in adolescents is an autosomal dominant monogenic genetic disease, which is mainly caused by glucose-stimulated insulin secretion dysfunction. β cell function often declines gradually with the prolongation of the disease course, and insulin resistance is not the cause of the disease^[1]。 The onset age of MODY is usually less than 25 years old, does not require insulin therapy at the beginning of the disease, and there is no autoimmunity. Thirteen MODY subtypes have been reported so far. Where MODY5 is caused by a hepatocyte nuclear factor 1 β (HNF-1 β) mutation. MODY5 is typically characterized by the presence of renal cysts and diabetes, also known as renal cysts and diabetes syndrome (RCAD syndrome)^[2,3]。 This paper reports a case of a young diabetic patient with multiple renal cysts and pancreatic dysplasia, and summarizes its clinical manifestations and diagnostic ideas.

250 years ago, sages described doctors prescribing drugs they were not familiar with, diagnosing conditions they didn't know much about, and judging human bodies they knew nothing about. One hundred years ago, William Osler, a medical educator and the father of modern medicine, pointed out the drawbacks of medical practice: the lack of historical insight, the break between science and humanity, and the alienation of technological progress and humanitarianism. These three problems still puzzle the development and reform of modern medicine and medical treatment^[1]。

Diabetic nephropathy is a common complication of diabetes. About 1/3 of diabetic patients are accompanied by renal function damage, which not only seriously affects the long-term prognosis of patients, but also brings a huge economic burden to patients. The pathogenesis of diabetic nephropathy is complex, and its treatment plan is still under further improvement. Incretins are a new class of hypoglycemic drugs used in clinic in recent years, mainly including glucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase IV (DPP-4) inhibitors. Clinical studies have shown that such drugs can not only effectively control blood sugar, but also reduce weight gain and the risk of hypoglycemia^[1]。 At the same time, clinical trials and animal studies have also found that incretin drugs have protective effects on diabetic nephropathy^[2,3]It provides new ideas for the treatment of diabetic nephropathy. This article reviews the research progress of incretin drugs in the treatment of diabetic nephropathy.

In June 2014, the American Diabetes Association (ADA) issued its first position statement specifically for type 1 diabetes (T1DM) (hereinafter referred to as the statement)^[1]。 Clinically, children are often considered to be the main key population for T1DM treatment. However, with the increase of the detection rate of new cases of T1DM [including adult latent immune diabetes mellitus (LADA)], the survival of children and adolescents with onset of disease is prolonged, and children and adolescents gradually transition to adulthood, resulting in an increase in the number of adult T1DM patients. In addition, all T1DM patients, including infants, children, young people and adults, need individualized treatment for their corresponding age groups due to their different growth stages, that is, the treatment of T1DM patients must be appropriately adjusted according to the needs of different age groups. This statement is intended to provide specific guidance for the management of patients with T1DM of all ages.

In clinical trials, randomized controlled trials are the gold standard for evaluating the merits and disadvantages of an intervention. Researchers will usually observe whether the results between different groups are statistically significant, but such comparisons sometimes do not directly reflect the patient's treatment outcome^[1]。 For example, in a diabetes clinical trial, the glycosylated hemoglobin (HbA) of patients in the intervention and control groups_1c) Reducing the degree of difference is statistically significant, but this does not mean that the treatment approach in the intervention group has clinical application value, because if HbA_1cIf the degree of reduction is limited, it may also fail to change the patient's outcome, that is, the patient's probability of developing diabetes-related complications is not reduced. In order to make clinical trial results simple and easy to understand, and at the same time acceptable to both doctors and patients, more than 20 years ago, Laupacis et al.^[2]The concept of number needed to treat (NNT) is proposed, which has been widely used so far. NNT refers to the number of cases that a clinician needs to treat in order to prevent an adverse event or to facilitate the occurrence of a favorable event in a patient over a certain period of time^[2,3]This concept skillfully solves the problem that most statistical indicators cannot directly reflect the treatment outcome, and the calculation is simple and easy to understand, which is favored by researchers. However, it is undeniable that in clinical trials, some researchers ignore the influencing factors in NNT calculation and the limitations of results interpretation^[4]Thus causing the deviation of the research conclusion. In order to make researchers understand the concept of NNT more comprehensively, this paper will explain the calculation method and clinical application of NNT in detail with examples in diabetes research.