Role of premixed insulin analogues in the treatment of patients with type 2 diabetes mellitus: A narrative review (预混胰岛素类似物在2型糖尿病治疗中的作用：叙述性综述)

Because of the progressive nature of type 2 diabetes mellitus (T2DM), insulin therapy will eventually become necessary in most patients. Recent evidence suggests that maintaining optimal glycemic control by early insulin therapy can reduce the risk of microvascular and macrovascular complications in patients with T2DM. The present review focuses on relevant clinical evidence supporting the use of premixed insulin analogues in T2DM when intensifying therapy, and as starter insulins in insulin‐naïve patients. Our aim is to provide relevant facts and clinical evidence useful in the decision‐making process of treatment selection and individualized treatment goal setting to obtain sustained blood glucose control.     

Current role of short‐term intensive insulin strategies in newly diagnosed type 2 diabetes (短期胰岛素强化治疗策略对初诊2型糖尿病患者的作用)

Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by worsening insulin resistance and a decline in β‐cell function. Achieving good glycemic control becomes more challenging as β‐cell function continues to deteriorate throughout the disease process. The traditional management paradigm emphasizes a stepwise approach, and insulin has generally been reserved as a final armament. However, mounting evidence indicates that short‐term intensive insulin therapy used in the early stages of type 2 diabetes could improve β‐cell function, resulting in better glucose control and more extended glycemic remission than oral antidiabetic agents. Improvements in insulin sensitivity and lipid profile were also seen after the early initiation of short‐term intensive insulin therapy. Thus, administering short‐term intensive insulin therapy to patients with newly diagnosed T2DM has the potential to delay the natural process of this disease, and should be considered when clinicians initiate treatment. Although the early use of insulin is advocated by some guidelines, the optimal time to initiate insulin therapy is not clearly defined or easily recognized, and a pragmatic approach is lacking. Herein we summarize the current understanding of early intensive insulin therapy in patients with newly diagnosed T2DM, focusing on its clinical benefit and problems, as well as possible biological mechanisms of action, and discuss our perspective.     

Intracellular and extracellular adenosine triphosphate in regulation of insulin secretion from pancreatic β cells (细胞内外三磷酸腺苷对胰岛β细胞胰岛素分泌的调控作用)

Adenosine triphosphate (ATP) synthesis and release in mitochondria play critical roles in regulating insulin secretion in pancreatic β cells. Mitochondrial dysfunction is mainly characterized by a decrease in ATP production, which is a central event in the progression of pancreatic β cell dysfunction and diabetes. ATP has been demonstrated to regulate insulin secretion via several pathways: (i) Intracellular ATP directly closes ATP‐sensitive potassium channel to open L‐type calcium channel, leading to an increase in free cytosolic calcium levels and exocytosis of insulin granules; (ii) A decrease in ATP production is always associated with an increase in production of reactive oxygen species, which exerts deleterious effects on pancreatic β cell survival and insulin secretion; and (iii) ATP can be co‐secreted with insulin from pancreatic β cells, and the released ATP functions as an autocrine signal to modulate insulin secretory process via P2 receptors on the cell membrane. In this review, the recent findings regarding the role and mechanism of ATP synthesis and release in regulation of insulin secretion from pancreatic β cells will be summarized and discussed.     

Type 2 diabetes mellitus‐related genetic polymorphisms in microRNAs and microRNA target sites (MicroRNAs中与2型糖尿病相关的基因多态性及microRNA靶位)

MicroRNAs (miRNAs) are important endogenous regulators in eukaryotic gene expression and a broad range of biological processes. MiRNA‐related genetic variations have been proved to be associated with human diseases, such as type 2 diabetes mellitus (T2DM). Polymorphisms in miRNA genes (primary miRNAs, precursor miRNAs, mature miRNAs, and miRNA regulatory regions) may be involved in the development of T2DM by changing the expression and structure of miRNAs and target gene expression. Genetic polymorphisms of the 3′‐untranslated region (UTR) in miRNA target genes may destroy putative miRNA binding sites or create new miRNA binding sites, which affects the binding of UTRs with miRNAs, finally resulting in susceptibility to and development of T2DM. Therefore, focusing on studies into genetic polymorphisms in miRNAs or miRNA binding sites will help our understanding of the pathophysiology of T2DM development and lead to better health management. Herein, we review the association of genetic polymorphisms in miRNA and miRNA targets genes with T2DM development.     

Omeprazole improves the anti‐obesity and antidiabetic effects of exendin‐4 in db/db mice (奥美拉唑改善唾液素‐4 对db/db小鼠的减肥与降糖作用)*

Background: In addition to its glucoregulatory actions, exendin‐4, a stable glucagon‐like peptide‐1 receptor agonist, exhibits protective effects in the pancreas and anti‐obesity effects. Suitable combination treatment with other anti‐obesity or pancreas protective agents would be an effective approach to optimize these additional effects. In the present study, we investigated the effects of the addition of omeprazole, a proton pump inhibitor, to exendin‐4 in db/db mice, an experimental model of obesity and type 2 diabetes. Methods: The effects repeated dose treatment for 14 days with exendin‐4 (8 μg/kg, s.c.) and omeprazole (30 mg/kg, s.c.) on glycemic control, food intake, and body weight were determined in obese and hyperglycemic db/db mice. The effects of these treatments on plasma gastrin, ghrelin, and leptin levels were determined, along with effects on nausea‐like symptoms. The pancreatic effects of the repeated dose treatment were assessed by measuring %HbA1c in the circulation as well as pancreatic insulin and glucagon content and glucokinase activity. Results: Combination treatment resulted in significant decreases in plasma leptin and ghrelin levels after repeated dosing. Omeprazole improved the anorectic and body weight‐lowering effects and reversed the inhibitory effect of exendin‐4 on gastrin levels after repeated dose treatment. The 14‐day combination treatment significantly reduced glucose excursion and improved insulin levels, with a concomitant decrease in %HbA1c levels. It also improved glucokinase activity and pancreatic insulin content, with a significant decrease in glucagon content. Conclusions: Combined treatment with omeprazole with exendin‐4 reduces food intake and body weight gain, most likely through changes in plasma ghrelin and leptin levels, and improves pancreatic insulin and glucagon content by improving glucokinase activity.     

FoxO6 in glucose metabolism (FoxO6在葡萄糖代谢中的作用)

The forkhead box O (FoxO) subfamily has four members, namely FoxO1, FoxO3, FoxO4, and FoxO6. Unlike the other three members of the FoxO family, FoxO6 has garnered considerably less attention because of earlier reports that FoxO6 expression was limited to the brain. Recent data indicate that FoxO6 is produced in the liver of both rodents and humans. Hepatic FoxO6 activity, which remains at low basal levels in fed states, is markedly induced in fasted mice. FoxO6 activity becomes abnormally higher in the liver of mice with dietary obesity or type 2 diabetes (T2D). Genetically engineered mice with elevated FoxO6 activity in the liver exhibit prediabetes, culminating in the development of glucose intolerance, fasting hyperglycemia, and hyperinsulinemia. Conversely, inhibition of FoxO6 activity in the insulin‐resistant liver results in a reduction in fasting hyperglycemia, contributing to the amelioration of hyperinsulinemia in T2D mice. These new data suggest that FoxO6 is an important regulator of hepatic glucose metabolism in response to insulin or physiological cues. Insulin inhibits FoxO6 activity by promoting its phosphorylation and disabling its activity in the nucleus without altering its subcellular distribution via a mechanism that is distinct from other members of the FoxO subfamily. In this article, we comprehensively review the role of FoxO6 in glucose metabolism in health and disease. We also address whether FoxO6 dysregulation is a contributing factor for the pathogenesis of fasting hyperglycemia and discuss whether FoxO6 is a potential therapeutic target for improving fasting hyperglycemia in T2D.     

Glucagon‐like peptide 1‐potentiated insulin secretion and proliferation of pancreatic β‐cells GLP‐1促进胰岛素分泌和胰岛β细胞增殖的机制

Glucagon‐like peptide‐1 (GLP‐1) is the primary incretin hormone secreted from the intestine upon uptake of food to stimulate insulin secretion from pancreatic β‐cells. GLP‐1 exerts its effects by binding to its G‐protein coupled receptors and subsequently activating adenylate cyclase, leading to generation of cyclic adenosine monophosphate (cAMP). cAMP stimulates insulin secretion via activation of its effectors PKA and Epac2 in pancreatic β‐cells. In addition to its insulinotropic effects, GLP‐1 also preserves pancreatic β‐cell mass by stimulating β‐cell proliferation. Unlike the action of sulphonylureas in lowering blood glucose levels, action of GLP‐1 is affected by and interplays with glucose levels. Due to such advantages, GLP‐1‐based therapeutics have been rapidly developed and used clinically for treatment of type 2 diabetes. However, molecular mechanisms underlying how GLP‐1 potentiates diminished glucose‐stimulated insulin secretion and β‐cell proliferation under diabetic conditions are not well understood. Here, we review the actions of GLP‐1 in regulation of insulin secretion and pancreatic β‐cell proliferation.     

Empagliflozin for the treatment of type 2 diabetes mellitus: An overview of safety and efficacy based on Phase 3 trials 艾格列净治疗2型糖尿病：基于3期试验的安全性与有效性概述

In the treatment of type 2 diabetes mellitus (T2DM), a relatively new class of oral agents inhibits sodium–glucose cotransporter 2 (SGLT2), reducing reabsorption of filtered glucose and increasing urinary glucose excretion. Numerous SGLT2 inhibitors have been approved for the treatment of T2DM in adults, most recently empagliflozin, which was approved in Europe and the US in 2014. The Phase 3 program has enrolled >14 000 patients and has assessed the efficacy and safety of empagliflozin as monotherapy and in combination. These studies have demonstrated improvements in glycemic control, and modest reductions in body weight and blood pressure. Empagliflozin was generally well tolerated, with no increased risk of hypoglycemia versus placebo as monotherapy or as add‐on therapy, except when given with sulfonylurea. The studies showed an increased risk of urinary tract and genital infections with empagliflozin, although most infections were mild to moderate in intensity. Furthermore, small (but clinically insignificant) increases in hematocrit and lipid levels have been observed for empagliflozin. Due to the mode of action of empagliflozin, care should be exercised when treating patients at risk of volume depletion. The risks and benefits must be weighed for each patient, but the data reviewed herein show promise for empagliflozin as a treatment for patients with T2DM.     

Diabetes and cancer relationships (糖尿病与肿瘤的关联性)

Diabetes and cancer are both heterogeneous and multifactorial diseases with tremendous impact on health worldwide. Epidemiologic evidence suggests that certain malignancies may be associated with diabetes, as well as with diabetes risk factors and, perhaps, with certain diabetes treatments. Numerous biological mechanisms could account for these relationships. Insulin‐like growth factor (IGF)‐1, IGF‐2, IGF‐1 receptors, insulin, and the insulin receptor play roles in the development and progression of cancers. Although evidence from randomized controlled trials does not support or refute associations of diabetes and its treatments with either increased or reduced risk of cancer incidence or prognosis, consideration of malignancy incidence rates and the magnitude of the trials that would be required to address these issues explains why such studies may not be readily undertaken.     

Role of prostaglandin D2 and the autonomic nervous system in niacin‐induced flushing (前列腺素D2与自主神经系统在烟酸引起的脸红中的作用)

Background: Although niacin often has beneficial effects on the lipoprotein profile, flushing is an untoward effect associated with its use. Aspirin can only reduce the flushing response by 30–40%. Thus, the aim of the present study was to investigate the mechanisms of niacin‐induced flushing, with and without aspirin, in normal, healthy individuals. Methods: Niacin‐induced flushing was evaluated in 30 healthy individuals after oral administration of 1000 mg niacin alone or with 325 mg aspirin. Neurological, autonomic nervous system, and skin blood flow measurements (using laser Doppler on the glabrous and hairy skin of each participant) were made at various times after drug administration. In addition, the systemic release of 9α,11β‐prostaglandin (PG) F₂ was determined. Flushing symptoms of redness, warmth, tingling, itching, and intensity were recorded using the modified Flushing ASsessment Tool (FAST). Results: After aspirin, the mean flushing scores for all symptoms decreased significantly; however, 36–53% of participants still had some degree of symptoms, even though aspirin completely blocked 11β‐PGF₂ synthesis. Maximum skin blood flow (MaxSkBF) in both the glabrous and hairy forearm increased significantly after niacin, but decreased significantly after aspirin only in hairy skin. Regression analysis showed that, in glabrous skin, both PGF₂ and parasympathetic activity were significant predictors of MaxSkBF after niacin, contributing 26% and 14%, respectively (total R² = 40%). Conclusions: The present study indicates, for the first time, that the parasympathetic nervous system, in addition to PGD₂, may play an important role in niacin‐induced flushing. Changing the sympathetic/parasympathetic balance in favor of parasympathetic activation may be a good therapeutic target to reduce niacin‐induced flushing.     

Diabetic cystopathy: A review 综述：糖尿病性膀胱病

Herein we review and discuss epidemiological, clinical, and experimental studies on diabetic cystopathy, a common chronic complication of diabetes mellitus with a variety of lower urinary tract symptoms, providing directions for future research. A search of published epidemiological, clinical, or preclinical trial literature was performed using the key words “diabetes”, “diabetic cystopathy”, “diabetic bladder dysfunction”, “diabetic lower urinary tract dysfunction”, “diabetic detrusor instability”. The classic symptoms of diabetic cystopathy are decreased bladder sensation, increased bladder capacity, and impaired bladder emptying with resultant increased post‐void residual volume. However, recent clinical evidence indicates a presence of storage symptoms, such as overactive bladder symptoms. The pathophysiology of diabetic cystopathy is multifactorial, including disturbances of the detrusor, neuron, urothelium, and urethra. Hyperglycemia, oxidative stress, and polyuria play important roles in inducing voiding dysfunction in diabetic individuals. Treatment choice depends on clinical symptoms and urodynamic abnormalities. Urodynamic evaluation is the cornerstone of diagnosis and determines management strategies. Diabetes mellitus could cause a variety of lower urinary tract symptoms, leading to diabetic cystopathy with broadly varied estimates of the prevalence rates. The exact prevalence and pathogenesis of diabetic cystopathy remains to be further investigated and studied in multicenter, large‐scaled, or randomized basic and clinical trials, and a validated and standardized workup needs to be made, improving diabetic cystopathy management in clinical practice. Further studies involving only female diabetics are recommended.     

Who needs an artificial pancreas? (怎样的患者需要一个人工胰腺？)

The development of a closed‐loop “artificial pancreas” would be a welcome advance for both endocrinologists and diabetic patients struggling to attain near normal glycemic control. While great strides in automatically controlling blood sugar in the fasting, sedentary state have been made through complex mathematical modeling, management of blood sugar excursions due to food and exercise have been more problematic. An artificial pancreas is not feasible at this time because of limitations inherent in the currently available technology.     

Antioxidant potential of zinc–flavonol complex studied in streptozotocin‐diabetic rats (锌黄酮醇复合物在链脲霉素‐糖尿病大鼠中的抗氧化作用)

Background: Diabetic oxidative stress coexists with a reduction in the antioxidant status, which can further increase the deleterious effects of free radicals. Zinc is an essential trace element with significant antidiabetic activity. However, the acceptance of zinc compounds as promising therapeutic antidiabetic agents has been slowed due to concerns regarding chronic toxicity. Recently, we have designed, synthesized and characterized a novel zinc–flavonol complex and evaluated its antidiabetic efficacy in streptozotocin (STZ)‐diabetic rats. The aim of the present study was to evaluate the role of the zinc–flavonol complex in the antioxidant status of diabetic rats. Methods: Diabetes was induced in rats by i.p. injection of STZ. Diabetic rats were then treated with the zinc–flavonol complex (5 mg/kg, p.o.) for 30 days. The extent of oxidative stress was assessed by determining lipid peroxide levels, pancreatic tissue antioxidant enzyme activities and plasma concentrations of non‐enzymatic antioxidants. In addition, nuclear levels of nuclear factor (NF)‐κB p65, pancreatic nitric oxide (NO), and plasma levels of tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β and IL‐6 were determined. Pancreatic tissues were examined histologically. Results: Oral treatment with the zinc–flavonol complex significantly improved antioxidant levels and alleviated levels of oxidative stress markers. Furthermore, significant increases were seen in NF‐κB p65, NO, TNF‐α, IL‐1β and IL‐6 levels. Histological observations revealed that the zinc–flavonol complex effectively protects pancreatic β‐cells against oxidative damage. Conclusion: The results of the present study indicate that the zinc–flavonol complex has an antioxidative and anti‐inflammatory role in the diabetic milieu.     

Continuous spectrum of glucose dysmetabolism due to the KCNJ11 gene mutation—Case reports and review of the literature

The KCNJ11 gene encodes the Kir6.2 subunit of the adenosine triphosphate‐sensitive potassium (K_ATP) channel, which plays a key role in insulin secretion. Monogenic diseases caused by KCNJ11 gene mutation are rare and easily misdiagnosed. It has been shown that mutations in the KCNJ11 gene are associated with neonatal diabetes mellitus (NDM), maturity‐onset diabetes of the young 13 (MODY13), type 2 diabetes mellitus (T2DM), and hyperinsulinemic hypoglycemia. We report four patients with KCNJ11 gene mutations and provide a systematic review of the literature. A boy with diabetes onset at the age of 1 month was misdiagnosed as type 1 diabetes mellitus (T1DM) for 12 years and received insulin therapy continuously, resulting in poor glycemic control. He was diagnosed as NDM with KCNJ11 E322K gene mutation, and glibenclamide was given to replace exogenous insulin. The successful transfer time was 4 months, much longer than the previous unsuccessful standard of 4 weeks. The other three patients were two sisters and their mother; the younger sister was misdiagnosed with T1DM at 13 years old, while the elder sister was diagnosed with diabetes (type undefined) at 16 years old. They were treated with insulin for 3 years, with poor glycemic control. Their mother was diagnosed with T2DM and achieved good glycemia control with glimepiride. They were diagnosed as MODY13 because of the autosomal dominant inheritance of two generations, early onset of diabetes before 25 years of age in the two sisters, and the presence of the KCNJ11 N48D gene mutation. All patients successfully transferred to sulfonylureas with excellent glycemic control. Therefore, the wide spectrum of clinical phenotypes of glucose dysmetabolism caused by KCNJ11 should be recognized to reduce misdiagnosis and implement appropriate treatment.     

What next after basal insulin? Treatment intensification with lixisenatide in Asian patients with type 2 diabetes mellitus

There is increasing evidence that the pathophysiology of type 2 diabetes mellitus (T2DM) in Asian patients differs from that in Western patients, with early phase insulin deficiencies, increased postprandial glucose excursions, and increased sensitivity to insulin. Asian patients may also experience higher rates of gastrointestinal adverse events associated with glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), such as nausea and vomiting, compared with their Western counterparts. These factors should be taken into consideration when selecting therapy for basal insulin treatment intensification in Asian patients. However, the majority of studies to establish various agents for treatment intensification in T2DM have been conducted in predominantly Western populations, and the levels of evidence available in Chinese or Asian patients are limited. This review discusses the different mechanisms of action of short‐acting, prandial, and long‐acting GLP‐1RAs in addressing hyperglycemia, and describes the rationale and available clinical data for basal insulin in combination with the short‐acting prandial GLP‐1RA lixisenatide, with a focus on treatment of Asian patients with T2DM.     

Expert consensus on blood pressure management of diabetic patients in China (中国糖尿病患者血压管理专家共识)

This Expert Consensus proposed by the Chinese Society of Endocrinology (CSE) updates concepts on hypertension management in patients with diabetes. It focuses on clinical outcomes literature published within the past 5 years and currently in press, and incorporates these new observations into modifications of established guidelines. Complications and mortality in diabetic patients are increased when hypertension is present. The present update focuses on questions such as what to do when a diabetic patient has an elevated blood pressure level when therapy is initiated and whether combinations of agents should be used as soon as possible. Although the strategies and principles of treatment remain unchanged, approaches to specific patient‐related issues influencing cardiovascular outcomes in people with diabetes have changed. Finally, an updated integrated management of multiple cardiovascular risk factors is provided and is suggested as a starting point to achieve blood pressure goals. In addition to controlling blood pressure, the CSE suggests that individualized strategies are equally important and that attention should be paid to other factors, including safety (which is the most important), feasibility, and health economic evaluation.