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.     

Improving postprandial hyperglycemia in patients with type 2 diabetes already on basal insulin therapy: Review of current strategies

A large number of patients with type 2 diabetes (T2D) on basal insulin do not reach their HbA1c goals and require additional therapy to address postprandial hyperglycemia. Guidelines from expert bodies have outlined several approaches to accomplish postprandial glucose (PPG) control, and recent literature suggests several more. This article provides strategies for primary care physicians caring for patients with T2D who do not achieve glycemic control with basal insulin alone. Current treatment guidelines and strategies for improving PPG control are reviewed, including the efficacy, safety, and cost‐effectiveness of rapid‐acting insulin (RAI) analogs, premixed insulin, glucagon‐like peptide‐1 (GLP‐1) receptor agonists (RAs), dipeptidyl peptidase 4 inhibitors, sodium–glucose cotransporter 2 inhibitors, and α‐glucosidase inhibitors. Other approaches, such as combinations of newer basal insulin plus RAI and a fixed‐ratio combination of basal insulin and a GLP‐1 RA, are also described.     

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.     

Regional evidence and international recommendations to guide lipid management in Asian patients with type 2 diabetes with special reference to renal dysfunction

The anticipated increase in the prevalence and incidence of type 2 diabetes in Asia, and its associated cardiovascular–renal complications, will place a significant burden on patients, caregivers, and society. Despite the proven effectiveness of lipid management in reducing these complications, there are major treatment gaps, especially in Asian patients with young‐onset diabetes and chronic kidney disease (CKD). Recent international guidelines recommended the adoption of absolute risk estimation of atherosclerosis and cardiovascular disease to guide treatment intensity. These recommendations replaced the previous strategy of using low‐density lipoprotein cholesterol targets to guide initiation and intensification of lipid lowering, albeit still widely practiced in Asia. The latest guidelines also highlight the high risk of atherosclerosis and cardiovascular disease (ASCVD) for people with diabetes, who should be protected with statins, except for young patients without other risk factors, who will need yearly monitoring of blood lipid levels. Given the propensity of Asian patients with diabetes to develop CKD and the amplifying effect of CKD on ASCVD, the use of statins in Asian patients is particularly important. Due to interethnic differences in drug metabolism, rosuvastatin, which is largely cleared by the kidney, should be prescribed in low dosages (5–10 mg daily) in Asian populations. Conversely, epidemiological and experimental data confirm pleotropic and organ‐protective effects of atorvastatin, with proven safety in Asian populations within a daily dose range of 10–40 mg. Thus, there is a need for Asian countries to review and align their lipid‐lowering treatment guidelines to reduce the substantial burden of diabetes in the Asian region.     

The incretin hormone GLP‐1 and mechanisms underlying its secretion

Glucagon‐like peptide‐1 (GLP‐1) is a cell type‐specific post‐translational product of proglucagon. It is encoded by the proglucagon gene and released primarily from intestinal endocrine L‐cells in response to hormonal, neuronal, and nutritional stimuli. In addition to serving as an incretin in mediating the effect of meal consumption on insulin secretion, GLP‐1 exerts other functions in pancreatic islets, including regulation of β‐cell proliferation and protection of β‐cells against metabolic stresses. Furthermore, GLP‐1 exerts numerous other functions in extrapancreatic organs, whereas brain GLP‐1 signaling controls satiety. Herein we review the discovery of two incretins and the development of GLP‐1‐based drugs. We also describe the development of cellular models for studying mechanisms underlying GLP‐1 secretion over the past 30 years. However, the main content of this review is a summary of studies on the exploration of mechanisms underlying GLP‐1 secretion. We not only summarize studies conducted over the past three decades on elucidating the role of nutritional components and hormonal factors in regulating GLP‐1 secretion, but also present a few very recent studies showing the possible role of dietary polyphenols. Finally, the emerging role of gut microbiota in metabolic homeostasis with the potential implication on GLP‐1 secretion is discussed.     

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.     

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.     

GLP‐1 and insulin regulation of skeletal and cardiac muscle microvascular perfusion in type 2 diabetes

Muscle microvasculature critically regulates skeletal and cardiac muscle health and function. It provides endothelial surface area for substrate exchange between the plasma compartment and the muscle interstitium. Insulin fine‐tunes muscle microvascular perfusion to regulate its own action in muscle and oxygen and nutrient supplies to muscle. Specifically, insulin increases muscle microvascular perfusion, which results in increased delivery of insulin to the capillaries that bathe the muscle cells and then facilitate its own transendothelial transport to reach the muscle interstitium. In type 2 diabetes, muscle microvascular responses to insulin are blunted and there is capillary rarefaction. Both loss of capillary density and decreased insulin‐mediated capillary recruitment contribute to a decreased endothelial surface area available for substrate exchange. Vasculature expresses abundant glucagon‐like peptide 1 (GLP‐1) receptors. GLP‐1, in addition to its well‐characterized glycemic actions, improves endothelial function, increases muscle microvascular perfusion, and stimulates angiogenesis. Importantly, these actions are preserved in the insulin resistant states. Thus, treatment of insulin resistant patients with GLP‐1 receptor agonists may improve skeletal and cardiac muscle microvascular perfusion and increase muscle capillarization, leading to improved delivery of oxygen, nutrients, and hormones such as insulin to the myocytes. These actions of GLP‐1 impact skeletal and cardiac muscle function and systems biology such as functional exercise capacity. Preclinical studies and clinical trials involving the use of GLP‐1 receptor agonists have shown salutary cardiovascular effects and improved cardiovascular outcomes in type 2 diabetes mellitus. Future studies should further examine the different roles of GLP‐1 in cardiac as well as skeletal muscle function.     

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.     

Vitamin D and Type 2 diabetes mellitus (维生素D与2型糖尿病)

Based on increasing evidence from animal and human studies, vitamin D deficiency is now regarded as a potential risk factor for Type 2 diabetes mellitus (T2DM). Vitamin D is involved in the pathogenesis of pancreatic β‐cell dysfunction, insulin resistance, and systemic inflammation, conditions that contribute to the development of T2DM. Vitamin D can affect the progress of this disease directly through the activation of its own receptor, and indirectly via the regulation of calcium homeostasis. Observational studies have revealed the association between vitamin D deficiency and incident T2DM. More double‐blind randomized control studies that investigate the effects of vitamin D supplementation on insulin sensitivity, insulin secretion, and the occurrence of T2DM are needed.     

GLP‐1 Receptor Agonists: Effects on Cardiovascular Risk Reduction

Comorbid obesity, dyslipidemia, and hypertension place patients with type 2 diabetes (T2DM) at greatly increased risk of cardiovascular (CV) disease‐related morbidity and mortality. An urgent need exists for effective treatment for patients with T2DM that encompasses glycemic control, weight loss, and reduction in CV risk factors. The glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) liraglutide and exenatide are incretin‐based antidiabetes agents. This review examines CV‐associated effects of liraglutide and exenatide in animal models and clinical trials with patients with T2DM. Studies support the effectiveness of GLP‐1 RAs in reducing hyperglycemia. Further, GLP‐1 RAs represent a significant advance in T2DM treatment because they uniquely affect a broad array of CV risk factors through significant weight and systolic blood pressure reduction, improved lipid levels, and possibly, as shown in in vitro studies and animal models, through direct effects on cardiac myocytes and endothelium.     

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.     

Hypoglycemia in diabetes: The dark side of diabetes treatment. A patient‐centered review

Hypoglycemia is a frequent occurrence in patients with diabetes who are treated with insulin and insulin secretagogues. Hypoglycemia is the limiting factor that prevents patients from achieving the glycemic control known to reduce the microvascular complications of diabetes. Recurrent episodes of hypoglycemia can lead to impaired awareness of hypoglycemia where the first symptom of a low blood sugar is unconsciousness. The fear of hypoglycemia has a significant effect on the quality of life of patients and their families. In the acute setting, hypoglycemia can kill, and clinical trials have demonstrated that a single episode of severe hypoglycemia increases the risk of subsequent mortality and cardiovascular events. Clinicians must make efforts to recognize and prevent hypoglycemia in order to prevent the adverse events associated with this event. Patient education is central to these efforts. Recent developments in glucose monitoring and drug development have provided more approaches that can be used to reduce the risk of hypoglycemia in patients with diabetes.     

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.     

Pharmacologic strategies to reduce cardiovascular disease in type 2 diabetes mellitus: focus on SGLT‐2 inhibitors and GLP‐1 receptor agonists

Patients with type 2 diabetes mellitus (T2D) present an increased risk for cardiovascular (CV) complications. In addition to improvement in glycaemic control, glucose‐lowering therapies, such as glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and sodium‐dependent glucose cotransporter (SGLT)‐2 inhibitors, have been shown to significantly reduce CV events. In 2008, the US Food and Drug Administration mandated that all new glucose‐lowering drugs undergo CV outcomes trials (CVOTs) to determine their CV safety. These trials have largely demonstrated no major CV safety concerns. Most notably, the GLP‐1RAs and SGLT‐2 inhibitors have been found to be not only safe, but also cardioprotective compared to placebo. The SGLT‐2 inhibitors have opened a new perspective for clinicians treating patients with T2D and established CV disease in light of their ‘pleiotropic’ effects, specifically on heart failure, while GLP‐1RAs seem to present more favourable effects on atherosclerotic events. In this review, we discuss the role of GLP‐1RAs and SGLT‐2 inhibitors to reduce CV risk in T2D patients and suggest an individualized therapeutic approach in this population based on the presence of metabolic and CV comorbidities.     

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.     

Glucocorticoid‐induced hyperglycemia (糖皮质激素诱导的高血糖)

Corticosteroid‐induced hyperglycemia is a common medical problem that can lead to frequent emergency room visits, hospital admissions and prolonged hospital stay, in addition to the well known morbidity associated with hyperglycemia. However, the diagnosis and treatment of corticosteroid‐induced hyperglycemia is surprisingly undervalued by most professionals, probably because of the lack of quality studies to determine specific strategies of action. In the present review, we discuss the pathophysiology of corticosteroid‐induced hyperglycemia, focusing on diverse patterns of hyperglycemia induced by the different formulations, and provide clues for diagnosis based on the duration of treatment and the administration schedule of corticosteroids. We propose a treatment strategy based on both the pathophysiology of the process and the mechanism of action of different corticosteroids, and take into account dosing and administration timing to predict the duration of therapy. Finally, we propose treatment goals that differ slightly between the transient and continuous use of corticosteroids based on evidence from clinical practice guidelines of diabetes care both in ambulatory and hospital settings.     

Therapeutic approaches for latent autoimmune diabetes in adults: One size does not fit all

Recent advances in the understanding of latent autoimmune diabetes in adults (LADA) pathophysiology make it increasingly evident that people with LADA comprise a heterogenous group of patients. This makes the establishment of a standard treatment algorithm challenging. On top of its glucose‐lowering action, insulin may exert anti‐inflammatory effects, rendering it an attractive therapeutic choice for a type of diabetes in which autoinflammation and beta cell insufficiency play major pathogenetic roles. However, there is growing evidence that other antidiabetic drugs, such as metformin, dipeptidyl peptidase‐4 inhibitors, glucagon‐like peptide‐1 receptor agonists, and thiazolidinediones, might have a role in optimizing glycemic control and preserving beta cell function in individuals with LADA, either alone or in combination with insulin. Although most of these drugs have been routinely used in the daily clinical setting for years, large prospective randomized trials are needed to assess whether they are capable of delaying progression to insulin dependence as well as their effects on diabetic complications. The aim of the present review is to discuss the current state and future perspectives of LADA therapy, emphasizing the need for individualized and patient‐centered therapeutic approaches.