Weight Gain and Management Concerns in Patients on Insulin Therapy

Background: The benefits of tight glycemic control in preventing the onset and progression of microvascular complications in patients with type 2 diabetes mellitus (DM) are unarguable. The majority of patients with type 2 DM will eventually require insulin to achieve adequate glycemic control. Using insulin earlier rather than later in the course of type 2 DM may diminish the deleterious effects of hyperglycemia on β-cell function and therefore help prolong good glycemic control and prevent the occurrence of microvascular complications. However, weight gain is a potential adverse effect of insulin therapy.Objective: The goal of this article was to describe the benefit of insulin therapy early in the course of type 2 DM, review the association of weight gain with insulin therapy, and examine potential detrimental effects that insulin-associated weight gain could have in patients with type 2 DM.Methods: Materials used for this article were identified through a search of MEDLINE (1966–2006). English-language articles were chosen using the search terms diabetes mellitus type 2, insulin, and obesity.Results: Intensive insulin therapy is often associated with weight gain. Although there is concern that weight gain in patients with type 2 DM may have adverse effects on risk factors for cardiovascular disease, unfavorable changes in blood pressure and lipid levels have not been consistently observed in clinical trials. Furthermore, clinical evidence, including data from the United Kingdom Prospective Diabetes Study, supports the view that intensive insulin therapy does not increase the risk for cardiovascular disease.Conclusions: Early insulin therapy in patients with type 2 DM may be a strategy that will help patients achieve and maintain good glycemic control, thereby reducing the risk of developing microvascular complications. Although weight gain is commonly associated with insulin therapy, it does not appear to put these patients at greater risk for cardiovascular disease.     

Berberine improves insulin-induced diabetic retinopathy through exclusively suppressing Akt/mTOR-mediated HIF-1α/VEGF activation in retina endothelial cells

Background: Insulin therapy is the major treatment of glycaemic control in type I diabetes mellitus (DM) and advanced type II DM patients who fail to respond to oral hypoglycemic agents. Nonetheless, insulin therapy is deemed unsuccessful in controlling the incidence of diabetic retinopathy (DR) and is likely a risk factor. Berberine, an isoquinoline alkaloid, has caught great attention towards its anti-diabetic mechanisms. This study aims to investigate the effect of berberine in decelerating DR progression in insulin-treated DM.Methods: To better understand the therapeutic potential of berberine in the presence of insulin, we elaborated the action of mechanism whether berberine inhibited retinal expression of HIF-1α and VEGF through regulating AKT/mTOR pathway. Suppression of insulin-induced neovasculature of retina endothelial cells by berberine was also studied. Lastly, the in vivo efficacy and safety of berberine as adjuvant therapy for the treatment of DR were systemically investigated in experimental type I and type II DM mice with insulin treatment.Results: Among various types of retinal cells, the activity of HIF-1α and VEGF in retinal endothelial cells could be particularly and exclusively stimulated by insulin intervention, which could be inhibited by berberine treatment in a dose- and time-dependent manner. Berberine suppressed Akt/mTOR activity in these cells, and restoration of Akt/mTOR signalling attenuated berberine''s inhibition on HIF-1α and VEGF expression. Berberine suppressed the progression of DR in experimental type I and type II diabetic mice receiving insulin therapy.Conclusion: Berberine improves insulin-induced diabetic retinopathy in type I and II diabetes through inhibiting insulin-induced activation of retinal endotheliocytes via Akt/mTOR/ HIF-1α/VEGF pathway.     

Diabetic Retinopathy,Classified Using the Lesion-Aware Deep Learning System,Predicts Diabetic End-Stage Renal Disease in Chinese Patients

Objective: To characterize the relationship between diabetic retinopathy (DR) and diabetic nephropathy (DN) in Chinese patients and to determine whether the severity of DR predicts end-stage renal disease (ESRD).Methods: Bilateral fundic photographs of 91 Chinese type 2 diabetic patients with biopsy-confirmed DN, not in ESRD stage, were obtained at the time of renal biopsy in this longitudinal study. The baseline severity of DR was determined using the Lesion-aware Deep Learning System (RetinalNET) in an open framework for deep learning and was graded using the Early Treatment Diabetic Retinopathy Study severity scale. Cox proportional hazard models were used to estimate the hazard ratio (HR) for the effect of the severity of diabetic retinopathy on ESRD.Results: During a median follow-up of 15 months, 25 patients progressed to ESRD. The severity of retinopathy at the time of biopsy was a prognostic factor for progression to ESRD (HR 2.18, 95% confidence interval 1.05 to 4.53, P = .04). At baseline, more severe retinopathy was associated with poor renal function, and more severe glomerular lesions. However, 30% of patients with mild retinopathy and severe glomerular lesions had higher low-density lipo-protein-cholesterol and more severe proteinuria than those with mild glomerular lesions. Additionally, 3% of patients with severe retinopathy and mild glomerular changes were more likely to have had diabetes a long time than those with severe glomerular lesions.Conclusion: Although the severity of DR predicted diabetic ESRD in patients with type 2 diabetes mellitus and DN, the severities of DR and DN were not always consistent, especially in patients with mild retinopathy or microalbuminuria.Abbreviations: CI = confidence interval; DM = diabetic mellitus; DN = diabetic nephropathy; DR = diabetic retinopathy; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; HbA1c = hemoglobin A1c; HR = hazard ratio; NPDR = nonproliferative diabetic retinopathy; PDR = proliferative diabetic retinopathy; SBP = systolic blood pressure; T2DM = type 2 diabetes mellitus; VEGF = vascular endothelial growth factor     

Insulin and endothelial function: A brief review

Background: In recent years, the novel effects of insulin beyond control of glucose metabolism have been appreciated, especially those that impact vascular function. A better understanding of insulin's protective interactions with the endothelium has provided clinicians with a justification for more aggressive use of insulin—not only to control glucose levels, but also to potentially reduce the progression of atherosclerosis and its pathogenic sequelae.Objective: In this brief review, we provide a snapshot of the available research and clinical findings signifying beneficial effects of insulin on the endothelium.Methods: We conducted a MEDLINE search of articles published in English from 1965 through 2007 using the search terms insulin, endothelium, and anti-inflammatory. Articles with a focus on “insulin resistance” per se were excluded from this review.Results: The literature search identified 200 articles that addressed the effects of insulin on endothelium and the interaction between insulin and the vasculature.Conclusions: In addition to mitigating hyperglycemic toxicity, insulin has multiple beneficial interactions with the endothelium in physiologic and disease states. The anti-inflammatory actions of insulin confer beneficial effects in preventing and minimizing morbidity and mortality due to atherosclerosis, especially in acute settings like myocardial infarction.     

Estrogens and the diabetic kidney

Background: Across all ages, the incidence and rate of progression of most nondiabetic renal diseases are markedly higher in men compared with age-matched women. These observations suggest that female sex may be renoprotective. In the setting of diabetes, however, this female protection against the development and progression of renal disease is diminished.Objective: This review aimed to summarize our current understanding of sex differences in the development and progression of diabetic renal disease, and of the contribution of sex hormones, particularly estrogens, to the pathophysiology of this disease. We also attempted to answer why female sex does not protect the diabetic kidney.Methods: Using terms such as gender, sex, diabetes, diabetic nephropathy, estrogens, and sex hormones, the PubMed database was searched for English-language articles; targeted searches were conducted using terms such as gender/sex differences in diabetic renal disease. No restrictions were imposed on publication dates.Results: Although the existing data regarding the sex differences in the incidence and progression of diabetic renal disease are inconclusive, the undisputed fact is that women with either type 1 or type 2 diabetes mellitus exhibit a much higher incidence of renal disease compared with nondiabetic women. It is conceivable that the loss of female sex as a renoprotective factor in diabetes may be related to the abnormal regulation of sex hormone concentrations. Both clinical and experimental data suggest that diabetes may be associated with an imbalance in estradiol concentrations. Supplementation with 17β-estradiol or administration of selective estrogen receptor modulators reduces the incidence of diabetes and attenuates the progression of diabetic renal disease.Conclusions: Serum concentrations of ovarian hormones may provide a new means for predicting future risk of renal complications in diabetes. Exogenous steroid hormones may be an effective treatment for attenuating the progression of diabetic nephropathy.     

Biosimilars and New Insulin Versions

Objective: To provide clinicians with an overview of similar biologic products including biosimilars and new insulin versions available in the U.S. and of key issues associated with such products, including differences in manufacturing and regulatory approaches and their impact on clinical use.Methods: We reviewed the relevant clinical and regulatory literature.Results: Patent protections for many biologics including several insulin preparations have or will expire shortly. This opens the door for new insulin versions to enter the U.S. and global marketplace. The development, manufacturing, and approval process for similar biologic products is more complex than for generic versions of small molecules. Most similar biologic products in the U.S. will be submitted for approval under section 351(k), a newly created biosimilar regulatory pathway. However, some biologics, including new insulin versions, will be submitted via the existing 505(b) regulatory pathway. These regulatory pathways have implications for how such products may be labeled, how they may be dispensed, and how patients may perceive them. The immunogenicity of biologics can affect safety and efficacy and can be altered through subtle changes in manufacturing. With the arrival of new insulin versions, health care providers will need to understand the implications of interchangeability, therapeutic equivalence, substitution, switching, and new delivery devices.Conclusion: An understanding of the above topics will be important as physicians, payers, and patients choose between similar versions of a reference listed biologic product.Abbreviations:BLA = biologics license applicationBPCIA = Biologics Price Competition and Innovation ActEU = European UnionFDA = Food and Drug AdministrationINN = international nonproprietary nameNDA = new drug applicationPD = pharmacodynamicPK = pharmacokineticPRCA = pure red cell aplasia     

Management of Type 2 Diabetes Mellitus with Basal-Prandial Insulin Therapy: A Case-Based Review

Background: Diabetes mellitus (DM) is a growing epidemic in the United States—20.8 million people are affected and 90% to 95% of all diagnosed cases are type 2 DM. Nevertheless, implementation of insulin therapy is often delayed in patients with type 2 DM. This delay can increase the risk of DM-related complications, including microvascular neuropathy, nephropathy, retinopathy, and cardiovascular disease.Objective: This article provides a case-based review outlining a novel strategy for advancing therapy with a modified basal and prandial insulin regimen to achieve recommended glycemic targets in type 2 DM as quickly as possible. Evidence-based treatment strategies are also discussed.Methods: Materials used for this article were identified through an English-language literature search of MEDLINE (1967-2007) using the following terms: insulin, postprandial glucose control, and type 2 diabetes.Results: As shown with this male 46-year-old case study patient, type 2 DM is treated initially with diet and exercise, followed by oral antidiabetic drugs (OADs). However, oral therapy typically reduces glycosylated hemoglobin values only by -1.5% to 2.0%. Intensive therapy with once-daily basal insulin in combination with a previously prescribed OAD regimen can achieve normoglycemia and reduce the long-term complications of DM. In patients with postprandial glucose excursions, prandial insulin can be added using a rapid-acting insulin analogue (aspart, lispro, or glulisine).Conclusions: A key factor in this case patient's ability to reach glycemic targets within I year of diagnosis of type 2 DM was the accelerated implementation of insulin therapy. Such a therapeutic approach obviates the risk for uncontrolled hyperglycemia, which is associated with the standard practice of beginning treatment with diet and exercise alone and slowly advancing by i OAD at a time, ending with insulin therapy as a last resort. (Insulin. 2007;2:118-126)     

Inpatient insulin therapy

Background: Many diabetic, as well as nondiabetic, hospitalized patients develop hyperglycemia. Numerous studies have demonstrated that critically ill, as well as noncritically ill, hospitalized patients who develop hyperglycemia are at increased risk for morbidity and mortality.Objective: The objective of this article was to review the risks associated with hyperglycemia in hospitalized patients, the biologic rationale for using insulin to prevent increases in glucose levels, and strategies for managing hyperglycemia in the hospital setting.Methods: We conducted a computerized search of biomedical journal literature from MEDLINE, PubMed, and Ovid published from 1994 to March 2008. We reviewed English-language original and review articles found under the subject headings “hospitalization and insulin therapy,” “inpatient diabetes and complications,” and “insulin and inflammation.”Results: More than 200 references were found during the literature search. According to the literature, the adverse outcomes that are associated with hyperglycemia may be attributed to the inflammatory and pro-oxidant effects of elevated glucose levels. The use of insulin, which has anti-inflammatory, vasodilatory, and antioxidant properties as well as the ability to inhibit lipolysis and platelet aggregation, can prevent many of these adverse outcomes.Conclusions: Hospitals should have protocols in place for using insulin to treat and prevent hyperglycemia. Subcutaneous insulin may be used for both purposes in most noncritically ill patients, whereas intravenous infusion of insulin is preferred in critically ill patients.     

Addressing Pitfalls in Management of Diabetic Ketoacidosis with a Standardized Protocol

Objective: To determine the efficacy and safety of a diabetic ketoacidosis (DKA)-Power Plan (PP) for guiding intravenous (IV) insulin infusions prior to anion gap (AG) closure and administering subcutaneous (SC) insulin ≥1 hour before discontinuing IV insulin.Methods: Retrospective chart review of patients with DKA before (pre-PP) (n = 60) and following (post-PP) (n = 60) implementation of a DKA-PP. Groups were compared for percentage of patients for whom IV insulin therapy was continued until AG closure, the percentage of patients receiving SC insulin ≥1 hour before discontinuation of IV insulin, and percentage of patients with rebound DKA during the index hospitalization.Results: Admission plasma glucose (514 mg/dL vs. 500 mg/dL; P = .36) and venous pH (7.2 vs. 7.2; P = .57) were similar in pre- and post-PP groups. Inappropriate discontinuation of IV insulin occurred less frequently in post-PP patients (28% vs. 7%; P = .007), with a lower frequency of rebound DKA (40% vs. 8%; P = .001) following acute management. More post-PP patients received SC insulin ≥1 hour before discontinuation of IV insulin (65% vs. 78%; P = .05).Conclusion: Implementation of a DKA-PP was associated with appropriate discontinuation of IV insulin in more patients, more frequent administration of SC insulin ≥1 hour prior to discontinuation of IV insulin, and fewer episodes of rebound DKA.Abbreviations: ADA = American Diabetes Association; AG = anion gap; BG = blood glucose; DKA = diabetic ketoacidosis; DKA-PP = DKA-Power Plan; ICU = intensive care unit; IQR = interquartile range; IV = intravenous; IVF = IV fluid; LOS = length of stay; SC = subcutaneous     

Brain Function Alterations in Patients with Diabetic Nephropathy Complicated by Retinopathy Under Resting State Conditions Assessed by Voxel-Mirrored Homotopic Connectivity

Objective: The voxel-mirrored homologous connection (VHMC) technique was applied to detect resting brain function alterations in patients with diabetic nephropathy and retinopathy (DNR), and their relationships with clinical manifestations in the kidneys and eyes are discussed.Methods: Twenty-two patients with DNR and 22 healthy controls (HCs) similarly matched in age, sex, and educational background were recruited. Resting-state functional magnetic resonance imaging scans were performed for all subjects. Retinal fundus photography and renal biopsy were employed to observe the clinical features of the kidney and retina. Pearson correlation analysis was used to analyze the relationship between clinical manifestations and experimental results.Results: Compared with the HCs, patients with DNR showed decreased mean VMHC values in the bilateral middle temporal gyrus, bilateral middle occipital gyrus (BMOG), and bilateral medial frontal gyrus. The receiver operating characteristic curve analysis of each brain region confirmed that the accuracy of the area under the curve was excellent. The results showed that the average VHMC value of BMOG signals was positively correlated with the urinary protein to creatinine ratio in female subjects (r = 0.626; P<.05). Nonetheless, no such correlation was noted among the male subjects.Conclusion: There were significant changes in brain function in DNR patients compared to the control group. Changes in the central nervous system in patients with DNR were mainly due to the dual negative effects of kidney function and diabetes mellitus.Abbreviations: ACR = albumin/creatinine ratio; BMFG = bilateral medial frontal gyrus; BMOG = bilateral middle occipital gyrus; BMTG = bilateral middle temporal gyrus; DN = diabetic nephropathy; DNR = diabetic nephropathy complicated by retinopathy; DR = diabetic retinopathy; fMRI = functional magnetic resonance imaging; HC = healthy control; MRI = magnetic resonance imaging; PCR = protein to creatinine ratio; ROC = receiver operating characteristic; VHMC = voxel-mirrored homologous connection     

Incorporating postprandial and fasting plasma glucose into clinical management strategies

Background: Targeting plasma glucose is a widely accepted practice in the treatment of both type 1 and type 2 diabetes mellitus (DM). Although clinicians have traditionally relied on fasting plasma glucose (FPG) levels for diagnosis and as a target for therapy, the focus has expanded to include the contribution of postprandial glucose (PPG) to glycosylated hemoglobin (A1C) levels.Objective: This article examines the contributions of FPG and PPG to A1C levels in patients with diabetes and discusses the impact of these findings on insulin treatment strategies for patients who fail to achieve recommended A1C goals.Methods: Relevant articles were identified through a PubMed search of the literature (1975–2007) using the following search terms: fasting plasma glucose, postprandial glucose, postprandial hyperglycemia, and glycemic control.Results: Changes in PPG levels are typically the first signs of abnormal glucose metabolism associated with type 2 DM, and they are a useful measure of glycemic control in patients with near-normal FPG and high A1C levels. A substantial proportion of patients considered to have good glycemic control (A1C <7.0%) may continue to experience elevated PPG levels, which have been linked to an increased risk of cardiovascular disease. FPG levels may predict the degree of postprandial hyperglycemia and the extent of PPG excursion. Conversely, correction of PPG levels may reduce FPG levels by suppressing hepatic glucose production. Evidence indicates that therapy targeting both FPG and PPG is associated with optimal reductions in A1C levels. At very high A1C levels (>9%-10%), FPG may play a greater role in overall glucose control than does PPG, but PPG becomes a more important contributor as A1C levels decrease. Increasing evidence supports the long-term benefits of early initiation of intensive insulin therapy. In particular, prandial insulin therapy may address the issue of postprandial hyperglycemia, which may be insufficiently controlled with oral agents and/or basal insulin alone.Conclusions: Both FPG and PPG affect A1C levels and are important contributors to determining overall glycemic control. Alternative insulin therapies (eg, inhaled insulin) that minimize barriers to insulin therapy and the appropriate targeting of FPG and PPG levels may improve long-term outcomes in patients with diabetes.     

Quality of Life and Insulin Therapy in Type 2 Diabetes Mellitus

Background: A frequently cited barrier to insulin use in type 2 diabetes mellitus (DM) is concern about the adverse effects on quality of life. Results of studies in this area have been mixed, with insulin use showing decreased, enhanced, or no impact on quality of life.Objective: The purpose of this paper is to discuss the state of the science regarding the effects of insulin on quality of life and to present strategies providers can implement in their clinical practices to decrease barriers to insulin use among patients with type 2 DM.Methods: An English-language MEDLINE search of the current literature using the terms insulin and quality of life was conducted for this article.Results: Although patient-identified concerns regarding insulin use represent some aspects of quality of life, study results have been mixed. However, 2 large studies examining the use of insulin glargine and its effects on quality of life found that glargine was associated with significantly greater improvements in quality of life when added to oral antidiabetic agents (OADs) than was the use of OADs alone. Another study examined the effects of intensive multi- therapy (monthly visits, self-management diabetes education, and medication adjustments) on quality of life among patients with type 2 DM and found that quality-of-life scores improved among patients who initiated insulin therapy during the trial. The effects of insulin delivery systems on quality of life have also been assessed. In these studies, patients preferred insulin pens over vials and syringes and inhaled over injected insulin. Health care providers can facilitate acceptance of insulin by employing strategies to help patients overcome psychological barriers to insulin therapy.Conclusions: Although patient concerns about the effects of insulin use are legitimate, insulin therapy is often needed to achieve treatment targets. Providers can reduce the impact on quality of life by addressing barriers, helping patients improve metabolic control, and providing ongoing information and support.     

The Association of Serum Bilirubin on Kidney Clinicopathologic Features and Renal Outcome in Patients with Diabetic Nephropathy: A Biopsy-Based Study

Objective: To explore the relationship between serum bilirubin concentration and clinicopathologic features and renal outcome in biopsy-diagnosed diabetic nephropathy (DN) in patients with type 2 diabetes mellitus.Methods: In this retrospective study, 118 patients with DN were enrolled. Participants were divided into two groups according to their median baseline serum bilirubin concentration: Group 1 (serum bilirubin ≤7.5 μmol /L); Group 2 (serum bilirubin >7.5 μmol /L). Basic clinical parameters were measured at the time of renal biopsy, and the relationships between serum bilirubin and the clinicopathologic features and renal outcome were analyzed.Results: Patients in Group 1 often had inferior renal function. Compared with Group 2, the glomerular classification and interstitial inflammation were more severe in subjects of Group 1, while arteriolar hyalinosis and interstitial fibrosis and tubular atrophy (IFTA) were comparable between the groups. Serum bilirubin was negatively correlated with the severity of the glomerular classification, interstitial inflammation, and IFTA. In the prognostic analysis, higher serum bilirubin level was associated with a lower risk of progression to end-stage renal disease, which was independent of the effects of age, gender, duration of diabetes, anemia, serum glucose, and hypertension but not of estimated glomerular filtration rate (hazard ratio, 0.406; 95% confidence interval, 0.074 to 2.225; P = .299).Conclusion: Our study showed a negative correlation between serum bilirubin level and renal pathologic lesions in patients with DN; serum bilirubin showed an inverse association with DN progression, but this was not independent.Abbreviations: CI = confidence interval; CKD = chronic kidney disease; DM = diabetes mellitus; DN = diabetic nephropathy; DR = diabetic retinopathy; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; HbA1c = glycated hemoglobin; HO-1 = heme oxygenase 1; HR = hazard ratio; IFTA = interstitial fibrosis and tubular atrophy; log-BIL = log-transformed baseline serum bilirubin; T2DM = type 2 diabetes mellitus     

Clinicopathologic Features and Prognosis of Type 2 Diabetes Mellitus and Diabetic Nephropathy in Different Age Groups: More Attention to Younger Patients

Objective: Our study sought to investigate the clinicopathologic features and renal prognosis of patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) in different age groups.Methods: A total of 315 patients with T2DM and biopsy-proven DN were enrolled and divided into three groups by age: the Youth group (≤44 years old), the Middle-aged group (45 to 59 years old), and the Elderly group (≥60 years old).Results: The Youth group, Middle-aged group, and Elderly group accounted for 19.05% (60/315), 59.37% (187/315), and 21.59% (68/315) of the patients in our study, respectively. The patients in the Youth group had a higher estimated glomerular filtration rate (calculated using the Chronic Kidney Disease–Epidemiology collaboration formula) (P<.001), a higher incidence of diabetic retinopathy (P = .044), and a higher incidence of being in the lower-risk chronic kidney disease heat map category (P = .046) but lower duration of diabetes (P = .016). Histologically, patients in the Youth group had the highest incidence of glomerular classification in class I (P = .006) and arteriolar hyalinosis score of 0 (P = .005). The renal survival among the three groups was comparable (P>.05).Conclusion: This study indicated that there were different clinicopathologic features among Chinese DN patients in different age groups. Although the Youth group had a relatively lower rapid kidney disease progression rate, there were no significant differences in renal survival rate among the three groups, which calls more attention to early supervision and prevention for younger DN patients.Abbreviations: CKD = chronic kidney disease; DN = diabetic nephropathy; DR = diabetic retinopathy; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; G&Y&O = green and yellow and orange; IFTA = interstitial fibrosis and tubular atrophy; T2DM = type 2 diabetes mellitus     

Sorbitol dehydrogenase overexpression potentiates glucose toxicity to cultured retinal pericytes

The polyol pathway consists of two enzymes, aldose reductase (AR) and sorbitol dehydrogenase (SDH). There is a growing body of evidence to suggest that acceleration of the polyol pathway is implicated in the pathogenesis of diabetic vascular complications. However, a functional role remains to be elucidated for SDH in the development and progression of diabetic retinopathy. In this study, cultured bovine retinal capillary pericytes were used to investigate the effects of SDH overexpression on glucose toxicity. High glucose modestly increased reactive oxygen species (ROS) generation, decreased DNA synthesis, and up-regulated vascular endothelial growth factor (VEGF) mRNA levels in cultured pericytes. SDH overexpression was found to significantly stimulate ROS generation in high glucose-exposed pericytes and subsequently potentiate the cytopathic effects of glucose. Fidarestat, a newly developed AR inhibitor, and N-acetylcysteine, an antioxidant, completely prevented these deleterious effects of SDH overexpression on pericytes. Furthermore, fidarestat administration was found to significantly prevent vascular hyperpermeability, the characteristic changes of the early phase of diabetic retinopathy, in streptozotocin-induced diabetic rats. Our present results suggest that SDH-mediated conversion of sorbitol to fructose and the resultant ROS generation may play an active role in the pathogenesis of diabetic retinopathy. Blockage of sorbitol formation by fidarestat could be a promising therapeutic strategy for the treatment of early phase of diabetic retinopathy.     

VEGF165b对糖尿病大鼠视网膜神经节细胞保护作用的研究

目的:VEGF165b是新发现的血管内皮生长因子的变构体之一,本研究将观察其对糖尿病大鼠视网膜神经节细胞的抗凋亡作用.方法:采用四氧嘧啶诱发糖尿病大鼠模型,分为正常对照组(CON),糖尿病组(DM),糖尿病VEGF165b低剂量治疗组(DMT1)、中剂量治疗组(DMT2),糖尿病高剂量治疗组(DMT3),糖尿病单纯胰岛素治疗组(DMT4),所有治疗组在糖尿病成模后1个月开始治疗.2个月后处死各组大鼠,摘取眼球进行光镜形态学观察、核苷酸末端转移酶介导的dUTP缺口翻译法(TUNEL法)视网膜神经节细胞凋亡检测.结果:VEGF165b治疗使糖尿病大鼠视网膜光镜形态学改变减轻,能有效的抑制视网膜神经节细胞凋亡.VEGF165b治疗组视网膜神经节凋亡细胞数较DM组明显减少(P＜0.01),与糖尿病大鼠单纯胰岛素治疗组相比差异也有统计学意义.随着VEGF165b浓度的增加视网膜神经节细胞凋亡个数减少,但1ng/μL组与10ng/μL组相比差异无统计学意义.结论:VEGF165b对视网膜神经节细胞有保护作用,可能对糖尿病视网膜病变具有治疗有意义.     

Risk Factors for Hypoglycemia in Inpatients with Total Parenteral Nutrition and Type 2 Diabetes: A Post HOC Analysis of the Insupar Study

Objective: Treatment of hyperglycemia with insulin is associated with increased risk of hypoglycemia in type 2 diabetes mellitus (T2DM) patients receiving total parenteral nutrition (TPN). The aim of this study was to determine the predictors of hypoglycemia in hospitalized T2DM patients receiving TPN.Methods: Post hoc analysis of the INSUPAR study, which is a prospective, open-label, multicenter clinical trial of adult inpatients with T2DM in a noncritical setting with indication for TPN.Results: The study included 161 patients; 31 patients (19.3%) had hypoglycemic events, but none of them was severe. In univariate analysis, hypoglycemia was significantly associated with the presence of diabetes with end-organ damage, duration of diabetes, use of insulin prior to admission, glycemic variability (GV), belonging to the glargine insulin group in the INSUPAR trial, mean daily grams of lipids in TPN, mean insulin per 10 grams of carbohydrates, duration of TPN, and increase in urea during TPN. Multiple logistic regression analysis showed that the presence of diabetes with end-organ damage, GV, use of glargine insulin, and TPN duration were risk factors for hypoglycemia.Conclusion: The presence of T2DM with end-organ damage complications, longer TPN duration, belonging to the glargine insulin group, and greater GV are factors associated with the risk of hypoglycemia in diabetic noncritically ill inpatients with parenteral nutrition.Abbreviations: ADA = American Diabetes Association; BMI = body mass index; CV% = coefficient of variation; DM = diabetes mellitus; GI = glargine insulin; GV = glycemic variability; ICU = intensive care unit; RI = regular insulin; T2DM = type 2 diabetes mellitus; TPN = total parenteral nutrition     

The Emerging Role Of Adjunctive Noninsulin Antihyperglycemic Therapy In The Management Of Type 1 Diabetes

Objective: Review available data on adjunctive therapies for type 1 diabetes (T1D), with a special focus on newer antihyperglycemic agents.Methods: Published data on hypoglycemia, obesity, mortality, and goal attainment in T1D were reviewed to determine unmet therapeutic needs. PubMed databases and abstracts from recent diabetes meetings were searched using the term “type 1 diabetes” and the available and investigational sodium-glucose cotransporter (SGLT) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 inhibitors, and metformin.Results: The majority of patients with T1D do not meet glycated hemoglobin (A1C) goals established by major diabetes organizations. Hypoglycemia risks and a rising incidence of obesity and metabolic syndrome featured in the T1D population limit optimal use of intensive insulin therapy. Noninsulin antihyperglycemic agents may enable T1D patients to achieve target A1C levels using lower insulin doses, which may reduce the risk of hypoglycemia. In pilot studies, the SGLT2 inhibitor dapagliflozin and the GLP-1 receptor agonist liraglutide reduced blood glucose, weight, and insulin dose in patients with T1D. Phase 2 studies with the SGLT2 inhibitor empagliflozin and the dual SGLT1 and SGLT2 inhibitor sotagliflozin, which acts in the gut and the kidney, have demonstrated reductions in A1C, weight, and glucose variability without an increased incidence of hypoglycemia.Conclusion: Newer antihyperglycemic agents, particularly GLP-1 agonists, SGLT2 inhibitors, and dual SGLT1 and SGLT2 inhibitors, show promise as adjunctive treatment for T1D that may help patients achieve better glucose control without weight gain or increased hypoglycemia.Abbreviations:A1C = glycated hemoglobinBMI = body mass indexCI = confidence intervalDKA = diabetic ketoacidosisDPP-4 = dipeptidyl peptidase 4GLP-1 = glucagonlike peptide 1PYY = polypeptide tyrosine tyrosineSGLT = sodium-glucose cotransporterSGLT1 = sodium-glucose cotransporter 1SGLT2 = sodium-glucose cotransporter 2T1D = type 1 diabetesT2D = type 2 diabetesTDD = total daily dosage     

Increased levels of vascular endothelial growth factor and advanced glycation end products in aqueous humor of patients with diabetic retinopathy.

Clinical studies have shown a relationship between diabetic retinopathy and vascular endothelial growth factor (VEGF) levels in ocular fluid. Advanced glycation end products (AGEs) have been implicated in diabetes complications, including diabetic retinopathy. Nepsilon-(carboxymethyl) lysine (CML) is a glycoxidation product that may be a marker of oxidative stress. In this study, we used enzyme-linked immunosorbent assays to determine the levels of VEGF, non-CML AGE and CML in the aqueous humor and serum of 82 Japanese patients with type 2 diabetes and 60 non-diabetic subjects. VEGF, non-CML AGE, and CML concentrations in aqueous humor and serum were then compared with the severity of diabetic retinopathy. Immunohistochemical detection analysis of non-CML AGE and CML was also performed using retinal tissues from patients with progressive diabetic retinopathy. Aqueous levels of VEGF, non-CML AGE and CML increased along with the progression of diabetic retinopathy compared to age-matched controls. After coagulation therapy, the VEGF, non-CML AGE, and CML levels were significantly reduced. Immunostaining showed diffuse co-localization of non-CML AGE and CML around microvessels and in the glial cells of proliferative membranes from patients with progressive diabetic retinopathy. These findings suggest that glycation and glycoxidation reactions (or oxidation, as revealed by CML) may contribute to both the onset and progression of diabetic retinopathy.