Residual Hyperglycemia Research Articles

Residual hyperglycemia after successful treatment of a patient with severe copper sulfate poisoning

Residual hyperglycemia after successful treatment of a patient with severe copper sulfate poisoning

IGlarLixi Effectively Reduces Residual Hyperglycemia in Patients with Type 2 Diabetes on Basal Insulin—A Post-Hoc Analysis from the LixiLan-L Study

Residual hyperglycemia (glycated hemoglobin [HbA1c] over target despite fasting plasma glucose [FPG] at target) presents an obstacle in achieving glycemic control in T2D. GLP-1 receptor agonist (RA) therapy can target excessive postprandial glycemia (PPG) and thereby address residual hyperglycemia. This analysis investigated the effect of iGlarLixi, a fixed-ratio combination of insulin glargine (iGlar) U100 and the GLP-1 RA lixisenatide (Lixi), on the proportion of patients with T2D with discordant HbA1c/FPG (HbA1c ≥7% and FPG <140 mg/dL) in the LixiLan-L trial. Patients who had suboptimal glycemic control despite basal insulin ± oral antidiabetes drugs (OADs) stopped all OADs but metformin and, after 6 weeks of iGlar run-in, were randomized to iGlarLixi or iGlar for 30 weeks (N=736). At baseline (post-run-in), proportions with discordant HbA1c/FPG were similar in the two arms. After 12-week randomized treatment, proportions with discordant HbA1c/FPG were 32.1% (iGlarLixi) and 49.9% (iGlar; p<0.0001; Figure). After 30 weeks, the prevalence of discordant HbA1c/FPG was further reduced with iGlarLixi vs. iGlar (22.7% vs. 45.9%; p<0.0001). In conclusion, iGlarLixi reduces the proportion of T2D patients with discordant HbA1c/FPG levels more than iGlar does, reflecting its capacity to address residual hyperglycemia by targeting both FPG and PPG. Disclosure F. Giorgino: Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim GmbH. Research Support; Self; Eli Lilly and Company, Johnson & Johnson Services, Inc.. Consultant; Self; MedImmune, Merck Sharp & Dohme Corp., Roche Diabetes Care Health and Digital Solutions, Sanofi. Research Support; Self; Takeda Development Centre Europe Ltd. R. Retnakaran: Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Sanofi, Eli Lilly and Company. J. Vidal: None. V. Aroda: Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc., AstraZeneca, Calibra Medical, Eisai Inc., Sanofi. Consultant; Self; Sanofi. Research Support; Self; Theracos, Inc.. Employee; Spouse/Partner; Merck & Co., Inc.. Other Relationship; Self; American Diabetes Association. Consultant; Self; ADOCIA. A. Saremi: Employee; Self; Sanofi US. M. Liu: Employee; Self; Sanofi.

A global study of the unmet need for glycemic control and predictor factors among patients with type 2 diabetes mellitus who have achieved optimal fasting plasma glucose control on basal insulin.

BackgroundThis study used data from different sources to identify the extent of the unmet need for postprandial glycemic control in patients with type 2 diabetes mellitus (T2DM) after the initiation of basal insulin therapy in Europe, Asia Pacific, the United States, and Latin America.MethodsDifferent levels of evidence were used as available for each country/region, with data extracted from seven randomized controlled trials (RCTs), three clinical trial registries (CTRs), and three electronic medical record (EMR) databases. Glycemic status was categorized as “well controlled” (glycated hemoglobin [HbA1c] at target [<7%]), “residual hyperglycemia” (fasting plasma glucose [FPG] but not HbA1c at target [FPG <7.2/7.8 mmol/L, <130/140 mg/dL, depending on country‐specific recommendations]), or “uncontrolled” (both FPG and HbA1c above target). Predictor factors were identified from the RCT data set using logistic regression analysis.ResultsRCT data showed that 16.9% to 28.0%, 42.7% to 54.4%, and 16.9% to 38.1% of patients with T2DM had well‐controlled glycemia, residual hyperglycemia, and uncontrolled hyperglycemia, respectively. In CTRs, respective ranges were 21.8% to 33.6%, 31.5% to 35.6%, and 30.7% to 46.8%, and in EMR databases were 4.4% to 21.0%, 23.9% to 31.8%, and 53.6% to 63.8%. Significant predictor factors of residual hyperglycemia identified from RCT data included high baseline HbA1c (all countries/regions except Brazil), high baseline FPG (United Kingdom/Japan), longer duration of diabetes (Brazil), and female sex (Europe/Latin America).ConclusionsIrrespective of intrinsic differences between data sources, 24% to 54% of patients with T2DM globally had residual hyperglycemia with HbA1c not at target, despite achieving FPG control, indicating a significant unmet need for postprandial glycemic control.

Chronic oxidative stress as a mechanism for glucose toxicity of the beta cell in Type 2 diabetes

Type 2 diabetes is characterized by a relentless decline in pancreatic islet beta cell function and worsening hyperglycemia despite optimal medical treatment. Our central hypothesis is that residual hyperglycemia, especially after meals, generates reactive oxygen species (ROS), which in turn causes chronic oxidative stress on the beta cell. This hypothesis is supported by several observations. Exposure of isolated islets to high glucose concentrations induces increases in intracellular peroxide levels. The beta cell has very low intrinsic levels of antioxidant proteins and activities and thus is very vulnerable to ROS. Treatment with antioxidants protects animal models of type 2 diabetes against complete development of phenotypic hyperglycemia. The molecular mechanisms responsible for the glucose toxic effect on beta cell function involves disappearance of two important regulators of insulin promoter activity, PDX-1 and MafA. Antioxidant treatment in vitro prevents disappearance of these two transcription factors and normalizes insulin gene expression. These observations suggest that the ancillary treatment with antioxidants may improve outcomes of standard therapy of type 2 diabetes in humans.

Thinking Like a Pancreas: Perioperative Glycemic Control

Peter J. Pronovost, MD, PhD*† Perioperative glycemic control is related to patient outcome. Although guidelines for glucose management in hospitalized patients have undergone dramatic changes over the last 5 years, most hospital-based physicians, including anesthesiologists, have not changed their approach to glucose management (1). In this editorial, we discuss the article by Duncan et al. (2) appearing in this issue of Anesthesia & Analgesia, review recent recommendations for perioperative glucose management, and highlight areas of uncertainty. We endeavor to improve perioperative glucose management for patients. There is considerable uncertainty regarding how to manage surgical patients who are taking metformin, an oral hypoglycemic drug. The potential for postoperative lactic acidosis in patients taking this drug has prompted some clinicians and health care systems to routinely cancel surgical procedures if metformin is taken within 48 h of surgery. Other clinicians or health care systems continue metformin, both before and after the surgical procedure. Duncan et al. (2) conducted a retrospective review of a large cohort of diabetic patients admitted for cardiac surgery at their institution who recently took an oral hypoglycemic drug. They compared outcomes among patients who took metformin versus patients taking a non-metformin oral hypoglycemic drug. The authors found that patients taking metformin had lower risks for several complications, and concluded that metformin appeared to be safe for use in the perioperative period. The article raises several points worthy of reflection. First, the authors used a propensity score to try to account for differences among patients who were taking, versus not taking, metformin. This statistical method used logistic regression, in which metformin becomes the dependent variable. Predictor variables are included in the model (in this case 54 variables) to identify those patient characteristics associated with metformin treatment. The output of this analysis includes a C statistic that is interpreted to mean that, for any given pair of patients, in which one patient received metformin and one did not, how often did the model identify the one receiving metformin? In this analysis, the C statistic was 0.68, suggesting that more than 3 of 10 patients were not correctly classified. Thus, there is the potential that unmeasured differences between groups, and not metformin treatment or nontreatment, could influence the results. Other evidence suggests that propensity scores are no better than standard regressions at controlling for selection bias (3). Second, the authors evaluated a variety of outcomes, though many were uncommon and did not include explicit definitions, and concluded that metformin was safe. It would be helpful to consider the precise safety of these estimates (3). For example, even if none of the 523 metformin patients had an adverse event in this study, the upper limit of that confidence interval is seven events in 1000 patients. This rate would likely warrant concern from clinicians and lead to alterations of their practice. Rather than thinking of drug safety as a dichotomous variable, (i.e., safe versus unsafe) it may be helpful to think of safety as a continuous variable to help regulators, clinicians, and consumers make a more informed risk/benefit assessment. From the Departments of *Anesthesiology and Critical Care Medicine and †Surgery, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Accepted for publication October 26, 2006. Conflicts of Interest: Dr. Martinez has agreed to be a consultant for Bay City Capital LLC, but has not received any compensation as of this submission. The authors have no other potential conflicts of interest to disclose. Reprints will not be available from the authors. Address correspondence to Elizabeth A. Martinez, MD, MHS, ACCM/Adult Critical Care Division, 600 N. Wolfe St., Meyer 296, Baltimore, MD 21287. Address e-mail to emartine@jhmi.edu. Copyright © 2006 International Anesthesia Research Society DOI: 10.1213/01.ane.0000252348.81206.7f

Effects of combined insulin and sorbinil treatment on diabetes-induced vascular dysfunction in rats

These experiments were undertaken to assess the effects of combined treatment with insulin (designed to partially restore metabolic control) and sorbinil (an aldose reductase inhibitor [ARI]) versus the effects of sorbinil alone or of two insulin regimens providing different degrees of glycemic control on diabetes-induced metabolic derangements and vascular function. Streptozocin-diabetic rats were divided into the following five groups: (1) untreated (D); (2) treated with approximately 1 U NPH insulin/100 g body weight/d administered in one subcutaneous (SC) injection (DI-1); (3) treated with the same total daily dose of insulin administered in two SC injections (DI-2); (4) treated with approximately 0.2 mmol sorbinil in the diet/kg body weight/d (DS); and (5) treated with once-daily insulin plus sorbinil (DSI-1). Two groups of nondiabetic rats, untreated (C) and sorbinil-treated (CS), served as controls. Metabolic parameters were unaffected by sorbinil treatment in controls and diabetics, whereas insulin administration in the diabetics virtually normalized body growth, food consumption, urine volume, and plasma glucose levels, and markedly decreased hemoglobin A 1 (HbA 1) levels. Two daily injections were more effective than one in improving metabolic control as measured by HbA 1 levels. Regional vascular 131I-albumin permeation was increased about twofold to threefold by diabetes in ocular tissues, sciatic nerve, aorta, diaphragm, and new granulation tissue; it was decreased (but not normalized) by insulin treatment in accordance with improved metabolic control, and was completely normalized by sorbinil. 131I-albumin kidney clearance, as well as urinary albumin and IgG excretion, were markedly increased in diabetic rats and were significantly decreased but not completely normalized by sorbinil and by twice-daily insulin treatment. The combined therapy significantly ameliorated the effect of insulin alone (which still did not completely normalize glucose and HbA 1 levels despite prevention of diabetes-induced weight loss and polyuria), although it did not produce an effect on vascular function beyond that of sorbinil alone (which had no impact on glycemia, HbA 1 level, urine volume, or weight gain). These findings suggest that a dual pharmacologic approach, ie, treatment with a combination of insulin, designed to decrease glucose levels (without risking hypoglycemia), and ARIs, to block excess flux of glucose via the sorbitol pathway due to the residual hyperglycemia, may be advantageous for promoting normal growth and metabolism and for preventing vascular complications while minimizing the risk of increased incidence of hypoglycemia.

Ether Hyperglycemia

Glycosuria following etherization was first observed by Reynoso, while the increase of blood sugar accompanying ether anesthesia was first reported by Seelig. Section of the nerves to the liver does not prevent the hyperglycemia resulting from the administration of ether. If the adrenals are inactivated, however, this rise in blood sugar is in large part prevented, as Keeton and Ross showed. That adrenin rather than the action of sympathetic impulses is the potent factor in liberating sugar from the liver has been shown by Bulatao and Cannon and by Britton. Reid had advanced evidence that the hyperglycemia resulting from etherization is due to secretion of adrenin. But after removal of the adrenal factor ether still produces an increase of blood sugar. The demonstration by Cannon and Bacq, that stimulation of the sympathetic nerves produces sympathin and that sympathin resembles adrenin in action, suggested that the residual hyperglycemia from etherization after adrenal influence had been excluded might result from the action of sympathin. If this idea were correct the level of blood sugar should not rise when ether is administered to completely sympa-thectomized animals. Healthy adult cats were maintained in good condition on an adequate diet and fasted for 24 hours before the experiment. Blood (0.1 cc.) was drawn from an ear vein for sugar determinations, which were made in duplicate by the Folin-Svedberg method. The sugar level was determined before etherization and every 15 minutes thereafter, during the administration of the ether, for one hour. A final analysis was made one hour after cessation of the anesthesia. The ether was administered carefully in order to avoid struggle and to minimize emotional reactions. As soon as relaxation was obtained a tube was inserted between the vocal cords into the trachea, and artificial respiration was started in order to avoid asphyxia. The depth of the anesthesia was regulated so that the corneal reflex was just present. Experiments were performed on normal cats, on cats with the left adrenal denervated, the right removed and the hepatic nerves cut, and on cats completely sympathec-tomized. The completeness of the sympathectomy was assured by noting absence of erection of the hairs on exposure to cold or during emotional excitement. Careful necropsy verified these findings. Summary. The elevation of the blood-sugar level in cats on etherization (Fig. 1A) is considerably reduced by inactivating the adrenals and cutting the liver nerves (Fig. 1B). The residual increase persists in the completely sympathectomized animal (Fig. 1C), and therefore does not result from the production of sympathin. The persistent hyperglycemia does not depend upon direct stimulation of adrenal secretion by ether since it is still present when both adrenals have been removed in the completely sympathectomized cat (Fig. 1E).