Discovery of potent and orally bioavailable indazole-based glucagon receptor antagonists for the treatment of type 2 diabetes

Type 2 diabetes mellitus (T2DM) is characterized by chronically elevated plasma glucose levels. The inhibition of glucagon-induced hepatic glucose output via antagonism of the glucagon receptor (GCGR) using a small-molecule antagonist is a promising mechanism for improving glycemic control in the diabetic state. The present work discloses the discovery of indazole-based β-alanine derivatives as potent GCGR antagonists through an efficient enantioselective synthesis and structure-activity relationship (SAR) exploration and optimization. Compounds within this class exhibited excellent pharmacokinetic properties in multiple preclinical species. In an acute dog glucagon challenge test, compound 13K significantly inhibited glucagon-mediated blood glucose increase when dosed orally at 10 mg/kg.     

Effect of Sitagliptin on Post-Prandial Glucagon and GLP-1 Levels in Patients With Type 1 Diabetes: Investigator-Initiated,Double-Blind,Randomized, Placebo-Controlled Trial

ObjectivePeripheral insulin resistance in type 1 diabetes may be related to a paradoxical postprandial glucagon increase. This study evaluated the effects of sitagliptin (dipeptidyl peptidase-IV [DPP-IV] inhibitor, approved for patients with type 2 diabetes), in adults with type 1 diabetes to improve glycemic control through decreasing postprandial glucagon.MethodsThis investigator-initiated, double-blind, randomized-parallel 20-week study enrolled 141 subjects. Subjects received sitagliptin 100 mg/day or placebo for 16 weeks. A subset of 85 patients wore blinded continuous glucose monitors (CGM) for 5 separate 7-day periods. The primary outcome was post-meal (Boost™) reduction in 4-hour glucagon area under the curve (AUC). Secondary endpoints included changes in glycated hemoglobin (A1c), CGM data, insulin dose, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and C-peptide levels.ResultsThere were no differences at screening between groups; however, after a 4-week run-in phase, A1c was significantly lower in the sitagliptin vs. placebo group. Post-meal GLP-1 levels were higher (P<.001) and GIP levels lower (P = .03), with glucagon suppression at 30 minutes (LS means 23.2 ± 1.9 versus 16.0 ± 1.8; P = .006) in the sitagliptin group at 16 weeks. There were no differences between the groups in change in A1c, insulin dose, weight, or C-peptide after 16 weeks of treatment. However, C-peptide positive patients randomized to sitagliplin had a non-significant trend toward decrease in A1c, mean glucose, and time spent in hyperglycemia.ConclusionSitagliptin use in type 1 diabetes did not change glucagon AUC, A1c, insulin dose, or weight despite post-meal rise in GLP-1 levels. C-peptide positive subjects treated with sitagliptin had a nonsignificant trend in decreasing hyperglycemia, which needs further evaluation. (Endocr Pract. 2013;19:19-28)     

Synthesis and biological evaluation of C-glucosides with azulene rings as selective SGLT2 inhibitors for the treatment of type 2 diabetes mellitus: Discovery of YM543

Here, a series of C-glucosides with azulene rings in the aglycon moiety was synthesized and the inhibitory activities toward hSGLT1 and hSGLT2 were evaluated. Starting from the azulene derivative 7 which had relatively good SGLT2 inhibitory activity, compound 8a which has a 3-[(azulen-2-yl)methyl]phenyl group was identified as a lead compound for further optimization. Introduction of a phenolic hydroxyl group onto the central benzene ring afforded a potent and selective SGLT2 inhibitor 8e, which reduced blood glucose levels in a dose-dependent manner in rodent diabetic models. A mono choline salt of 8e (YM543) was selected as a clinical candidate for use in treating type 2 diabetes mellitus.     

The Role of Glucagon in the Pathophysiology and Management of Diabetes

Objective: There is general recognition that insulin and glucagon are the main hormones involved in the pathophysiology of diabetes, but the role of glucagon in diabetes is complex and in some circumstances controversial. The increasing appreciation of the role of glucagon in currently used hypoglycemic agents and the ongoing development of glucagon-targeted therapies underscores glucagon's important contribution in optimizing diabetes management. The current review provides a background on glucagon physiology and pathophysiology and an update for investigators, endocrinologists, and other healthcare providers on glucagon-modulating therapies.Methods: A literature review was conducted utilizing published literature in PubMed and AccessMedicine including the years 1922–2015 using the following key words: glucagon, bihormonal, diabetes mellitus, glucagon antagonists, glucagon-targeted therapies.Results: Glucagon is a counterregulatory hormone that promotes hepatic glucose production, thus preventing hypoglycemia in normal physiology. In patients with diabetes mellitus, glucagon secretion may be unregulated, which contributes to problems with glucose homeostasis. Several of the most effective therapies for diabetes have been found to suppress glucagon secretion or action, which may contribute to their success. Additionally, glucagon-specific targeted therapies, such as glucagon receptor antagonists, are being studied at a basic and clinical level.Conclusion: Glucagon plays an important role in contributing to hyperglycemia in patients with diabetes. Utilizing hypoglycemic agents that decrease glucagon secretion or inhibit glucagon action can help improve glycemic control, making these agents a valuable resource in diabetes therapy.Abbreviations:cAMP = cyclic adenosine monophosphateDPP-4 = dipeptidyl peptidase 4GLP-1 = glucagon-like peptide 1GR^-/- = glucagon receptor knockoutGR-ASO = antisense oligonucleotides targeted against the glucagon receptorHbA1c = hemoglobin A1cHGP = hepatic glucose productionSGLT-2 = sodium-glucose cotrans-porter 2T1DM = type 1 diabetes mellitusT2DM = type 2 diabetes mellitus     

Discovery of novel pyridazine derivatives as glucose transporter type 4 (GLUT4) translocation activators

We report herein the synthesis and structure-activity relationships (SAR) of a series of pyridazine derivatives with the activation of glucose transporter type 4 (GLUT4) translocation. Through a cell-based phenotype screening in L6-GLUT4-myc myoblasts and functional glucose uptake assays, lead compound 1a was identified as a functional small molecule. After further derivatization, the thienopyridazine scaffold as the central ring (B-part) was revealed to have potent GLUT4 translocation activities. Consequently, we obtained promising compound 26b, which showed a significant blood glucose lowering effect in the severe diabetic mice model (10-week aged db/db mice) after oral dosing even at 10 mg/kg, implying that our pyridazine derivatives have potential to become novel therapeutic agents for diabetes mellitus.     

A Mixed Mirror-image DNA/RNA Aptamer Inhibits Glucagon and Acutely Improves Glucose Tolerance in Models of Type 1 and Type 2 Diabetes

Excessive secretion of glucagon, a functional insulin antagonist, significantly contributes to hyperglycemia in type 1 and type 2 diabetes. Accordingly, immunoneutralization of glucagon or genetic deletion of the glucagon receptor improved glucose homeostasis in animal models of diabetes. Despite this strong evidence, agents that selectively interfere with endogenous glucagon have not been implemented in clinical practice yet. We report the discovery of mirror-image DNA-aptamers (Spiegelmer®) that bind and inhibit glucagon. The affinity of the best binding DNA oligonucleotide was remarkably increased (>25-fold) by the introduction of oxygen atoms at selected 2′-positions through deoxyribo- to ribonucleotide exchanges resulting in a mixed DNA/RNA-Spiegelmer (NOX-G15) that binds glucagon with a K_d of 3 nm. NOX-G15 shows no cross-reactivity with related peptides such as glucagon-like peptide-1, glucagon-like peptide-2, gastric-inhibitory peptide, and prepro-vasoactive intestinal peptide. In vitro, NOX-G15 inhibits glucagon-stimulated cAMP production in CHO cells overexpressing the human glucagon receptor with an IC₅₀ of 3.4 nm. A single injection of NOX-G15 ameliorated glucose excursions in intraperitoneal glucose tolerance tests in mice with streptozotocin-induced (type 1) diabetes and in a non-genetic mouse model of type 2 diabetes. In conclusion, the data suggest NOX-G15 as a therapeutic candidate with the potential to acutely attenuate hyperglycemia in type 1 and type 2 diabetes.     

Design,synthesis and anti-diabetic activity of triazolotriazine derivatives as dipeptidyl peptidase-4 (DPP-4) inhibitors

Type 2 diabetes mellitus (T2DM) is one of the major global metabolic disorders characterized by insulin resistance and chronic hyperglycemia. Inhibition of the enzyme, dipeptidyl peptidase-4 (DPP-4) has been proved as successful and safe therapy for the treatment of T2DM since last decade. In order to design novel DPP-4 inhibitors, various in silico studies such as 3D-QSAR, pharmacophore modeling and virtual screening were performed and on the basis of the combined results of them, total 50 triazolo[5,1-c][1,2,4]triazine derivatives were designed and mapped on the best pharmacophore model. From this, best 25 derivatives were docked onto the active site of DPP-4 enzyme and in silico ADMET properties were also predicted. Finally, top 17 derivatives were synthesized and characterized using FT-IR, Mass, ¹H NMR and ¹³C NMR spectroscopy. Purity of compounds was checked using HPLC. These derivatives were then evaluated for in vitro DPP-4 inhibition. The most promising compound 15q showed 28.05 μM DPP-4 IC₅₀ with 8–10-fold selectivity over DPP-8 and DPP-9 so selected for further in vivo anti-diabetic evaluation. During OGTT in normal C57BL/6J mice, compound 15q reduced blood glucose excursion in a dose-dependent manner. Chronic treatment for 28 days with compound 15q improved the serum glucose levels in type 2 diabetic Sprague Dawley rats wherein diabetes was induced by high fat diet and low dose streptozotocin. This suggested that compound 15q is a moderately potent and selective hit molecule which can be further optimized structurally to increase the efficacy and overall pharmacological profile as DPP-4 inhibitor.     

The Rationale for use of Incretins in the Management of new Onset Diabetes After Transplantation (NODAT)

Objective: Owing to advances in transplant science, increasing numbers of patients are receiving solid organ transplantation. New onset diabetes after transplantation (NODAT) frequently develops in transplant patients and requires acute and often ongoing management of hyperglycemia. The metabolic derangements of NODAT are similar to those of classic type 2 diabetes, and treatment has typically followed diabetes standards of care. Best practices for NODAT management remain to be developed.Methods: The mechanistic suitability of incretins to treat NODAT pathogenesis has been hitherto underappreciated. This review details the specific mechanistic value of incretins in patients with immunosuppression-associated hyperglycemia.Results: Corticosteroids have long been known to exert their effects on glucose metabolism by decreasing glucose utilization and enhancing hepatic gluconeogenesis. Corticosteroids also significantly and directly reduce insulin secretion, as do calcineurin inhibitors (CNIs), another commonly used group of immunosuppressive drugs that cause hyperglycemia and NODAT. The ability of incretins to counteract immunosuppressant-induced disruptions in insulin secretion suggest that the insulinotropic, glucagonostatic, and glucose-lowering actions of incretins are well suited to treat immunosuppressant-induced hyperglycemia in NODAT. Additional benefits of incretins include decreased glucagon levels and improved insulin resistance. In the case of glucagon-like peptide-1 (GLP-1) receptor agonists, weight loss is another benefit, countering the weight gain that is a common consequence of both hyperglycemia and transplantation. These benefits make incretins very attractive and deserving of more investigation.Conclusion: Among diabetes treatment options, incretin therapies uniquely counteract immunosuppressant drugs' interference with insulin secretion. We propose an incretin-based treatment paradigm for NODAT management.Abbreviations: CNI = calcineurin inhibitor DPP-4 = dipeptidyl peptidase 4 GLP-1 = glucagon-like peptide-1 HbA1c = glycated hemoglobin HLA = human leukocyte antigen NODAT = new onset diabetes after transplantation     

GALNT2 Expression Is Reduced in Patients with Type 2 Diabetes: Possible Role of Hyperglycemia

Impaired insulin action plays a major role in the pathogenesis of type 2 diabetes, a chronic metabolic disorder which imposes a tremendous burden to morbidity and mortality worldwide. Unraveling the molecular mechanisms underlying insulin resistance would improve setting up preventive and treatment strategies of type 2 diabetes. Down-regulation of GALNT2, an UDPN-acetyl-alpha-D-galactosamine polypeptideN-acetylgalactosaminyltransferase-2 (ppGalNAc-T2), causes impaired insulin signaling and action in cultured human liver cells. In addition, GALNT2 mRNA levels are down-regulated in liver of spontaneously insulin resistant, diabetic Goto-Kakizaki rats. To investigate the role of GALNT2 in human hyperglycemia, we measured GALNT2 mRNA expression levels in peripheral whole blood cells of 84 non-obese and 46 obese non-diabetic individuals as well as of 98 obese patients with type 2 diabetes. We also measured GALNT2 mRNA expression in human U937 cells cultured under different glucose concentrations. In vivo studies indicated that GALNT2 mRNA levels were significantly reduced from non obese control to obese non diabetic and to obese diabetic individuals (p<0.001). In vitro studies showed that GALNT2 mRNA levels was reduced in U937 cells exposed to high glucose concentrations (i.e. 25 mmol/l glucose) as compared to cells exposed to low glucose concentration (i.e. 5.5 mmol/l glucose +19.5 mmol/l mannitol). In conclusion, our data indicate that GALNT2 is down-regulated in patients with type 2 diabetes and suggest that this association is, at least partly, secondary to hyperglycemia. Further studies are needed to understand whether GALNT2 down-regulation plays a pathogenic role in maintaining and/or aggravating the metabolic abnormalities of diabetic milieu.     

A novel Steroid from Elephantopus scaber L. an Ethnomedicinal plant with antidiabetic activity

Acetone extract of Elephantopus scaber, an ethnomedicnal plant, reduced the blood glucose levels in streptozotocin-induced diabetic rats significantly. Acute toxicity studies revealed the non-toxic nature of the crude extract. Fractionation of the acetone extract yielded a new steroid, 28Nor-22(R)Witha 2,6,23-trienolide. Biological testing of the compound demonstrated a significant antidiabetic activity by reducing the elevated blood glucose levels and restoring the insulin levels in streptozotocin-induced diabetic rats. This compound can be a useful candidate to treat diabetes.     

Diabetes: A Cardiac Condition Manifesting as Hyperglycemia

ObjectiveTo investigate the reasons for the increased risk of cardiovascular events and mortality in individuals with type 2 diabetes mellitus.MethodsFrom January 1990 to March 2008, literature relevant to low-density lipoprotein (LDL) and highdensity lipoprotein (HDL) cholesterol, hemoglobin A1c, acute hyperglycemia, postprandial hyperglycemia, systolic blood pressure, insulin resistance, endothelial dysfunction, microalbuminuria, diabetic cardiomyopathy, left ventricular hypertrophy, function inhibitors of the renin-angiotensin system and sympathetic nervous system, statins, and antiplatelet therapy as related to cardiac events and mortality in type 2 diabetic patients was reviewed.ResultsIncreased numbers of cardiac events and mortality in type 2 diabetes are associated with low HDL and high LDL cholesterol, high hemoglobin A1c, and high systolic blood pressure. Acute hyperglycemia, postprandial hyperglycemia, and possibly use of traditional sulfonylureas also increase incidence of cardiac events and mortality. The presence of microalbuminuria signifies endothelial dysfunction and an increased risk of cardiac events. Hypertension should be treated to goals that are lower in the diabetic patient with multiple therapies, which include suppressors of the renin-angiotensin and sympathetic nervous systems. Decreased improvement in outcomes for the diabetic patient with cardiovascular disease may be accounted for by the failure to treat insulin resistance and ventricular dysfunction. The high incidence of heart failure in the diabetic patient is due to the toxic triad of diabetic cardiomyopathy, left ventricular hypertrophy, and extensive coronary artery disease.ConclusionHigh risk of cardiovascular events, heart failure, and mortality in type 2 diabetes can be lowered with risk factor reduction and therapies that prevent or improve ventricular function. (Endocr Pract. 2008;14:924-932)     

Fasting Versus Postprandial Hyperglycemia as a Treatment Target to Lower Elevated Hemoglobin A1C

Objective: Postprandial hyperglycemia (PPHG) may need addressing when glycemic control cannot be maintained in patients with type 2 diabetes mellitus. We investigated whether glycated hemoglobin A_1c (A_1c) levels ≥7.0% can indicate postprandial defects warranting prandial therapy after optimized basal insulin therapy.Methods: From 6 clinical trials of insulin glargine treatment, data were pooled from 496 patients with A_1c ≥7.0% after 24 weeks. Patient characteristics and clinical outcomes were summarized according to fasting plasma glucose (FPG) target achievement (<130 mg/dL), postprandial blood glucose (PPBG) levels, and PPBG increments (ΔPPBG). Basal and postprandial contributions to hyperglycemia were determined.Results: After 24 weeks of insulin glargine titration, A_1c change from baseline was greater in patients with FPG <130 mg/dL versus ≥130 mg/dL (-1.35% versus -1.11%, respectively; P = .0275), but with increased confirmed hypoglycemia rates (blood glucose <70 mg/dL; 4.06 events/patient-year versus 3.31 events/patient-year; P = .0170). However, increased severe hypoglycemia rates were observed in patients with FPG ≥130 mg/dL. At week 24, postprandial contributions to hyperglycemia increased (>60% regardless of PPBG). Patients with high FPG had lower, but substantial, relative postprandial contributions versus patients achieving FPG target. A similar pattern was observed according to whether patients had a ΔPPBG ≥50 mg/dL after any meal.Conclusion: After optimized basal insulin therapy, elevated A_1c is the most effective indicator of residual PPHG, regardless of existent FPG or PPBG. When confronted with an uncontrolled A_1c after reasonable titration of basal insulin, clinicians should be aware of probable postprandial contributions to hyperglycemia and consider prandial therapy.Abbreviations:A_1c = glycated hemoglobin A_1cAUC = area under the curveAUC_B = area under the curve (basal hyperglycemia)AUC_G = total area under the curve (total glucose)AUC_N = area under the curve (normal glycemic exposure)AUC_P = area under the curve (postprandial hyperglycemia)BHG = basal hyperglycemiaFBG = fasting blood glucoseFPG = fasting plasma glucoseGLP-1 = glucagon-like peptide 1HE = hyperglycemic exposureOADs = oral antidiabetes drugsPPBG = postprandial blood glucoseΔPPBG = change in postprandial blood glucosePPHG = postprandial hyperglycemiaSMBG = self-monitored blood glucoseT2DM = type 2 diabetes mellitus     

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.     

Synthesis,nitric oxide release,and dipeptidyl peptidase-4 inhibition of sitagliptin derivatives as new multifunctional antidiabetic agents

Nitric oxide (NO) dysfunction has been found to be an important factor in both the development and progression of diabetic complications due to its many roles in the vascular system. Multifunctional compounds with hypoglycemic and endothelial protective action will be promising agents for the treatment of diabetes and its complications. In this study, a series of novel NO-donating sitagliptin derivatives and relevant metabolites were synthesized and evaluated as potential multifunctional hypoglycemic agents. All of synthetic compounds shown remarkable inhibitory activity against dipeptidyl peptidase IV (DPP-IV) in vitro and demonstrated excellent hypoglycemic activities in diabetic mice, similar to the activity of sitagliptin, and compounds T1-T4 shown different extents of NO-releasing abilities and potent antioxidant abilities in vivo. By screening in DPP-4, compound T4 was recognized as a potent DPP-4 inhibitor with the IC₅₀ value of 0.060?μM. Docking study revealed compound T4 has a favorable binding mode. Furthermore, compounds T1-T4 exhibited different extents of NO-releasing abilities and excellent anti-platelet aggregation in vitro. The overall results suggested that T4 could help to the amelioration of endothelial dysfunction by reducing blood glucose, lessening oxidative stress and raising NO levels as well as inhibiting platelet aggregation. Based on this research, compound T4 deserves further investigation as potential new multifunctional anti-diabetic agent with antioxidant, anti-platelet aggregation and endothelial protective properties.     

Reducing oxidative stress in patients with type 2 diabetes mellitus: A primary care call to action

Background: Oxidative stress is believed to be the primary cause of the microvascular and macrovascular complications of type 2 diabetes mellitus (DM).Objective: This paper examines the evidence linking oxidative stress with long-term complications of type 2 DM and explores methods to minimize its effect.Methods: A literature search was performed to identify relevant studies for this review. Articles published in English from 2000 to 2008 were identified through searches of PubMed, Diabetes Care, and Google using the search terms oxidative stress, postprandial hyperglycemia, ACCORD Trial, and endothelial cell dysfunction.Results: The literature search identified 423 articles. Although chronic hyperglycemia can be effectively monitored and targeted using glycosylated hemoglobin concentrations, postprandial glucose levels are also important. Postprandial glucose excursions are exhibited by almost all patients with type 2 DM and are independent risk factors for cardiovascular morbidity and mortality. Furthermore, glucose fluctuations during the postprandial period elicit more oxidative stress than chronic, sustained hyperglycemia and can lead to endothelial dysfunction, vascular inflammation, and microvascular complications. In turn, endothelial dysfunction has been implicated in the development of vascular pathologies such as atherosclerosis. Pharmacologic interventions (eg, rapid-acting insulin analogues that target post-prandial glucose excursions) reduce oxidative stress and vascular inflammation and improve endothelial dysfunction.Conclusions: Given the important role of oxidative stress in the development of complications of type 2 DM, physi-cians should consider methods to reduce oxidative stress that may occur during both acute (postprandial) and chronic hyperglycemia. One critical aspect is to reduce postprandial glucose levels to <180 mg/dL while lowering fasting glucose levels to <110 mg/dL. By coaching patients to reach these goals, physicians and other health care professionals can minimize the risk of long-term complications of type 2 DM.     

Diabetes and Hyperglycemia Quality Improvement Efforts in Hospitals in the United States: Current Status,Practice Variation,and Barriers to Implementation

ObjectiveTo determine the status of diabetes and hyperglycemia quality improvement efforts in hospitals in the United States.MethodsWe designed and administered a survey to a convenience sample of hospitals, and the responses were analyzed statistically.ResultsWe received 269 responses from 1,151 requested surveys. The sample was similar to hospitals in the United States on the basis of hospital type and geographic region (P = no significant difference) but not on the basis of number of beds (P < .001). Among responding hospitals, 39%, 21%, and 15% had fully implemented inpatient diabetes and hyperglycemia quality improvement programs for critically ill, non-critically ill, and perioperative patients, respectively. Moreover, 77%, 44%, and 49% had fully implemented protocols for hypoglycemia, hyperglycemic crises, and diabetic ketoacidosis, respectively. Variations in glucose target ranges were noted. The responding hospitals had no standard biochemical definition of hypoglycemia; 47% defined hypoglycemia as a glucose level ≤ 70 mg/dL, but 29%, 8%, 6%, and 4% used < 60, ≤ce:hsp sp="0.10"/>50, < 40, and < 80 mg/dL, respectively. Almost a third of reporting hospitals had no metric to track the quality of inpatient diabetes and hyperglycemia care. More than half (59%) indicated that they did not have an automated capability to extract and analyze glucose data. The most frequent barrier to implementing a glycemic control program was concern regarding hypoglycemia (61%).ConclusionHospitals are addressing the issue of inpatient diabetes and glycemic control but face obstacles to implementation of quality improvement programs and vary in their approach to management. Improving the consistency of glucose control practices within hospitals in the United States should help enhance patient care and safety. Future efforts to help hospitals overcome barriers to introducing glucose control programs could include developing standardized glycemic control metrics, improving data collection and reporting methods, and providing improved tools that enable clinicians to control glucose safely. (Endocr Pract. 2010;16:219-230)     

Influence Of Diabetes And Hyperglycemia On Duration Of Stay In Patients Hospitalized With Congestive Heart Failure

ObjectiveTo analyze the influence of diabetes and hyperglycemia on duration of stay in patients hospitalized with congestive heart failure (CHF).MethodsWe conducted a retrospective review of data for patients admitted during a 6-month period with CHF to a community teaching hospital in Baltimore, Maryland. Patients were divided into diabetic and nondiabetic groups, and patients with diabetes were stratified by mean fasting plasma glucose levels into the following groups: < 110 mg/dL, 110 to 180 mg/dL, and > 180 mg/dL. The primary outcome was duration of hospitalization. Other variables included sex, age, ejection fraction, admission glucose, brain natriuretic peptide, creatinine, and other comorbidities.ResultsThe study cohort consisted of 142 patients, 49% of whom had diabetes. The duration of hospitalization was 3.23 days in the patients with diabetes versus 3.11 days in those without diabetes (P = .875). Patients with diabetes were significantly younger (71.8 versus 76.6 years; P = .027) and had a higher baseline mean creatinine level (1.4 versus 1.2 mg/dL; P = .010). Patients with diabetes in the 110 to 180 mg/dL blood glucose group had shorter hospitalizations than did those in the < 110 mg/dL group (2.94 versus 3.41 days; P = .259). Only 9 patients had blood glucose levels > 180 mg/dL, and these patients had the longest hospitalizations (mean duration, 3.78 days).ConclusionThe prevalence of diabetes was higher in our study than in previously published studies of patients with CHF. Although patients with diabetes did not have significantly longer hospitalizations than those without diabetes, they were significantly younger and had higher baseline creatinine values. Hyperglycemia was an infrequent phenomenon among patients without diabetes. The patients with diabetes in the 110 to 180 mg/dL blood glucose group had shorter hospitalizations than did those in the < 110 mg/dL group, although this difference did not reach statistical significance. Many of the initial studies of tight glucose control were conducted in the surgical intensive care unit, but recently published evidence has raised doubt about applying these results to medical patients. We conclude that there may be no significant benefit in terms of duration of hospitalization in assigning patients with diabetes who have CHF exacerbations to tight glucose control regimens. A more liberal approach of maintaining glucose levels at 110 to 180 mg/dL may be acceptable. (Endocr Pract. 2008;14:691-696)     

Exaggeration of Postprandial Hyperglycemia in Patients with type 2 Diabetes by Administration of Caffeine in Coffee

ObjectiveTo test whether caffeine administered in coffee increases postprandial hyperglycemia in patients with type 2 diabetes who are habitual coffee drinkers.MethodsThe study used a within-subject, double-blind, placebo-controlled experimental design. Twenty adult coffee drinkers (11 women and 9 men) with type 2 diabetes treated with diet, exercise, orally administered antidiabetic agents, or some combination of these factors completed two mixed-meal tolerance tests (MMTT) after an overnight fast. Before the MMTT, each study participant received 250 mg of caffeine in 16 oz (475 mL) of decaffeinated coffee or decaffeinated coffee alone, with the treatment order counterbalanced in the group. Fasting and 1-hour and 2-hour postprandial blood samples were collected for measurement of plasma glucose and insulin concentrations.ResultsGlucose and insulin responses to the MMTT were quantified by the incremental areas under the 2-hour concentration-time curves (AUC_2h). Administration of caffeine in decaffeinated coffee increased postprandial glucose and insulin responses (both P = 0.02). The mean plasma glucose AUC_2h was 28% larger and the mean plasma insulin AUC_2h was 19% larger after administration of caffeine than after administration of placebo.ConclusionOther constituents in coffee did not prevent the exaggeration of postprandial hyperglycemia by caffeine in these patients with type 2 diabetes, who were habitual coffee drinkers. Repeated on a daily basis, such effects could impair long-term glucose control in those patients with type 2 diabetes who habitually drink coffee or other caffeinated beverages. (Endocr Pract. 2007;13: 239-243)