Betsy B. Dokken

Role of glycogen synthase kinase-3 in insulin resistance and type 2 diabetes

A reduced ability of insulin to activate glucose transport in skeletal muscle, termed insulin resistance, is a primary defect leading to the development of impaired glucose tolerance and type 2 diabetes. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with important roles in the regulation of glycogen synthesis, protein synthesis, gene transcription, and cell differentiation in various cell types. An emerging body of evidence has implicated GSK-3 in the multifactorial etiology of skeletal muscle insulin resistance in obese animal models and in obese human type 2 diabetic subjects. Overexpression and overactivity of GSK-3 in skeletal muscle of rodent models of obesity and obese type 2 diabetic humans are associated with an impaired ability of insulin to activate glucose disposal and glycogen synthase. New insights into the importance of GSK-3 as a regulator of insulin action on glucose transport activity in muscle have come from studies utilizing selective and sensitive inhibitors of GSK-3. These studies have demonstrated that selective inhibition of GSK-3 in insulin-resistant skeletal muscle causes improvements in insulin-stimulated glucose transport activity that are likely caused by enhanced post-insulin receptor insulin signaling and GLUT-4 glucose transporter translocation. An additional important action of these GSK-3 inhibitors in the context of obese-associated type 2 diabetes is a reduction of hepatic glucose production, likely via downregulation of genes associated with gluconeogensis. It is clear from these studies that selectively targeting GSK-3 in skeletal muscle may be an important new strategy for the treatment of obesity-associated insulin-resistant states characterized by GSK-3 overactivity in insulin-sensitive tissues.

Glucagon-like peptide-1 (GLP-1), immediately prior to reperfusion, decreases neutrophil activation and reduces myocardial infarct size in rodents.

Glucagon-like peptide-1 (GLP-1) is an incretin that has glucoregulatory effects as well as protective effects in a variety of tissues, including the heart. We hypothesized that GLP-1 may have a direct effect on neutrophils (PMNs) after myocardial ischemia, to ameliorate reperfusion injury. Deeply anesthetized Sprague-Dawley rats underwent 30 min of left coronary artery occlusion followed by 120 min of reperfusion. Immediately prior to reperfusion, rats were treated with either GLP-1 (human rGLP-1, 30 pM/kg/min) or PBS as placebo. GLP-1 significantly decreased myocardial infarct size [73.2±11.7% INF/AAR in PBS (n=4) vs. 15.7 ±5.52% INF/AAR in GLP-1-treated animals (n=5),  p<0.05], PMN activation in blood in vivo (fMLP-stimulated CD11b surface expression: PBS 2.78±1.14 vs. GLP-1 1.7±0.21, TFI, p<0.05), and accumulation in myocardium (PBS: 6.52±0.31 vs. GLP-1: 4.78±0.90, n=4-6 animals/group, p<0.05). In addition, we found that GLP-1 mitigated PMN CD11b surface expression in whole rat blood in vitro, an effect that was abolished by GLP-1 receptor blockade (PBS 6.52±0.31 vs. GLP-1 4.78±0.90, TFI, p<0.05). These findings suggest that one mechanism by which GLP-1 decreases reperfusion injury may be the attenuation of PMN-mediated reperfusion injury.

Glucagon-like peptide-1 (GLP-1) attenuates post-resuscitation myocardial microcirculatory dysfunction

AIM OF THE STUDY Post-resuscitation syndrome leads to death in approximately 2 out of every 3 successfully resuscitated victims, and myocardial microcirculatory dysfunction is a major component of this syndrome. The aim of this study was to determine if glucagon-like peptide-1 (GLP-1) improves post-resuscitation myocardial microcirculatory function. METHODS Ventricular fibrillation (VF) was induced electrically in 20 anesthetized domestic swine (30-35 kg). Following 8 min of untreated VF, animals were resuscitated with aggressive advanced cardiac life support (ACLS). Animals were blindly randomized to receive a continuous infusion of either GLP-1 (10 pM/kg/min) or equal volume saline as placebo (PBO) for 4h, beginning 1 min after return of spontaneous circulation (ROSC). Left ventricular (LV) haemodynamics, LV ejection fraction, cardiac output, and coronary flow reserve (CFR) [using a standard technique of intracoronary Doppler flow measurements before and after intracoronary administration of 60 microg adenosine] were performed pre-arrest and at 1 and 4h post-resuscitation. In the present study, CFR is a measure of myocardial microcirculatory function since these swine had no obstructive coronary artery disease. Twenty-four hour post-resuscitation survival and neurological functional scores were also determined. RESULTS CFR was significantly increased in GLP-1-treated animals, 1h (1.79+/-0.13 in control animals vs. 2.05+/-0.12 in GLP-1-treated animals, P = <0.05) and 4h (1.82+/-0.16 in control animals vs. 2.31+/-0.13 in GLP-1-treated animals, P = <0.05) after ROSC. In addition, compared to PBO-treated animals, GLP-1 increased cardiac output 1h after ROSC (2.1+/-0.1 in control animals vs. 2.7+/-0.2 in GLP-1-treated animals, P = <0.05). There was no statistically significant difference in survival between GLP-1-treated (100%) and PBO-treated animals (78%). CONCLUSIONS In this swine model of prolonged VF followed by successful resuscitation, myocardial microcirculatory function was enhanced with administration of GLP-1. However, GLP-1 treatment was not associated with a clinically significant improvement in post-resuscitation myocardial function.

Glucagon-like peptide-1 preserves coronary microvascular endothelial function after cardiac arrest and resuscitation: potential antioxidant effects

Glucagon-like peptide-1 (GLP-1) has protective effects in the heart. We hypothesized that GLP-1 would mitigate coronary microvascular and left ventricular (LV) dysfunction if administered after cardiac arrest and resuscitation (CAR). Eighteen swine were subjected to ventricular fibrillation followed by resuscitation. Swine surviving to return of spontaneous circulation (ROSC) were randomized to receive an intravenous infusion of either human rGLP-1 (10 pmol·kg(-1)·min(-1); n = 8) or 0.9% saline (n = 8) for 4 h, beginning 1 min after ROSC. CAR caused a decline in coronary flow reserve (CFR) in control animals (pre-arrest, 1.86 ± 0.20; 1 h post-ROSC, 1.3 ± 0.05; 4 h post-ROSC, 1.25 ± 0.06; P < 0.05). GLP-1 preserved CFR for up to 4 h after ROSC (pre-arrest, 1.31 ± 0.17; 1 h post-ROSC, 1.5 ± 0.01; 4 h post-ROSC, 1.55 ± 0.22). Although there was a trend toward improvement in LV relaxation in the GLP-1-treated animals, overall LV function was not consistently different between groups. 8-iso-PGF(2α), a measure of reactive oxygen species load, was decreased in post-ROSC GLP-1-treated animals [placebo, control (NS): 38.1 ± 1.54 pg/ml; GLP-1: 26.59 ± 1.56 pg/ml; P < 0.05]. Infusion of GLP-1 after CAR preserved coronary microvascular and LV diastolic function. These effects may be mediated through a reduction in oxidative stress.

The mannose-binding lectin pathway is a significant contributor to reperfusion injury in the type 2 diabetic heart

The severity of ischaemic heart disease is markedly enhanced in type 2 diabetes.We recently reported that complement activation exacerbates I/R injury in the type 2 diabetic heart.The purpose of this study was to isolate and examine MBL pathway activation following I/R injury in the diabetic heart. ZLC and ZDF rats underwent 30 minutes of left coronary artery occlusion followed by 120 minutes of reperfusion.Two different groups of ZDF rats were treated with either FUT-175, a broad complement inhibitor, or P2D5, a monoclonal antibody raised against rat MBL-A. ZDF rats treated with FUT175 and P2D5 had significantly decreased myocardial infarct size, C3 deposition and neutrophil accumulation compared with untreated ZDF controls.Taken together, these findings indicate that the MBL pathway plays a key role in the severity of complement-mediated I/R injury in the type 2 diabetic heart.

Managing diabetes with integrated teams: maximizing your efforts with limited time.

Abstract The importance of glycemic control has been well established. In response, the American Diabetes Association has established goals for glycemic control and other cardiovascular parameters, including blood pressure and low–density and high–density lipoprotein cholesterol. However, the National Health and Nutrition Examination Survey has shown that only about half (57%) of patients with diabetes meet a glycated hemoglobin A1c (HbA1c) goal of < 7%, approximately 45% meet blood pressure and total cholesterol goals, and only 12% achieve all 3 treatment goals. While treating hyperglycemia remains the primary treatment goal, careful selection of pharmacotherapies that do not adversely affect cardiovascular risk factors or long–term glycemic control is an important consideration for patients with type 2 diabetes mellitus. During the past 5 years, the number of treatment options and the complexity of treatment guidelines for diabetes have increased markedly, which makes treatment decisions more complicated and time–consuming, and greatly impacts the workload of the primary care physicians who deliver care to the majority of this population. To provide optimal diabetes care when time and resources are limited, primary care physicians may want to enlist the support of other providers, such as nurse practitioners, physician assistants, diabetes educators, dietitians, and social and case workers. The use of team care, coupled with appropriately chosen pharmacologic therapy and patient education that fosters the development of critical thinking skills and the ability to make self–management decisions, have been shown to improve glycemic control and cardiovascular outcomes.

Inhibition of nitric oxide synthases, but not inducible nitric oxide synthase, selectively worsens left ventricular function after successful resuscitation from cardiac arrest in swine.

OBJECTIVES Nitric oxide (NO) is a critical regulator of vascular tone and signal transduction in the cardiovascular system. NO is synthesized by three unique enzymes (nitric oxide synthases [NOS]): endothelial and neuronal NOS, both constitutively expressed, and inducible NOS (iNOS), which is induced by proinflammatory stimuli and subsequently produces a burst of NO. NO has been implicated as both an injurious and a beneficial mediator after cardiac arrest and resuscitation. A previous study in swine found that iNOS expression is absent in the myocardium prior to cardiac arrest and that it increases after 10 minutes of untreated ventricular fibrillation (VF), decreases somewhat during the early postresuscitation period, and then steadily increases up to 6 hours postresuscitation. Because this time course of iNOS expression mirrors that of postresuscitation myocardial dysfunction, this study was designed to test the hypothesis that selective inhibition of iNOS improves postresuscitation outcomes in swine. METHODS Thirty-two domestic swine of either sex were randomly assigned to receive one of the following treatments 15 minutes after return of spontaneous circulation (ROSC): (1) N(G) -nitro-l-arginine methyl ester (l-NAME), a global NO inhibitor; (2) aminoguanidine (AG), a selective iNOS inhibitor; or (3) saline as control. After 10 minutes of untreated VF, swine received a standard resuscitation protocol. Twenty-four-hour survival, neurological status, left ventricular (LV) function, and hemodynamic measurements were obtained. RESULTS Return of spontaneous circulation occurred in 28 of 32 animals (88%). Only successfully resuscitated animals were assigned to treatment groups and completed the study. There were no differences in survival or neurological outcomes between groups. There were also no differences in LV function or hemodynamic variables found between the control group and the AG group. Global inhibition of NOS with l-NAME post-ROSC increased aortic pressure and transiently decreased pulse pressure. Treatment with l-NAME also increased LV end diastolic pressure and decreased cardiac output within 30 minutes post-ROSC, which was sustained throughout the 4-hour measurements, compared to both the control and the AG groups. In addition, LV ejection fraction recovered to baseline measurements in both the control and AG groups, but failed to recover in the l-NAME group. CONCLUSIONS Global inhibition of NOS after cardiac arrest and resuscitation markedly worsens hemodynamic variables. Selective inhibition of iNOS after cardiac arrest and resuscitation does not prevent postresuscitation myocardial stunning. There were no significant differences in neurological outcome or survival between treatment groups.

The Role of Dietary Fat in Insulin Resistance and Type 2 Diabetes

• The role of dietary fat in health and disease is controversial as fatty acids act as signaling molecules in a variety of metabolic pathways and dietary fat has a role in both the etiology and prevention of insulin resistance and type 2 diabetes.