Antisense oligonucleotide targeting hepatic Serum Amyloid A limits the progression of angiotensin II-induced abdominal aortic aneurysm formation.

BACKGROUND AND AIMS: Obesity increases the risk for abdominal aortic aneurysms (AAA) in humans and enhances angiotensin II (AngII)-induced AAA formation in C57BL/6 mice. We reported that deficiency of Serum Amyloid A (SAA) significantly reduces AngII-induced inflammation and AAA in both hyperlipidemic apoE-deficient and obese C57BL/6 mice. The aim of this study is to investigate whether SAA plays a role in the progression of early AAA in obese C57BL/6 mice. METHODS: Male C57BL/6J mice were fed a high-fat diet (60% kcal as fat) throughout the study. After 4 months of diet, the mice were infused with AngII until the end of the study. Mice with at least a 25% increase in the luminal diameter of the abdominal aorta after 4 weeks of AngII infusion were stratified into 2 groups. The first group received a control antisense oligonucleotide (Ctr ASO), and the second group received ASO that suppresses SAA (SAA-ASO) until the end of the study. RESULTS: Plasma SAA levels were significantly reduced by the SAA ASO treatment. While mice that received the control ASO had continued aortic dilation throughout the AngII infusion periods, the mice that received SAA-ASO had a significant reduction in the progression of aortic dilation, which was associated with significant reductions in matrix metalloprotease activities, decreased macrophage infiltration and decreased elastin breaks in the abdominal aortas. CONCLUSIONS: We demonstrate for the first time that suppression of SAA protects obese C57BL/6 mice from the progression of AngII-induced AAA. Suppression of SAA may be a therapeutic approach to limit AAA progression.

Antisense Oligonucleotide Targeting Hepatic Serum Amyloid A Limits the Progression of Angiotensin II-Induced Abdominal Aortic Aneurysm Formation.

OBJECTIVE: Obesity increases the risk for abdominal aortic aneurysms (AAA) in humans and enhances angiotensin II (AngII)-induced AAA formation in C57BL/6 mice. Obesity is also associated with increases in serum amyloid A (SAA). We previously reported that deficiency of SAA significantly reduces AngII-induced inflammation and AAA in both hyperlipidemic apoE-deficient and obese C57BL/6 mice. In this study, we investigated whether SAA plays a role in the progression of early AAA in obese C57BL/6 mice. APPROACH AND RESULTS: Male C57BL/6J mice were fed a high-fat diet (60% kcal as fat) throughout the study. After 4 months of diet, the mice were infused with angiotensin II (AngII) until the end of the study. Mice with at least a 25% increase in the luminal diameter of the abdominal aorta after 4 weeks of AngII infusion were stratified into 2 groups. The first group received a control antisense oligonucleotide (Ctr ASO), and the second group received ASO that suppresses SAA (SAA-ASO) until the end of the study. Plasma SAA levels were significantly reduced by the SAA ASO treatment. While mice that received the control ASO had continued aortic dilation throughout the AngII infusion periods, the mice that received SAA-ASO had a significant reduction in the progression of aortic dilation, which was associated with significant reductions in matrix metalloprotease activities, decreased macrophage infiltration and decreased elastin breaks in the abdominal aortas. CONCLUSION: We demonstrate for the first time that suppression of SAA protects obese C57BL/6 mice from the progression of AngII-induced AAA. Suppression of SAA may be a therapeutic approach to limit AAA progression.

Risk of adrenal crisis in dental patients: results of a systematic search of the literature.

BACKGROUND: The authors performed a systematic search of the literature to identify the frequency of, risk of experiencing and factors associated with adrenal crises in dental patients. METHODS: The authors searched PubMed and Ovid MEDLINE (1947-June 20, 2012) and Embase (1974-2012) for English-language articles related to cases of adrenal crisis in dentistry and extracted and analyzed data from the articles. The six authors determined whether the cases identified met a consensus definition of adrenal crisis. RESULTS: Of 148 articles identified in the initial screening, 34 articles were included in the final review, from which six cases met the criteria of adrenal crisis. The authors categorized four cases as "suggestive of adrenal crisis" and two cases as "consistent with adrenal crisis." Risk factors were significant adrenal insufficiency, pain, infection, having undergone an invasive procedure, having received a barbiturate general anesthetic, and poor health status and stability at the time of presentation. The authors estimated risk to be less than one in 650,000 in patients with adrenal insufficiency. CONCLUSIONS: Adrenal crisis is rare in dental patients, with only six reports of it having been published in the past 66 years. Risk is associated with unrecognized adrenal insufficiency, poor health status and stability at the time of treatment, pain, infection, having undergone an invasive procedure and having received a barbiturate general anesthetic. CLINICAL IMPLICATIONS: Risk of adrenal crisis is reduced through proper evaluation of the patient, identification of risk factors and following appropriate preventive measures.

Pathophysiology and management strategies for hyperglycemia for patients with acute illness during and following a hospital stay.

Hyperglycemia in the inpatient setting is associated with poor clinical outcomes and is often suboptimally managed. This review addresses the pathophysiology of hyperglycemia, current recommendations for management of inpatient hyperglycemia in the general medical and surgical care setting, the transition between different diabetes treatments, and the transition from inpatient to outpatient therapy. The preferred drug for management of inpatient hyperglycemia is insulin. Successful use of intravenous and subcutaneous insulin in the hospital is based on the implementation of standardized protocols. Current guidelines recommend basal-bolus subcutaneous insulin in non-critically ill patients. The methods of switching from intravenous to subcutaneous, sliding-scale to basal-bolus, and biphasic to basal-bolus are discussed. Transition from an inpatient to an outpatient insulin regimen, especially in patients new to insulin therapy, requires special attention to ensure that patients have the knowledge to administer insulin safely and effectively. The optimal regimen at discharge must be individualized. Patients with acute infections may benefit from insulin therapy until the infection is resolved. Strategies to optimize diabetes therapy after discharge are discussed. Prompt outpatient follow-up is crucial to ensure optimal glycemic control. Despite the challenges, improved glycemic control in individuals with acute illness has the potential to reduce morbidity and mortality in individuals with this widespread metabolic illness.

Extended longitudinal analysis of arterial pressure and heart rate control in unanesthetized rats with type 1 diabetes.

We recorded arterial pressure (BP) and heart rate (HR) in type-1 diabetic rats vs. controls for >6 months. Diabetic rats (DIAB) were maintained on insulin from the day glucose >250 mg/dl ("Day 0"). Weight was similar between groups until ~3 weeks before Day 0 when the weight in DIAB transiently lagged the controls (CONT); this difference was maintained throughout the study, but both groups otherwise gained weight in parallel. Plasma glucose attained 371 ± 109 (SD) mg/dl by day 1 in DIAB. Mean BP was similar across groups, and declined through the initial 4-6 months in both the CONT (at -0.06 ± 0.04 mmHg/day) and in the DIAB (at -0.14 ± 0.21 mmHg/day; NS vs. CONT). HR in the CONT (Month 1: 341 ± 13 bpm) exceeded DIAB (325 ± 25 bpm) through ~6 months after Day 0, and also decreased progressively over this period in CONT (-0.19 ± 0.14 bpm/day) and DIAB (-0.29 ± 0.23 bpm/day; NS vs. CONT) before leveling. The BP power within 0.35-0.45 Hz changed during the 90 min before vs. after the transition from dark to light, and light to dark; there were no between group differences. The slope of the log-log linear portion of the BP power spectrum between 1.0/h and 1/min was similar across groups, and increased in both from month 1 to month 6. Regulatory mechanisms maintain similar profiles in BP and HR in diabetic vs. control animals through the initial half year of the disease.

Blood pressure regulation in diabetic patients with and without peripheral neuropathy.

Cardiac and vascular dysfunctions resulting from autonomic neuropathy (AN) are complications of diabetes, often undiagnosed. Our objectives were to: 1) determine sympathetic and parasympathetic components of compromised blood pressure (BP) regulation in patients with peripheral neuropathy and 2) rank noninvasive indexes for their sensitivity in diagnosing AN. We continuously measured electrocardiogram, arterial BP, and respiration during supine rest and 70° head-up tilt in 12 able-bodied subjects, 7 diabetics without, 7 diabetics with possible, and 8 diabetics with definite, sensory, and/or motor neuropathy (D2). During the first 3 min of tilt, systolic BP (SBP) of D2 decreased [-10.9 ± 4.5 (SE) mmHg] but increased in able-bodied (+4.8 ± 5.4 mmHg). Compared with able-bodied, D2 had smaller low-frequency (0.04-0.15 Hz) spectral power of diastolic BP, lower baroreflex effectiveness index (BEI), and more SBP ramps. Except for low-frequency power of SBP, D2 had greater SBP and smaller RR interval harmonic and nonharmonic components at rest across the 0.003- to 0.45-Hz region. In addition, our results support previous findings of smaller HF RR interval power, smaller numbers of baroreflex sequences, and lower baroreflex sensitivity in D2. We conclude that diabetic peripheral neuropathy is accompanied by diminished parasympathetic and sympathetic control of heart rate and peripheral vasomotion and diminished baroreflex regulation. A novel finding of this study lies in the sensitivity of BEI to detect AN, presumably because of its combination of parameters that measure reductions in both sympathetic control of vasomotion and parasympathetic control of heart rate.

Longitudinal analysis of arterial blood pressure and heart rate response to acute behavioral stress in rats with type 1 diabetes mellitus and in age-matched controls.

We recorded via telemetry the arterial blood pressure (BP) and heart rate (HR) response to classical conditioning following the spontaneous onset of autoimmune diabetes in BBDP/Wor rats vs. age-matched, diabetes-resistant control (BBDR/Wor) rats. Our purpose was to evaluate the autonomic regulatory responses to an acute stress in a diabetic state of up to 12 months duration. The stress was a 15-s pulsed tone (CS+) followed by a 0.5-s tail shock. The initial, transient increase in BP (i.e., the "first component," or C(1)), known to be derived from an orienting response and produced by a sympathetic increase in peripheral resistance, was similar in diabetic and control rats through ∼9 months of diabetes; it was smaller in diabetic rats 10 months after diabetes onset. Weakening of the C(1) BP increase in rats that were diabetic for >10 months is consistent with the effects of sympathetic neuropathy. A longer-latency, smaller, but sustained "second component" (C(2)) conditional increase in BP, that is acquired as a rat learns the association between CS+ and the shock, and which results from an increase in cardiac output, was smaller in the diabetic vs. control rats starting from the first month of diabetes. A concomitant HR slowing was also smaller in diabetic rats. The difference in the C(2) BP increase, as observed already during the first month of diabetes, is probably secondary to the effects of hyperglycemia upon myocardial metabolism and contractile function, but it may also result from effects on cognition. The small HR slowing concomitant with the C(2) pressor event is probably secondary to differences in baroreflex activation or function, though parasympathetic dysfunction may contribute later in the duration of diabetes. The nearly immediate deficit after disease onset in the C(2) response indicates that diabetes alters BP and HR responses to external challenges prior to the development of structural changes in the vasculature or autonomic nerves.

Circadian Variations in Blood Pressure, Heart Rate, and HR-BP Cross-Correlation Coefficient during Progression of Diabetes Mellitus in Rat.

Circadian changes in cardiovascular function during the progression of diabetes mellitus in the diabetes prone rat (BBDP) (n = 8) were studied. Age-matched diabetes-resistant rats (BBDR) served as controls. BP was recorded via telemetry in contiguous 4 hr time periods over 24 hours starting with 12 midnight to 4 am as period zero (P0). Prior to onset of diabetes BP was high at P0, peaked at P2, and then fell again at P3; BP and heart rate (HR) then increased gradually at P4 and leveled off at P5, thereby exhibiting a bipodal rhythm. These patterns changed during long-term diabetes. The cross-correlation coefficient of BP and HR was not significantly different across groups at onset, but it fell significantly at 9 months of duration of diabetes (BBDP: 0.39 ± 0.06; BBDR: 0.65 ± 0.03; P < .05). These results show that changes in circadian cardiovascular rhythms in diabetes mellitus became significant at the late stage of the disease.

Intensive insulin protocol implementation and outcomes in the medical and surgical wards at a Veterans Affairs Medical Center.

BACKGROUND: Hyperglycemia is an important marker for clinical outcomes and mortality in hospitalized patients. New national standards have been established emphasizing the importance of improving inpatient glycemic control in individuals with diabetes or new-onset hyperglycemia. Implementation of these new standards is complex and requires a multidisciplinary team approach. A basal-bolus insulin regimen approach has been shown to improve inpatient glycemic control. Few studies have been published regarding basal-bolus insulin protocol outcomes in the non-intensive care unit (ICU) setting. OBJECTIVE: To evaluate the efficacy of a basal-bolus insulin protocol on inpatient glycemic control in a non-ICU setting, as measured by mean blood glucose and number of hypoglycemic episodes per patient admission. METHODS: A retrospective, observational, single-center study was conducted to compare blood glucose control pre- (October 2006-March 2007) and postprotocol (November 2007-January 2008) implementation. Inclusion criteria consisted of patient admission to a medical or surgical ward for at least 72 hours, with a diagnosis of diabetes, or presentation with 2 blood glucose readings greater than 180 mg/dL. Patients admitted to the ICU or those not admitted to a medical or surgical ward were excluded. RESULTS: Following protocol implementation, the mean +/- SD blood glucose level increased from 174 +/- 88 mg/dL to 188 +/- 95 mg/dL (p < 0.001) and the hypoglycemic incidents significantly decreased, from 1.11 to 0.51 events per patient admission (p < 0.0025). CONCLUSIONS: In this pilot study, implementation of a basal-bolus insulin protocol significantly reduced hypoglycemic events; however, mean blood glucose values increased. These results suggest that a basal-bolus insulin protocol can reduce hypoglycemia; however, factors such as protocol compliance, barriers in overcoming the use of the traditional sliding scale insulin regimens, staff education, and change of work-flow habits can influence the overall efficacy and impact of a basal-bolus insulin protocol on inpatient glycemic control.

Differential effects of rosiglitazone and insulin glargine on inflammatory markers, glycemic control, and lipids in type 2 diabetes.

Type 2 diabetes remains a difficult clinical challenge characterized by progressive insulin deficiency and frequent cardiovascular events requiring multiple therapeutic decisions. In this randomized clinical trial, we assessed the comparative effects of rosiglitazone (RSG) and insulin glargine (IG) on inflammatory biomarkers, glycemic control, and lipids. Forty subjects with type 2 diabetes and inadequate glycemic control on sulfonylurea and metformin therapy received 24 weeks of add-on therapy with either RSG 4mg daily or IG 10 units daily. Subjects on RSG with fasting glucose values >120mg/dl at 12 weeks were increased from 4 to 8mg. Subjects on IG increased insulin doses until fasting glucose was <120mg/dl. Markers of glycemic control and inflammation including HbA1c, hsCRP, PAI-1, plasma F2-isoprostanes, and lipids were measured at baseline, 12, 18, and 24 weeks. RSG and IG demonstrated similar efficacy in reducing HbA1c levels by 1.5 and 1.4%, respectively, with greater weight gain with RSG. Hypoglycemic events occurred with equal frequency. IG did not reduce hsCRP, but RSG reduced hsCRP levels 45% from baseline. Both IG and RSG reduced F2-isoprostanes similarly. IG did not affect PAI-1 levels, but did reduce total, LDL, and non-HDL cholesterol levels. Despite similar HbA1c reductions with RSG and IG, differential effects were found on inflammatory biomarkers and lipids that deserve consideration in the clinical decision process of selecting a therapeutic agent.

Nitric oxide stimulates insulin release in liver cells expressing human insulin.

The establishment of surrogate islet beta cells is important for the treatment of diabetes. Hepatocytes have a similar glucose sensing system as beta cells and have the potential to serve as surrogate beta cells. In this report, we demonstrate that infection of Hepa1-6 liver cells with a lentivirus expressing the human insulin cDNA results in expression and secretion of human insulin. Furthermore, we show that l-arginine at low levels of glucose significantly stimulates the release of insulin from these cells, compared to exposure to high concentration of glucose. The arginine-induced insulin release is via the production of nitric oxide, since treatment with N(G)-nitro-l-arginine, an inhibitor of nitric oxide synthase, blocks insulin secretion induced by l-arginine. These results indicate that nitric oxide plays a role in l-arginine-stimulated insulin release in hepatocytes expressing the human insulin gene, and provides a new strategy to induce insulin secretion from engineered non-beta cells.

Emerging technology in diabetes mellitus: glucose monitoring and new insulins.

Modern diabetes management requires intensive self-monitoring of blood glucose levels, often coupled with a multicomponent insulin program. Recent advances include alternate site blood glucose testing devices, which facilitate more frequent sampling by individuals with diabetes. Continuous glucose monitoring through interstitial fluid analysis is now available and appears to give a more representative picture of the glycemic variations typical for type 1 diabetes. Recombinant DNA technology has led to the development of new insulin analogs that provide more physiologic insulin delivery. Inhaled and oral insulin formulations may replace multiple injections in future insulin therapy regimens.

Combined use of calcium infusion localization and a minimally invasive surgical procedure in the management of insulinoma.

OBJECTIVE: To review our experience with current diagnostic localization techniques and a minimally invasive laparoscopic surgical procedure in the management of insulinoma. METHODS: We describe five patients with insulinoma, the results of diagnostic studies, and a proposed algorithm for management of this rare tumor. RESULTS: Four female patients and one male patient (age range, 34 to 72 years) underwent supervised fasting (mean duration, 12 hours; range, 3 to 28 hours) to establish the diagnosis of insulinoma. These patients had glucose values that ranged from 38 to 41 mg/dL and associated serum insulin levels of 11.3 to 61 microU/mL. C-peptide values ranged from 3.4 to 11.5 ng/mL, and proinsulin levels (measured in four patients) were 32.9 to 82 pmol/L. These biochemical findings were diagnostic for insulin-mediated hypoglycemia, and the high proinsulin and C-peptide levels, in conjunction with negative results of serum measurements for sulfonylureas, excluded an exogenous source of insulin as the cause of hypoglycemia. Four of the five study patients had nondiagnostic results of noninvasive localization studies and underwent selective arterial injection of calcium with hepatic venous sampling to help localize the insulinomas within the pancreas. This procedure correctly localized the lesion in three patients and was associated with no complications. In all five patients, surgical resection of a solitary insulinoma (with use of laparoscopic procedures in four, one of which was converted to an open procedure) yielded resolution of the hypoglycemia. CONCLUSION: The combination of calcium infusion localization and a minimally invasive surgical procedure is an efficient management approach in the diagnosis and treatment of insulinoma.