Cecilia C. Low Wang

Cardiovascular Disease in Diabetes: Where Does Glucose Fit In?

CONTEXT Recent prospective clinical trials have failed to confirm a unique benefit from normalization of glycemia on cardiovascular disease outcomes, despite evidence from basic vascular biology, epidemiological, and cohort studies. EVIDENCE ACQUISITION The literature was searched using the http://www.ncbi.nlm.nih.gov search engine including over 20 million citations on MEDLINE (1970 to present). Keyword searches included: atherosclerosis, cardiovascular, and glucose. Epidemiological, cohort, and interventional data on cardiovascular disease outcomes and glycemic control were reviewed along with analysis of recent reviews on this topic. EVIDENCE SYNTHESIS High glucose activates a proatherogenic phenotype in all cell types in the vessel wall including endothelial cells, vascular smooth muscle cells, inflammatory cells, fibroblasts, and platelets, leading to a feedforward atherogenic response. EPIDEMIOLOGICAL AND COHORT STUDIES: Epidemiological and cohort evidence indicates a clear and consistent correlation of glycemia with cardiovascular disease. A recent report of over 25,000 subjects with diabetes in the Swedish National Diabetes Registry verifies this relationship in contemporary practice. Interventional Studies: Prospective randomized interventions targeting a hemoglobin A1c of 6-6.5% for cardiovascular disease prevention failed to consistently decrease cardiovascular events or all-cause mortality. CONCLUSIONS Basic vascular biology data plus epidemiological and cohort evidence would predict that glucose control should impact cardiovascular events. Prospective clinical trials demonstrate that current strategies that improve blood glucose do not achieve this goal but suggest that a period of optimal control may confer long-term cardiovascular disease benefit. Clinicians should target a hemoglobin A1c of 7% for the prevention of microvascular complications, individualized to avoid hypoglycemia.

Evidence that androgenic and estrogenic metabolites contribute to the effects of dehydroepiandrosterone on cognition in postmenopausal women

Prior studies of the effects of dehydroepiandrosterone (DHEA) on cognition have produced complex and inconsistent results. We hypothesize that these results may arise, in part, because of DHEAs metabolism into estrogens and androgens that produce opposing effects on cognition. Our study administered 50 mg of oral DHEA daily for 4 weeks in a placebo-controlled crossover design to six postmenopausal women. We measured blood levels of androgens (total testosterone, free testosterone, DHEA, DHEAS), estrogens (estradiol, estrone), and cognitive performance on recognition memory, perceptual identification, digit span memory, and visual attentional vigilance under both drug and placebo conditions. Multiple regression models incorporating the factors of age and body mass index (BMI) were used to ascertain the relation between sex steroids and cognitive performance. Our results demonstrated that estrogens produced a positive effect on recognition memory, while androgens produced a negative effect. This pattern reversed in perceptual identification with estrogens producing a negative effect and androgens producing a positive effect. In addition, BMI produced a negative effect on digit span memory, age produced a negative effect on perceptual identification, and androgens produced a negative effect on visual attentional vigilance. These results help, in part, to explain DHEAs complex effects on cognition. The diverse effects of sex steroids across tasks underscore the importance of identifying the specific cognitive mechanisms influenced by sex steroids and emphasizes that one should not expect sex steroids to produce homogeneous effects across cognitive tasks.

Acute effects of different diet compositions on skeletal muscle insulin signalling in obese individuals during caloric restriction

OBJECTIVE The cellular effects of restricting fat versus carbohydrate during a low-calorie diet are unclear. The aim of this study was to examine acute effects of energy and macronutrient restriction on skeletal muscle insulin signalling in obesity. MATERIALS/METHODS Eighteen obese individuals without diabetes underwent euglycemic-hyperinsulinemic clamp and skeletal muscle biopsy after: (a) 5days of eucaloric diet (30% fat, 50% carbohydrate), and (b) 5days of a 30% calorie-restricted diet, either low fat/high carbohydrate (LF/HC: 20% fat, 60% carbohydrate) or high-fat/low carbohydrate (HF/LC: 50% fat, 30% carbohydrate). RESULTS Weight, body composition, and insulin sensitivity were similar between groups after eucaloric diet. Weight loss was similar between groups after hypocaloric diet, 1.3±1.3kg (p<0.0001 compared with eucaloric). Whole-body insulin sensitivity was unchanged after calorie restriction and similar between groups. However, ex vivo skeletal muscle insulin signalling differed depending on macronutrient composition of calorie-restricted diet. Skeletal muscle of the LF/HC group had increased insulin-stimulated tyrosine phosphorylation of IRS-1, decreased insulin-stimulated Ser307 phosphorylation of IRS-1, and increased IRS-1-associated phosphatidylinositol (PI)3-kinase activity. Conversely, insulin stimulation of tyrosine phosphorylated IRS-1 was absent and serine 307 phosphorylation of IRS-1 was increased on HF/LC, with blunting of IRS-1-associated PI3-kinase activity. CONCLUSION Acute caloric restriction with an LF/HC diet alters skeletal muscle insulin signalling in a way that improves insulin sensitivity, while acute caloric restriction with an HF/LC diet induces changes compatible with insulin resistance. In both cases, ex vivo changes in skeletal muscle insulin signalling appear prior to changes in whole body insulin sensitivity.

Round Table Discussion on Inpatient Use of Continuous Glucose Monitoring at the International Hospital Diabetes Meeting

In May 2015 the Diabetes Technology Society convened a panel of 27 experts in hospital medicine and endocrinology to discuss the current and potential future roles of continuous glucose monitoring (CGM) in delivering optimum health care to hospitalized patients in the United States. The panel focused on 3 potential settings for CGM in the hospital, including (1) the intensive care unit (ICU), (2) non-ICU, and (3) continuation of use of home CGM in the hospital. The group reviewed barriers to use and solutions to overcome the barriers. They concluded that CGM has the potential to improve the quality of patient care and can provide useful information to help health care providers learn more about glucose management. Widespread adoption of CGM by hospitals, however, has been limited by added costs and insufficient outcome data.In May 2015 the Diabetes Technology Society convened a panel of 27 experts in hospital medicine and endocrinology to discuss the current and potential future roles of continuous glucose monitoring (CGM) in delivering optimum health care to hospitalized patients in the United States. The panel focused on 3 potential settings for CGM in the hospital, including (1) the intensive care unit (ICU), (2) non-ICU, and (3) continuation of use of home CGM in the hospital. The group reviewed barriers to use and solutions to overcome the barriers. They concluded that CGM has the potential to improve the quality of patient care and can provide useful information to help health care providers learn more about glucose management. Widespread adoption of CGM by hospitals, however, has been limited by added costs and insufficient outcome data.

Insulin Use in Hospitalized Patients With Diabetes: Navigate With Care

“ A man walks into a bar …” These classic words introduce countless humorous situations. “ A man enters a hospital …” Unfortunately, these words introduce distinctly serious situations that occur at the rate of > 35 million per year across the United States.1 These words introduce a story in peoples lives that all too often includes mistakes, misadventures, and even preventable deaths. The hospital is a dangerous place. Approximately one-third of all deaths in this country occur in hospitals.2,3 On any given day, up to 30% of all hospitalized patients have diabetes, placing almost one-third of inpatients at greater risk for complications that may adversely affect their hospital stay. The majority of these hospitalized patients with diabetes are treated with insulin, a medication that occupies a prominent place on the list of high-alert medications of the Institute for Safe Medication Practices.4 It is the leading medication implicated in adverse events requiring treatment in a hospital emergency department.5 Moreover, insulin is responsible for more drug errors during acute hospital care than other commonly used hospital medications.6 What is the best approach to using insulin in the hospital setting? What skills and knowledge must providers have to make the most effective use of insulin and yet minimize the danger of hypoglycemia? There are no simple answers for these questions. As depicted in Figure 1, a single hospitalization often involves multiple transitions, each requiring a careful approach to insulin therapy. The transitions begin when patients enter the hospital. Patients may be admitted to a ward or to the intensive care unit (ICU), proceed directly to the operating room, or undergo various invasive procedures. Patients then move within the hospital among different levels of care with overlapping or sequential interventions such as nothing-by-mouth (nil per …

Arterial insulin resistance in Yucatan micropigs with diet-induced obesity and metabolic syndrome

AIM Metabolic syndrome affects a large proportion of the population and increases cardiovascular disease risk. Because metabolic syndrome often co-exists clinically with atherosclerosis, it is difficult to distinguish the respective contributions of the components to vascular abnormalities. Accordingly, we utilized a porcine dietary model of metabolic syndrome without atherosclerosis to investigate early abnormalities of vascular function and signaling. METHODS Thirty-two Yucatan micropigs were fed either a high-fat, high-simple-sugar, high-calorie (HFHS) or standard chow diet (STD) for 6 months. Neither diet contained added cholesterol. Blood pressure and flow-mediated vasodilatation were assessed at baseline and 6 months. Aortas were harvested at 6 months to assess histology, insulin signaling, and endothelial nitric oxide (eNOS) phosphorylation. RESULTS HFHS pigs developed characteristics of metabolic syndrome including obesity, dyslipidemia, and insulin resistance, but without histologic evidence of atherosclerosis. Although arterial intima-media thickness did not differ between groups, vascular dysfunction in HFHS was manifest by increased blood pressure and impaired flow-mediated vasodilation of the femoral artery. Compared with STD, aortas from HFHS exhibited increased p85α expression and Ser307 IRS-1 phosphorylation, and blunted insulin-stimulated IRS-1-associated phosphatidylinositol (PI) 3-kinase activity. In the absence of insulin stimulation, aortic Akt Ser473-phosphorylation was greater in HFHS than in STD. With insulin stimulation, Akt phosphorylation increased in STD, but not HFHS. Insulin-induced Ser1177-phosphorylation of eNOS was decreased in HFHS, compared with STD. CONCLUSIONS Pigs with metabolic syndrome develop early vascular dysfunction and aortic insulin signaling abnormalities, and could be a useful model for early human vascular abnormalities in this condition.

IMPACT OF GLUCOSE MANAGEMENT TEAM ON OUTCOMES OF HOSPITALIZARON IN PATIENTS WITH TYPE 2 DIABETES ADMITTED TO THE MEDICAL SERVICE

OBJECTIVE To improve glycemic control of hospitalized patients with diabetes and hyperglycemia, many medical centers have established dedicated glucose management teams (GMTs). However, the impact of these specialized teams on clinical outcomes has not been evaluated. METHODS We conducted a retrospective study of 440 patients with type 2 diabetes admitted to the medical service for cardiac or infection-related diagnosis. The primary endpoint was a composite outcome of several well-recognized markers of morbidity, consisting of: death during hospitalization, transfer to intensive care unit, initiation of enteral or parenteral nutrition, line infection, new in-hospital infection or infection lasting more than 20 days of hospitalization, deep venous thrombosis or pulmonary embolism, rise in plasma creatinine, and hospital re-admissions. RESULTS Medical housestaff managed the glycemia in 79% of patients (usual care group), while the GMT managed the glycemia in 21% of patients (GMT group). The primary outcome was similar between cohorts (0.95 events per patient versus 0.99 events per patient in the GMT and usual care cohorts, respectively). For subanalysis, the subjects in both groups were stratified into those with average glycemia of <180 mg/dL versus those with glycemia >180 mg/dL. We found a significant beneficial impact of glycemic management by the GMT on the composite outcome in patients with average glycemia >180 mg/dL during their hospital stay. The number of patients who met primary outcome was significantly higher in the usual care group (40 of 83 patients, 48%) than in the GMT-treated cohort (8 of 33 patients, 25.7%) (P<.02). CONCLUSION Our data suggest that GMTs may have an important role in managing difficult-to-control hyperglycemia in the inpatient setting. ABBREVIATIONS BG = blood glucose GMT = glucose management team HbA1c = hemoglobin A1c ICU = intensive care unit POC = point of care T2D = type 2 diabetes.

Practical approach to management of inpatient hyperglycemia in select patient populations.

Abstract Hospitalized patients frequently transition between various levels of care and changing clinical situations. Optimal management of hospitalized patients with hyperglycemia includes awareness of situations that may significantly affect glucose and/or insulin metabolism. A review of published clinical trials reveals practical approaches to the management of hyperglycemia in select patient populations that may prove useful for the hospital clinician. We outline approaches to the management of hyperglycemia in hospitalized patients receiving glucocorticoids, patients with severe or end-stage renal disease undergoing hemo- or peritoneal dialysis, and patients receiving total parenteral or enteral feeding, in addition to patients transitioning from intravenous insulin infusion to subcutaneously administered insulin. Key considerations underlying these management methods include a proactive approach, frequent blood glucose monitoring, daily review of blood glucose patterns, and daily reassessment of the insulin regimen and associated orders.

Insulin Resistance and Cardiovascular Disease

Keywords atherosclerosis , insulin resistance , type 2 diabetes mellitus , cardiovascular disease , metabolic syndrome X , visceral adiposity , compensatory hyperinsulinemia , inflammation , oxidative stress , endothelium , vascular smooth muscle , intracellular signaling proteins , early growth response 1 protein , primary prevention , lifestyle risk reduction