ß-cell loss and ß-cell apoptosis in human type 2 diabetes are related to islet amyloid deposition.

Amyloid deposition and reduced ß-cell mass are pathological hallmarks of the pancreatic islet in type 2 diabetes; however, whether the extent of amyloid deposition is associated with decreased ß-cell mass is debated. We investigated the possible relationship and, for the first time, determined whether increased islet amyloid and/or decreased ß-cell area quantified on histological sections is correlated with increased ß-cell apoptosis. Formalin-fixed, paraffin-embedded human pancreas sections from subjects with (n = 29) and without (n = 39) diabetes were obtained at autopsy (64 ± 2 and 70 ± 4 islets/subject, respectively). Amyloid and ß cells were visualized by thioflavin S and insulin immunolabeling. Apoptotic ß cells were detected by colabeling for insulin and by TUNEL. Diabetes was associated with increased amyloid deposition, decreased ß-cell area, and increased ß-cell apoptosis, as expected. There was a strong inverse correlation between ß-cell area and amyloid deposition (r = -0.42, P < 0.001). ß-Cell area was selectively reduced in individual amyloid-containing islets from diabetic subjects, compared with control subjects, but amyloid-free islets had ß-cell area equivalent to islets from control subjects. Increased amyloid deposition was associated with ß-cell apoptosis (r = 0.56, P < 0.01). Thus, islet amyloid is associated with decreased ß-cell area and increased ß-cell apoptosis, suggesting that islet amyloid deposition contributes to the decreased ß-cell mass that characterizes type 2 diabetes.

Pharmacokinetics of metformin during pregnancy.

Our objective was to evaluate the pharmacokinetics of metformin during pregnancy. Serial blood and urine samples were collected over one steady-state dosing interval in women treated with metformin during early to late pregnancy (n = 35) and postpartum (n = 16). Maternal and umbilical cord blood samples were obtained at delivery from 12 women. Metformin concentrations were also determined in breast milk samples obtained over one dosing interval in 6 women. Metformin renal clearance increased significantly in mid (723 +/- 243 ml/min, P < 0.01) and late pregnancy (625 +/- 130 ml/min, P < 0.01) compared with postpartum (477 +/- 132 ml/min). These changes reflected significant increases in creatinine clearance (240 +/- 70 ml/min, P < 0.01 and 207 +/- 56 ml/min, P < 0.05 versus 165 +/- 44 ml/min) and in metformin net secretion clearance (480 +/- 190 ml/min, P < 0.01 and 419 +/- 78 ml/min, P < 0.01 versus 313 +/- 98 ml/min) in mid and late pregnancy versus postpartum, respectively. Metformin concentrations at the time of delivery in umbilical cord plasma ranged between nondetectable (<5 ng/ml) and 1263 ng/ml. The daily infant intake of metformin through breast milk was 0.13 to 0.28 mg, and the relative infant dose was <0.5% of the mother's weight-adjusted dose. Our results indicate that metformin pharmacokinetics are affected by pregnancy-related changes in renal filtration and net tubular transport and can be roughly estimated by the use of creatinine clearance. At the time of delivery, the fetus is exposed to metformin concentrations from negligible to as high as maternal concentrations. In contrast, infant exposure to metformin through the breast milk is low.

Effect of pregnancy on the pharmacokinetics of antihypertensive drugs.

In the US, approximately 12% of women have hypertension during their pregnancy. Antihypertensive drugs are often given to lower maternal blood pressure in those with severe hypertension to prevent stroke and hypertensive crises. There is no conclusive evidence that antihypertensive treatment is beneficial to the mother in mild to moderate hypertension; however, approximately 3% of all pregnant women receive an antihypertensive drug at some time during their pregnancy. There are only limited data on the effects of pregnancy on the pharmacokinetics of antihypertensive drugs. However, knowledge of the pharmacokinetic properties of a drug in the nonpregnant adult and use of a mechanistic-based approach allow an estimation of the effect of pregnancy on the pharmacokinetics of drugs when data are limited or not available. In general, an increased plasma volume and decreased protein binding can alter the volume of distribution of the drug. Clearance can increase or decrease, depending on the pathway of elimination of the drug. Through changes in the volume of distribution and clearance, pregnancy can cause a change in the elimination half-life, resulting in the need for modification of the dosing frequency. The few studies in pregnant women with hypertension have included small numbers of women in the third trimester and postpartum, with little or no data in early pregnancy. In addition, many studies evaluating the efficacy of antihypertensive medications have been performed using dosing regimens of medications that have not been substantiated by pharmacological data in pregnant women. There is a need for well designed pharmacokinetic and pharmacodynamic studies of antihypertensive medications that include analysis during all three trimesters of pregnancy and postpartum. Higher doses and altered dosage intervals may be needed for antihypertensive drugs used in pregnant women.

Reduced adipogenic gene expression in thigh adipose tissue precedes human immunodeficiency virus-associated lipoatrophy.

CONTEXT: The expression of adipogenic genes in sc adipose tissue has been reported to be lower among patients with HIV-associated lipoatrophy than HIV-uninfected controls. It is unclear whether this is a result or cause of lipoatrophy. OBJECTIVE: The objective of the study was to investigate the temporal relationships among changes in adipogenic gene expression in sc adipose tissue and changes in body fat distribution and metabolic complications in HIV-infected subjects on antiretroviral therapy. DESIGN: This was a prospective longitudinal study. SETTING: The study was conducted at HIV clinics in Seattle, Washington. PARTICIPANTS: The study population included 31 HIV-infected and 12 control subjects. INTERVENTIONS: Subjects were followed up for 12 months after they initiated or modified their existing antiretroviral regimen. MAIN OUTCOME MEASURES: Changes in body composition, plasma lipids, insulin sensitivity, and gene expression in sc abdominal and thigh adipose tissue. RESULTS: Subjects who developed lipoatrophy (n=10) had elevated fasting triglycerides [3.16 (sd 2.79) mmol/liter] and reduced insulin sensitivity as measured by frequently sampled iv glucose tolerance test [1.89 (sd 1.27)x10(-4) min(-1)/microU.ml] after 12 months, whereas those without lipoatrophy (n=21) did not show any metabolic complications [triglycerides 1.32 (sd 0.58) mmol/liter, P=0.01 vs. lipoatrophy; insulin sensitivity 3.52 (sd 1.91)x10(-4) min(-1)/microU.ml, P=0.01 vs. lipoatrophy]. In subjects developing lipoatrophy, the expression of genes involved in adipocyte differentiation, lipid uptake, and local cortisol production in thigh adipose tissue was significantly reduced already at the 2-month visit, several months before any loss of extremity fat mass was evident. CONCLUSIONS: In HIV-infected subjects, lipoatrophy is associated with elevated fasting triglycerides and insulin resistance and might be caused by a direct or indirect effect of antiretroviral drugs on sc adipocyte differentiation.

The impact of duration of labor induction on cesarean rate.

OBJECTIVE: We sought to determine maternal factors that influence success of labor induction and whether the probability of cesarean delivery changed with time during induction. STUDY DESIGN: We performed a retrospective cohort study of 1650 singleton pregnancies induced at a gestation of 37 weeks or longer, with birthweights of 2500 g or greater, and without congenital anomalies. We used multivariate logistic regression to calculate odds ratios for cesarean. RESULTS: Nulliparity (odds ratio [OR] 7.8, 95% confidence interval [CI] 5.7 to 11), hypertension (OR 1.4, 95% CI 1.1 to 1.8), diabetes (OR 2.2, 95% CI 1.6 to 3.1), maternal age 28.8 years old or older (OR 1.3, 95% CI 1.2 to 1.4), and birthweight of 3441 g or greater (OR 1.6, 95% CI 1.2 to 2.0) were significantly associated with cesarean. Cesarean risk increased linearly with time by an average of 3.8% per 6 hours. CONCLUSION: Risk of cesarean increases over the duration of induction but does not reach clinical certainty. Cesarean probability is greater with nulliparity, hypertension, diabetes, older maternal age, or higher birthweight. Inductions without stated indications may not carry an increased risk of cesarean.

Use of "shuttered" hospitals to expand surge capacity.

INTRODUCTION: With limited available hospital beds in most urban areas, there are very few options when trying to relocate patients already within the hospital to make room for incoming patients from a mass-casualty incident (MCI) or epidemic (a patient surge). This study investigates the possibility and process for utilizing shuttered (closed or former) hospitals to accept medically stable, ambulatory patients transferred from a tertiary medical facility. METHODS: Two recently closed, acute care hospitals were evaluated critically to determine if they could be made ready to accept inpatients within 3-7 days of a MCI. This surge facility ideally would be able to support 200-300 patients/beds. Two generic scenarios were used for planning: (1) a patient surge (including one caused by conventional war or terrorism, weapons of mass destruction, or a disaster caused by natural hazards) requiring transfer of ambulatory, medically-stable inpatients to another facility in an effort to increase capacity at existing hospitals; and (2) a bio-event or epidemic where a shuttered hospital could be used as an isolation facility. RESULTS: Both recently closed hospitals had significant, but different challenges to reopening, although with careful planning and resource allocation it would be possible to reopen them within 3-7 days. Planning was the most conclusive recommendation. It does not appear possible to reopen shuttered hospitals with major structural deterioration or a complete lack of current mission (i.e., no current utilities). Staffing would represent the most challenging issue as a surge facility would represent an incremental additional need for existing and scarce human resources. CONCLUSIONS: With careful planning, a shuttered hospital could be reopened and ready to accept patients within 3-7 days of a MCI or epidemic.

Maternal hemodynamic changes associated with furosemide treatment.

OBJECTIVE: To assess the pharmacodynamic effects of furosemide in pregnancy. METHODS: Twenty-one pregnant women who received furosemide 20 mg daily had cardiac output (CO), stroke volume (SV), and total peripheral resistance (TPR) measured by Doppler technique before and after treatment. RESULTS: Furosemide was initiated at 22.4 +/- 6.0 weeks gestation. CO and SV decreased (mean +/- SD: 1.2 +/- 0.2 L/min and 17+/-3 mL, respectively), whereas TPR increased (101+/-26 dyne.sec.cm(-5); p < 0.001 for all) after 2.9+/-1.4 weeks. Hemodynamics did not approach the expected mean for pregnancy. CONCLUSIONS: While furosemide improved the hyperdynamic circulation in pregnancy, it did not lower blood pressure or cause clinically significant vasoconstriction.

Dysregulation of the hypothalamic-pituitary-adrenal axis in postpartum depression.

Postpartum depression (PPD) affects at least 10% to 15% of postpartum women, including more than 600,000 American mothers in 2003 alone. Dramatic changes in the hypothalamic-pituitary-adrenal (HPA) system in the transition from pregnancy to postpartum coupled with research on the psychobiology of depression provided the foundation for this study. The purpose of this study was to compare the reactivity and regulation of the HPA axis components, adrenocorticotropic hormone (ACTH) and cortisol, in depressed and nondepressed postpartum women. A comparative, longitudinal study design was used with 22 normal, healthy, nondepressed pregnant women. Physiologic and postpartum depression data were collected at 6 and 12 weeks postpartum at a university clinical research center. Maximal treadmill exercise stimulated plasma ACTH and serum cortisol levels which were measured before, during, and after 20 min of exercise. Postpartum depression was measured with the Postpartum Depression Screening Scale. Lag within-subject ACTH levels predicting cortisol regression slopes were significantly different between the depressed and nondepressed groups at both 6 and 12 weeks. The depressed group showed no relationship between their ACTH and cortisol levels, with higher ACTH and lower cortisol levels when compared with the nondepressed group. The expected regulated relationship with cortisol levels rising in response to rising ACTH levels was found in the non-depressed group. These findings indicate that the HPA axis was dysregulated in the depressed group, but regulated in the nondepressed group at 6 and 12 weeks postpartum. This pattern of higher ACTH levels to stimulate less cortisol is similar to patterns found in women with early life stresses.

Impact of differences in fasting glucose and glucose tolerance on the hyperbolic relationship between insulin sensitivity and insulin responses.

OBJECTIVE: To determine whether the hyperbolic relationship between insulin sensitivity and the acute insulin response to glucose (AIRg) exists in subjects with impaired fasting glucose (IFG) or decreased glucose tolerance. RESEARCH DESIGN AND METHODS: We studied 219 healthy subjects (88 male and 131 female subjects, aged 26-75 years) with fasting plasma glucose (FPG) <6.11 mmol/l. Subjects underwent an intravenous glucose tolerance test to determine the insulin sensitivity index (Si), AIRg, and the glucose disappearance constant (Kg), the latter a measure of intravenous glucose tolerance. RESULTS: Si and AIRg were inversely related for the entire cohort, and this relationship was not significantly different from hyperbolic. The inverse relationship between Si and AIRg was not significantly different when compared between groups based on fasting glucose (normal fasting glucose [NFG], FPG <5.56 mmol/l vs. IFG, FPG 5.56-6.11 mmol/l) or by the Kg quartile. However, the curve relating Si and AIRg was left shifted in the IFG compared with NFG group (P < 0.001) and was progressively more left shifted with decreasing Kg (P < 0.001), consistent with decreasing beta-cell function. These changes were not observed for the curves relating Si and fasting insulin, suggesting that in the fasting state beta-cell function is maintained even in patients with mild IFG. Finally, the disposition index (DI) (Si x AIRg) was calculated as a measure of beta-cell function. The DI progressively decreased with increasing FPG, even in the group of subjects classified as NFG. CONCLUSIONS: The inverse relationship between insulin sensitivity and AIRg is consistent with a hyperbola not only in subjects with normal glucose tolerance but also with mild IFG or decreased Kg. Based on a hyperbolic relationship, a decrease in beta-cell function can be detected as FPG increases, even in patients who are normal glucose tolerant.

Gestational diabetes mellitus increases the risk of cardiovascular disease in women with a family history of type 2 diabetes.

OBJECTIVE: We sought to determine whether a history of gestational diabetes mellitus (GDM) further increases the risk of cardiovascular disease (CVD) in parous women with first-degree relatives with type 2 diabetes. RESEARCH DESIGN AND METHODS: Women with (n = 332) and without (n = 663) a history of GDM were compared regarding 1) the revised National Cholesterol Education Program Adult Treatment Panel III metabolic syndrome criteria, 2) the prevalence of type 2 diabetes, and 3) self-reported CVD. RESULTS: Women with prior GDM were younger (48.6 +/- 0.7 vs. 52.4 +/- 0.6 years [means +/- SE];P < 0.001) and less likely to be postmenopausal (48.3 vs. 57.9%; P < 0.005). Although both groups were obese (BMI 34.4 +/- 1.2 vs. 33.7 +/- 0.6 kg/m(2)), women with prior GDM were more likely to have metabolic syndrome (86.6 vs. 73.5%; P < 0.001) and type 2 diabetes (93.4 vs. 63.3%; P < 0.001). Moreover, they had a higher prevalence of CVD (15.5 vs. 12.4%; adjusted odds ratio 1.85 [95% CI 1.21-2.82];P = 0.005) that occurred at a younger age (45.5 +/- 2.2 vs. 52.5 +/- 1.9 years;P = 0.02) and was independent of metabolic syndrome (1.74 [1.10-2.76]; P = 0.02) and type 2 diabetes (1.56 [1.002-2.43];P < 0.05). CONCLUSIONS: Among women with a family history of type 2 diabetes, those with prior GDM were even more likely to not only have CVD risk factors, including metabolic syndrome and type 2 diabetes, but also to have experienced CVD events, which occurred at a younger age. Thus, women with both a family history of type 2 diabetes and personal history of GDM may be especially suitable for early interventions aimed at preventing or reducing their risk of CVD and diabetes.

Long-term treatment with rosiglitazone and metformin reduces the extent of, but does not prevent, islet amyloid deposition in mice expressing the gene for human islet amyloid polypeptide.

Islet amyloid deposition in type 2 diabetes is associated with reduced beta-cell mass. Therefore, interventions aimed at reducing islet amyloid formation may help preserve beta-cell mass in type 2 diabetes. Rosiglitazone and metformin act by different mechanisms to improve insulin sensitivity and thereby reduce beta-cell secretory demand, resulting in decreased release of insulin and islet amyloid polypeptide (IAPP), the unique constituent of islet amyloid deposits. We hypothesized that this reduced beta-cell secretory demand would lead to reduced islet amyloid formation. Human IAPP (hIAPP) transgenic mice, a model of islet amyloid, were treated for 12 months with rosiglitazone (1.5 mg.kg(-1).day(-1), n = 19), metformin (1 g.kg(-1).day(-1), n = 18), or control (n = 17). At the end of the study, islet amyloid prevalence (percent islets containing amyloid) and severity (percent islet area occupied by amyloid), islet mass, beta-cell mass, and insulin release were determined. Islet amyloid prevalence (44 +/- 8, 13 +/- 4, and 11 +/- 3% for control, metformin-, and rosiglitazone-treated mice, respectively) and severity (9.2 +/- 3.0, 0.22 +/- 0.11, and 0.10 +/- 0.05% for control, metformin-, and rosiglitazone-treated mice, respectively) were markedly reduced with both rosiglitazone (P < 0.001 for both measures) and metformin treatment (P < 0.001 for both measures). Both treatments were associated with reduced insulin release assessed as the acute insulin response to intravenous glucose (2,189 +/- 857, 621 +/- 256, and 14 +/- 158 pmol/l for control, metformin-, and rosiglitazone-treated mice, respectively; P < 0.05 for metformin vs. control and P < 0.005 for rosiglitazone vs. control), consistent with reduced secretory demand. Similarly, islet mass (33.4 +/- 7.0, 16.6 +/- 3.6, and 12.2 +/- 2.1 mg for control, metformin-, and rosiglitazone-treated mice, respectively) was not different with metformin treatment (P = 0.06 vs. control) but was significantly lower with rosiglitazone treatment (P < 0.05 vs. control). When the decreased islet mass was accounted for, the islet amyloid-related decrease in beta-cell mass (percent beta-cell mass/islet mass) was ameliorated in both rosiglitazone- and metformin-treated animals (57.9 +/- 3.1, 64.7 +/- 1.4, and 66.1 +/- 1.6% for control, metformin-, and rosiglitazone-treated mice, respectively; P < 0.05 for metformin or rosiglitazone vs. control). In summary, rosiglitazone and metformin protect beta-cells from the deleterious effects of islet amyloid, and this effect may contribute to the ability of these treatments to alleviate the progressive loss of beta-cell mass and function in type 2 diabetes.

A reduced-fat diet and aerobic exercise in Japanese Americans with impaired glucose tolerance decreases intra-abdominal fat and improves insulin sensitivity but not beta-cell function.

Lifestyle modification reduces the risk of developing type 2 diabetes and may have its effect through improving insulin sensitivity, beta-cell function, or both. To determine whether diet and exercise improve insulin sensitivity and/or beta-cell function and to evaluate these effects over time, we quantified insulin sensitivity and the acute insulin response to glucose (AIRg) in 62 Japanese Americans (age 56.5 +/- 1.3 years; mean +/- SE) with impaired glucose tolerance (IGT) who were randomized to the American Heart Association (AHA) Step 2 diet plus endurance exercise (n = 30) versus the AHA Step 1 diet plus stretching (n = 32) for 24 months. beta-Cell function (disposition index [DI]) was calculated as S(i) x AIRg, where S(i) is the insulin sensitivity index. The incremental area under the curve for glucose (incAUCg) was calculated from a 75-g oral glucose tolerance test. Intra-abdominal fat (IAF) and subcutaneous fat (SCF) areas were measured by computed tomography. At 24 months, the Step 2/endurance group had lower weight (63.1 +/- 2.4 vs. 71.3 +/- 2.9 kg; P = 0.004) and IAF (75.0 +/- 7.9 vs. 112.7 +/- 10.4 cm(2); P = 0.03) and SCF (196.5 +/- 18.0 vs. 227.7 +/- 19.9 cm(2); P < 0.001) areas, greater S(i) (4.7 +/- 0.5 vs. 3.3 +/- 0.3 x 10(-5) min . pmol(-1) . l(-1); P = 0.01), and a trend toward lower AIRg (294.9 +/- 50.0 vs. 305.4 +/- 30.0 pmol/l; P = 0.06) and incAUCg (8,217.3 +/- 350.7 vs. 8,902.0 +/- 367.2 mg . dl(-1) . 2 h(-1); P = 0.08) compared with the Step 1/stretching group after adjusting for baseline values. There was no difference in the DI (P = 0.7) between the groups. S(i) was associated with changes in weight (r = -0.426, P = 0.001) and IAF (r = -0.395, P = 0.003) and SCF (r = -0.341, P = 0.01) areas. Thus, the lifestyle modifications decreased weight and central adiposity and improved insulin sensitivity in Japanese Americans with IGT. However, such changes did not improve beta-cell function, suggesting that this degree of lifestyle modifications may be limited in preventing type 2 diabetes over the long term.

Diabetic nephropathy in pregnancy: suboptimal hypertensive control associated with preterm delivery.

BACKGROUND: Nephropathy complicates 5% to 10% of pregnancies in women with diabetes and is associated with adverse outcomes. Given the importance of blood pressure (BP) control in reducing cardiovascular and renal complications outside of pregnancy, we hypothesized that poorly controlled hypertension in early pregnancy among women with diabetic nephropathy would be associated with adverse outcomes. METHODS: To examine the impact of hypertensive control in early pregnancy on perinatal outcomes, we performed a retrospective cohort study of pregnancies complicated by diabetic nephropathy with "Above Target" mean arterial pressure (> or = 100 mm Hg; N = 21) and "Below Target" mean arterial pressure (< 100 mm Hg; N = 22), which approximates the American Diabetes Association and the Seventh Report of the Joint National Committee recommended target of 130/80 mm Hg, measured at < 20 weeks' gestation. RESULTS: There were no differences in maternal age (mean +/- SEM: 27.2 +/- 1.2 v 29.5 +/- 1.0 years), duration of diabetes (median, range: 17.5, 13 to 24 v 16, 1 to 25 years), or glucose control (glycosylated hemoglobin [HbA1c] 8.0% +/- 0.3% v 8.1% +/- 0.4%) between the Above and Below Target groups. The Above Target group had more proteinuria (4.69 +/- 1.08 v 1.65 +/- 0.43 g/24 h; P = .007) and higher serum creatinine levels (1.23 +/- 0.17 v 0.85 +/- 0.06 mg/dL; P = .02). The Above Target group was more likely to deliver at < 32 weeks' gestation (38.1% v 4.6%; P = .007). The increased risk of preterm delivery remained significant after adjusting for duration of diabetes and glucose control. CONCLUSIONS: Suboptimal control of hypertension in early pregnancy in women with diabetic nephropathy is associated with a significant risk of preterm delivery. Improved preconceptional control of hypertension may reduce adverse perinatal outcomes in women with diabetic nephropathy.

Impact of intra-abdominal fat and age on insulin sensitivity and beta-cell function.

The prevalence of glucose intolerance and type 2 diabetes increases with age. To determine whether the hyperbolic relationship between insulin sensitivity and the insulin response is affected by age and whether the decline in beta-cell function with age is related to increases in intra-abdominal fat or age per se, we studied 220 healthy subjects with fasting glucose <6.1 mmol/l (89 men and 131 women, aged 26-75 years, BMI 18.7-40.4 kg/m(2)). The insulin sensitivity index (S(i)) and the acute insulin response to glucose (AIRg) were determined, and from these beta-cell function was estimated as the disposition index (S(i) x AIRg). Intra-abdominal fat and subcutaneous fat areas were quantified by computed tomography. S(i) (5.40 +/- 0.5 vs. 7.86 +/- 0.7 x10(-5) min(-1)/[pmol/l]), P < 0.01) was decreased and intra-abdominal fat (117 +/- 10 vs. 81 +/- 9 cm(2), P < 0.05) was increased in the oldest (age 60-75 years) versus the youngest (age 26-44 years) quartile. The hyperbolic relationship between S(i) and AIRg was present independent of age; thus, beta-cell function measured as the disposition index (1,412 +/- 120 vs. 2,125 +/- 150 x10(-5) min(-1), P < 0.01) was lower in the oldest versus the youngest quartile. In multiple regression, intra-abdominal fat (r = -0.470, P < 0.001) but not age was associated with S(i), but both intra-abdominal fat (r = -0.198, P = 0.003) and age (r = -0.131, P = 0.05) were correlated with the disposition index. These data suggest that although intra-abdominal fat is a strong determinant of insulin sensitivity and beta-cell function, age has an independent effect on beta-cell function that may contribute to the increased prevalence of type 2 diabetes in older populations.

Intra-abdominal fat is a major determinant of the National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome.

The underlying pathophysiology of the metabolic syndrome is the subject of debate, with both insulin resistance and obesity considered as important factors. We evaluated the differential effects of insulin resistance and central body fat distribution in determining the metabolic syndrome as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III. In addition, we determined which NCEP criteria were associated with insulin resistance and central adiposity. The subjects, 218 healthy men (n = 89) and women (n = 129) with a broad range of age (26-75 years) and BMI (18.4-46.8 kg/m2), underwent quantification of the insulin sensitivity index (Si) and intra-abdominal fat (IAF) and subcutaneous fat (SCF) areas. The metabolic syndrome was present in 34 (15.6%) of subjects who had a lower Si [median: 3.13 vs. 6.09 x 10(-5) min(-1)/(pmol/l)] and higher IAF (166.3 vs. 79.1 cm2) and SCF (285.1 vs. 179.8 cm2) areas compared with subjects without the syndrome (P < 0.001). Multivariate models including Si, IAF, and SCF demonstrated that each parameter was associated with the syndrome. However, IAF was independently associated with all five of the metabolic syndrome criteria. In multivariable models containing the criteria as covariates, waist circumference and triglyceride levels were independently associated with Si and IAF and SCF areas (P < 0.001). Although insulin resistance and central body fat are both associated with the metabolic syndrome, IAF is independently associated with all of the criteria, suggesting that it may have a pathophysiological role. Of the NCEP criteria, waist circumference and triglycerides may best identify insulin resistance and visceral adiposity in individuals with a fasting plasma glucose <6.4 mmol/l.

The concurrent accumulation of intra-abdominal and subcutaneous fat explains the association between insulin resistance and plasma leptin concentrations : distinct metabolic effects of two fat compartments.

Obesity is associated with insulin resistance, particularly when body fat has a central distribution. However, insulin resistance also frequently occurs in apparently lean individuals. It has been proposed that these lean insulin-resistant individuals have greater amounts of body fat than lean insulin-sensitive subjects. Alternatively, their body fat distribution may be different. Obesity is associated with elevated plasma leptin levels, but some studies have suggested that insulin sensitivity is an additional determinant of circulating leptin concentrations. To examine how body fat distribution contributes to insulin sensitivity and how these variables are related to leptin levels, we studied 174 individuals (73 men, 101 women), a priori classified as lean insulin-sensitive (LIS, n = 56), lean insulin-resistant (LIR, n = 61), and obese insulin-resistant (OIR, n = 57) based on their BMI and insulin sensitivity index (S(I)). Whereas the BMI of the two lean groups did not differ, the S(I) of the LIR subjects was less than half that of the LIS group. The subcutaneous and intra-abdominal fat areas, determined by computed tomography, were 45 and 70% greater in the LIR subjects (P < 0.001) and 2.5- and 3-fold greater in the OIR group, as compared with the LIS group. Fasting plasma leptin levels were moderately increased in LIR subjects (10.8 +/- 7.1 vs. 8.1 +/- 6.4 ng/ml in LIS subjects; P < 0.001) and doubled in OIR subjects (21.9 +/- 15.5 ng/ml; P < 0.001). Because of the confounding effect of body fat, we examined the relationships between adiposity, insulin sensitivity, and leptin concentrations by multiple regression analysis. Intra-abdominal fat was the best variable predicting insulin sensitivity in both genders and explained 54% of the variance in S(I). This inverse relationship was nonlinear (r = -0.688). On the other hand, in both genders, fasting leptin levels were strongly associated with subcutaneous fat area (r = 0.760) but not with intra-abdominal fat. In line with these analyses, when LIS and LIR subjects were matched for subcutaneous fat area, age, and gender, they had similar leptin levels, whereas their intra-abdominal fat and insulin sensitivity remained different. Thus, accumulation of intra-abdominal fat correlates with insulin resistance, whereas subcutaneous fat deposition correlates with circulating leptin levels. We conclude that the concurrent increase in these two metabolically distinct fat compartments is a major explanation for the association between insulin resistance and elevated circulating leptin concentrations in lean and obese subjects.

Pharmacokinetics and pharmacodynamics of atenolol during pregnancy and postpartum.

Preexisting hypertension complicates 5% of all pregnancies. The objective of this study was to evaluate steady-state atenolol pharmacokinetics and pharmacodynamics (n = 17) during the second trimester (2nd T), third trimester (3rd T), and 3 months postpartum. Pregnancy as compared to 3 months postpartum (nonpregnant control) resulted in significant (P < .05) changes, including the following: 42% (2nd T) and 50% (3rd T) increase in creatinine clearance, 38% (2nd T) and 36% (3rd T) increase in atenolol renal clearance, 12% (2nd T) and 11% (3rd T) decrease in atenolol half-life, 20% (2nd T) and 28% (3rd T) increase in cardiac output, 15% (2nd T) and 23% (3rd T) increase in resting heart rate, and 22% (2nd T) and 21% (3rd T) decrease in total peripheral resistance in subjects on steady-state oral atenolol for treatment of hypertension in pregnancy. In conclusion, the renal clearance of atenolol along with creatinine clearance is increased during pregnancy. However, this does not translate into an increase in apparent oral clearance of atenolol, possibly related to the high variability in bioavailability. Atenolol administration did not appear to change the pattern of the increase in cardiac output and the decrease in total peripheral resistance, which normally occurs during pregnancy.

Creating a network of high-quality skilled nursing facilities: preliminary data on the postacute care quality improvement experiences of an accountable care organization.

Postacute care (PAC) is an important source of cost growth and variation in the Medicare program and is critical to accountable care organization (ACO) and bundled payment efforts to improve quality and value in the Medicare program, but ACOs must often look outside their walls to identify high-value external PAC partners, including skilled nursing facilities (SNFs). As a solution to this problem, the integrated health system, Partners HealthCare System (PHS) and its Pioneer ACO launched the PHS SNF Collaborative Network in October 2013 to identify and partner with high-quality SNFs. This study details the method by which PHS selected SNFs using minimum criteria based on public scores and secondary criteria based on self-reported measures, describes the characteristics of selected and nonselected SNFs, and reports SNF satisfaction with the collaborative. The selected SNFs (n = 47) had significantly higher CMS Five-Star scores than the nonselected SNFs (n = 93) (4.6 vs 3.2, P < .001) and were more likely than nonselected SNFs that met the minimum criteria (n = 35) to have more than 5 days of clinical coverage (17.0% vs 2.9%, P = .02) and to have a physician see admitted individuals within 24 (38.3% vs 17.1%, P = .02) and 48 hours (93.6% vs 80.0%, P = .03). A survey sent to collaborative SNFs found high satisfaction with the process (average satisfaction, 4.6/5, with 1 = very dissatisfied and 5 = very satisfied, n = 19). Although the challenges of improving care in SNFs remain daunting, this approach can serve as a first step toward greater clinical collaboration between acute and postacute settings that will lead to better outcomes for frail older adults.

Diet-induced weight loss is associated with an improvement in beta-cell function in older men.

Although weight loss in older subjects has been shown to improve insulin sensitivity, it is unclear what effect this lifestyle intervention has on beta-cell function. To determine whether diet-induced weight loss can improve beta-cell function in older subjects, we studied 19 healthy male subjects (age, 65.4 +/- 0.9 yr; body mass index, 30.9 +/- 0.6 kg/m2; mean +/- SEM) before and after a 3-month 1200-kcal/d diet. The insulin sensitivity index (SI) was quantified using Bergman's minimal model. The acute insulin response to glucose (AIRg) and the maximal glucose-potentiated insulin response (AIRmax) were determined and then adjusted for SI (SI x AIRg and SI x AIRmax), thus providing measures of beta-cell function. Subjects demonstrated significant weight loss (95.6 +/- 2.4 to 86.1 +/- 2.5 kg; P < 0.001). Both fasting plasma glucose [97.3 +/- 1.6 to 95.1 +/- 1.3 mg/dl (5.4 +/- 0.09 to 5.3 +/- 0.07 mM); P = 0.05] and insulin [18.5 +/- 1.3 to 12.2 +/- 1.0 microU/ml (110.9 +/- 7.7 to 73.5 +/- 5.9 pM); P < 0.001] levels decreased. With weight loss, SI increased [1.59 +/- 0.24 to 2.49 +/- 0.32 x 10(-4) min(-1)/(microU/ml) (2.65 +/- 0.4 to 4.15 +/- 0.5 x 10(-5) min(-1)/pM); P < 0.001], whereas both AIRg [63.4 +/- 13.4 to 51.0 +/- 10.7 microU/ml (380 +/- 80 to 306 +/- 64 pM); P < 0.05] and AIRmax [314 +/- 31.4 to 259.9 +/- 33.4 microU/ml (1886 +/- 188 to 1560 +/- 200 pM); P < 0.05] decreased. Overall beta-cell function improved (SI x AIRg, 9.63 +/- 2.28 to 12.78 +/- 2.58 x 10(-3) min(-1), P < 0.05; and SI x AIRmax, 51.01 +/- 9.2 to 72.69 +/- 13.4 x 10(-3) min(-1), P < 0.05). Thus, the weight loss-associated improvements in both insulin sensitivity and beta-cell function may explain the beneficial effects of a lifestyle intervention on delaying the development of diabetes in older subjects.

The effect of common clinical contaminants on amniotic fluid fluorescence polarization results.

OBJECTIVE: To determine the effect of blood, meconium, and vaginal secretions on amniotic fluid (AF) fluorescence polarization results. METHODS: Amniotic fluid was collected by transabdominal amniocentesis from women at 20-41 weeks of gestation and contaminated with blood, meconium, and vaginal secretions to concentrations of 0.5, 1, 2, 5, and 10%. An additional 20% concentration was performed with meconium and vaginal secretions. Fluorescence polarization was determined by a TDx Analyzer with the NBD-PC fluorescent probe. Results were compared for each contaminant by concentration level using repeated-measures analysis of variance. RESULTS: Forty-eight samples from women at a mean gestational age of 35 weeks (range 20-41.5 weeks) were evaluated. Before contamination, 16 (33%) samples had fluorescence polarization values greater than 290 mPol (immature), 10 (21%) were 260- 289 mPol (transitional), and 22 (46%) were less than 260 mPol (mature). Contamination with blood significantly altered fluorescence polarization values in AF samples with baseline values in the immature and mature categories such that values trended toward the transitional range. Contamination of baseline immature samples with vaginal secretions at 20% contamination level resulted in more mature fluorescence polarization values. Contamination with meconium more than 2% in the baseline immature category or more than 20% in the baseline transitional category also resulted in significantly more mature fluorescence polarization values. CONCLUSION: Amniotic fluid contamination with blood can result in more transitional range fluorescence polarization values, whereas contamination with meconium and vaginal secretions can result in more mature fluorescence polarization values.