OBJECTIVE:--We sought to determine whether an oral disposition index (DIO) predicts the development of diabetes over a 10-year period. First, we assessed the validity of the DIO by demonstrating that ...a hyperbolic relationship exists between oral indexes of insulin sensitivity and β-cell function. RESEARCH DESIGN AND METHODS--A total of 613 Japanese-American subjects (322 men and 291 women) underwent a 75-g oral glucose tolerance test (OGTT) at baseline, 5 years, and 10 years. Insulin sensitivity was estimated as 1/fasting insulin or homeostasis model assessment of insulin sensitivity (HOMA-S). Insulin response was estimated as the change in insulin divided by change in glucose from 0 to 30 min (ΔI₀₋₃₀/ΔG₀₋₃₀). RESULTS:--ΔI₀₋₃₀/ΔG₀₋₃₀ demonstrated a curvilinear relationship with 1/fasting insulin and HOMA-S with a left and downward shift as glucose tolerance deteriorated. The confidence limits for the slope of the loge-transformed estimates included -1 for ΔI₀₋₃₀/ΔG₀₋₃₀ versus 1/fasting insulin for all glucose tolerance groups, consistent with a hyperbolic relationship. When HOMA-S was used as the insulin sensitivity measure, the confidence limits for the slope included -1 only for subjects with normal glucose tolerance (NGT) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) but not diabetes. On the basis of this hyperbolic relationship, the product of ΔI₀₋₃₀/ΔG₀₋₃₀ and 1/fasting insulin was calculated (DIO) and decreased from NGT to IFG/IGT to diabetes (P < 0.001). Among nondiabetic subjects at baseline, baseline DIO predicted cumulative diabetes at 10 years (P < 0.001) independent of age, sex, BMI, family history of diabetes, and baseline fasting and 2-h glucose concentrations. CONCLUSIONS:--The DIO provides a measure of β-cell function adjusted for insulin sensitivity and is predictive of development of diabetes over 10 years.
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.
Amyloid deposition and reduced β-cell mass are pathological hallmarks of the pancreatic islet in type 2 diabetes; however, whether the extent of amyloid deposition is associated with decreased β-cell ...mass is debated. We investigated the possible relationship and, for the first time, determined whether increased islet amyloid and/or decreased β-cell area quantified on histological sections is correlated with increased β-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 β cells were visualized by thioflavin S and insulin immunolabeling. Apoptotic β cells were detected by colabeling for insulin and by TUNEL. Diabetes was associated with increased amyloid deposition, decreased β-cell area, and increased β-cell apoptosis, as expected. There was a strong inverse correlation between β-cell area and amyloid deposition ( r = −0.42, P < 0.001). β-Cell area was selectively reduced in individual amyloid-containing islets from diabetic subjects, compared with control subjects, but amyloid-free islets had β-cell area equivalent to islets from control subjects. Increased amyloid deposition was associated with β-cell apoptosis ( r = 0.56, P < 0.01). Thus, islet amyloid is associated with decreased β-cell area and increased β-cell apoptosis, suggesting that islet amyloid deposition contributes to the decreased β-cell mass that characterizes type 2 diabetes.
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.
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.
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).
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.
OBJECTIVE:--The relative roles of insulin resistance and β-cell dysfunction in the pathogenesis of impaired glucose tolerance (IGT) and type 2 diabetes are debated. First-degree relatives of ...individuals with type 2 diabetes are at increased risk of developing hyperglycemia. RESEARCH DESIGN AND METHODS--We evaluated the evolution of insulin sensitivity, β-cell function, glucose effectiveness, and glucose tolerance over 7 years in 33 nondiabetic, first-degree relatives of type 2 diabetic individuals using frequently sampled tolbutamide-modified intravenous and oral glucose tolerance tests. RESULTS:--Subjects gained weight, and their waist circumference increased (P < 0.05). Insulin sensitivity, the acute insulin response to glucose, and glucose effectiveness did not change significantly. However, when we accounted for the modulating effect of insulin sensitivity on insulin release, β-cell function determined as the disposition index decreased by 22% (P < 0.05). This decrease was associated with declines in intravenous and oral glucose tolerance (P < 0.05 and P < 0.001, respectively). Of the subjects with normal glucose tolerance at the first assessment, we compared those who progressed to IGT with those who did not. The disposition index was 50% lower in the progressors than in the nonprogressors at follow-up (P < 0.05). CONCLUSIONS:--The decline in glucose tolerance over time in first-degree relatives of type 2 diabetic individuals is strongly related to the loss of β-cell function. Thus, early interventions to slow the decline in β-cell function should be considered in high-risk individuals.
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.
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.
OBJECTIVE:--To determine whether 1-h oral glucose challenge test (OGCT) or 3-h oral glucose tolerance test (OGTT) results below gestational diabetes mellitus (GDM) criteria are associated with ...developing diabetes. RESEARCH DESIGN AND METHODS--A retrospective cohort study was performed among women without GDM who had a pregnancy OGCT (n = 24,780) or OGTT (n = 6,222). Subsequent diabetes was ascertained by ICD-9 codes or pharmacy or laboratory data over a median follow-up of 8.8 years. RESULTS:--Diabetes risk increased across OGCT quartiles: adjusted hazard ratio (HR) 1.67 (95% CI 1.07-2.61) for 5.4-6.2 mmol/l, 2.13 (1.39-3.25) for 6.3-7.3 mmol/l, and 3.60 (2.41-5.39) for >=7.4 mmol/l compared with <=5.3 mmol/l. Women with one abnormal OGTT result had a higher risk compared with those with normal values (HR 2.08 95% CI 1.35-3.20). CONCLUSIONS:--Women with modestly elevated glucose levels below the threshold for GDM had a higher risk for diabetes.
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.
Abstract Purpose Confirmatory factor analysis (CFA) was used to test the hypothesis whether adipocytokines are associated with the risk factor cluster that characterizes the metabolic syndrome ...(MetS). Methods Data from 134 nondiabetic subjects were analyzed using CFA. Insulin sensitivity (SI ) was quantified using intravenous glucose tolerance tests, visceral fat area by computed tomography and fasting high-density lipoprotein, triglycerides, monocyte chemoattractant protein-1 (MCP-1), serum amyloid A (SAA), tumor necrosis factor (TNF)-α, adiponectin, resistin, leptin, interleukin (IL)-6, C-reactive protein (CRP), and plasminogen activator inhibitor (PAI)-1 were measured. Results The basic model representing the MetS included six indicators comprising obesity, SI , lipids, and hypertension, and demonstrated excellent goodness of fit. Using multivariate analysis, MCP-1, SAA, and TNF-α were not independently associated with any of the MetS variables. Adiponectin, resistin, leptin, CRP, and IL-6 were associated with at least one of the risk factors, but when added to the basic model decreased all goodness-of-fit parameters. PAI-1 was associated with all cardiometabolic factors and improved goodness-of-fit compared with the basic model. Conclusions Addition of PAI-1 increased the CFA model goodness of fit compared with the basic model, suggesting that this protein may represent an added feature of the MetS.
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