Citations

OBJECTIVE—To examine the influence of obesity and prevention of weight gain on the incidence of type 2 diabetes. RESEARCH DESIGN AND METHODS—We examined participants in the San Antonio Heart Study, a prospective population-based study of Mexican Americans and non-Hispanic whites residing in San Antonio, Texas. BMI was stratified into four categories: normal (<25 kg/m2), overweight (≥25 kg/m2 and <30 kg/m2), obese (≥30 kg/m2 and <35 kg/m2), and very obese (≥35 kg/m2). The number and proportion of incident cases prevented by targeting each BMI category were estimated. In addition, we calculated the decrease in risk of developing type 2 diabetes associated with weight gain prevention across both the BMI and age spectra. RESULTS—Preventing normal individuals from becoming overweight would result in the greatest reduction in incidence of type 2 diabetes. This would result in a 62 and 74% reduction in the incidence of type 2 diabetes in Mexican Americans and non-Hispanic whites, respectively. Preventing the entire population from gaining, on average, 1 BMI unit would result in a reduction in incidence of type 2 diabetes of 12.4 and 13.0% in Mexican Americans and non-Hispanic whites, respectively. CONCLUSIONS—The majority of cases of type 2 diabetes were in individuals who were overweight or mildly obese with a family history of type 2 diabetes. Public health resources should be directed toward the prevention of weight gain among normal and overweight individuals in order to prevent the maximum number of cases of type 2 diabetes.

OBJECTIVE—Increasing obesity within the general population has been accompanied by rising rates of diabetes. The extent to which obesity has increased among people with diabetes is unknown, as are the potential consequences for diabetes outcomes. RESEARCH DESIGN AND METHODS—Community medical records (hospital and ambulatory) of all Rochester, Minnesota, residents aged ≥30 years who first met standardized research criteria for diabetes from 1970 to 1989 (n = 1,306) were reviewed to obtain data on BMI and related characteristics as of the diabetes identification date (±3 months). Vital status as of 31 December 1999 and date of death for those who died were obtained from medical records, State of Minnesota death tapes, and active follow-up. RESULTS—As of the identification date, data on BMI were available for 1,290 cases. Of the 272 who first met diabetes criteria in 1970–1974, 33% were obese (BMI ≥30), including 5% who were extremely obese (BMI ≥40). These proportions increased to 49% (P < 0.001) and 9% (P = 0.012), respectively, for the 426 residents who first met diabetes criteria in 1985–1989. BMI increased significantly with increasing calendar year of diabetes identification in multivariable regression analysis. Analysis of survival revealed an increased hazard of mortality for BMI ≥41, relative to BMI of 23–25 (hazard ratio 1.60, 95% CI 1.09–2.34, P = 0.016). CONCLUSIONS—The prevalence of obesity and extreme obesity among individuals at the time they first met criteria for diabetes has increased over time. This is disturbing in light of the finding that diabetic individuals who are extremely obese are at increased risk of mortality compared with their nonobese diabetic counterparts.

OBJECTIVE The American Diabetes Association (ADA) has recommended that the fasting plasma glucose (FPG) level used to diagnose diabetes be changed from 7.8 mmol/l (the level recommended by the National Diabetes Data Group [NDDG] in 1979) to 7.0 mmol/l. We examined the impact of this change on rates of progression to overt diabetes from different levels of FPG. RESEARCH DESIGN AND METHODS Using the laboratory database of Mayo Clinic, we assembled a cohort of 8,098 nondiabetic Olmsted County residents 40 years of age or older on 1 July 1983. Subjects were followed for a median of 9 years. RESULTS Among 7,567 individuals with follow-up FPG data, 778 (10.3%) progressed to ADA diabetes and 513 (6.8%; P < 0.0001) progressed to NDDG diabetes. The risk of developing ADA diabetes was 7, 19, and 39% for individuals with initial FPG values in the ranges of <5.6, 5.6–6.0, and 6.1–6.9 mmol/l, respectively. For progression to NDDG diabetes, the respective risks were 3, 11, and 25%. A clear gradient of risk was observed within the “normal” range of FPG (<5.6 mmol/l). Among the 793 individuals who developed ADA diabetes, 222 (29%) developed NDDG diabetes simultaneously and 291 (37%) developed NDDG diabetes later. In all FPG subgroups, progression to ADA diabetes occurred ∼7 years sooner than progression to NDDG diabetes. CONCLUSIONS The baseline level of FPG is a major predictor of an individual's risk of developing diabetes. The proposed change in the diagnostic criteria for diabetes will lead to earlier diagnosis among individuals who are destined to develop the disease.

OBJECTIVE Despite widespread acceptance of continuous insulin infusion (CII) over bolus insulin injection (BII) for treatment of diabetic ketoacidosis (DKA), there are no population-based studies demonstrating whether CII has resulted in lower morbidity and mortality. RESEARCH DESIGN AND METHODS We addressed this issue using a provider-linked database and retrospectively reviewing the complete medical records of all incidence cases of diabetes among Rochester, Minnesota, residents from 1950 to 1989 with a discharge diagnosis of DKA. This population-based study describes the consequences of the widespread change in treatment modality outside the confines of a controlled clinical trial. RESULTS Among the diabetes incident cohort, there were 59 subjects with confirmed first episodes of DKA during 1950-1992; 29 of 30 subjects treated with BII occurred before 1970. All 29 CII cases occurred between 1976 and 1992. Sex, etiology, diabetes duration, and age at DKA were similar for the two groups. The proportion of obese individuals (BII = 2/28, CII = 8/21; P = 0.01) differed between groups. The CII group exhibited higher glucose values (BII = 24.9 ± 8.5 mmol/l, CII = 37.1 ± 15.1 mmol/l; P = 0.002) and lower bicarbonate values (BII = 7.7 ± 3.0 nmol/l, CII = 6.2 ± 2.9 nmol/l; P = 0.04) upon admission. The mean quantity of insulin administered was higher in the BII group than in the CII group (179 ± 140 and 99 ± 70 U, P < 0.006). The outcome of hypoglycemia occurred more frequently in the BII group than in the CII group (BII = 8/30, CII = 1/29; P = 0.03). The proportion with hypokalemia, neurological deficit, myocardial arrhythmia, or mortality did not differ significantly between groups. CONCLUSIONS Our findings suggest the introduction of CII was accompanied by a decreased incidence of hypoglycemia.

Abstract 17-Allylamino-demethoxygeldanamycin (17-AAG), currently in phase I and II clinical trials as an anticancer agent, binds to the ATP pocket of heat shock protein (Hsp90). This binding induces a cellular stress response that up-regulates many proteins including Hsp27, a member of the small heat shock protein family that has cytoprotective roles, including chaperoning of cellular proteins, regulation of apoptotic signaling, and modulation of oxidative stress. Therefore, we hypothesized that Hsp27 expression may affect cancer cell sensitivity to 17-AAG. In colony-forming assays, overexpression of Hsp27 increased cell resistance to 17-AAG whereas down-regulation of Hsp27 by siRNA increased sensitivity. Because Hsp27 is known to modulate levels of glutathione (GSH), we examined cellular levels of GSH and found that it was decreased in cells transfected with Hsp27 siRNA when compared with control siRNA. Treatment with buthionine sulfoximine, an inhibitor of GSH synthesis, also sensitized cells to 17-AAG. Conversely, treatment of Hsp27 siRNA–transfected cells with N-acetylcysteine, an antioxidant and GSH precursor, reversed their sensitivity to 17-AAG. A cell line selected for stable resistance to geldanamycin relative to parent cells showed increased Hsp27 expression. When these geldanamycin- and 17-AAG-resistant cells were transfected with Hsp27 siRNA, 17-AAG resistance was dramatically diminished. Our results suggest that Hsp27 up-regulation has a significant role in 17-AAG resistance, which may be mediated in part through GSH regulation. Clinical modulation of GSH may therefore enhance the efficacy of Hsp90-directed therapy. (Cancer Res 2006; 66(22): 10967-75)

Abstract We used QCT scans obtained in 687 men and women, 21–97 years of age, to estimate the factor of risk for vertebral fracture, Φvert, defined as the ratio of spinal loading to vertebral strength. With age, vertebral strength declined and Φvert increased significantly more in women than men. Age- and sex-specific differences in Φvert closely resembled previously reported vertebral fracture incidence. Introduction: Despite the high prevalence of vertebral fractures, little is known about the interaction between spinal loading and vertebral fragility. Materials and Methods: We assessed the ratio of spinal loading to vertebral strength (i.e., the factor of risk, Φvert) in an age- and sex-stratified population-based sample of 700 women and men 21–97 years of age. We measured volumetric BMD (vBMD, mg/cm3) and cross-sectional area (CSA, cm2) of the midvertebral bodies of L1–L3 using QCT and computed vertebral compressive strength from these data using engineering beam theory. A biomechanical model of the trunk was used to estimate compressive forces applied to the L3 vertebral body during standing, bending forward, and bending forward while lifting 10 kg. The factor of risk for fracture, Φvert, was computed as the ratio of spinal compressive force to vertebral strength for each activity. Results: Men had a higher vertebral strength at all ages, largely because of their greater CSA. Whereas both sexes exhibited a marked decline in vertebral compressive strength with age (p < 0.001), the decline was greater in women than men (−43% versus −31%, p = 0.008). Compressive forces on L3 were greater in men than women, because of their greater body weight and height. For both sexes, forces during bending and lifting were 8-fold higher than those experienced during upright standing. For all activities, Φvert increased with age, but significantly more so in women than men (p < 0.001). For bending and lifting, Φvert-bending exceeded 1.0 in 30% of women and 12% of men ≥50 years of age, values that are similar to the reported frequency of vertebral fracture. Conclusion: These findings illustrate potential mechanisms underlying vertebral fractures and provide strong rationale for further evaluation of this QCT-based biomechanical approach for assessment of fracture risk.