ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca2+ Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ.

ATPase inhibitory factor-1 (IF1) preserves cellular ATP under conditions of respiratory collapse, yet the function of IF1 under normal respiring conditions is unresolved. We tested the hypothesis that IF1 promotes mitochondrial dysfunction and pathological cardiomyocyte hypertrophy in the context of heart failure (HF). Methods and results: Cardiac expression of IF1 was increased in mice and in humans with HF, downstream of neurohumoral signaling pathways and in patterns that resembled the fetal-like gene program. Adenoviral expression of wild-type IF1 in primary cardiomyocytes resulted in pathological hypertrophy and metabolic remodeling as evidenced by enhanced mitochondrial oxidative stress, reduced mitochondrial respiratory capacity, and the augmentation of extramitochondrial glycolysis. Similar perturbations were observed with an IF1 mutant incapable of binding to ATP synthase (E55A mutation), an indication that these effects occurred independent of binding to ATP synthase. Instead, IF1 promoted mitochondrial fragmentation and compromised mitochondrial Ca2+ handling, which resulted in sarcoplasmic reticulum Ca2+ overloading. The effects of IF1 on Ca2+ handling were associated with the cytosolic activation of calcium-calmodulin kinase II (CaMKII) and inhibition of CaMKII or co-expression of catalytically dead CaMKIIδC was sufficient to prevent IF1 induced pathological hypertrophy. Conclusions: IF1 represents a novel member of the fetal-like gene program that contributes to mitochondrial dysfunction and pathological cardiac remodeling in HF. Furthermore, we present evidence for a novel, ATP-synthase-independent, role for IF1 in mitochondrial Ca2+ handling and mitochondrial-to-nuclear crosstalk involving CaMKII.

Diabetes and ischaemic stroke outcome.

AIM: To compare all-cause mortality, stroke recurrence and functional outcomes in people who have experienced stroke, with and without diabetes. METHODS: We captured data on population-based ischaemic strokes (2006-2012) in Nueces County, Texas. Data were collected from participant interviews and medical records. Differences in cumulative mortality and stroke recurrence risk by diabetes status were estimated at 30 days and 1 year using Cox models. Differences in 90-day functional outcomes (activities of daily living/instrumental activities of daily living score: range 1-4; higher scores worse) by diabetes status were assessed using Tobit regression. Effect modification by ethnicity was examined. RESULTS: There were 1301 ischaemic strokes, 46% with history of known diabetes. The median (interquartile range) age was 70 (58-81) years and 61% were Mexican American. People with diabetes were younger and more likely to be Mexican American compared with those without diabetes. After adjustment, diabetes predicted mortality (30-day hazard ratio 1.44, 95% CI 0.97-2.12; 1-year hazard ratio 1.47, 95% CI 1.09-1.97) but not stroke recurrence (1-year hazard ratio 1.27, 95% CI 0.78-2.07). People with diabetes had a worse functional outcome score that was explained by cardiovascular risk factors and pre-stroke factors. Diabetes was not associated with functional outcome in the fully adjusted model (final adjusted activities of daily living/instrumental activities of daily living score difference 0.11, 95% CI -0.07 to 0.30). Effect modification by ethnicity was not significant (P>0.3 for all models). CONCLUSIONS: Diabetes was associated with higher mortality and worse functional outcome but not stroke recurrence. Interventions are needed to decrease the adverse outcomes associated with diabetes, particularly in Mexican-American people.

Sweet taste preferences before and after an intensive medical weight loss intervention.

OBJECTIVE: Medical weight loss could change sweet taste threshold and preferences. The decrease in sweet taste preferences may, in turn, help in the maintenance of weight loss. This study examined the association between sweet taste preferences at baseline and weight change during a medical weight management programme and the impact of diet-induced weight loss on sweet taste preferences. METHODS: Adult patients with body mass index ≥32 kg m-2 were recruited from a medical weight management clinic. Sweet taste preference was assessed using a forced-choice, paired-comparison tracking method before and after a very-low-calorie diet (VLCD). RESULTS: Twenty participants were included in the analysis: mean age was 53.1 (standard deviation [SD]: 11.4) years, and 14 were female. The mean body mass index was 41.4 (SD: 7.5) kg m-2. The median preferred sucrose concentration before VLCD was 0.45 M. Following VLCD, mean change in weight was -13.3 (SD: 6.6) kg, and percentage weight change was -11.3% (SD: 5.9%). Based on mixed models with and without adjustment for demographic factors, diabetes status and smoking history, preferred sucrose concentration at baseline did not predict change in longer-term body weight. The change of preferred sucrose concentration following 12 weeks of VLCD was not significant (P-value 0.95). CONCLUSIONS: Change in weight during and after VLCD was not associated with sweet taste preferences at baseline. After diet-induced weight loss, sweet taste preferences did not change.

Glycaemic control and risk of incident urinary incontinence in women with Type 1 diabetes: results from the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study.

AIMS: To study the impact of glycaemic control on urinary incontinence in women who participated in the Diabetes Control and Complications Trial (DCCT; 1983-1993) and its observational follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC; 1994-present). METHODS: Study participants were women who completed, at both years 10 (2003) and 17 (2010) of the EDIC follow-up, the urological assessment questionnaire (UroEDIC). Urinary incontinence was defined as self-reported involuntary leakage of urine that occurred at least weekly. Incident urinary incontinence was defined as weekly urinary incontinence present at EDIC year 17 but not at EDIC year 10. Multivariable regression models were used to examine the association of incident urinary incontinence with comorbid prevalent conditions and glycaemic control (mean HbA1c over the first 10 years of EDIC). RESULTS: A total of 64 (15.3%) women with Type 1 diabetes (mean age 43.6 ± 6.3 years at EDIC year 10) reported incident urinary incontinence at EDIC year 17. When adjusted for clinical covariates (including age, DCCT cohort assignment, DCCT treatment arm, BMI, insulin dosage, parity, hysterectomy, autonomic neuropathy and urinary tract infection in the last year), the mean EDIC HbA1c was associated with increased odds of incident urinary incontinence (odds ratio 1.03, 95% CI 1.01-1.06 per mmol/mol increase; odds ratio 1.41, 95% CI 1.07-1.89 per % HbA1c increase). CONCLUSIONS: Incident urinary incontinence was associated with higher HbA1c levels in women with Type 1 diabetes, independent of other recognized risk factors. These results suggest the potential for women to modify their risk of urinary incontinence with improved glycaemic control. (Clinical Trials Registry no: NCT00360815 and NCT00360893).

Diabetes, Gray Matter Loss, and Cognition in the Setting of Parkinson Disease.

RATIONALE AND OBJECTIVES: Parkinson disease (PD) is a progressive neurodegenerative disorder affecting motor and cognitive functions. Prior studies showed that patients with PD and diabetes (DM) demonstrate worse clinical outcomes compared to nondiabetic subjects with PD. Our study aimed at defining the relationship between DM, gray matter volume, and cognition in patients with PD. MATERIALS AND METHODS: This study included 36 subjects with PD (12 with DM, 24 without DM, mean age = 66). Subjects underwent high-resolution T1-weighted brain magnetic resonance imaging, [(11)C]dihydrotetrabenazine positron emission tomography imaging to quantify nigrostriatal dopaminergic denervation, clinical, and cognitive assessments. Magnetic resonance images were postprocessed to determine total and lobar cortical gray matter volumes. Cognitive testing scores were converted to z-scores for specific cognitive domains and a composite global cognitive z-score based on normative data computed. Analysis of covariance, accounting for effects of age, gender, intracranial volume, and striatal [(11)C]dihydrotetrabenazine binding, was used to test the relationship between DM and gray matter volumes. RESULTS: Impact of DM on total gray matter volume was significant (P = 0.02). Post hoc analyses of lobar cortical gray matter volumes revealed that DM was more selectively associated with lower gray matter volumes in the frontal regions (P = 0.01). Cognitive post hoc analyses showed that interaction of total gray matter volume and DM status was significantly associated with composite (P = 0.007), executive (P = 0.02), and visuospatial domain cognitive z-scores (P = 0.005). These associations were also significant for the frontal cortical gray matter. CONCLUSION: DM may exacerbate brain atrophy and cognitive functions in PD with greater vulnerability in the frontal lobes. Given the high prevalence of DM in the elderly, delineating its effects on patient outcomes in the PD population is of importance.

The effect of lifestyle intervention and metformin on preventing or delaying diabetes among women with and without gestational diabetes: the Diabetes Prevention Program outcomes study 10-year follow-up.

CONTEXT: Gestational diabetes (GDM) confers a high risk of type 2 diabetes. In the Diabetes Prevention Program (DPP), intensive lifestyle (ILS) and metformin prevented or delayed diabetes in women with a history of GDM. OBJECTIVE: The objective of the study was to evaluate the impact of ILS and metformin intervention over 10 years in women with and without a history of GDM in the DPP/Diabetes Prevention Program Outcomes Study. DESIGN: This was a randomized controlled clinical trial with an observational follow-up. SETTING: The study was conducted at 27 clinical centers. PARTICIPANTS: Three hundred fifty women with a history of GDM and 1416 women with previous live births but no history of GDM participated in the study. The participants had an elevated body mass index and fasting glucose and impaired glucose tolerance at study entry. INTERVENTIONS: Interventions included placebo, ILS, or metformin. OUTCOMES MEASURE: Outcomes measure was diabetes mellitus. RESULTS: Over 10 years, women with a history of GDM assigned to placebo had a 48% higher risk of developing diabetes compared with women without a history of GDM. In women with a history of GDM, ILS and metformin reduced progression to diabetes compared with placebo by 35% and 40%, respectively. Among women without a history of GDM, ILS reduced the progression to diabetes by 30%, and metformin did not reduce the progression to diabetes. CONCLUSIONS: Women with a history of GDM are at an increased risk of developing diabetes. In women with a history of GDM in the DPP/Diabetes Prevention Program Outcomes Study, both lifestyle and metformin were highly effective in reducing progression to diabetes during a 10-year follow-up period. Among women without a history of GDM, lifestyle but not metformin reduced progression to diabetes.

Use of the Michigan Neuropathy Screening Instrument as a measure of distal symmetrical peripheral neuropathy in Type 1 diabetes: results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications.

AIMS: The Michigan Neuropathy Screening Instrument (MNSI) is used to assess distal symmetrical peripheral neuropathy in diabetes. It includes two separate assessments: a 15-item self-administered questionnaire and a lower extremity examination that includes inspection and assessment of vibratory sensation and ankle reflexes. The purpose of this study was to evaluate the performance of the MNSI in detecting distal symmetrical peripheral neuropathy in patients with Type 1 diabetes and to develop new scoring algorithms. METHODS: The MNSI was performed by trained personnel at each of the 28 Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications clinical sites. Neurologic examinations and nerve conduction studies were performed during the same year. Confirmed clinical neuropathy was defined by symptoms and signs of distal symmetrical peripheral neuropathy based on the examination of a neurologist and abnormal nerve conduction findings in ≥ 2 anatomically distinct nerves among the sural, peroneal and median nerves. RESULTS: We studied 1184 subjects with Type 1 diabetes. Mean age was 47 years and duration of diabetes was 26 years. Thirty per cent of participants had confirmed clinical neuropathy, 18% had ≥ 4 and 5% had ≥ 7 abnormal responses on the MNSI questionnaire, and 33% had abnormal scores (≥ 2.5) on the MNSI examination. New scoring algorithms were developed and cut points defined to improve the performance of the MNSI questionnaire, examination and the combination of the two. CONCLUSIONS: Altering the cut point to define an abnormal test from ≥ 7 abnormal to ≥ 4 abnormal items improves the performance of the MNSI questionnaire. The MNSI is a simple, non-invasive and valid measure of distal symmetrical peripheral neuropathy in Type 1 diabetes.

Is the physical functioning of older adults with diabetes associated with the processes and outcomes of care? Evidence from Translating Research Into Action for Diabetes (TRIAD).

AIMS: To examine the relationship between physical function limitations and diabetes self-management, processes of care and intermediate outcomes in adults ≥ 65 years of age with Type 2 diabetes. METHODS: We studied 1796 participants 65 years of age and older in managed care health plans enrolled in Translating Research into Action for Diabetes (TRIAD). Physical functioning was assessed at baseline with the Physical Component Summary of the Short Form-12 Health Survey. Diabetes self-management was assessed with follow-up surveys, and processes of care (eye examinations, urine microalbumin testing, foot examinations, etc.) and intermediate health outcomes (HbA(1c), blood pressure, LDL cholesterol) were assessed with medical chart reviews. Multivariate regression models were constructed to examine the associations between physical function limitations and outcomes. RESULTS: Frequency of eye examinations (odds ratio 0.69, 95% CI 0.49-0.99) was the only process of care that was worse for participants with physical function limitations (n = 573) compared with those without limitations (n = 618). Neither self-management nor intermediate outcomes differed by whether patients had or did not have physical function limitations. CONCLUSION: Limitations in physical functioning as assessed by the Short Form-12 were not associated with substantial difference in diabetes care in adults ≥ 65 years of age enrolled in managed care health plans.

Getting heavier, younger: trajectories of obesity over the life course.

CONTEXT: Although recent trends in obesity have been well documented, generational patterns of obesity from early childhood through adulthood across birth cohorts, which account for the recent epidemic of childhood obesity, have not been well described. Such trends may have implications for the prevalence of obesity-associated conditions among population subgroups, including type 2 diabetes. OBJECTIVE: Our objective was to evaluate trajectories of obesity over the life course for the US population, overall and by gender and race. DESIGN, SETTING AND PARTICIPANTS: We conducted an age, period and birth cohort analysis of obesity for US individuals who participated in the National Health and Nutrition Examination Surveys (NHANES) (1971-2006). MAIN OUTCOME MEASURES: Obesity was defined as a body mass index >or=95th percentile for individuals aged 2-16 years or >or=30 kg m(-2) among individuals older than 16 years. Age was represented by the age of the individual at each NHANES, period was defined by the year midpoint of each survey, and cohort was calculated by subtracting age from period. RESULTS: Recent birth cohorts are becoming obese in greater proportions for a given age, and are experiencing a greater duration of obesity over their lifetime. For example, although the 1966-1975 and 1976-1985 birth cohorts had reached an estimated obesity prevalence of at least 20% by 20-29 years of age, this level was only reached by 30-39 years for the 1946-1955 and 1956-1965 birth cohorts, by 40-49 years for the 1936-1945 birth cohort and by 50-59 years of age for the 1926-1935 birth cohort. Trends are particularly pronounced for female compared with male, and black compared with white cohorts. CONCLUSIONS: The increasing cumulative exposure to excess weight over the lifetime of recent birth cohorts will likely have profound implications for future rates of type 2 diabetes, and mortality within the US population.

Physicians' participatory decision-making and quality of diabetes care processes and outcomes: results from the triad study.

OBJECTIVES: In participatory decision-making (PDM), physicians actively engage patients in treatment and other care decisions. Patients who report that their physicians engage in PDM have better disease self-management and health outcomes. We examined whether physicians' diabetes-specific treatment PDM preferences as well as their self-reported practices are associated with the quality of diabetes care their patients receive. METHODS: 2003 cross-sectional survey and medical record review of a random sample of diabetes patients (n=4198) in 10 US health plans across the country and their physicians (n=1217). We characterized physicians' diabetes care PDM preferences and practices as 'no patient involvement,' 'physician-dominant,' 'shared,' or 'patient-dominant' and conducted multivariate analyses examining their effects on the following: (1) three diabetes care processes (annual hemoglobin A1c test; lipid test; and dilated retinal exam); (2) patients'satisfaction with physician communication; and (3) whether patients' A1c, systolic blood pressure (SBP), and low-density lipoprotein cholesterol (LDL) were in control. RESULTS: Most physicians preferred 'shared' PDM (58%) rather than 'no patient involvement' (9%), 'physician-dominant' (28%) or 'patient dominant' PDM (5%). However, most reported practicing 'physician-dominant' PDM (43%) with most of their patients, rather than 'no patient involvement' (13%), 'shared' (37%) or 'patient-dominant' PDM (7%). After adjusting for patient and physician-level characteristics and clustering by health plan, patients of physicians who preferred 'shared' PDM were more likely to receive A1c tests [90% vs. 82%, AOR: 2.05, 95% CI: 1.03-3.07] and patients of physicians who preferred 'patient-dominant' treatment decision-making were more likely to receive lipid tests [60% vs. 50%, AOR: 1.58, 95% CI: 1.04-2.39] than those of providers who preferred 'no patient involvement' in treatment decision-making. There were no differences in patients' satisfaction with their doctor's communication or control of A1c, SBP or LDL depending on their physicians' PDM preferences. Physicians' self-reported PDM practices were not associated with any of the examined aspects of diabetes care in multivariate analyses. CONCLUSIONS: Patients whose physicians prefer more patient involvement in decision-making are more likely than patients whose physicians prefer more physician-directed styles to receive some recommended risk factor screening tests, an important first step toward improved diabetes outcomes. Involving patients in treatment decision-making alone, however, appears not to be sufficient to improve biomedical outcomes.

A Diabetes Outcome Progression Trial (ADOPT): baseline characteristics of Type 2 diabetic patients in North America and Europe.

AIMS: To examine baseline characteristics of patients recruited into ADOPT, a multinational trial comparing three oral glucose-lowering monotherapies. METHODS: Between April 2000 and June 2002, 4360 patients aged 30-75 years with Type 2 diabetes diagnosed for < 3 years and remaining on diet therapy alone with fasting plasma glucose levels (FPG) between 7.0 and 10.0 mmol/l were enrolled by 488 North American and European centres. Medical histories, anthropometric data and laboratory measurements were determined using common methodologies. RESULTS: The mean (SD) age of the patients was 57 (10) years, body mass index 32.2 (6.4) kg/m(2), HbA(1c) 7.4 (0.9)%; 58% were male, 88% Caucasian and 15% smoked. North American Caucasians (NAC) were younger, more obese, and more insulin resistant than European Caucasians (EUC), but had better pancreatic B-cell function. NAC had lower total, low-density lipoprotein- and high-density liporpotein-cholesterol concentrations with higher triglyceride concentrations and were more often on lipid-lowering treatment. They had lower blood pressure levels but were equally likely to be on antihypertensive treatment. Metabolic syndrome was more frequent and microalbuminuria less frequent in NAC. Within North America, NAC had lower HbA(1c) concentrations than Blacks, Hispanics and Asians despite similar or higher FPG and 30-min postchallenge glucose concentrations. CONCLUSIONS: Caucasian North American and European ADOPT patients differ with respect to adiposity, insulin resistance and metabolic syndrome prevalence. North American Blacks, Hispanics and Asians had lower HbA(1c) concentrations than NAC despite similar or higher glucose concentrations. These phenotypic differences may influence the progression of Type 2 diabetes and the response to initial oral glucose-lowering monotherapy.

A multivariate logistic regression equation to screen for dysglycaemia: development and validation.

AIMS: To develop and validate an empirical equation to screen for dysglycaemia [impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and undiagnosed diabetes]. METHODS: A predictive equation was developed using multiple logistic regression analysis and data collected from 1032 Egyptian subjects with no history of diabetes. The equation incorporated age, sex, body mass index (BMI), post-prandial time (self-reported number of hours since last food or drink other than water), systolic blood pressure, high-density lipoprotein (HDL) cholesterol and random capillary plasma glucose as independent covariates for prediction of dysglycaemia based on fasting plasma glucose (FPG)>or=6.1 mmol/l and/or plasma glucose 2 h after a 75-g oral glucose load (2-h PG)>or=7.8 mmol/l. The equation was validated using a cross-validation procedure. Its performance was also compared with static plasma glucose cut-points for dysglycaemia screening. RESULTS: The predictive equation was calculated with the following logistic regression parameters: P=1+1/(1+e-X)=where X=-8.3390+0.0214 (age in years)+0.6764 (if female)+0.0335 (BMI in kg/m2)+0.0934 (post-prandial time in hours)+0.0141 (systolic blood pressure in mmHg)-0.0110 (HDL in mmol/l)+0.0243 (random capillary plasma glucose in mmol/l). The cut-point for the prediction of dysglycaemia was defined as a probability>or=0.38. The equation's sensitivity was 55%, specificity 90% and positive predictive value (PPV) 65%. When applied to a new sample, the equation's sensitivity was 53%, specificity 89% and PPV 63%. CONCLUSIONS: This multivariate logistic equation improves on currently recommended methods of screening for dysglycaemia and can be easily implemented in a clinical setting using readily available clinical and non-fasting laboratory data and an inexpensive hand-held programmable calculator.

Glycemia and the quality of well-being in patients with diabetes.

OBJECTIVES: To investigate the cross-sectional relationships among self-reported frequencies of symptomatic hyperglycemia and hypoglycemia, HbA1c, and symptoms in the Quality of Well-Being Self-Administered (QWB-SA), and to examine the associations among these measures of glycemia and health-utility scores. METHODS: The study group included 1522 patients with diabetes who attended University of Michigan Health System clinics. Published studies were reviewed to identify symptoms in the QWB-SA that might be associated with measures of glycemia. Linear-regression analyses were performed to evaluate the strength of the associations among the frequency of self-reported measures of glycemia, QWB-SA symptoms, and QWB-SA-derived health-utility scores. RESULTS: Frequency of hyperglycemic symptoms was associated with 3% of the variance in the QWB-SA-derived health-utility score in type-1 diabetes and with 5% of the variance in type-2 diabetes. Frequency of hypoglycemic symptoms was not associated with the QWB-SA-derived health-utility score in type-1 diabetes but was associated with 1% of the variance in type-2 diabetes. HbAlc levels were not significantly associated with QWB-SA-derived health-utility scores. After controlling for age, gender, and complications, frequency of hyperglycemic symptoms was significantly associated with QWB-SA-derived health-utility scores in type-1 and type-2 diabetes. CONCLUSIONS: Reported frequency of hyperglycemic symptoms is associated with symptoms included in the QWB-SA and with QWB-SA-derived health-utility scores. The QWB-SA may be an appropriate measure to assess the health burden of hyperglycemia.

Does microalbuminuria predict diabetic nephropathy?

OBJECTIVE: To describe risk factors associated with microalbuminuria (MA) in subjects with diabetes, investigate the predictive value of MA as a marker of risk for diabetic nephropathy (DN), and define risk factors associated with the development and progression of MA. RESEARCH DESIGN AND METHODS: We conducted a prospective longitudinal study of 23 diabetic subjects with persistent MA and 209 diabetic subjects without MA who attended diabetes clinics at the University of Michigan Medical Center in 1989 and 1990. Both groups were examined at baseline and after 7 years. At baseline, urinary albumin-to-creatinine ratios were studied in random, first morning, and 24-h urine samples. At follow-up, a 12-h overnight urine sample was collected and analyzed for albumin and creatinine. At baseline, MA was defined by at least two separate urine specimens with albumin-to-creatinine ratios between 30 and 299 microg albumin per milligram of creatinine. RESULTS: MA regressed in 56% of subjects with baseline MA without systematic application of corrective measures and developed in 16% of subjects without baseline MA. The predictive value positive of MA as a marker of risk for DN was 43%, and the predictive value negative was 77%. In the combined cohort, the incidence and progression of MA were significantly associated with poor glycemic control and duration of diabetes between 10 and 14 years. CONCLUSIONS: MA may not be as sensitive and specific a predictor of DN as previously suggested. Other markers of risk for DN are needed for optimal clinical management.

Screening for type 2 diabetes.

Definitive studies of the effectiveness of screening for type 2 diabetes are currently not available. RCTs would be the best means to assess effectiveness, but several barriers prevent these studies from being conducted. Prospective observational studies may characterize some of the benefits of screening by creating screened and unscreened groups for comparison. The availability of better data systems and health services research techniques will facilitate such comparisons. Unfortunately, the interpretation of the results of such studies is extremely problematic. Several screening tests have been evaluated. Risk assessment questionnaires have generally performed poorly as stand-alone tests. Screening with biochemical tests performs better. Venous and capillary glucose measurements may perform more favorably than urinary glucose or HbA(1c) measurements, and measuring postprandial glucose levels may have advantages over measuring fasting levels. However, performance of all screening tests is dependent on the cutoff point selected. Unfortunately, there are no well-defined and validated cutoff points to define positive tests. A two-stage screening test strategy may assist with a more efficient use of resources, although such approaches have not been rigorously tested. The optimal interval for screening is unknown. Even though periodic, targeted, and opportunistic screening within the existing health care system seems to offer the greatest yield and likelihood of appropriate follow-up and treatment, much of the reported experience with screening appears to be episodic poorly targeted community screening outside of the existing health care system. Statistical models have helped to answer some of the key questions concerning areas in which there is lack of empirical data. Current models need to be refined with new clinical and epidemiological information, such as the UKPDS results (200). In addition, future models need to include better information on the natural history of the preclinical phase of diabetes. Data from ongoing clinical trials of screening and treatment of impaired glucose tolerance, such as the Diabetes Prevention Program, may eventually offer more direct evidence for early detection and treatment of asymptomatic hyperglycemia (201). It will be important to use comprehensive cardiovascular disease modules that assess the conjoint influence of glucose and cardiovascular risk factor reduction, information on QOL, and refined economic evaluations using common outcome measures (cost per life-year or QALY gained) (11,178,202-204). Such studies should consider all of the costs associated with a comprehensive screening program, including, at a minimum, the direct costs of screening, diagnostic testing, and care for patients with diabetes detected through screening. Finally, combinations of screening tests and different screening intervals should be evaluated within economic studies to allow selection of the optimal approach within the financial and resource limitations of the health care system.

Elevated endothelin-1 in tubular epithelium is associated with renal allograft rejection.

Vascular endothelin-1 (ET-1) levels are elevated in patients with renal allograft rejection, and the mitogenic and pressor actions of ET-1 might contribute to transplant vasculopathy, posttransplantation hypertension, and ischemia-reperfusion injury. In contrast, relatively little is known about tubular expression of ET-1 in acute or chronic rejection of renal allografts. We sought to determine whether tubular ET-1 levels were altered in patients with acute or chronic renal allograft rejection. Immunohistochemical analysis of tubular ET-1 was performed in renal biopsy specimens from 18 patients with acute rejection, 7 patients with chronic rejection, and 5 normal kidneys excised for localized neoplasm. The diagnosis of acute or chronic rejection in each patient was verified and graded using the Banff schema. Renal tubular epithelium from patients with allograft rejection had markedly elevated staining for ET-1 compared with normal kidneys. Tubular ET-1 levels were elevated in 18 of 18 patients with acute rejection and 5 of 7 patients with chronic rejection. Tubular ET-1 staining was graded from 0 to +3 as follows: normal kidneys, 1.2 +/- 0.2; acute rejection, 2.3 +/- 0.4 (P < 0.01); and chronic rejection, 2.2 +/- 0.5 (P < 0.01). ET-1 staining was prominent in both proximal and distal tubules, and we observed abundant ET-1 secretion from proximal tubular epithelium in culture. Moreover, ET-1 activated the c-fos immediate early gene promoter in proximal tubular cells transfected with a c-fos luciferase reporter. We conclude that elevated tubular ET-1 levels are associated with acute and chronic rejection of renal allografts. Our results also suggest distinct pathophysiological roles for the tubular and vascular ET-1 systems in renal allograft rejection.

Ammonium perchlorate contamination of Colorado River drinking water is associated with abnormal thyroid function in newborns in Arizona.

The Colorado River below Lake Mead, which supplies drinking water for approximately 20,000,000 people, is contaminated by ammonium perchlorate. We identified populations who were exposed and unexposed to perchlorate-contaminated drinking water and compared median newborn thyroid-stimulating hormone (TSH) levels after adjusting for age in days at measurement and for race/ethnicity. Median newborn TSH levels in a city whose drinking water supply was 100% perchlorate-contaminated water from the Colorado River below Lake Mead were significantly higher than those in a city totally supplied with non-perchlorate-contaminated drinking water, even after adjusting for factors known or suspected to elevate newborn TSH levels. This ecological study demonstrates a statistically significant association between perchlorate exposure and newborn TSH levels. It suggests that even low-level perchlorate contamination of drinking water may be associated with adverse health effects in neonates and highlights the need for both further study and control of human low-level perchlorate exposure.

Reduced pancreatic polypeptide response to hypoglycemia and amylin response to arginine in subjects with a mutation in the HNF-4alpha/MODY1 gene.

Subjects with the Q268X mutation in the hepatocyte nuclear factor (HNF)-4alpha gene (RW pedigree/maturity-onset diabetes of the young [MODY]-1) have diminished insulin and glucagon secretory responses to arginine. To determine if pancreatic polypeptide (PP) secretion is likewise involved, we studied PP responses to insulin-induced hypoglycemia in 17 RW pedigree members: 6 nondiabetic mutation-negative [ND(-)], 4 nondiabetic mutation-positive [ND(+)], and 7 diabetic mutation-positive [D(+)]. Subjects received 0.08 U/kg body wt human regular insulin as an intravenous bolus to produce moderate self-limited hypoglycemia. PP areas under the curve (PP-AUCs) were compared among groups. With hypoglycemia, the PP-AUC was lower in the D(+) group (14,907 +/- 6,444 pg/ml, P = 0.03) and the ND(+) group (14,622 +/- 6,015 pg/ml, P = 0.04) compared with the ND(-) group (21,120 +/- 4,158 pg/ml). In addition, to determine if the beta-cell secretory defect in response to arginine involves amylin in addition to insulin secretion, we analyzed samples from 17 previously studied RW pedigree subjects. We compared the AUCs during arginine infusions for the 3 groups both at euglycemia and hyperglycemia as well as their C-peptide-to-amylin ratios. The D(+) and ND(+) groups had decreased amylin AUCs during both arginine infusions compared with the ND(-) group, but had similar C-peptide-to-amylin ratios. These results suggest that the HNF-4alpha mutation in the RW/MODY1 pedigree confers a generalized defect in islet cell function involving PP cells in addition to beta- and alpha-cells, and beta-cell impairment involving proportional deficits in insulin and amylin secretion.