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Biomedical subjects

W H Herman

Publications and source records attributed to W H Herman.

At least 55 records · Page 3Linked to original sources
PubMed1997

Diminished insulin and glucagon secretory responses to arginine in nondiabetic subjects with a mutation in the hepatocyte nuclear factor-4alpha/MODY1 gene.

Nondiabetic subjects with the Q268X mutation in the hepatocyte nuclear factor (HNF)-4alpha/MODY1 gene have impaired glucose-induced insulin secretion. To ascertain the effects of the nonglucose secretagogue arginine on insulin and glucagon secretion in these subjects, we studied 18 members of the RW pedigree: 7 nondiabetic mutation negative (ND[-]), 7 nondiabetic mutation positive (ND[+]), and 4 diabetic mutation positive (D[+]). We gave arginine as a 5-g bolus, followed by a 25-min infusion at basal glucose concentrations, and after glucose infusion to clamp plasma glucose at approximately 200 mg/dl. The acute insulin response (AIR), the 10-60 min insulin area under the curve (AUC), and the insulin secretion rate (ISR) were compared, as were the acute glucagon response (AGR) and glucagon AUC. The ND[+] and D[+] groups had decreased insulin AUC and ISR and decreased glucose potentiation of AIR, insulin AUC, and ISR to arginine administration when compared with the ND[-] group. At basal glucose concentrations, glucagon AUC was greatest for the ND[-] group, intermediate for the ND[+] group, and lowest for the D[+] group. During the hyperglycemic clamp, there was decreased suppression of glucagon AUC for both ND[+] and D[+] groups compared with the ND[-] group. The decreased ISR to arginine in the ND[+] group compared with the ND[-] group, magnified by glucose potentiation, indicated that HNF-4alpha affects the signaling pathway for arginine-induced insulin secretion. The decrease in glucagon AUC and decreased suppression of glucagon AUC with hyperglycemia suggest that mutations in HNF-4alpha may lead to alpha-cell as well as beta-cell secretory defects or a reduction in pancreatic islet mass.

Adult↗
PubMed1997

Model of complications of NIDDM. I. Model construction and assumptions.

OBJECTIVE: To develop a model of NIDDM for analyzing prevention strategies for NIDDM. RESEARCH DESIGN AND METHODS: A Markov type model with Monte Carlo techniques was used. Age, sex, and ethnicity of cohort was based on U.S. data. Incidence rates of complications were also based on community and population studies. RESULTS: Nonproliferative retinopathy, proliferative retinopathy, and macular edema are predicted in 79, 19, and 52%, respectively, of people with NIDDM; 19% are predicted to develop legal blindness. Microalbuminuria, gross proteinuria, and end-stage renal disease related to diabetes are predicted in 53, 40, and 17%, respectively. Symptomatic sensorimotor neuropathy and lower-extremity amputation are predicted in 31 and 17%, respectively. Cardiovascular disease is predicted in 39%. Higher rates of complications (1.1-3.0x) are predicted in minority populations. Predicted average life expectancy is 17 years after diagnosis. CONCLUSIONS: A probabilistic model of NIDDM predicts the vascular complications of NIDDM in a cohort representative of the incident cases of diabetes in the U.S. before age 75 years. Predictions of complications and mortality are consistent with the known epidemiology of NIDDM. The model is suitable for evaluating the effect of preventive interventions on the natural history of NIDDM.

Adult↗
PubMed1997

Model of complications of NIDDM. II. Analysis of the health benefits and cost-effectiveness of treating NIDDM with the goal of normoglycemia.

OBJECTIVE: To analyze the health benefits and economics of treating NIDDM with the goal of normoglycemia. RESEARCH DESIGN AND METHODS: Incidence-based simulation model of NIDDM was used. Hazard rates for complications were adjusted for glycemia using risk gradients from the Diabetes Control and Complications Trial. Treatment costs were estimated from national survey data and clinical trials. Incremental costs and benefits were expressed in present value dollars (3% discount rate). Life-years were adjusted for quality of life, yielding quality-adjusted life-years (QALYs). RESULTS: Comprehensive treatment of NIDDM that maintains an HbA1c value of 7.2% is predicted to reduce the cumulative incidence of blindness, end-stage renal disease, and lower-extremity amputation by 72, 87, and 67%, respectively. Cardiovascular disease risk increased by 3% (no effect of treating glycemia is assumed). Life expectancy increased 1.39 years. The cost of treating hyperglycemia increased by almost twofold, which is partially offset by reductions in the cost of complications. The estimated incremental cost/QALY gained is $16,002. Treatment is more cost-effective for those with longer glycemic exposure (earlier onset of diabetes), minorities, and those with higher HbA1c under standard care. CONCLUSIONS: The incremental effectiveness of treating NIDDM with the goal of normoglycemia is estimated to be approximately $16,000/QALY gained, which is in the range of interventions that are generally considered cost-effective.

Adult↗
PubMed1997

Comparison of fasting and 2-hour glucose and HbA1c levels for diagnosing diabetes. Diagnostic criteria and performance revisited.

OBJECTIVE: Nearly two decades ago, the National Diabetes Data Group (NDDG) and the World Health Organization (WHO) Expert Committee on Diabetes Mellitus published diagnostic criteria for diabetes. We undertook this study to compare the performance of three glycemic measures for diagnosing diabetes and to evaluate the performance of the WHO criteria. RESEARCH DESIGN AND METHODS: In a cross-sectional population-based sample of 1,018 Egyptians > or = 20 years of age, fasting and 2-h glucose and HbA1c levels were measured, and diabetic retinopathy was assessed by retinal photograph. Evidence for bimodal distributions was examined for each glycemic measure by fitting models for the mixture of two distributions using maximum likelihood estimates. Sensitivity and specificity for cutpoints of each glycemic measure were calculated by defining the true diabetes state (gold standard) as 1) the upper (diabetic) component of the fitted bimodal distribution for each glycemic measure, and 2) the presence of diabetic retinopathy. Receiver operating characteristic (ROC) curves were constructed to determine the performance of the glycemic measures in detecting diabetes as defined by diabetic retinopathy. RESULTS: In the total population, the point of intersection of the lower and upper components that minimized misclassification for the fasting and 2-h glucose and HbA1c were 7.2 mmol/l (129 mg/dl), 11.5 mmol/l (207 mg/dl), and 6.7%, respectively. When diabetic retinopathy was used to define diabetes, ROC curve analyses found that fasting and 2-h glucose values were superior to HbA1c (P < 0.01). The performance of a fasting glucose of 7.8 mmol/l (140 mg/dl) was similar to a 2-h glucose of 12.2-12.8 mmol/l (220-230 mg/dl), and the performance of a 11.1 mmol/l (200 mg/dl) 2-h glucose was similar to a fasting glucose of 6.9-7.2 mmol/l (125-130 mg/dl). CONCLUSIONS: Optimal cutpoints for defining diabetes differ according to how diabetes itself is defined. When diabetes is defined as the upper component of the bimodal population distribution, a fasting glucose level somewhat lower than the current WHO cutpoint and a 2-h glucose level somewhat higher than the current WHO cutpoint minimized misclassification. When diabetic retinopathy defines diabetes, we found that the current fasting diagnostic criterion favors specificity and the current 2-h criterion favors sensitivity. These results should prove valuable for defining the optimal tests and cutpoint values for diagnosing diabetes.

Adult↗
PubMed1996

A generalized linear model for analysing receiver operating characteristic curves.

We present a continuation ratio model for analysing ordinal categorical data and we apply the model to the problem of estimating receiver operating characteristic (ROC) curves. We apply the methods to post-prandial capillary blood glucose measurements as a criterion for a potential screening test for diabetes mellitus. One can obtain point estimates of sensitivity and specificity and their associated standard errors at any value along the observed range of post-prandial capillary blood glucose measurements. Also, in comparison to the models for ROCs described by Tosteson and Begg, ROC curves based on the continuation ratio model have the desired features that allow ROCs to be concave but not necessarily symmetric.

Adult↗
PubMed1996

Nuclear signaling by endothelin-1 requires Src protein-tyrosine kinases.

In response to changes in vascular homeostasis, endothelial cells secrete endothelin-1 (ET-1), which in turn regulates gene expression and phenotype in underlying vascular cells. We characterized a nuclear signaling cascade in which Src protein-tyrosine kinases link the ET-1 receptor to induction of c-fos transcription. A dominant negative SrcK- kinase mutant blocked ET-1-stimulated c-fos transcription. Expression of the COOH-terminal Src kinase (Csk), which represses Src kinases, also blocked induction of c-fos transcription by ET-1. Activation of the c-fos promoter by ET-1 required both the CArG DNA sequence of the c-fos serum response element and the Ca2+/cAMP response element. In contrast, Src-induced c-fos transcription required only the CArG cis-element, demonstrating a divergence in signals regulating c-fos transcription. Thus, Src kinases contribute to a nuclear signaling cascade linking an ET-1 receptor to the CArG element of the c-fos serum response element. A Src-based pathway might play a more general role to propagate ET-1 nuclear signals that regulate cell growth and development. In addition, these results point to a widening role for nonreceptor protein-tyrosine kinases in propagating signals from G protein-coupled receptors.

Animals↗
PubMed1996

The onset of NIDDM and its relationship to clinical diagnosis in Egyptian adults.

The onset of diabetes relative to clinical diagnosis was estimated in Egyptians with non-insulin-dependent diabetes mellitus (NIDDM) based on the relationship between retinopathy and duration of diabetes. Between July 1992 and October 1993 the Diabetes in Egypt (DIE) Project performed a cross-sectional, population-based survey with clinical and laboratory follow-up to describe the prevalence of microvascular, neuropathic, and macrovascular complications among Egyptians > or = 20 years of age with diagnosed diabetes, previously undiagnosed diabetes, impaired glucose tolerance, and normal glucose tolerance. The sample of persons with diabetes diagnosed prior to the survey had medical examinations which included a dilated eye examination and retinal photographs. Generalized linear models were used to relate the probability of retinopathy to duration of diabetes. Among 218 persons with diabetes diagnosed prior to the DIE project, 87 (40%) had diabetic retinopathy. The onset of retinopathy was estimated to occur 2.6 years (p = 0.04) prior to clinical diagnosis. The estimated annual incidence of retinopathy was 5% and the estimated prevalence at the time of clinical diagnosis of diabetes was 12%. On the basis of reports that retinopathy does not occur until approximately 5 years after the development of diabetes, the onset of NIDDM was estimated to occur 7.6 years prior to its clinical diagnosis. This estimate of the onset of NIDDM in Egyptians is comparable to other estimates reported for US and Australian populations.

Adult↗
PubMed1996

Ca2+ channels mediate protein tyrosine kinase activation by endothelin-1.

To investigate the novel interaction between endothelin-1 (ET-1) and cellular protein tyrosine kinases (PTK), we asked whether Ca2+ influx links ET-1 receptors to PTK activation. In glomerular mesangial cells, ET-1 stimulated a biphasic increase in PTK activity in anti-phosphotyrosine immunoprecipitates that temporally correlated with increased tyrosine phosphorylation of cellular proteins. ET-1 increased tyrosine phosphorylation of proteins in the cytosol and in a puncture distribution consistent with focal adhesions. Addition of ionomycin to increase Ca2+ influx stimulated PTK activity, and inhibition of extracellular Ca2+ influx blocked PTK activation by ET-1. ET-1 increased autophosphorylation of pp60c-src, which was mimicked by addition of ionomycin and inhibited by chelation of extracellular Ca2+. In addition, a selective PTK inhibitor blocked induction of c-fos mRNA by ionomycin, suggesting that Ca(2+)-stimulated PTKs contribute to a signaling pathway regulating immediate early gene expression. Taken together, these results demonstrate that ET-1 stimulates nonreceptor PTK activity, including pp60c-src, by activating Ca2+ channels and subsequent influx of extracellular Ca2+.

Animals↗
PubMed1995

Nuclear signaling by endothelin-1. A Ras pathway for activation of the c-fos serum response element.

Endothelin-1 (ET-1) regulates gene expression and growth of vascular cells by triggering signals that link its cognate, G protein-coupled receptor in the plasma membrane to transcriptional activation of immediate early genes in the nucleus. To define the nature of these signals, we asked whether Ras proteins contribute to activation of the c-fos serum response element (SRE) by ET-1 in mesangial cells, a microvascular cell from the renal glomerulus. ET-1 stimulated Ras by increasing Ras GTP loading. Addition of ET-1 or transfection with a plasmid expressing v-Ha-Ras stimulated SRE-dependent transcription. Activation of the c-fos SRE by ET-1 was blocked by a dominant negative Asn-17 c-Ha-Ras mutant. Expression of v-Ha-Ras reversed inhibition of ET-1-stimulated SRE transcriptional activity by Asn-17 c-Ha-Ras. ET-1 also stimulated kinase activity of c-Raf-1, a downstream effector in Ras signaling cascades. Activation of the c-fos SRE by transfection with a plasmid expressing constitutively activated delta Raf-1 was consistent with a role for Ras-Raf-1 in ET-1 signaling. Interestingly, Ras-dependent SRE activation in cells treated with ET-1 was blocked by point mutations in the SRE CArG DNA sequence, which binds the serum response factor, but not by mutations that inhibit binding of ternary complex factors (p62TCF) to the Ets DNA sequence of the SRE. Thus, Ras contributes to a nuclear signaling cascade linking ET-1 receptors to transcriptional activation through the CArG cis-element of the c-fos SRE.

Adenosine Triphosphate↗
PubMed1995

Trends in renal disease morbidity and mortality in the United States, 1979 to 1990.

Four indices of morbidity and mortality due to seven groups of renal diseases are evaluated in the United States for the period 1979 through 1990. These indices include mortality, hospitalization, doctor's office visits, and prevalence. Age-adjusted and age-specific rates are calculated. Estimates are provided for racial-, ethnic-, and gender-specific subpopulations. The burden of some diseases had decreased, especially renal infections. Most indices of the burden of diabetes with renal involvement and hypertensive renal disease have increased, especially among segments of the population that are growing. For many groups of disorders examined, men have experienced an increasing burden of disease over the 12 years evaluated. These data support current trends in renal failure and serve to generate hypotheses regarding renal disease patterns. The magnitude of the burden of renal disease and the trends toward increasing rates indicate that renal disease is a large and growing clinical and public health problem. Major improvements are needed in the range and accuracy of diagnosis and of reporting renal-related conditions, and additional resources need to be brought to the problem of renal-related morbidity. This is a US government work. There are no restrictions on its use.

Adult↗
PubMed1995

Diabetes mellitus in Egypt: risk factors and prevalence.

Major sociodemographic changes have occurred in Egypt to promote the development of noncommunicable diseases. We have performed a cross-sectional, population-based survey of persons > or = 20 years of age in Cairo and surrounding rural villages to describe the prevalence of diabetes risk factors, diagnosed diabetes, previously undiagnosed diabetes, and impaired glucose tolerance by age, sex, rural and urban residence, and socioeconomic status (SES). In the survey, we identified 6052 eligible households: 76% of household respondents completed a household examination and 72% of selected household respondents subsequently completed a medical examination. Exercise was assessed by questionnaire; adiposity by measurement of height, weight, and girths; and diabetes by history and 2-h 75 g oral glucose tolerance test. In rural areas, 52% of persons > or = 20 years of age were sedentary, 16% were obese, and 4.9% had diabetes. In lower SES urban areas, 73% were sedentary, 37% were obese, and 13.5% had diabetes. In higher SES urban areas, 89% were sedentary, 49% were obese, and 20% had diabetes. The combined prevalence of diagnosed and undiagnosed diabetes in the Egyptian population > or = 20 years of age was estimated to be 9.3%. Approximately half the diabetes was diagnosed and the other half was previously undiagnosed. The prevalence of diabetes in Egypt is high, and the gradient in risk factors and disease from rural to urban areas and in urban areas from lower to higher SES suggest that diabetes is a major, emerging clinical and public health problem in Egypt.

Adult↗
PubMed1995

Two proximal CArG elements regulate SM alpha-actin promoter, a genetic marker of activated phenotype of mesangial cells.

Mesangial cells express smooth muscle alpha-actin (SM alpha-actin) in response to glomerular injury in vivo, and SM alpha-actin gene expression serves as a genetic marker characterizing the activated phenotype of mesangial cells. We used a molecular genetic approach to analyze the SM alpha-actin promoter and evaluate transcriptional mechanisms that might direct the genetic switch of mesangial cells to the activated phenotype. The sequence spanning -894 to +1 of the SM alpha-actin promoter directed high levels of transcription that were attenuated in serum-restricted cells and upregulated upon treatment with serum or endothelin-1. Deletional analysis revealed a core promoter fragment, from positions -122 to +1, that was necessary and sufficient for transcription. This core activity was modulated by upstream sequences between -670 and -122. The 122-bp core promoter contains two highly conserved CArG box motifs (designated CB1 and CB2), and introduction of deletion mutations of either CB1 or CB2 reduced transcription in mesangial cells to near basal levels. Further analysis revealed that CB1 and CB2 acted synergistically when subcloned upstream of a heterologous, minimal thymidine kinase promoter. CB2 alone was sufficient to confer serum inducibility to a heterologous promoter, but both CB2 and CB1 were required for maximal levels of serum-induced transcription. Collectively, these results demonstrate that CB1 and CB2 cooperate to mediate serum-induced activation of the SM alpha-actin promoter in mesangial cells.

Actins↗
PubMed1995

Leisure-time physical activity patterns in the U.S. diabetic population. Findings from the 1990 National Health Interview Survey--Health Promotion and Disease Prevention Supplement.

OBJECTIVE: Despite the scientific community's recognition of the importance of exercise, little is known about the epidemiology of exercise among persons with diabetes in the U.S. Our goals were to examine whether people with diabetes were more sedentary than people without diabetes, to examine the effect of activity limitations on the prevalence of exercise, and to examine whether the choice of activities differs among people with and without diabetes. RESEARCH DESIGN AND METHODS: We examined the 1990 Health Promotion and Disease Prevention Supplement of the National Health Interview Survey to describe leisure-time physical activity patterns in a representative sample of the U.S. population with diabetes. RESULTS: People with diabetes were less likely to report exercising regularly than people without this disease (34.3 +/- 2.2% vs. 40.9 +/- 0.5%, P < 0.05). When the data were stratified by activity limitation status, no significant differences were observed. People with diabetes were equally likely to have engaged in exercise in the preceding 2 weeks and to have expended > or = 2,000 kcal/week as people without diabetes. Walking was the activity of choice for both groups: 49.2 +/- 2.1% of people with diabetes reported walking during the previous 2 weeks compared with 44.2 +/- 0.5% of people without diabetes (P < 0.05). People with diabetes were less likely to engage in jogging, aerobics, dancing, calisthenics, bicycling, weight lifting, several ball sports, and skiing than people without diabetes. CONCLUSIONS: After adjusting for activity limitations and age, people with and without diabetes are equally likely to exercise. The majority of people with diabetes, like their nondiabetic counterparts, are not meeting national physical activity goals. Individuals with diabetes should be encouraged to exercise regularly in accordance with their capabilities, physical limitations, and personal interests.

Adolescent↗
PubMed1995

Screening for NIDDM in nonpregnant adults. A review of principles, screening tests, and recommendations.

The economic burden of diabetes in the U.S. is now more than 90 billion dollars per year (113-115). In the diabetes community, there is a feeling that aggressive measures to detect diabetes in earlier stages may be warranted. Regardless of whether evidence is convincing that there are benefits from early detection of diabetes (3,116,117), screening activities have been sanctioned by many organizations and are now taking place. Operational research is needed to define more clearly the who, when, where, and how of screening and the effectiveness of screening programs (4,118). Diabetes screening programs should be comprehensive and should educate about diabetes and provide appropriate interpretation of both positive and negative screening results. It is essential that programs have diagnostic follow-up and refer those with newly diagnosed diabetes for treatment. In addition, individuals with previously diagnosed diabetes encountered during screening activities should be made aware of the importance of glycemic control and follow-up with their health care providers.

Adult↗
PubMed1995

Diabetes and pregnancy. Factors associated with seeking pre-conception care.

OBJECTIVE: To define sociodemographic characteristics, medical factors, knowledge, attitudes, and health-related behaviors that distinguish women with established diabetes who seek pre-conception care from those who seek care only after conception. RESEARCH DESIGN AND METHODS: A multicenter, case-control study of women with established diabetes making their first pre-conception visit (n = 57) or first prenatal visit without having received pre-conception care (n = 97). RESULTS: Pre-conception subjects were significantly more likely to be married (93 vs. 51%), living with their partners (93 vs. 60%), and employed (78 vs. 41%); to have higher levels of education (73% beyond high school vs. 41%) and income (86% > $20,000 vs. 60%); and to have insulin-dependent diabetes mellitus (IDDM) (93 vs. 81%). Pre-conception subjects with IDDM were more likely to have discussed pre-conception care with their health care providers (98 vs. 51%) and to have been encouraged to get it (77 vs. 43%). In the prenatal group, only 24% of pregnancies were planned. Pre-conception patients were more knowledgeable about diabetes, perceived greater benefits of pre-conception care, and received more instrumental support. CONCLUSIONS: Only about one-third of women with established diabetes receive pre-conception care. Interventions must address prevention of unintended pregnancy. Providers must regard every visit with a diabetic woman as a pre-conception visit. Contraception must be explicitly discussed, and pregnancies should be planned. In counseling, the benefits of pre-conception care should be stressed and the support of families and friends should be elicited.

Adult↗
PubMed1995

A new and simple questionnaire to identify people at increased risk for undiagnosed diabetes.

OBJECTIVE: To develop a simple questionnaire to prospectively identify individuals at increased risk for undiagnosed diabetes. RESEARCH DESIGN AND METHODS: People with newly diagnosed diabetes (n = 164) identified in the Second National Health and Nutrition Examination Survey and those with neither newly diagnosed diabetes nor a history of physician-diagnosed diabetes (n = 3,220) were studied. Major historical risk factors for undiagnosed non-insulin-dependent diabetes were defined, and classification trees were developed to identify people at higher risk for previously undiagnosed diabetes. The sensitivity, specificity, and predictive value of the classification trees were described and compared with those of an existing questionnaire. RESULTS: The selected classification tree incorporated age, sex, history of delivery of a macrosomic infant, obesity, sedentary lifestyle, and family history of diabetes. In a representative sample of the U.S. population, the sensitivity of the tree was 79%, the specificity was 65%, and the predictive value positive was 10%. CONCLUSIONS: This classification tree performed significantly better than an existing questionnaire and should serve as a simple, noninvasive, and potentially cost-effective tool for diagnosing diabetes in the U.S.

Adult↗
PubMed1995

Screening for diabetes mellitus in adults. The utility of random capillary blood glucose measurements.

OBJECTIVE: Because half of the people with non-insulin-dependent diabetes mellitus (NIDDM) are undiagnosed and because near-normal glycemic control can prevent diabetic complications, we evaluated the use of field-based random capillary blood glucose measurement as a screening test for NIDDM. RESEARCH DESIGN AND METHODS: A cross-sectional sample of 828 Egyptians > or = 20 years of age underwent both a random capillary blood glucose measurement performed with a portable reflectance meter in the field and an oral glucose tolerance test in the laboratory. The sensitivity and specificity of random capillary blood glucose measurements in predicting the presence of NIDDM were evaluated. RESULTS: Multivariate analyses showed that the screening test performed better when subjects had eaten shortly before the test (area under receiver operating characteristic curve, 0.87 for a 1-h postprandial period compared with 0.69 for an 8-h postprandial period) and that the optimal capillary blood glucose cutoff points to define a positive test increased with age. For a postprandial period of 1 h, cutoff points of 115 mg/dl for individuals 30 years of age and 140 mg/dl for those 75 years of age yielded similar performance characteristics (sensitivity 82% and specificity 78% for those 30 years old; sensitivity 81% and specificity 80% for those 75 years old). CONCLUSIONS: Adjusting random capillary blood glucose measurements for the postprandial period and using age-specific cutoff point values can improve performance of the screening test.

Adult↗