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Objective: Standardized, reproducible, and feasible quantification of β-cell function (BCF) is necessary for the evaluation of interventions to improve insulin secretion and important for comparison across studies. We therefore characterized the responses to, and reproducibility of, standardized methods of in vivo BCF across different glucose tolerance states.Research Design and Methods: Participants classified as having normal glucose tolerance (NGT; n = 23), prediabetes (PDM; n = 17), and type 2 diabetes mellitus (T2DM; n = 22) underwent two standardized mixed-meal tolerance tests (MMTT) and two standardized arginine stimulation tests (AST) in a test-retest paradigm and one frequently sampled intravenous glucose tolerance test (FSIGT).Results: From the MMTT, insulin secretion in T2DM was >86% lower compared with NGT or PDM (P < 0.001). Insulin sensitivity (Si) decreased from NGT to PDM (∼50%) to T2DM (93% lower [P < 0.001]). In the AST, insulin secretory response to arginine at basal glucose and during hyperglycemia was lower in T2DM compared with NGT and PDM (>58%; all P < 0.001). FSIGT showed decreases in both insulin secretion and Si across populations (P < 0.001), although Si did not differ significantly between PDM and T2DM populations. Reproducibility was generally good for the MMTT, with intraclass correlation coefficients (ICCs) ranging from ∼0.3 to ∼0.8 depending on population and variable. Reproducibility for the AST was very good, with ICC values >0.8 across all variables and populations.Conclusions: Standardized MMTT and AST provide reproducible and complementary measures of BCF with characteristics favorable for longitudinal interventional trials use. [ABSTRACT FROM AUTHOR]

Obesity continues to be a major public health problem in the United States and worldwide. While recent statistics have demonstrated that obesity rates have begun to plateau, more severe classes of obesity are accelerating at a faster pace with important implications in regards to treatment. Bariatric surgery has a profound and durable effect on weight loss, being to date one of the most successful interventions for obesity. Objective To provide updates to the possible role of gut hormones in post bariatric surgery weight loss and weight loss maintenance. Design and Methods The current review examines the changes in gastro-intestinal hormones with bariatric surgery and the potential mechanisms by which these changes could result in decreased weight and adiposity. Results The mechanism by which bariatric surgery results in body weight changes is incompletely elucidated, but it clearly goes beyond caloric restriction and malabsorption. Conclusion Changes in gastro-intestinal hormones, including increases in GLP-1, PYY, and oxyntomodulin, decreases in GIP and ghrelin, or the combined action of all these hormones might play a role in induction and long-term maintenance of weight loss. [ABSTRACT FROM AUTHOR]

Obesity is a growing problem in the United States and throughout the world. It is a risk factor for many chronic diseases. The BMI has been used to assess body fat for almost 200 years. BMI is known to be of limited accuracy, and is different for males and females with similar %body adiposity. Here, we define an alternative parameter, the body adiposity index (BAI = ((hip circumference)/((height)1.5)-18)). The BAI can be used to reflect %body fat for adult men and women of differing ethnicities without numerical correction. We used a population study, the 'BetaGene' study, to develop the new index of body adiposity. %Body fat, as measured by the dual-energy X-ray absorptiometry (DXA), was used as a 'gold standard' for validation. Hip circumference (R = 0.602) and height (R = −0.524) are strongly correlated with %body fat and therefore chosen as principal anthropometric measures on which we base BAI. The BAI measure was validated in the 'Triglyceride and Cardiovascular Risk in African-Americans (TARA)' study of African Americans. Correlation between DXA-derived %adiposity and the BAI was R = 0.85 for TARA with a concordance of C_b = 0.95. BAI can be measured without weighing, which may render it useful in settings where measuring accurate body weight is problematic. In summary, we have defined a new parameter, the BAI, which can be calculated from hip circumference and height only. It can be used in the clinical setting even in remote locations with very limited access to reliable scales. The BAI estimates %adiposity directly. [ABSTRACT FROM AUTHOR]

The article presents the different approaches in order to address the increasing rates of type 2 diabetes in the U.S., in westernized countries, and in the third world. Understanding the pathogenesis of diabetes would lead to better approaches to diagnose, prevent and to treat existing cases. In the reductionist approach, knowledge of disease would result from describing events at increasingly more microscopic levels. In the systems approach, mathematical or computer models are used.

Protein tyrosine phosphatase (PTP)-1B, encoded by the PTPN1 gene, catalyzes the dephosphorylation of proteins at tyrosyl residues. PTP-1B has been implicated in negatively regulating insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor. The genetic contribution of PTPN1 to measures of glucose homeostasis has been assessed in 811 Hispanic subjects from the Insulin Resistance Atherosclerosis Study Family Study (IRASFS). Thirty-five single nucleotide polymorphisms (SNPs) spanning 161 kb and containing the PTPN1 gene were genotyped and tested for association. All 20 SNPs with minor allele frequencies >0.1 in a single haplotype block covering the PTPN1 genomic sequence show significant association with the insulin sensitivity index (S(i)) (P = 0.044-0.003) and fasting glucose (P = 0.029 to <0.001). In contrast, there is no evidence for association of PTPN1 polymorphisms with acute insulin response (a measure of beta-cell function). Haplotype analysis of eight SNP haplotypes that have independently been shown to be associated with type 2 diabetes risk and protection in Caucasian type 2 diabetic subjects are associated with lower (P = 0.007) and higher (P = 0.0002) S(i) and higher (P = 0.00007) and lower (P = 0.001) fasting glucose, respectively, in the IRASFS. This comprehensive genetic analysis of PTPN1 reveals significant association with metabolic traits consistent with the proposed in vivo role for the PTP-1B protein. [ABSTRACT FROM AUTHOR]

The Finland-United States Investigation Of NIDDM Genetics (FUSION) study aims to identify genetic variants that predispose to type 2 diabetes by studying affected sibling pair families from Finland. Chromosome 20 showed our strongest initial evidence for linkage. It currently has a maximum logarithm of odds (LOD) score of 2.48 at 70 cM in a set of 495 families. In this study, we searched for diabetes susceptibility variant(s) at 20q13 by genotyping single nucleotide polymorphism (SNP) markers in case and control DNA pools. Of 291 SNPs successfully typed in a 7.5-Mb interval, the strongest association confirmed by individual genotyping was with SNP rs2144908, located 1.3 kb downstream of the primary β-cell promoter P2 of hepatocyte nuclear factor-4α (HNF4A). This SNP showed association with diabetes disease status (odds ratio [OR] 1.33, 95% CI 1.06-1.65, P = 0.011) and with several diabetes-related traits. Most of the evidence for linkage at 20q13 could be attributed to the families carrying the risk allele. We subsequently found nine additional associated SNPs spanning a 64-kb region, including the P2 and P1 promoters and exons 1-3. Our results and the independent observation of association of SNPs near the P2 promoter with diabetes in a separate study population of Ashkenazi Jewish origin suggests that variant(s) located near or within HNF4A increases susceptibility to type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to compare insulin resistance relative to body fat and the associated compensatory responses in 57 healthy children living in Los Angeles, California (14 Caucasians, 15 African-Americans, and 28 Hispanics).Research Design and Methods: Insulin sensitivity and acute insulin response were determined by intravenous glucose tolerance test. Insulin secretion, hepatic insulin extraction, and insulin clearance were estimated by C-peptide and insulin modeling.Results: Insulin sensitivity was significantly lower in Hispanics and African-Americans compared with Caucasian children, and acute insulin response was significantly higher in African-American children. No ethnic differences were noted in the first-phase secretion, but second-phase insulin secretion was significantly higher in Hispanic children than in African-American children (200 +/- 53 vs. 289 +/- 41 nmol/min; P = 0.03). The greater acute insulin response in African-Americans, despite lower secretion, was explained by a lower hepatic insulin extraction in African-Americans compared with Hispanics (36.6 +/- 2.9 vs. 47.3 +/- 2.2%; P = 0.0006).Conclusions: In conclusion, Hispanic and African-American children are more insulin resistant than Caucasian children, but the associated compensatory responses are different across ethnic groups. [ABSTRACT FROM AUTHOR]

Central adiposity is highly correlated with insulin resistance, which is an important risk factor for type 2 diabetes and other chronic diseases. However, in normal individuals, central adiposity can be tolerated for many years without development of impaired glucose tolerance or diabetes. Here we examine longitudinally the mechanisms by which glucose tolerance can be maintained in the face of substantial insulin resistance. Normal dogs were fed a diet enriched with moderate amounts of fat (2 g x kg(-1) x day(-1)), similar to that seen in modern "cafeteria" diets, and the time course of metabolic changes in these animals was examined over 12 weeks. Trunk adiposity as assessed by magnetic resonance imaging increased from 12 to 19%, but body weight remained unchanged. Insulin sensitivity (SI) as determined by frequently sampled intravenous glucose tolerance tests was measured over a 12-week period. SI decreased 35% by week 1 and remained impaired for the entire 12 weeks. Intravenous glucose tolerance was reduced transiently for 1 week, recovered to baseline, and then again began to decline after 8 weeks. First-phase insulin response began to increase after week 2, peaked by week 6 (190% of basal), and then declined. The increase in insulin response was due partially to enhanced beta-cell function (22%) but due also to an approximately 50% reduction in insulin clearance. This compensation by insulin clearance was also confirmed with insulin clamps performed in fat-fed versus control dogs. The present study confirms the ability of the normal individual to compensate for fat-induced insulin resistance by enhanced insulin response, such that the product of insulin sensitivity x secretion is little changed. However, the compensation is due as much to reduced insulin clearance as increased beta-cell sensitivity to glucose. Reduced hepatic extraction of insulin may be the first line of defense providing a higher proportion of secreted insulin to the periphery and sparing the beta-cells during compensation for the insulin-resistant state. [ABSTRACT FROM AUTHOR]

The author comments on the lack of financial support for promising junior scientists causing them to bail out of basic and clinical research. He suggests that the funding agencies should protect the pay line of original research to ensure that scientists could continue to contribute, without having to spend half their time raising money or leaving research for lucrative careers in the private sector. He believes that it is about time that advocates of research advancement to guarantee a future for biomedical research in the U.S. and elsewhere.

The author talks about the placement of the economic stimulus effort in the U.S. to enhance many aspects of research, which includes an extra 12 billion dollars to the National Institutes of Health (NIH). He says that the fund allotted to the NIH will enhance the future of biomedical research and stimulate many aspects of the economy. He cites issues regarding the distribution of funds to the NIH. He compares the NIH review process to a fly over of a 747 aircraft over New York City ordered by Louis Caldera, director of the White House Military Office.

Woolcott, Orison O., and Richard N. Bergman. Mortality attributed to COVID-19 in high-altitude populations. High Alt Med Biol . 21:409-416, 2020. Background: Since partial oxygen pressure decreases as altitude increases, environmental hypoxia could worsen Coronavirus Disease 2019 (COVID-19) patient's hypoxemia. We compared COVID-19 mortality at different altitudes. Methods: Retrospective analysis of population-level data on COVID-19 deaths was conducted in the United States (1,016 counties) and Mexico (567 municipalities). Mixed-model Poisson regression analysis of the association between altitude and COVID-19 mortality was conducted using individual-level data from 40,168 Mexican subjects with COVID-19, adjusting for multiple covariates. Results: Between January 20 and April 13, 2020, mortality rates were higher in U.S. counties located at ≥2,000 m elevation versus those located <1,500 m (12.3 vs. 3.2 per 100,000; p  < 0.001). In Mexico, between March 13 and May 13, 2020, mortality rates were higher in municipalities located at ≥2,000 m versus those located <1,500 m (5.3 vs. 3.9 per 100,000; p  < 0.001). Among Mexican subjects younger than 65 years, the risk of death was 36% higher in those living at ≥2,000 m versus those living at <1,500 m (adjusted incidence rate ratio [IRR]: 1.36; confidence interval [95% CI], 1.05-1.78; p  = 0.022). Among Mexican men, the risk of death was 31% higher at ≥2,000 m versus that at <1,500 m (adjusted IRR: 1.31; 95% CI, 1.03-1.66; p  = 0.025). No association between altitude and COVID-19 mortality was found among Mexican women or among Mexican subjects 65 years of age and older. Conclusions: Altitude is associated with COVID-19 mortality in men younger than 65 years.

Background/objectives: We have recently proposed and validated a simple and accurate method to estimate whole-body fat percentage in adults, the relative fat mass (RFM), derived from the ratio of height to waist circumference. We aimed to identify RFM cutoffs to diagnose obesity based on the association between RFM and all-cause mortality., Subjects/methods: We used data from adult participants (≥20 years of age, n = 43,793) of the National Health and Nutrition Examination Survey (NHANES) 1999-2014 linked with death certificate records from the National Death Index. Optimal RFM cutoffs were determined using receiver-operating characteristic analysis (the Youden's index and the Euclidean minimum distance to the coordinate (0,1))., Results: Final dataset for analyses comprised 31,008 adults. During a median follow-up of 8.3 years (IQR, 7.6-13.7), 2,517 deaths occurred. Youden and Euclidean optimal cutoffs of baseline RFM for all-cause mortality were 40.8% and 41.6% for women, and 30.9% and 28.9% for men, respectively. Similar cutoffs were obtained using measured whole-body fat percentage by dual energy X-ray absorptiometry. Adjusting for age, BMI category, ethnicity, education level, and smoking status, the hazard ratio for mortality using Cox proportional hazard regression was 1.41 (95% CI, 1.02-1.95) among women who had an RFM of 40.0-44.9% compared with women who had an RFM <35% (P = 0.035). Among men, the hazard ratio was 1.57 (95% CI, 1.07-2.30) among those with an RFM of 30.0-34.9% compared with men who had an RFM <25% (P = 0.020). Similar adjusted hazard ratios for same RFM categories were obtained in our validation population (NHANES III, n = 12,650, median follow-up: 23.3 years): 1.42 (95% CI, 1.01-2.00) among women (P = 0.043) and 1.50 (95% CI, 1.07-2.10) among men (P = 0.021)., Conclusions: We suggest rounded RFM cutoffs of 40% for women and 30% for men to diagnose obesity and identify individuals at higher risk of death.

High whole-body fat percentage is independently associated with increased mortality. We aimed to identify a simple anthropometric linear equation that is more accurate than the body mass index (BMI) to estimate whole-body fat percentage among adult individuals. National Health and Nutrition Examination Survey (NHANES) 1999-2004 data (n = 12,581) were used for model development and NHANES 2005-2006 data (n = 3,456) were used for model validation. From the 365 anthropometric indices generated, the final selected equation was as follows: 64 - (20 × height/waist circumference) + (12 × sex), named as the relative fat mass (RFM); sex = 0 for men and 1 for women. In the validation dataset, compared with BMI, RFM better predicted whole-body fat percentage, measured by dual energy X-ray absorptiometry (DXA), among women and men. RFM showed better accuracy than the BMI and had fewer false negative cases of body fat-defined obesity among women and men. RFM reduced total obesity misclassification among all women and all men and, overall, among Mexican-Americans, European-Americans and African-Americans. In the population studied, the suggested RFM was more accurate than BMI to estimate whole-body fat percentage among women and men and improved body fat-defined obesity misclassification among American adult individuals of Mexican, European or African ethnicity.

Background: This study compares a previously developed Diabetes Risk Score to commonly used clinical tools for type 2 diabetes risk evaluation in the Insulin Resistance Atherosclerosis Study (IRAS) cohort, a multi-ethnic US cohort. Available as a clinical test, the PreDx® Diabetes Risk Score uses fasting concentrations of adiponectin, C-reactive protein, ferritin, interleukin-2 receptor alpha, HbA(1c) , glucose and insulin, plus age and gender to predict 5-year risk of diabetes. It was developed in a Northern European population., Methods: The Diabetes Risk Score was measured using archived fasting plasma specimens from 722 non-diabetic IRAS participants, 17.6% of whom developed diabetes during 5.2 years median follow-up (inter-quartile range: 5.1-5.4 years). The study included non-Hispanic whites (41.8%), Hispanics (34.5%) and African Americans (23.7%). Performance of the algorithm was evaluated by area under the receiver operating characteristic curve (AROC) and risk reclassification against other tools., Results: The Diabetes Risk Score discriminates participants who developed diabetes from those who did not significantly better than fasting glucose (AROC = 0.763 versus 0.710, p = 0.003). The Diabetes Risk Score performed equally well in subpopulations defined by race/ethnicity or gender. The Diabetes Risk Score provided a significant net reclassification improvement of 0.24 (p = 0.01) when comparing predefined low/moderate/high Diabetes Risk Score categories to metabolic syndrome risk factor counting. The Diabetes Risk Score complemented the use of the oral glucose tolerance test by identifying high risk patients with impaired fasting glucose but normal glucose tolerance, 33% of whom converted., Conclusions: Measuring the Diabetes Risk Score of elevated-risk US patients could help physicians decide which patients warrant more intensive intervention. The Diabetes Risk Score performed equally well across the ethnic subpopulations present in this cohort., (Copyright © 2012 John Wiley & Sons, Ltd.)

Plasma insulin and glucose concentrations are important quantitative phenotypes related to diabetes and the metabolic syndrome. Reports purporting to identify quantitative trait loci (QTLs) that contribute to the variation in fasting insulin and glucose concentrations are discrepant. As part of the Insulin Resistance Atherosclerosis Study (IRAS) Family Study, a genome scan was performed in African-American (n = 42) and Hispanic (n = 90) extended families to identify regions that may contain positional candidate genes for fasting insulin and fasting glucose (n = 1,604 subjects). There was significant evidence for linkage of fasting insulin to the short arm of chromosome 17 (logarithm of odds [LOD] = 3.30; 54 cM between D17S1294 and D17S1299, P = 1.0 x 10(-4)). The strongest evidence for linkage over all pedigrees for fasting glucose was also observed in this region (LOD = 1.44; 58 cM, P = 9.9 x 10(-3)). The results of this study provide impetus for future positional cloning of QTLs regulating insulin and glucose levels. Identifying genes in these regions should provide insight into the nature of genetic factors regulating plasma glucose and insulin concentrations.