Wesley M. Granger

Associations of Total and Undercarboxylated Osteocalcin With Peripheral and Hepatic Insulin Sensitivity and β-Cell Function in Overweight Adults

CONTEXT Animal studies indicate that osteocalcin (OC), particularly the undercarboxylated isoform (unOC), affects insulin sensitivity and secretion, but definitive data from humans are lacking. OBJECTIVE The objectives of the study were to determine whether total OC and unOC are independently associated with insulin sensitivity and β-cell response in overweight/obese adults; whether glucose tolerance status affects these associations; and whether the associations are independent of bone formation, as reflected in procollagen type 1 amino propeptide (P1NP). DESIGN, SETTING, AND PARTICIPANTS This was a cross-sectional study conducted at a university research center involving 63 overweight/obese adults with normal (n = 39) or impaired fasting glucose (IFG; n = 24). MAIN OUTCOME MEASURES Serum concentrations of total/undercarboxylated OC and P1NP were assessed by RIA; insulin sensitivity was determined by iv glucose tolerance test (S(I)-IVGTT), liquid meal test (S(I) meal), and homeostasis model assessment of insulin resistance; β-cell response to glucose [basal β-cell response to glucose; dynamic β-cell response to glucose; static β-cell response to glucose; and total β-cell response to glucose] was derived using C-peptide modeling of meal test data; and intraabdominal adipose tissue was measured using computed tomography scanning. RESULTS Multiple linear regression, adjusting for intraabdominal adipose tissue and P1NP, revealed that total OC was positively associated with S(I)-iv glucose tolerance test (P < .01) in the total sample. OC was not associated with S(I) meal or homeostasis model assessment of insulin resistance. In participants with IFG, unOC was positively associated with static β-cell response to glucose and total β-cell response to glucose (P < .05), independent of insulin sensitivity. CONCLUSIONS In overweight/obese individuals, total OC may be associated with skeletal muscle but not hepatic insulin sensitivity. unOC is uniquely associated with β-cell function only in individuals with IFG. Further research is needed to probe the causal inference of these relationships and to determine whether indirect nutrient sensing pathways underlie these associations.

Overweight status and intrauterine exposure to gestational diabetes are associated with children's metabolic health.

Offspring of women with gestational diabetes (OGD) have greater risk for obesity and impaired metabolic health. Whether impaired metabolic health occurs in the absence of obesity is not clear.

Ethnic differences in glucose disposal, hepatic insulin sensitivity, and endogenous glucose production among African American and European American women

Intravenous glucose tolerance tests have demonstrated lower whole-body insulin sensitivity (S(I)) among African Americans (AA) compared with European Americans (EA). Whole-body S(I) represents both insulin-stimulated glucose disposal, primarily by skeletal muscle, and insulins suppression of endogenous glucose production (EGP) by liver. A mathematical model was recently introduced that allows for distinction between disposal and hepatic S(I). The purpose of this study was to examine specific indexes of S(I) among AA and EA women to determine whether lower whole-body S(I) in AA may be attributed to insulin action at muscle, liver, or both. Participants were 53 nondiabetic, premenopausal AA and EA women. Profiles of EGP and indexes of Disposal S(I) and Hepatic S(I) were calculated by mathematical modeling and incorporation of a stable isotope tracer ([6,6-(2)H(2)]glucose) into the intravenous glucose tolerance test. Body composition was assessed by dual-energy x-ray absorptiometry. After adjustment for percentage fat, both Disposal S(I) and Hepatic S(I) were lower among AA (P = .009 for both). Time profiles for serum insulin and EGP revealed higher peak insulin response and corresponding lower EGP among AA women compared with EA. Indexes from a recently introduced mathematical model suggest that lower whole-body S(I) among nondiabetic AA women is due to both hepatic and peripheral components. Despite lower Hepatic S(I), AA displayed lower EGP, resulting from higher postchallenge insulin levels. Future research is needed to determine the physiological basis of lower insulin sensitivity among AA and its implications for type 2 diabetes mellitus risk.

Favourable metabolic effects of a eucaloric lower‐carbohydrate diet in women with PCOS

Diet‐induced reduction in circulating insulin may be an attractive nonpharmacological treatment for women with polycystic ovary syndrome (PCOS) among whom elevated insulin may exacerbate symptoms by stimulating testosterone synthesis. This study was designed to determine whether a modest reduction in dietary carbohydrate (CHO) content affects β‐cell responsiveness, serum testosterone concentration and insulin sensitivity in women with PCOS.

A higher-carbohydrate, lower-fat diet reduces fasting glucose concentration and improves β-cell function in individuals with impaired fasting glucose.

The objective was to examine the effects of diet macronutrient composition on insulin sensitivity, fasting glucose, and β-cell response to glucose. Participants were 42 normal glucose-tolerant (NGT; fasting glucose <100 mg/dL) and 27 impaired fasting glucose (IFG), healthy, overweight/obese (body mass index, 32.5 ± 4.2 kg/m(2)) men and women. For 8 weeks, participants were provided with eucaloric diets, either higher carbohydrate/lower fat (55% carbohydrate, 18% protein, 27% fat) or lower carbohydrate/higher fat (43:18:39). Insulin sensitivity and β-cell response to glucose (basal, dynamic [PhiD], and static) were calculated by mathematical modeling using glucose, insulin, and C-peptide data obtained during a liquid meal tolerance test. After 8 weeks, NGT on the higher-carbohydrate/lower-fat diet had higher insulin sensitivity than NGT on the lower-carbohydrate/higher fat diet; this pattern was not observed among IFG. After 8 weeks, IFG on the higher-carbohydrate/lower-fat diet had lower fasting glucose and higher PhiD than IFG on the lower-carbohydrate/higher-fat diet; this pattern was not observed among NGT. Within IFG, fasting glucose at baseline and the change in fasting glucose over the intervention were inversely associated with baseline PhiD (-0.40, P < .05) and the change in PhiD (-0.42, P < .05), respectively. Eight weeks of a higher-carbohydrate/lower-fat diet resulted in higher insulin sensitivity in healthy, NGT, overweight/obese individuals, and lower fasting glucose and greater glucose-stimulated insulin secretion in individuals with IFG. If confirmed, these results may have an impact on dietary recommendations for overweight individuals with and without IFG.

Adiposity and β-cell function: relationships differ with ethnicity and age.

The prevalence of type 2 diabetes is higher among African Americans (AA) vs. European Americans (EA), is highest at middle age, and is related to obesity. This study was conducted to test the hypothesis that the association of adiposity (percent body fat (%fat)) with indexes of insulin sensitivity (SI) and β‐cell function would differ with ethnicity and age. Subjects were 168 healthy, normoglycemic AA and EA girls and women aged 7–12 years, 18–32 years, and 40–70 years. An intravenous glucose tolerance test (IVGTT) was used to assess indexes of insulin secretion and action: SI, acute C‐peptide secretion (X0); basal, first‐phase, second‐phase, and total β‐cell responsivity to glucose (PhiB, Phi1, Phi2, and PhiTOT, respectively); and the disposition index (DI = SI × PhiTOT). %Fat was assessed with dual energy X‐ray absorptiometrys. Adiposity was significantly associated with SI among EA (−0.57, P < 0.001) but not AA (−0.20, P = 0.09). Adiposity appeared stimulatory to β‐cell function in the two groups of younger subjects and in EA, but inhibitory in postmenopausal women, particularly AA postmenopausal women. Among AA postmenopausal women, %fat was inversely associated with Phi1 (r = −0.57, P < 0.05) and PhiTOT (r = −0.68, P < 0.01). These results suggest that the impact of adiposity on insulin secretion and action differs with age and ethnicity.

Age-related changes in insulin sensitivity and β-cell function among European-American and African-American women.

Type 2 diabetes (T2D) is more prevalent among African‐American (AA) than European‐American (EA) women for reasons that are unknown. Ethnic differences in physiological processes related to insulin sensitivity (SI) and secretion, and age‐related changes in these processes, may play a role. The purpose of this study was to identify ethnicity‐ and age‐related differences in SI and β‐cell responsivity among AA and EA females, and to determine whether these differences are independent of body composition and fat distribution. Healthy, normoglycemic females aged 7–12 years (n = 62), 18–32 years (n = 57), and 40–70 years (n = 49) were recruited for entry into this study. Following an overnight fast, SI, intravenous glucose tolerance (Kg), acute C‐peptide secretion (X0), and basal, first‐phase, second‐phase, and total β‐cell responsivity to glucose (PhiB, Phi1, Phi2, and PhiTOT, respectively) were measured by an intravenous glucose tolerance test. Total % body fat was assessed by dual‐energy X‐ray absorptiometry, and intra‐abdominal adiposity (IAAT) by computed tomography. Main effects of age group and ethnicity were measured with analysis of covariance, adjusting for % fat, IAAT, and SI as indicated. AA had lower SI, and higher Kg, X0, Phi1, and PhiTOT (P < 0.05), which remained after adjustment for % fat and IAAT. Greater X0, Phi1, and PhiTOT among AA were independent of SI. Advancing age was associated with greater Phi2 among both EA and AA. To conclude, inherent ethnic differences in β‐cell function exist independently of adiposity and SI. Future research should examine whether ethnic differences in β‐cell physiology contribute to disparities in T2D risk.

Dietary macronutrient composition affects β cell responsiveness but not insulin sensitivity

BACKGROUND Altering dietary carbohydrate or fat content may have chronic effects on insulin secretion and sensitivity, which may vary with individual metabolic phenotype. OBJECTIVE The objective was to evaluate the contribution of tightly controlled diets differing in carbohydrate and fat content for 8 wk to insulin sensitivity and β cell responsiveness and whether effects of diet would vary with race, free-living diet, or insulin response. DESIGN Healthy overweight men and women (36 European Americans, 33 African Americans) were provided with food for 8 wk and received either a eucaloric standard diet (55% carbohydrate, 27% fat) or a eucaloric reduced-carbohydrate (RedCHO)/higher-fat diet (43% carbohydrate, 39% fat). Insulin sensitivity and β cell responsiveness were assessed at baseline and 8 wk by using a liquid meal tolerance test. RESULTS Insulin sensitivity did not change with diet (P = 0.1601). Static β cell response to glucose (ФS) was 28.5% lower after the RedCHO/higher-fat diet. Subgroup analyses indicated that lower ФS with the RedCHO/higher-fat diet occurred primarily among African Americans. A significant inverse association was observed for change in glucose area under the curve compared with change in ФS. CONCLUSIONS Consumption of a eucaloric 43% carbohydrate/39% fat diet for 8 wk resulted in down-regulation of β cell responsiveness, which was influenced by baseline phenotypic characteristics. Further study is needed to probe the potential cause-and-effect relation between change in ФS and change in glucose tolerance. This trial is registered at clinicaltrials.gov as NCT00726908.

Race Differences in the Association of Oxidative Stress With Insulin Sensitivity in African- and European-American Women

Excessive metabolism of glucose and/or fatty acids may impair insulin signaling by increasing oxidative stress. The objective of this study was to examine the association between insulin sensitivity and protein carbonyls, a systemic marker of oxidative stress, in healthy, nondiabetic women, and to determine if the relationship differed with race. Subjects were 25 African‐Americans (AA, BMI 28.4 ± 6.2 kg/m2, range 18.8–42.6 kg/m2; age 33.1 ± 13.5 years, range 18–58 years) and 28 European‐Americans (EA, BMI 26.2 ± 5.9 kg/m2, range 18.7–48.4 kg/m2; age 31.6 ± 12.4 years, range 19–58 years). Insulin sensitivity was determined using an intravenous glucose tolerance test incorporating [6,6‐2H2]‐glucose, and a two‐compartment mathematical model. Multiple linear regression results indicated that insulin sensitivity was inversely associated with protein carbonyls in AA (standardized regression coefficient −0.47, P < 0.05) but not EA (0.01, P = 0.945), after adjusting for %body fat. In contrast, %body fat was significantly and positively associated with insulin sensitivity in EA (−0.54, P < 0.01) but not AA (−0.24, P = 0.196). Protein carbonyls were associated with free fatty acids (FFA) in AA (r = 0.58, P < 0.01) but not EA (r = −0.11, P = 0.59). When subjects were divided based on median levels of fasting glucose and FFA, those with higher glucose/FFA concentrations had a significantly greater concentration of circulating protein carbonyls compared to those with lower glucose/FFA concentrations (P < 0.05). These results suggest that oxidative stress independently contributes to insulin sensitivity among AA women. Further, this association in AA may be mediated by circulating FFA and/or glucose.

Stethoscopes: What Are We Hearing?

This paper develops an objective methodology to test the audio quality of stethoscopes, classifies stethoscopes into five functional categories, and compares the audio performance of each of the five categories. These categories, based on the manufacturers recommended use, are basic assessment, cardiology, disposable, high-end cardiology, and physical assessment. The classification into categories is based on the intended performance of the stethoscopes as provided by the manufacturers. After developing the procedures and running more than 500 tests, the stethoscope with the least amount of loss over the spectrum was chosen from each of the five categories; the five were then compared to one another. Thirty-nine stethoscopes from 11 manufacturers were used in this study. The objective test methodology allows for side-by-side comparison of stethoscopes from various manufacturers that is independent of the manufacturers published test results.