Katherine H. Ingram

Limitations in the Use of Indices Using Glucose and Insulin Levels to Predict Insulin Sensitivity: Impact of Race and Gender and Superiority of the Indices Derived From Oral Glucose Tolerance Test in African Americans

OBJECTIVE To examine the utility of commonly used insulin sensitivity indices in nondiabetic European Americans (EAs) and African Americans (AAs). RESEARCH DESIGN AND METHODS Two-hundred forty nondiabetic participants were studied. Euglycemic-hyperinsulinemic clamp was the gold standard approach to assess glucose disposal rates (GDR) normalized by lean body mass. The homeostatic model assessment for insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI) were calculated from fasting plasma glucose and insulin (FIL). Oral glucose tolerance test (OGTT) was performed to determine Matsuda index, the simple index assessing insulin sensitivity (SIisOGTT), Avignon index, and Stomvoll index. Relationships among these indices with GDR were analyzed by multiple regression. RESULTS GDR values were similar in EA and AA subgroups; even so, AA exhibited higher FIL and were insulin-resistant compared with EA, as assessed by HOMA-IR, QUICKI, Matsuda index, SIisOGTT, Avignon index, and Stumvoll index. In the overall study population, GDR was significantly correlated with all studied insulin sensitivity indices (/r/ = 0.381–0.513); however, these indices were not superior to FIL in predicting GDR. Race and gender affected the strength of this relationship. In AA males, FIL and HOMA-IR were not correlated with GDR. In contrast, Matsuda index and SIisOGTT were significantly correlated with GDR in AA males, and Matsuda index was superior to HOMA-IR and QUICKI in AAs overall. CONCLUSIONS Insulin sensitivity indices based on glucose and insulin levels should be used cautiously as measures of peripheral insulin sensitivity when comparing mixed gender and mixed race populations. Matsuda index and SIisOGTT are reliable in studies that include AA males.

BMI, RQ, diabetes, and sex affect the relationships between amino acids and clamp measures of insulin action in humans.

Previous studies have used indirect measures of insulin sensitivity to link circulating amino acids with insulin resistance and identify potential biomarkers of diabetes risk. Using direct measures (i.e., hyperinsulinemic-euglycemic clamps), we examined the relationships between the metabolomic amino acid profile and insulin action (i.e., glucose disposal rate [GDR]). Relationships between GDR and serum amino acids were determined among insulin-sensitive, insulin-resistant, and type 2 diabetic (T2DM) individuals. In all subjects, glycine (Gly) had the strongest correlation with GDR (positive association), followed by leucine/isoleucine (Leu/Ile) (negative association). These relationships were dramatically influenced by BMI, the resting respiratory quotient (RQ), T2DM, and sex. Gly had a strong positive correlation with GDR regardless of BMI, RQ, or sex but became nonsignificant in T2DM. In contrast, Leu/Ile was negatively associated with GDR in nonobese and T2DM subjects. Increased resting fat metabolism (i.e., low RQ) and obesity were observed to independently promote and negate the association between Leu/Ile and insulin resistance, respectively. Additionally, the relationship between Leu/Ile and GDR was magnified in T2DM males. Future studies are needed to determine whether Gly has a mechanistic role in glucose homeostasis and whether dietary Gly enrichment may be an effective intervention in diseases characterized by insulin resistance.

Intramyocellular Lipid and Insulin Resistance: Differential Relationships in European and African Americans

Insulin resistance has been associated with the accumulation of fat within skeletal muscle fibers as intramyocellular lipid (IMCL). Here, we have examined in a cross‐sectional study the interrelationships among IMCL, insulin sensitivity, and adiposity in European Americans (EAs) and African Americans (AAs). In 43 EA and 43 AA subjects, we measured soleus IMCL content with proton‐magnetic resonance spectroscopy, insulin sensitivity with hyperinsulinemic–euglycemic clamp, and body composition with dual‐energy X‐ray absorptiometry. The AA and EA subgroups had similar IMCL content, insulin sensitivity, and percent fat, but only in EA was IMCL correlated with insulin sensitivity (r = −0.47, P < 0.01), BMI (r = 0.56, P < 0.01), percent fat (r = 0.35, P < 0.05), trunk fat (r = 0.47, P < 0.01), leg fat (r = 0.40, P < 0.05), and waist and hip circumferences (r = 0.54 and 0.55, respectively, P < 0.01). In a multiple regression model including IMCL, race, and a race by IMCL interaction, the interaction was found to be a significant predictor (t = 1.69, DF = 1, P = 0.0422). IMCL is related to insulin sensitivity and adiposity in EA but not in AA, suggesting that IMCL may not function as a pathophysiological factor in individuals of African descent. These results highlight ethnic differences in the determinants of insulin sensitivity and in the pathogenesis of the metabolic syndrome trait cluster.

Skeletal Muscle Lipid Peroxidation and Insulin Resistance in Humans

OBJECTIVE The relationships among skeletal muscle lipid peroxidation, intramyocellular lipid content (IMCL), and insulin sensitivity were evaluated in nine insulin-sensitive (IS), 13 insulin-resistant (IR), and 10 adults with type 2 diabetes (T2DM). DESIGN Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp [glucose disposal rate (GDR)]. Lipid peroxidation was assessed by 4-hydroxynonenal (HNE)-protein adducts and general oxidative stress by protein carbonyl content. All patients were sedentary. RESULTS Protein-HNE adducts were elevated 1.6-fold in T2DM compared with IS adults, whereas IR showed intermediate levels of HNE-modified proteins. Protein-HNE adducts correlated with GDR, waist circumference, and body mass index. IMCL was increased by 4.0- and 1.9-fold in T2DM and IR patients, respectively, compared with IS, and was correlated with GDR and waist circumference but not BMI. Protein carbonyls were not different among groups and did not correlate with any of the measured variables. Correlations were detected between IMCL and protein-HNE. CONCLUSION Our data show for the first time that skeletal muscle protein-HNE adducts are related to the severity of insulin resistance in sedentary adults. These results suggest that muscle lipid peroxidation could be involved in the development of insulin resistance.

Twenty year fitness trends in young adults and incidence of prediabetes and diabetes: the CARDIA study

Aims/hypothesisThe prospective association between cardiorespiratory fitness (CRF) measured in young adulthood and middle age on development of prediabetes, defined as impaired fasting glucose and/or impaired glucose tolerance, or diabetes by middle age remains unknown. We hypothesised that higher fitness levels would be associated with reduced risk for developing incident prediabetes/diabetes by middle age.MethodsParticipants were from the Coronary Artery Risk Development in Young Adults (CARDIA) study who were free from prediabetes/diabetes at baseline (year 0 [Y0]: 1985–1986). CRF was quantified by treadmill duration (converted to metabolic equivalents [METs]) at Y0, Y7 and Y20 and prediabetes/diabetes status was assessed at Y0, Y7, Y10, Y15, Y20 and Y25. We use an extended Cox model with CRF as the primary time-varying exposure. BMI was included as a time-varying covariate. The outcome was development of either prediabetes or diabetes after Y0. Model 1 included age, race, sex, field centre, CRF and BMI. Model 2 additionally included baseline (Y0) smoking, energy intake, alcohol intake, education, systolic BP, BP medication use and lipid profile.ResultsHigher fitness was associated with lower risk for developing incident prediabetes/diabetes (difference of 1 MET: HR 0.99898 [95% CI 0.99861, 0.99940], p < 0.01), which persisted (difference of 1 MET: HR 0.99872 [95% CI 0.99840, 0.99904], p < 0.01] when adjusting for covariates.Conclusions/interpretationExamining participants who had fitness measured from young adulthood to middle age, we found that fitness was associated with lower risk for developing prediabetes/diabetes, even when adjusting for BMI over this time period. These findings emphasise the importance of fitness in reducing the health burden of prediabetes and diabetes.

Association of Run‐In Periods with Weight Loss in Obesity Randomized Controlled Trials

Study‐level design characteristics that inform the optimal design of obesity randomized controlled trials (RCTs) have been examined in few studies. A pre‐randomization run‐in period is one such design element that may influence weight loss. We examined 311 obesity RCTs published between 1 January 2007 and 1 July 2009 that examine d weight loss or weight gain prevention as a primary or secondary end‐point. Variables included run‐in period, pre‐post intervention weight loss, study duration (time), intervention type, percent female and degree of obesity. Linear regression was used to estimate weight loss as a function of (i) run‐in (yes/no) and (ii) run‐in, time, percent female, body mass index and intervention type. Interaction terms were also examined. Approximately 19% (18.6%) of the studies included a run‐in period, with pharmaceutical studies having the highest frequency. Although all intervention types were associated with weight loss (Mean = 2.80 kg, SD = 3.52), the inclusion of a pre‐randomization run‐in was associated with less weight loss (P = 0.0017) compared with studies that did not include a run‐in period. However, this association was not consistent across intervention types. Our results imply that in trials primarily targeting weight loss in adults, run‐in periods may not be beneficial for improving weight loss outcomes in interventions.

Nonalcoholic fatty liver disease and measures of early brain health in middle-aged adults: The CARDIA study

To assess associations between nonalcoholic fatty liver disease (NAFLD) and measures of brain health in a population‐based sample of adults.

Central fat accretion and insulin sensitivity: differential relationships in parous and nulliparous women

Background/Objectives:Childbearing is associated with a disproportionate accumulation of visceral fat and an increased risk of metabolic disease. However, it is unknown whether the visceral fat accretion associated with pregnancy modifies a woman’s risk for metabolic disease. The purpose of this study was to test whether the association between abdominal fat and insulin sensitivity differs by parity status in healthy overweight women.Subjects/Methods:Intra-abdominal adipose tissue (IAAT) via CT, body composition by DXA, insulin sensitivity via intravenous glucose tolerance test and minimal model (SI), HOMA-IR, and cardiorespiratory fitness (VO2max) were assessed in 212 non-diabetic, premenopausal, overweight non-Hispanic white and African–American women.Results:Nulliparous women (n=98) were younger, had less IAAT and higher VO2max, but similar SI, HOMA-IR and leg fat, compared to parous (n=114). In nulliparous women, IAAT was negatively associated with SI, controlling for age, race and body fat mass (r=−0.40, P<0.001), but this relationship was attenuated in parous women (r=−0.15, P=0.16). In multiple linear regression analysis, leg fat and IAAT were significant predictors of SI in nulliparous, but not parous women.Conclusions:Results suggest that greater IAAT in parous women does not lead to greater insulin resistance; rather, transient insulin resistance during pregnancy may encourage intra-abdominal fat accumulation that is metabolically benign. This underscores the need to consider parity when assessing cardiometabolic risk.

Association of Mediterranean diet and cardiorespiratory fitness with the development of pre-diabetes and diabetes: the Coronary Artery Risk Development in Young Adults (CARDIA) study

Objective To better understand the association between a modified Mediterranean diet pattern in young adulthood, cardiorespiratory fitness in young adulthood, and the odds of developing pre-diabetes or diabetes by middle age. Research design and methods Participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study who did not have pre-diabetes or diabetes at baseline (year 0 (Y0), ages 18–30) and who had data available at the Y0 and year 25 (Y25) visits were included in this analysis (n=3358). Polytomous logistic regression models were used to assess the association between baseline dietary intake and fitness data and odds of pre-diabetes or diabetes by middle age (Y25, ages 43–55). Results At the Y25 visit, 1319 participants (39%) had pre-diabetes and 393 (12%) had diabetes. Higher baseline fitness was associated with lower odds of pre-diabetes and of diabetes at Y25. After adjustment for covariates, each SD increment in treadmill duration (181 s) was associated with lower odds for pre-diabetes (OR 0.85, 95% CI 0.75 to 0.95, p=0.005) and for diabetes (OR 0.71, 95% CI 0.60 to 0.85, p=0.0002) when compared to normal glycemia. A modified Mediterranean diet pattern was not associated with either pre-diabetes or diabetes. No interaction between cardiorespiratory fitness and dietary intake was observed, but baseline fitness remained independently associated with incident pre-diabetes and diabetes following adjustment for diet. Conclusions Higher cardiorespiratory fitness in young adulthood, but not a modified Mediterranean diet pattern, is associated with lower odds of pre-diabetes and of diabetes in middle age. Trial registration number NCT00005130.

Prepregnancy fitness and risk of gestational diabetes: A longitudinal analysis

Purpose This study aimed to assess the associations of prepregnancy cardiorespiratory fitness, moderate- to vigorous-intensity physical activity (MVPA), and time spent watching television with subsequent development of gestational diabetes mellitus (GDM). Methods Participants were 1333 women enrolled in the Coronary Artery Risk Development in Young Adults study who did not have diabetes either at baseline (1985–86) or before births occurring after baseline. Baseline fitness was estimated using a graded symptom-limited maximal exercise treadmill test and expressed in MET units. Baseline MVPA (exercise units per day) was measured using the Coronary Artery Risk Development in Young Adults physical activity history questionnaire, and television viewing (h·d−1) was assessed by self-report in 1990–1991. Logistic regression analysis was used to derive odds ratios and 95% confidence intervals, adjusting for time from baseline to delivery and baseline study center, age, race, education, parity, family history of diabetes, smoking, alcohol, saturated fat intake, waist circumference, homeostasis model assessment of insulin resistance, and HDL cholesterol. Results Over 25 yr of follow-up, 164 women developed GDM. The odds of developing GDM were 21% lower for each 1 SD increment in baseline level of fitness (2.3 METs, odds ratio = 0.79, 95% confidence interval = 0.65–0.96). Prepregnancy MVPA and television viewing were not statistically associated with the development of GDM. Conclusion Study findings indicate that objectively assessed prepregnancy fitness, but not self-reported MVPA or television time, is associated with GDM. Clinicians should counsel women on the benefits of improving fitness in the preconception period, particularly among women at greater risk for GDM.