Two-Year Treatment With Metformin During Puberty Does Not Preserve ß-Cell Function in Youth With Obesity.

CONTEXT: Youth-onset type 2 diabetes is a disease of pubertal onset, associated with additional burden of pubertal insulin resistance on the ß-cell. OBJECTIVE: Evaluate the impact of metformin treatment during puberty, a critical window of cardiometabolic change, on insulin sensitivity (Si) and compensatory ß-cell response in youth with obesity. SETTING: Pediatric academic hospital clinical translational research center. PARTICIPANTS: Healthy youth in early puberty [Tanner stage (T) 2-3] with normoglycemia and obesity (n = 44). INTERVENTION: Double-blinded placebo-control trial of metformin during puberty (until T5). MAIN OUTCOME MEASURES: Insulin sensitivity (Si), insulin response [acute insulin response to glucose (AIRg)], and disposition index (DI), estimated from frequently sampled intravenous glucose tolerance testing; body fat (dual X-ray absorptiometry); and other laboratory parameters, collected at baseline, T4, and T5. Placebo-subtracted treatment effect was calculated using linear mixed models. RESULTS: At T5, metformin treatment, adjusting for sex, race, and baseline value, was associated with improved BMI z-score (-0.44 ±â€…0.16, P = 0.02), percentage body fat (%body fat; -3.4 ±â€…1.2%, P = 0.06), and waist circumference (-11.3 ±â€…3.2cm, P = 0.003). There were no significant treatment effects at T5 on Si or secretion: Si (0.85 ±â€…0.87 × 10-4/min-1/µIU/mL, P = 0.34), AIRg (-259 ±â€…386 µIU/mL, P = 0.51), or DI (508 ±â€…802 × 10-4/min-1, P = 0.53). High baseline DI predicted longitudinal decline in DI. CONCLUSIONS: Two years of metformin treatment in obese youth during puberty improved BMI and body fat, but not Si or ß-cell function. Of note, high DI in early puberty may be predictive of later decline in DI. Further studies are needed to develop strategies for preservation of ß-cell function in youth at risk for type 2 diabetes.

The Impact of Obesity On Insulin Sensitivity and Secretion During Pubertal Progression: A Longitudinal Study.

CONTEXT: Physiologic changes in glucose metabolism are well-described to occur during puberty. However, there are important gaps in understanding the interaction between obesity and the normal physiologic changes during puberty, as well as how these changes could contribute to the increased risk of comorbidities, such as type 2 diabetes and dyslipidemia, in youth with obesity. OBJECTIVE: The objective of this study was to compare longitudinal changes in insulin sensitivity (Si) and secretion during pubertal progression in youth with obesity versus those with normal weight. DESIGN: Longitudinal observational study evaluating youth from early puberty (Tanner [T]2-T3) until puberty completion (T5). SETTING: Pediatric academic hospital Clinical Translational Research Center. PARTICIPANTS: Pubertal youth with normal weight (n = 47; 22 female, 25 male) and obesity (n = 37; 23 female, 14 male). MAIN OUTCOME MEASURES: Si, insulin response (acute insulin response to glucose, AIRg) and disposition index (DI) by intravenous glucose tolerance test at baseline (T2-T3), T4, and T5. RESULTS: Youth with obesity had significantly lower Si and higher AIRg at each time point (P < 0.001), but DI was similar between the groups. There were no group differences in trajectory of Si, AIRg or DI over time. Leptin, insulin-like growth factor-1, and obesity were most strongly associated with Si and AIRg at all time points. CONCLUSIONS: Obesity significantly impacts Si during puberty, even at the earliest stages. However, in general, obese youth have adequate ß-cell compensation for the significantly reduced Si of puberty. Future studies are needed to better predict the subset of youth who fail to maintain ß-cell compensation during puberty.

Acute estradiol treatment reduces skeletal muscle protein breakdown markers in early- but not late-postmenopausal women.

OBJECTIVES: Menopause and decline in estradiol (E2) may contribute to sarcopenia (i.e., age-related decline in muscle mass and strength) in women. E2 may directly impact skeletal muscle protein breakdown via estrogen receptor (ER) signaling, primarily ERα. It is not yet known whether: 1) E2 regulates pathways of skeletal muscle protein breakdown; 2) E2-mediated changes in protein breakdown markers are associated with ERα activation and insulin sensitivity; and 3) the effects of E2 on protein breakdown markers differ by increasing time since menopause. STUDY DESIGN: We studied 27 women who were ≤6 years past menopause (early postmenopausal, EPM; n = 13) or ≥10 years past menopause (late postmenopausal, LPM; n = 14). Fasted skeletal muscle samples were collected following 1 week of transdermal E2 or placebo treatment in a randomized cross-over design. MAIN OUTCOME MEASURES: We analyzed for cytosolic protein content of the: 1) structural proteins myosin heavy chain (MHC) and tropomyosin; and 2) protein regulatory markers: protein kinase B (Akt), muscle-specific ring finger protein1 (MuRF1), atrogin1, and forkhead box O3 (FOXO3) using Western blot. RESULTS: In response to acute E2, FOXO3 activation (dephosphorylation) and MuRF1 protein expression decreased in EPM but increased in LPM women (p < 0.05). ERα activation was not associated with these protein breakdown markers, but FOXO3 activation tended to be inversely correlated (r = -0.318, p = 0.065) to insulin sensitivity. CONCLUSIONS: These preliminary studies suggest the effects of E2 on skeletal muscle protein breakdown markers were dependent on time since menopause, which is consistent with our previous study on insulin sensitivity.

Postprandial Triglycerides Predict Newborn Fat More Strongly than Glucose in Women with Obesity in Early Pregnancy.

OBJECTIVE: Maternal obesity (OB) accounts for the majority of large-for-gestational-age infants, and newborn percent fat (NB%fat) correlates strongest with childhood OB. In addition to maternal glucose, fasting triglycerides (TGs) may contribute, but postprandial triglycerides (PPTGs) are unstudied. It was hypothesized that fasting TGs and PPTGs are higher in women with OB compared with women with normal weight (NW) throughout pregnancy, correlate more strongly with NB%fat than glucose, and may relate to dietary chylomicron TGs. METHODS: Fasting TGs and PPTGs, free fatty acids, glucose, and insulin were prospectively measured 10 times over 4 hours after a controlled liquid breakfast early (14-16 weeks) and later (26-28 weeks) in pregnancy in 27 mothers with NW and 27 with OB. NB%fat was measured by dual x-ray absorptometry. RESULTS: Fasting TGs and PPTGs were already ≥ 30% higher in mothers with OB at 14 to 16 weeks (P < 0.001) versus mothers with NW. In mothers with OB, a simple 1-hour (r = 0.71; P < 0.01) or 2-hour (r = 0.69; P < 0.01) PPTG at 14 to 16 weeks correlated strongest with NB%fat. In mothers with NW, the increase in TGs from early to later pregnancy correlated strongest with NB%fat (r = 0.57; P < 0.01). Maternal glucose did not statistically add to prediction models. CONCLUSIONS: These novel data suggest that 1- or 2-hour PPTGs might be a new target for early intervention in pregnancies with OB to prevent excess newborn adiposity and attenuate child OB risk.

Placental lipoprotein lipase activity is positively associated with newborn adiposity.

INTRODUCTION: Recent data suggest that in addition to glucose, fetal growth is related to maternal triglycerides (TG). To reach the fetus, TG must be hydrolyzed to free fatty acids (FFA) and transported across the placenta, but regulation is uncertain. Placental lipoprotein lipase (pLPL) hydrolyzes TG, both dietary chylomicron TG (CM-TG) and very-low density lipoprotein TG (VLDL-TG), to FFA. This may promote fetal fat accretion by increasing the available FFA pool for placental uptake. We tested the novel hypothesis that pLPL activity, but not maternal adipose tissue LPL activity, is associated with newborn adiposity and higher maternal TG. METHODS: Twenty mothers (n = 13 normal-weight; n = 7 obese) were prospectively recruited. Maternal glucose, insulin, TG (total, CM-TG, VLDL-TG), and FFA were measured at 14-16, 26-28, and 36-37 weeks, and adipose tissue LPL was measured at 26-28 weeks. At term delivery, placental villous biopsies were immediately analyzed for pLPL enzymatic activity. Newborn percent body fat (newborn %fat) was assessed by skinfolds. RESULTS: Placental LPL activity was positively correlated with birthweight (r = 0.48;P = 0.03) and newborn %fat (r = 0.59;P = 0.006), further strengthened by correcting for gestational age at delivery (r = 0.75;P = 0.0001), but adipose tissue LPL was not. Maternal TG and BMI were not correlated with pLPL activity. Additionally, pLPL gene expression, while modestly correlated with enzymatic activity (r = 0.53;P < 0.05), was not correlated with newborn adiposity. DISCUSSION: This is the first study to show a positive correlation between pLPL activity and newborn %fat. Placental lipase regulation and the role of pLPL in pregnancies characterized by nutrient excess and fetal overgrowth warrant further investigation.

Factors Associated with Achievement of Clinically Significant Weight Loss by Women in a National Nonprofit Weight Loss Program.

BACKGROUND: Clinically significant weight loss (CSWL) is ≥5% of initial weight. The purpose of the study is to determine factors associated with women achieving CSWL in Take Off Pounds Sensibly (TOPS), a national, nonprofit weight loss program. METHODS: This is a retrospective analysis of 48,674 females who joined TOPS from 2005 to 2011 and had a birth date in the database. Predictors of CSWL were evaluated using log-binomial regression and adjusted relative risks [99% CI] for participant age, initial weight, number of members per chapter, and chapter age. RESULTS: Older women were more likely to achieve CSWL, with women ≥70 years 1.23 (1.18, 1.28) times more likely to achieve CSWL compared to women 18 to <45 years. Women who weighed 113 to <136 kg and ≥136 kg were 1.06 (1.02, 1.10) and 1.07 (1.02, 1.14) times more likely to achieve CSWL compared to women <80 kg, respectively. Women in chapters with 25 to <35 members and ≥35 members more were 1.09 (1.05, 1.13) and 1.14 (1.10, 1.18) times more likely to achieve CSWL than those in chapters with less than 15 members. Women in older chapters were less likely to achieve CSWL, with women in chapters 10 to 20 years old 0.95 (0.92, 0.99) times as likely to lose weight as those in chapters less than 10 years old. CONCLUSIONS: Women in TOPS were more likely to achieve CSWL if older, ≥113 kg, and in larger, newer chapters. Future studies should address ways to modify the program to improve achievement of CSWL.

Estradiol-mediated improvements in adipose tissue insulin sensitivity are related to the balance of adipose tissue estrogen receptor α and ß in postmenopausal women.

We recently demonstrated that short-term estradiol (E2) treatment improved insulin-mediated suppression of lipolysis in postmenopausal women, but to a greater extent in those who were late compared to early postmenopausal. In this follow-up study we tested whether subcutaneous adipose tissue (SAT) expression of estrogen receptors (ER) α and ß differs between early and late postmenopausal women. We further tested whether the balance of ERα to ERß in SAT determined the effect of E2 on SAT insulin sensitivity. The present study included 35 women who were ≤6 years past menopause (EPM; n = 16) or ≥10 years past menopause (LPM; n = 19). Fasted SAT samples were taken following 1-week transdermal E2 treatment or placebo (PL) in a random cross-over design. Samples were analyzed for nuclear/cytosolic protein content and mRNA expression using Western blot and qPCR, respectively. While ESR1 increased slightly (~1.4-fold) following E2 treatment in both groups, ERα and ERß protein expression did not differ between groups at baseline or in response to E2. However, the balance of ERα/ERß protein in the SAT nuclear fraction increased 10% in EPM compared to a 25% decrease in LPM women (group x treatment interaction, p<0.05). A greater proportion of ERα/ERß protein in the nuclear fraction of SAT at baseline (placebo day) was associated with greater reduction in SAT insulin resistance (i.e., better suppression of lipolysis, EC50) in response to E2 (r = -0.431, p<0.05). In conclusion, there do not appear to be differences in the proportion of adipose tissue ERα/ERß protein in late, compared to early, postmenopausal women. However, the balance of ERα/ERß may be important for E2-mediated improvement in adipose tissue insulin sensitivity. TRIAL REGISTRATION: Clinical Trials#: NCT01605071.

Sex Hormones and Cardiometabolic Health: Role of Estrogen and Estrogen Receptors.

With increased life expectancy, women will spend over three decades of life postmenopause. The menopausal transition increases susceptibility to metabolic diseases such as obesity, diabetes, cardiovascular disease, and cancer. Thus, it is more important than ever to develop effective hormonal treatment strategies to protect aging women. Understanding the role of estrogens, and their biological actions mediated by estrogen receptors (ERs), in the regulation of cardiometabolic health is of paramount importance to discover novel targeted therapeutics. In this brief review, we provide a detailed overview of the literature, from basic science findings to human clinical trial evidence, supporting a protective role of estrogens and their receptors, specifically ERα, in maintenance of cardiometabolic health. In so doing, we provide a concise mechanistic discussion of some of the major tissue-specific roles of estrogens signaling through ERα. Taken together, evidence suggests that targeted, perhaps receptor-specific, hormonal therapies can and should be used to optimize the health of women as they transition through menopause, while reducing the undesired complications that have limited the efficacy and use of traditional hormone replacement interventions.

Age- and menopause-related differences in subcutaneous adipose tissue estrogen receptor mRNA expression.

OBJECTIVES: Changes in estrogen receptor (ER) expression likely underlie differential metabolic effects of estrogen in pre- and postmenopausal women. The aim of the current study was to determine whether ER gene expression in abdominal and femoral subcutaneous adipose tissue (SAT) was associated with age, menopause, or regional adiposity. METHODS: We studied pre- and post-menopausal (n=23 and 22, respectively; age 35-65y) normal weight (mean±SD; BMI 23.7±2.5kg/m2) women with similar total fat mass. Abdominal and femoral SAT ERα (ESR1) and ERß (ESR2) mRNA expression was determined by qPCR. RESULTS: Total fat mass did not differ between pre- and postmenopausal women (22.7±5.3vs. 21.7±5.3kg). Compared to premenopausal women, ESR1 and the ratio of ESR1 to ESR2 were lower (p≤0.05) in postmenopausal abdominal and femoral SAT. ESR1 and ESR1:ESR2 were inversely associated with age in abdominal SAT (r=-0.380 and r=-0.463, respectively; p<0.05) and femoral SAT (r=-0.353 and r=-0.472, respectively; p<0.05). ESR2 was not related to age or menopause. The inverse association between ESR1 and age persisted after adjusting for trunk fat mass, estradiol, or leptin. CONCLUSION: Among healthy pre- and postmenopausal women, increased age was associated with a decreased balance of ERα to ERß in abdominal and femoral subcutaneous adipose tissue.

Time since menopause and skeletal muscle estrogen receptors, PGC-1α, and AMPK.

OBJECTIVE: Short-term administration of estradiol (E2) improves insulin-stimulated glucose disposal rate in early postmenopausal (EPM) women compared with a reduction in late postmenopausal (LPM) women. The underlying mechanisms by which E2 action on glucose disposal rate reversed from beneficial early to harmful late in menopause is unknown, but might include adverse changes in estrogen receptors (ERs) or other biomarkers of cellular energy metabolism with age or duration of estrogen deficiency. METHODS: We retrospectively analyzed skeletal muscle samples from 27 postmenopausal women who were 6 years or less past menopause (EPM; n = 13) or at least 10 years past menopause (LPM; n = 14). Fasted skeletal muscle (vastus lateralis) samples were collected after 1 week administration of transdermal E2 or placebo, in random cross-over design. RESULTS: Compared with EPM, LPM had reduced skeletal muscle ERα and ERß nuclear protein. Short-term E2 treatment did not change nuclear ERα or ERß, but decreased cytosolic ERα, so the proportion of ERα in the nucleus compared with the cytosol tended to increase. There was a group-by-treatment interaction (P < 0.05) for nuclear proliferator-activated receptor γ co-activator 1-α and phosphorylated adenosine monophosphate-activated protein kinase, such that E2 increased these proteins in EPM, but decreased these proteins in LPM. CONCLUSIONS: These preliminary studies of skeletal muscle from early and late postmenopausal women treated with E2 suggest there may be declines in skeletal muscle ER and changes in the E2-mediated regulation of cellular energy homeostasis with increasing time since menopause.

Region-specific effects of oestradiol on adipose-derived stem cell differentiation in post-menopausal women.

The goal of this study was to determine the effect of acute transdermal 17ß-oestradiol (E2 ) on the adipogenic potential of subcutaneous adipose-derived stem cells (ASC) in post-menopausal women. Post-menopausal women (n = 11; mean age 57 ± 4.5 years) were treated for 2 weeks, in a randomized, cross-over design, with transdermal E2 (0.15 mg) or placebo patches. Biopsies of abdominal (AB) and femoral (FEM) subcutaneous adipose tissue (SAT) were obtained after each treatment and mature adipocytes were analysed for cell size and ASC for their capacity for proliferation (growth rate), differentiation (triglyceride accumulation) and susceptibility to tumour necrosis factor alpha-induced apoptosis. Gene expression of oestrogen receptors α and ß (ESR1 and ESR2), perilipin 1 and hormone-sensitive lipase (HSL), was also assessed. In FEM SAT, but not AB SAT, 2 weeks of E2 significantly (P = 0.03) increased ASC differentiation and whole SAT HSL mRNA expression (P = 0.03) compared to placebo. These changes were not associated with mRNA expression of oestrogen receptors α and ß, but HSL expression was significantly increased in FEM SAT with transdermal E2 treatment. Adipose-derived stem cells proliferation and apoptosis did not change in either SAT depot after E2 compared with placebo. Short-term E2 appeared to increase the adipogenic potential of FEM, but not AB, SAT in post-menopausal women with possible implications for metabolic disease. Future studies are needed to determine longer term impact of E2 on regional SAT accumulation in the context of positive energy imbalance.

Women With Gestational Diabetes Mellitus Randomized to a Higher-Complex Carbohydrate/Low-Fat Diet Manifest Lower Adipose Tissue Insulin Resistance, Inflammation, Glucose, and Free Fatty Acids: A Pilot Study.

OBJECTIVE: Diet therapy in gestational diabetes mellitus (GDM) has focused on carbohydrate restriction but is poorly substantiated. In this pilot randomized clinical trial, we challenged the conventional low-carbohydrate/higher-fat (LC/CONV) diet, hypothesizing that a higher-complex carbohydrate/lower-fat (CHOICE) diet would improve maternal insulin resistance (IR), adipose tissue (AT) lipolysis, and infant adiposity. RESEARCH DESIGN AND METHODS: At 31 weeks, 12 diet-controlled overweight/obese women with GDM were randomized to an isocaloric LC/CONV (40% carbohydrate/45% fat/15% protein; n = 6) or CHOICE (60%/25%/15%; n = 6) diet. All meals were provided. AT was biopsied at 37 weeks. RESULTS: After ∼7 weeks, fasting glucose (P = 0.03) and free fatty acids (P = 0.06) decreased on CHOICE, whereas fasting glucose increased on LC/CONV (P = 0.03). Insulin suppression of AT lipolysis was improved on CHOICE versus LC/CONV (56 vs. 31%, P = 0.005), consistent with improved IR. AT expression of multiple proinflammatory genes was lower on CHOICE (P < 0.01). Infant adiposity trended lower with CHOICE (10.1 ± 1.4 vs. 12.6 ± 2%, respectively). CONCLUSIONS: A CHOICE diet may improve maternal IR and infant adiposity, challenging recommendations for a LC/CONV diet.

Regulation of Body Composition and Bioenergetics by Estrogens.

Evidence points to an important role of estradiol (E2) in the regulation of body composition and bioenergetics. Basic and preclinical research shows that the disruption of E2 signaling through either genetic manipulation or surgical intervention accelerates fat accumulation, with a disproportionate increase in abdominal fat. Clinical evidence for the regulation of body composition and bioenergetics by E2 is less consistent. Evidence exists both for and against menopause as the mediator of changes in body composition. Thus, a need remains to better understand the metabolic actions of estrogens in women and the potential impact on health after the menopause.

Femoral lipectomy increases postprandial lipemia in women.

Femoral subcutaneous adipose tissue (SAT) appears to be cardioprotective compared with abdominal SAT, possibly through better triglyceride (TG) sequestration. We hypothesized that removal of femoral SAT would increase postprandial TG through a reduction in dietary fatty acid (FA) storage. Normal-weight (means ± SD; BMI 23.9 ± 2.6 kg/m(2)) women (n = 29; age 45 ± 6 yr) were randomized to femoral lipectomy (LIPO) or control (CON) and followed for 1 yr. Regional adiposity was measured by DEXA and CT. A liquid meal labeled with [(14)C]oleic acid was used to trace the appearance of dietary FA in plasma (6-h postprandial TG), breath (24-h oxidation), and SAT (24-h [(14)C]TG storage). Fasting LPL activity was measured in abdominal and femoral SAT. DEXA leg fat mass was reduced after LIPO vs. CON (Δ-1.4 ± 0.7 vs. 0.1 ± 0.5 kg, P < 0.001) and remained reduced at 1 yr (-1.1 ± 1.4 vs. -0.2 ± 0.5 kg, P < 0.05), as did CT thigh subcutaneous fat area (-39.6 ± 36.6 vs. 4.7 ± 14.6 cm(2), P < 0.05); DEXA trunk fat mass and CT visceral fat area were unchanged. Postprandial TG increased (5.9 ± 7.7 vs. -0.6 ± 5.3 × 10(3) mg/dl, P < 0.05) and femoral SAT LPL activity decreased (-21.9 ± 22.3 vs. 10.5 ± 26.5 nmol·min(-1)·g(-1), P < 0.05) 1 yr following LIPO vs. CON. There were no group differences in (14)C-labeled TG appearing in abdominal and femoral SAT or elsewhere. In conclusion, femoral fat remained reduced 1 yr following lipectomy and was accompanied by increased postprandial TG and reduced femoral SAT LPL activity. There were no changes in storage of meal-derived FA or visceral fat. Our data support a protective role for femoral adiposity on circulating TG independent of dietary FA storage and visceral adiposity.

Effects of pioglitazone or exercise in older adults with mild cognitive impairment and insulin resistance: a pilot study.

AIMS: To examine the effects of pioglitazone or endurance exercise training on cognitive function in older adults with mild cognitive impairment (MCI) and insulin resistance. METHODS: Seventy-eight adults (mean age ± SD: 65 ± 7 years) with central obesity and MCI were randomized to 6 months of endurance exercise, pioglitazone or control. RESULTS: Sixty-six participants completed the study. Exercise training did not significantly increase peak oxygen uptake compared to control (p = 0.12). Compared to control, insulin resistance improved in the pioglitazone group (p = 0.002) but not in the exercise group (p = 0.25). There was no measureable effect of pioglitazone or exercise on cognitive performance compared to control. CONCLUSION: In this pilot study, pioglitazone improved insulin resistance but not cognitive performance in older adults with MCI and insulin resistance.

Postprandial triglycerides and adipose tissue storage of dietary fatty acids: impact of menopause and estradiol.

OBJECTIVES: Postprandial lipemia worsens after menopause, but the mechanism remains unknown. The hypothesized menopause-related postprandial lipemia would be (1) associated with reduced storage of dietary fatty acids (FA) as triglyceride (TG) in subcutaneous adipose tissue (SAT) and (2) improved by short-term estradiol (E2 ). METHODS: Twenty-three pre- (mean ± SD: 42 ± 4 years) and 22 postmenopausal (55 ± 4 years) women with similar total adiposity were studied. A subset of postmenopausal women (n = 12) were studied following 2 weeks of E2 (0.15 mg) and matching placebo in a random, cross-over design. A liquid meal containing (14) C-oleic acid traced appearance of dietary FA in: serum (postprandial TG), breath (oxidation), and abdominal and femoral SAT (TG storage). RESULTS: Compared to premenopausal women, healthy, lean, postmenopausal women had increased postprandial glucose and insulin and trend for higher TG but had similar dietary FA oxidation and storage. Adipocytes were larger in post- compared to premenopausal women, particularly in femoral SAT. Short-term E2 reduced postprandial TG and insulin but had no effect on oxidation or storage of dietary FA. E2 increased the proportion of small adipocytes in femoral (but not abdominal) SAT. CONCLUSIONS: Short-term E2 attenuated menopause-related increases in postprandial TG and increased femoral adipocyte hyperplasia but not through increased net storage of dietary FA.

A higher-complex carbohydrate diet in gestational diabetes mellitus achieves glucose targets and lowers postprandial lipids: a randomized crossover study.

OBJECTIVE: The conventional diet approach to gestational diabetes mellitus (GDM) advocates carbohydrate restriction, resulting in higher fat (HF), also a substrate for fetal fat accretion and associated with maternal insulin resistance. Consequently, there is no consensus about the ideal GDM diet. We hypothesized that, compared with a conventional, lower-carbohydrate/HF diet (40% carbohydrate/45% fat/15% protein), consumption of a higher-complex carbohydrate (HCC)/lower-fat (LF) Choosing Healthy Options in Carbohydrate Energy (CHOICE) diet (60/25/15%) would result in 24-h glucose area under the curve (AUC) profiles within therapeutic targets and lower postprandial lipids. RESEARCH DESIGN AND METHODS: Using a randomized, crossover design, we provided 16 GDM women (BMI 34 ± 1 kg/m2) with two 3-day isocaloric diets at 31 ± 0.5 weeks (washout between diets) and performed continuous glucose monitoring. On day 4 of each diet, we determined postprandial (5 h) glucose, insulin, triglycerides (TGs), and free fatty acids (FFAs) following a controlled breakfast meal. RESULTS: There were no between-diet differences for fasting or mean nocturnal glucose, but 24-h AUC was slightly higher (∼6%) on the HCC/LF CHOICE diet (P = 0.02). The continuous glucose monitoring system (CGMS) revealed modestly higher 1- and 2-h postprandial glucose on CHOICE (1 h, 115 ± 2 vs. 107 ± 3 mg/dL, P ≤ 0.01; 2 h, 106 ± 3 vs. 97 ± 3 mg/dL, P = 0.001) but well below current targets. After breakfast, 5-h glucose and insulin AUCs were slightly higher (P < 0.05), TG AUC was no different, but the FFA AUC was significantly lower (∼19%; P ≤ 0.01) on the CHOICE diet. CONCLUSIONS: This highly controlled study randomizing isocaloric diets and using a CGMS is the first to show that liberalizing complex carbohydrates and reducing fat still achieved glycemia below current treatment targets and lower postprandial FFAs. This diet strategy may have important implications for preventing macrosomia.

Subcutaneous adipose tissue insulin resistance is associated with visceral adiposity in postmenopausal women.

OBJECTIVE: Whole body and subcutaneous adipose tissue (SAT) insulin resistance association with regional fat mass (FM) was determined. METHODS: Postmenopausal women (mean ± SD; age 56 ± 4 years, n = 25) who were overweight or obese (BMI 29.9 ± 5.1 kg/m(2) ) were studied. Whole body and regional FM were measured by dual-energy X-ray absorptiometry (DXA) and computed tomography (CT). Women were studied during basal and insulin-stimulated (3-stage euglycemic clamp) conditions. Whole-body lipolysis was assessed by [(2) H5 ]-glycerol rate of appearance and abdominal and femoral SAT lipolysis by interstitial glycerol (microdialysis). RESULTS: Whole body insulin resistance in skeletal muscle (insulin-stimulated glucose disposal) and adipose tissue (insulin-suppressed lipolysis) were independently related to trunk FM (r = -0.336 and 0.484, respectively), but not leg FM (r = -0.142 and -0.148, respectively). Local antilipolytic insulin resistance in abdominal, but not femoral, SAT was positively related to trunk FM (r = 0.552) and visceral FM (r = 0.511) but not related to leg FM (r = -0.289). Whole body and abdominal, but not femoral, adipose tissue insulin sensitivity were strongly related to skeletal muscle insulin sensitivity (r = -0.727 and -0.674, respectively). CONCLUSIONS: The association of SAT insulin sensitivity (lipolysis) with adiposity and skeletal muscle insulin sensitivity was specific to the abdominal region.

A novel index of whole body antilipolytic insulin action.

OBJECTIVE: Assessment of antilipolytic insulin action is important in obesity research, but extensive isotopic tracer studies are not always feasible. We evaluated whether an index of antilipolytic insulin action could be derived from readily available insulin and glycerol concentrations obtained during clamps or oral glucose tolerance tests (OGTT). DESIGN AND METHODS: We evaluated data collected from 29 subjects who had undergone a 3-stage hyperinsulinemic-euglycemic clamp (4, 8, and 40 mU/m(2)/min) with infusion of [(2) H5 ]glycerol to calculate the glycerol rate of appearance (GLYRA). Exponential decay curves for GLYRA across insulin concentrations were generated for each individual and suppression of lipolysis was calculated as the insulin concentration needed to half-maximally suppress GLYRA (GLYRA EC50). Areas under the curve for glycerol (GLYAUC) and insulin (INSAUC) were calculated and their products (INSAUC × GLYAUC) were calculated as an index of insulin suppression of lipolysis. RESULTS: The clamp index was highly correlated with GLYRA EC50 (r = 0.862, P < 0.001), as was an OGTT-derived index (r = 0.720, P < 0.01). CONCLUSIONS: These findings suggest that the products of the insulin and glycerol AUC from either a clamp or an OGTT are good biomarkers of the antilipolytic action of insulin and are comparable with direct measurement by isotopic tracer methods.