Effect of Salsalate on Insulin Action, Secretion, and Clearance in Nondiabetic, Insulin-Resistant Individuals: A Randomized, Placebo-Controlled Study
2014; 37 (7): 1944-1950
Pancreatic beta cell function following liraglutide-augmented weight loss in individuals with prediabetes: analysis of a randomised, placebo-controlled study
2014; 57 (3): 455-462
Abnormalities of Lipoprotein Concentrations in Obstructive Sleep Apnea Are Related to Insulin Resistance.
Liraglutide can modulate insulin secretion by directly stimulating beta cells or indirectly through weight loss and enhanced insulin sensitivity. Recently, we showed that liraglutide treatment in overweight individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) led to greater weight loss (-7.7% vs -3.9%) and improvement in insulin resistance compared with placebo. The current study evaluates the effects on beta cell function of weight loss augmented by liraglutide compared with weight loss alone.This was a parallel, randomised study conducted in a single academic centre. Both participants and study administrators were blinded to treatment assignment. Individuals who were 40-70 years old, overweight (BMI 27-40 kg/m(2)) and with prediabetes were randomised (via a computerised system) to receive liraglutide (n = 35) or matching placebo (n = 33), and 49 participants were analysed. All were instructed to follow an energy-restricted diet. Primary outcome was insulin secretory function, which was evaluated in response to graded infusions of glucose and day-long mixed meals.Liraglutide treatment (n = 24) significantly (p ≤ 0.03) increased the insulin secretion rate (% mean change [95% CI]; 21% [12, 31] vs -4% [-11, 3]) and pancreatic beta cell sensitivity to intravenous glucose (229% [161, 276] vs -0.5% (-15, 14]), and decreased insulin clearance rate (-3.5% [-11, 4] vs 8.2 [0.2, 16]) as compared with placebo (n = 25). The liraglutide-treated group also had significantly (p ≤ 0.03) lower day-long glucose (-8.2% [-11, -6] vs -0.1 [-3, 2]) and NEFA concentrations (-14 [-20, -8] vs -2.1 [-10, 6]) following mixed meals, whereas day-long insulin concentrations did not significantly differ as compared with placebo. In a multivariate regression analysis, weight loss was associated with a decrease in insulin secretion rate and day-long glucose and insulin concentrations in the placebo group (p ≤ 0.05), but there was no association with weight loss in the liraglutide group. The most common side effect of liraglutide was nausea.A direct stimulatory effect on beta cell function was the predominant change in liraglutide-augmented weight loss. These changes appear to be independent of weight loss.ClinicalTrials.gov NCT01784965 FUNDING: The study was funded by the ADA.
View details for DOI 10.1007/s00125-013-3134-3
View details for Web of Science ID 000331558400003
Reply to DN Polesel et al.
American journal of clinical nutrition
2013; 98 (6): 1593-?
Habitual shortened sleep and insulin resistance: An independent relationship in obese individuals
METABOLISM-CLINICAL AND EXPERIMENTAL
2013; 62 (11): 1553-1556
Prevalence of cardiovascular disease (CVD) is increased in patients with obstructive sleep apnea (OSA), possibly related to dyslipidemia in these individuals. Insulin resistance is also common in OSA, but its contribution to dyslipidemia of OSA is unclear. The studys aim was to define the relationships among abnormalities of lipoprotein metabolism, clinical measures of OSA, and insulin resistance.Cross-sectional study. OSA severity was defined by the apnea-hypopnea index (AHI) during polysomnography. Hypoxia measures were expressed as minimum and mean oxygen saturation, and the oxygen desaturation index. Insulin resistance was quantified by determining steady-state plasma glucose (SSPG) concentrations during the insulin suppression test. Fasting plasma lipid/ lipoprotein evaluation was performed by vertical auto profile methodology.Academic medical center.107 nondiabetic, overweight/ obese adults.Lipoprotein particles did not correlate with AHI or any hypoxia measures, nor were there differences noted by categories of OSA severity. By contrast, even after adjustment for age, sex, and BMI, SSPG was positively correlated with triglycerides (r = 0.30, P < 0.01), very low density lipoprotein (VLDL) and its subclasses (VLDL1+2) (r = 0.21-0.23, P < 0.05), and low density lipoprotein subclass 4 (LDL4) (r = 0.30, P < 0.01). SSPG was negatively correlated with high density lipoprotein (HDL) (r = -0.38, P < 0.001) and its subclasses (HDL2 and HDL3) (r = -0.32, -0.43, P < 0.01), and apolipoprotein A1 (r = -0.33, P < 0.01). Linear trends of these lipoprotein concentrations across SSPG tertiles were also significant.Pro-atherogenic lipoprotein abnormalities in OSA are related to insulin resistance, but not to OSA severity or degree of hypoxia. Insulin resistance may represent the link between OSA-related dyslipidemia and increased CVD risk.
View details for PubMedID 25348129
Is measurement of non-HDL cholesterol an effective way to identify the metabolic syndrome?
NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES
2013; 23 (11): 1122-1127
Short sleep duration has been reported to be associated with obesity, type 2 diabetes, and pre-diabetes. Since excess weight, glucose abnormalities, and insulin resistance tend to cluster, the individual role insulin resistance may have in habitual shortened sleep is unclear. The study purpose was to assess whether habitual sleep curtailment is independently related to insulin resistance in obese individuals.Non-diabetic, overweight/obese individuals from the community were stratified as insulin-resistant (n=35) or insulin-sensitive (n=21) based on steady-state plasma glucose concentrations (SSPG) during the insulin suppression test. Seventy-five gram oral glucose tolerance tests were performed. Participants were asked, "On average, how many hours of sleep do you get per night?" Shortened sleep duration was defined as less than 7h of sleep per night.SSPG concentrations differed 2.5-fold (P<0.001) between insulin-resistant and insulin-sensitive individuals. Impaired fasting glucose and glucose intolerance were prevalent in both groups (>40%); however, body mass index, waist circumference, mean fasting or 2-h post-glucola glucose concentrations were not significantly different. Insulin-resistant individuals reported (mean±SD) fewer hours of sleep than did insulin-sensitive individuals (6.53±1.1 vs 7.24±0.9h, P<0.05). Shortened sleep duration was more prevalent among insulin-resistant as compared with insulin-sensitive individuals (60% vs 24%, P<0.05).Non-diabetic, insulin-resistant individuals averaged fewer hours of sleep and were more likely to report shortened sleep duration as compared with similarly obese insulin-sensitive individuals. There appears to be an independent association between habitual shortened sleep and insulin resistance among obese, dysglycemic adults without diabetes.
View details for DOI 10.1016/j.metabol.2013.06.003
View details for Web of Science ID 000330924500005
View details for PubMedID 23849514
Benefits of Liraglutide Treatment in Overweight and Obese Older Individuals With Prediabetes
2013; 36 (10): 3276-3282
BACKGROUND AND AIMS: The metabolic syndrome (MetS) has been shown to predict coronary heart disease (CHD). Non-high-density lipoprotein cholesterol (non-HDL-C) is also known to predict CHD, and recent evidence indicated non-HDL-C was able to predict MetS in adolescents. The study aim was to determine whether non-HDL-C serves as a useful metabolic marker for MetS in adults. METHODS AND RESULTS: Fasting non-HDL-C measurements were obtained in 366 non-diabetic adults not on lipid-lowering therapy. In addition to traditional non-HDL-C cut-points based on Adult Treatment Panel III guidelines, receiver-operating characteristic curve analysis was used to identify an optimal cut-point for predicting MetS. A secondary goal was to assess the relationship between non-HDL-C and insulin resistance, defined as the upper tertile of steady-state plasma glucose concentrations measured during the insulin suppression test. Prevalence of MetS was 40% among participants. Those with MetS had higher mean non-HDL-C (4.17 ± 1.0 vs 3.70 ± 0.85 mmol/L, p < 0.001), and the upper vs lower tertile of non-HDL-C concentrations was associated with 1.8-fold increased odds of MetS (p < 0.05). Traditional non-HDL-C cut-points ≥4.14 and ≥4.92 mmol/L demonstrated respective sensitivities 46% and 24% (specificities 72% and 89%) for identifying MetS. The optimal non-HDL-C cut-point ≥4.45 mmol/L had sensitivity 39% (specificity 82%). Comparable results were observed when non-HDL-C was used to identify insulin resistance. CONCLUSION: While MetS was associated with increased non-HDL-C, an effective non-HDL-C threshold to predict MetS in adults was not identified. Dyslipidemic nuances may explain why non-HDL-C may be less useful as a metabolic marker for MetS and/or insulin resistance than for CHD.
View details for DOI 10.1016/j.numecd.2012.12.001
View details for Web of Science ID 000326986800013
View details for PubMedID 23352957
The Winged Helix Transcription Factor Foxa3 Regulates Adipocyte Differentiation and Depot-Selective Fat Tissue Expansion
MOLECULAR AND CELLULAR BIOLOGY
2013; 33 (17): 3392-3399
OBJECTIVEThe aim was to evaluate the ability of liraglutide to augment weight loss and improve insulin resistance, cardiovascular disease (CVD) risk factors, and inflammation in a high-risk population for type 2 diabetes (T2DM) and CVD.RESEARCH DESIGN AND METHODSWe randomized 68 older individuals (mean age, 58 ± 8 years) with overweight/obesity and prediabetes to this double-blind study of liraglutide 1.8 mg versus placebo for 14 weeks. All subjects were advised to decrease calorie intake by 500 kcal/day. Peripheral insulin resistance was quantified by measuring the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. Traditional CVD risk factors and inflammatory markers also were assessed.RESULTSEleven out of 35 individuals (31%) assigned to liraglutide discontinued the study compared with 6 out of 33 (18%) assigned to placebo (P = 0.26). Subjects who continued to use liraglutide (n = 24) lost twice as much weight as those using placebo (n = 27; 6.8 vs. 3.3 kg; P < 0.001). Liraglutide-treated subjects also had a significant improvement in SSPG concentration (-3.2 vs. 0.2 mmol/L; P < 0.001) and significantly (P ≤ 0.04) greater lowering of systolic blood pressure (-8.1 vs. -2.6 mmHg), fasting glucose (-0.5 vs. 0 mmol/L), and triglyceride (-0.4 vs. -0.1 mmol/L) concentration. Inflammatory markers did not differ between the two groups, but pulse increased after liraglutide treatment (6.4 vs. -0.9 bpm; P = 0.001).CONCLUSIONSThe addition of liraglutide to calorie restriction significantly augmented weight loss and improved insulin resistance, systolic blood pressure, glucose, and triglyceride concentration in this population at high risk for development of T2DM and CVD.
View details for DOI 10.2337/dc13-0354
View details for Web of Science ID 000324749500073
Risk for obstructive sleep apnea in obese, nondiabetic adults varies with insulin resistance status
SLEEP AND BREATHING
2013; 17 (1): 333-338
Conversion of mesenchymal stem cells into terminally differentiated adipocytes progresses sequentially through regulated transcriptional steps. While it is clear that the late phases of adipocyte maturation are governed by the nuclear receptor PPARγ, less is known about the transcriptional control of the initial stages of differentiation. To identify early regulators, we performed a siRNA screen of Forkhead-box genes in adipocytes and show here for the first time that the winged helix factor Foxa3 promotes adipocyte differentiation by cooperating with C/EBPβ and δ to transcriptionally induce PPARγ expression. Furthermore we demonstrate that mice with genetic ablation of Foxa3 have a selective decrease in epididymal fat depot and a cell-autonomous defect to induce PPARγ specifically in their visceral adipocytes. In obese subjects, FOXA3 is differentially expressed in visceral and subcutaneous adipose depots. Overall our study implicates Foxa3 in the regulation of adipocyte differentiation and depot-selective adipose tissue expansion.
View details for DOI 10.1128/MCB.00244-13
View details for Web of Science ID 000322817600001
View details for PubMedID 23798556
Preferential Fat Deposition in Subcutaneous Versus Visceral Depots Is Associated with Insulin Sensitivity
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
2011; 96 (11): E1756-E1760
Obstructive sleep apnea (OSA) is an increasingly common sleep disorder, especially among obese adults. Early identification of adults at risk for OSA would be of substantial benefit; however, the magnitude of the obesity epidemic requires that screening be performed judiciously. The study's aim was to utilize questionnaires that assess OSA risk and symptoms to test the hypothesis that the most insulin-resistant subset of obese individuals is at highest risk for OSA.Nondiabetic, overweight to obese volunteers underwent direct quantification of insulin sensitivity by measuring steady-state plasma glucose concentrations during the insulin suppression test. Insulin-sensitive and insulin-resistant individuals were administered the Berlin and STOP questionnaires to determine OSA risk status, and Epworth Sleepiness Scale (ESS) to evaluate daytime sleepiness. Fasting insulin and lipid/lipoprotein measurements were performed.Insulin-mediated glucose disposal differed threefold (p < 0.001) between equally obese, insulin-resistant (n = 22) and insulin-sensitive (n = 14) individuals, associated with higher fasting insulin and triglyceride and lower high-density lipoprotein cholesterol (HDL-C) concentrations in insulin-resistant individuals. Fourteen (64 %) insulin-resistant as compared with 2 (14 %) insulin-sensitive individuals were found to be at high risk for OSA by both questionnaires (p < 0.01). Whereas half of insulin-resistant individuals met the ESS criteria for excessive daytime sleepiness, only one insulin-sensitive individual did (p = 0.011).High risk for OSA and excessive daytime sleepiness is prevalent among the insulin-resistant subgroup of obese individuals. Surrogate estimates of insulin resistance based on fasting insulin, triglycerides, and/or HDL-C can be used to help identify those obese adults who would benefit most from OSA screening and referral for polysomnography.
View details for DOI 10.1007/s11325-012-0696-0
View details for Web of Science ID 000315167200052
View details for PubMedID 22481243
Adiposity indices in the prediction of metabolic abnormalities associated with cardiovascular disease in non-diabetic adults
NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES
2011; 21 (8): 553-560
Studies on the relationship between regional fat and insulin resistance yield mixed results. Our objective was to determine whether regional fat distribution, independent of obesity, is associated with insulin resistance.Subjects included 115 healthy, overweight/moderately obese adults with body mass index (BMI) 25-36.9 kg/m(2) who met predetermined criteria for being insulin resistant (IR) or insulin sensitive (IS) based on the modified insulin suppression test. Computerized tomography was used to quantify visceral adipose tissue (VAT), sc adipose tissue (SAT), and thigh adipose tissue. Fat mass in each depot was compared according to IR/IS group, adjusting for BMI and sex.Despite nearly identical mean BMI in the IR vs. IS groups, VAT and %VAT were significantly higher in the IR group, whereas SAT, %SAT, and thigh sc fat were significantly lower. In logistic regression analysis, each sd increase in VAT increased the odds of being IR by 80%, whereas each increase in SAT decreased the odds by 48%; each increase in thigh fat decreased the odds by 59% and retained significance after adjusting for other depots. When grouped by VAT tertile, IS vs. IR individuals had significantly more SAT. There was no statistically significant interaction between sex and these relationships.These data demonstrate that after adjustment for BMI and VAT mass, sc abdominal and thigh fat are protective for insulin resistance, whereas VAT, after adjustment for SAT and BMI, has the opposite effect. Whether causal in nature or a marker of underlying pathology, these results clarify that regional distribution of fat-favoring sc depots is associated with lower risk for insulin resistance.
View details for DOI 10.1210/jc.2011-0615
View details for Web of Science ID 000296750600005
View details for PubMedID 21865361
Differential adipogenic and inflammatory properties of small adipocytes in Zucker Obese and Lean rats
DIABETES & VASCULAR DISEASE RESEARCH
2010; 7 (4): 311-318
The prevalence of insulin resistance and cardiovascular disease (CVD) increases with degree of obesity. Whether measurements of generalized and abdominal obesity differ in the ability to predict changes associated with increased CVD risk is widely debated. We compared the prevalence of metabolic abnormalities in 275 women and 204 men stratified by categories of body mass index (BMI) and waist circumference (WC), and assessed the ability of these adiposity indices in combination with metabolic risk variables to predict insulin resistance.Healthy, non-diabetic volunteers underwent measurements of BMI, WC, blood pressure, fasting plasma glucose (FPG), lipoprotein concentrations, and direct quantification of insulin-mediated glucose uptake. Insulin resistance was defined as the top tertile of steady-state plasma glucose (SSPG) concentrations. BMI and WC were highly correlated (P < 0.001) in both women and men. Abnormal SSPG and triglyceride concentrations were associated with increasing adiposity by either index in both genders. Among women, abnormal FPG and high density lipoprotein cholesterol (HDL-C) concentrations were associated with increasing BMI and WC. In men, abnormal HDL-C was associated with increasing BMI only. Elevated systolic blood pressure (SBP) was associated with increasing BMI in both genders. The odds of insulin resistance were greatest in women with elevated FPG and triglycerides (4.5-fold). In men, the best predictors were BMI and SBP, and WC and HDL-C (3-fold).BMI is at least comparable to WC in stratifying individuals for prevalence of metabolic abnormalities associated with increased CVD risk and predicting insulin resistance.
View details for DOI 10.1016/j.numecd.2009.12.009
View details for Web of Science ID 000293596800003
View details for PubMedID 20304617
Differential Intra-abdominal Adipose Tissue Profiling in Obese, Insulin-resistant Women
2009; 19 (11): 1564-1573
We recently reported that a preponderance of small adipose cells, decreased expression of cell differentiation markers, and enhanced inflammatory activity in human subcutaneous whole adipose tissue were associated with insulin resistance. To test the hypothesis that small adipocytes exhibited these differential properties, we characterised small adipocytes from epididymal adipose tissue of Zucker Obese (ZO) and Lean (ZL) rats. Rat epididymal fat pads were removed and adipocytes isolated by collagenase digestion. Small adipocytes were separated by sequential filtration through nylon meshes. Adipocytes were fixed in osmium tetroxide for cell size distribution analysis via Beckman Coulter Multisizer. Quantitative real-time PCR for cell differentiation and inflammatory genes was performed. Small adipocytes represented a markedly greater percentage of the total adipocyte population in ZO than ZL rats (58±4% vs. 12±3%, p<0.001). In ZO rats, small as compared with total adipocytes had 4-fold decreased adiponectin, and 4-fold increased visfatin and IL-6 levels. Comparison of small adipocytes in ZO versus ZL rats revealed 3-fold decreased adiponectin and PPAR? levels, and 2.5-fold increased IL-6. In conclusion, ZO rat adipose tissue harbours a large proportion of small adipocytes that manifest impaired cell differentiation and pro-inflammatory activity, two mechanisms by which small adipocytes may contribute to insulin resistance.
View details for DOI 10.1177/1479164110386126
View details for Web of Science ID 000285080700008
View details for PubMedID 20961992
Sexual initiation, substance use, and sexual behavior and knowledge among vocational students in northern Thailand
INTERNATIONAL FAMILY PLANNING PERSPECTIVES
2006; 32 (3): 126-135
We recently identified differences in abdominal subcutaneous adipose tissue (SAT) from insulin-resistant (IR) as compared to obesity-matched insulin sensitive individuals, including accumulation of small adipose cells, decreased expression of cell differentiation markers, and increased inflammatory activity. This study was initiated to see if these changes in SAT of IR individuals were present in omental visceral adipose tissue (VAT); in this instance, individuals were chosen to be IR but varied in degree of adiposity. We compared cell size distribution and genetic markers in SAT and VAT of IR individuals undergoing bariatric surgery.Eleven obese/morbidly obese women were IR by the insulin suppression test. Adipose tissue surgical samples were fixed in osmium tetroxide for cell size analysis via Beckman Coulter Multisizer. Quantitative real-time polymerase chain reaction for genes related to adipocyte differentiation and inflammation was performed.While proportion of small cells and expression of adipocyte differentiation genes did not differ between depots, inflammatory genes were upregulated in VAT. Diameter of SAT large cells correlated highly with increasing proportion of small cells in both SAT and VAT (r = 0.85, p = 0.001; r = 0.72, p = 0.01, respectively). No associations were observed between VAT large cells and cell size variables in either depot. The effect of body mass index (BMI) on any variables in both depots was negligible.The major differential property of VAT of IR women is increased inflammatory activity, independent of BMI. The association of SAT adipocyte hypertrophy with hyperplasia in both depots suggests a primary role SAT may have in regulating regional fat storage.
View details for DOI 10.1007/s11695-009-9949-9
View details for Web of Science ID 000271282900016
View details for PubMedID 19711137
Rapid whole-blood finger-stick test for HIV antibody: Performance and acceptability among women in Northern Thailand
JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES
2003; 33 (2): 194-198
Thailand has undergone dramatic social changes in the last two decades, yet little is known about factors related to sexual initiation among adolescents.A survey using the audio computer-assisted self-interviewing method was conducted to assess social and demographic characteristics, substance use, sexual behavior, and knowledge of HIV and STIs among 1,725 vocational school students aged 15-21 living in northern Thailand. Gender differences for these factors were evaluated using chi-square and Mann-Whitney U tests. Multivariate survival analysis using Cox proportional hazards models assessed associations between these variables and sexual initiation for each gender.Males initiated sexual intercourse at an earlier age than females (median ages of 17 and 18, respectively). At any given age, sexual initiation was associated with having a nonagricultural background and using alcohol or methamphetamine (adjusted rate ratios, 1.3-2.9). For males, initiation was also associated with having parents who did not live together, having a friend as a confidant, tobacco use, high perceived risk for HIV and high STI knowledge (1.3-1.7). For females, other factors associated with earlier initiation were younger age at interview, living away from family, lacking a family member as a confidant, high perceived risk for STIs and ever having smoked marijuana (1.3-2.4).Interventions to ameliorate the adverse consequences of early sexual initiation need to address social influences such as parents and peer groups. Programs should identify and target high-risk subgroups, such as those who are sexually experienced at an early age and those engaged in patterns of generalized risk-taking.
View details for Web of Science ID 000241370800003
View details for PubMedID 17015242
Although use of rapid HIV antibody tests of finger-stick blood specimens could expand voluntary counseling and testing in areas where fear of venipuncture and delays in learning test results are barriers, there is little information on performance and acceptability of these tests in Asia. We used the Hema. Strip HIV-1/2 test (Saliva Diagnostic Systems, Vancouver, WA) in a prospective cohort study of HIV seroincidence among women in northern Thailand from 1998 to 1999. Nurses obtained whole-blood specimens by finger-stick testing and provided test results and counseling at each visit. Acceptability of the rapid test was assessed at the first 6-month follow-up visit. HIV-1 seroprevalence among the 804 women screened at enrollment was 3.1%. Positive rapid test results from 25 women were confirmed by enzyme immunoassay and Western blot analysis using serum obtained by venipuncture. Of the 741 women who returned for follow-up, 56% preferred specimen collection by finger-stick testing to venipuncture, 80% preferred immediate rather than delayed test results, 79% preferred the rapid test method to typical testing methods, and 97% were satisfied with the test method used. Results from this study demonstrate the utility and acceptability of the rapid finger-stick test for HIV antibody among women in northern Thailand.
View details for Web of Science ID 000183815400013
View details for PubMedID 12794554