Patterns of Abdominal Fat Distribution: The Framingham Heart Study

OBJECTIVE—The prevalence of abdominal obesity exceeds that of general obesity. We sought to determine the prevalence of abdominal subcutaneous and visceral obesity and to characterize the different patterns of fat distribution in a community-based sample.RESEARCH DESIGN AND METHODS—Participants from the Framingham Heart Study (n = 3,348, 48% women, mean age 52 years) underwent multidetector computed tomography; subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes were assessed. Sex-specific high SAT and VAT definitions were based on 90th percentile cut points from a healthy referent sample. Metabolic risk factors were examined in subgroups with elevated SAT and VAT.RESULTS—The prevalence of high SAT was 30% (women) and 31% (men) and that for high VAT was 44% (women) and 42% (men). Overall, 27.8% of the sample was discordant for high SAT and high VAT: 19.9% had SAT less than but VAT equal to or greater than the 90th percentile, and 7.9% had SAT greater than but VAT less than the 90th percentile. The prevalence of metabolic syndrome was higher among women and men with SAT less than the 90th percentile and high VAT than in those with high SAT but VAT less than the 90th percentile, despite lower BMI and waist circumference. Findings were similar for hypertension, elevated triglycerides, and low HDL cholesterol.CONCLUSIONS—Nearly one-third of our sample has abdominal subcutaneous obesity, and >40% have visceral obesity. Clinical measures of BMI and waist circumference may misclassify individuals in terms of VAT and metabolic risk.Obesity is associated with an increased risk of multiple cardiometabolic risk factors. The prevalence of obesity in the U.S. has increased over the last two decades, with one-third of adults having a BMI ≥30 kg/m² (1). However, obesity is a heterogeneous condition with individual differences in the pattern of adipose tissue deposition. Accumulation of abdominal fat, particularly in the visceral compartment, may confer the majority of obesity-associated health risks (2).The prevalence of abdominal obesity (defined as waist circumference ≥88 cm in women and ≥102 cm in men) has increased over the last decade and now exceeds the prevalence of overall obesity, with rates of 42.4% in men and 61.3% in women (1,3). Notably, the largest relative increase in the prevalence of abdominal obesity has been among individuals with BMI <30 kg/m² (3). Although waist circumference is an easily obtainable index of abdominal adiposity, it does not distinguish between the subcutaneous and visceral adipose tissue compartments. We and others have previously reported that visceral adipose tissue (VAT) has a stronger association with metabolic risk factors and metabolic syndrome than subcutaneous adipose tissue (SAT) (4–6). These studies are limited, however, by the high correlations between SAT and VAT that make it difficult to distinguish between the contribution of SAT compared with that of VAT with regard to metabolic risk.Thus, the objectives of the present study were twofold. First, we sought to define the prevalence of abdominal obesity in terms of elevated volumes of VAT and SAT, as measured by a volumetric computed tomography (CT) method. To do this, we developed cut points for elevated SAT and VAT based on a healthy referent sample. Second, we examined the occurrence of different patterns of adipose tissue distribution and concomitant metabolic risk factor profiles. We hypothesized that metabolic risk factors would be more likely to track with elevated levels of VAT than with SAT.     

Five-Year Change in Visceral Adipose Tissue Quantity in a Minority Cohort: The Insulin Resistance Atherosclerosis Study (IRAS) Family Study

OBJECTIVE

To describe the 5-year change in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas.

RESEARCH DESIGN AND METHODS

Absolute change in VAT and SAT measured by abdominal computed tomography scans has been obtained at a 5-year interval from African Americans (n = 389) and Hispanic Americans (n = 844), aged 20–69 years, in 10-year age-groups.

RESULTS

Mean 5-year increases in VAT areas in women were 18, 7, 4, 0.4, and −3 cm² for African Americans and 13, 7, 3, 1, and −15 cm² for Hispanics, across the 5 age decades (trend not significant). Mean 5-year increases in SAT areas in women were 88, 46, 19, 17, and 14 cm² for African Americans and 53, 20, 17, 12, and 1 cm² for Hispanics, across the 5 age decades (P < 0.05 for both). Similar trends have been observed in men.

CONCLUSIONS

Accumulation of abdominal fat is greatest in young adulthood. These data may be useful in identifying subgroups at risk of type 2 diabetes.Longitudinal studies have shown a direct relationship between levels of visceral adipose tissue (VAT) and future risk of impaired glucose tolerance and type 2 diabetes, independent of total adiposity (1–4). The Diabetes Prevention Program showed that reductions in VAT and subcutaneous adipose tissue (SAT) led to decreased risk of type 2 diabetes (5). These studies suggest that central adiposity is an independent risk factor for type 2 diabetes. With IRAS (Insulin Resistance Atherosclerosis Study) Family Study data, we describe the natural progression of abdominal adiposity assessed by computed tomography over 5 years in African Americans and Hispanics.     

Comparative efficacy of preprandial or postprandial Humalog Mix75/25 versus glyburide in patients 60 to 80 years of age with type 2 diabetes mellitus

BACKGROUND: Humalog Mix75/25 (Mix75/25) is a novel premixed insulin containing 75% neutral protamine lispro (an intermediate-acting insulin) and 25% insulin lispro. OBJECTIVE: The purpose of this study was to compare glycemic control and hypoglycemia rates with Mix75/25 versus glyburide, and with preprandial versus postprandial Mix75/25, in patients aged 60 to 80 years with type 2 diabetes mellitus and persistent hyperglycemia on sulfonylurea therapy. METHODS: In this open-label, 16-week, parallel-group study, patients were randomized to 1 of 2 treatments: glyburide 15 mg/d (or up to the maximum daily dose) or Mix75/25. The Mix75/25 group was randomly subdivided into preprandial (immediately before breakfast and dinner) and postprandial (within 15 minutes after the start of breakfast and dinner) injection subgroups. The primary outcomes were glycemic control and rate of hypoglycemia. RESULTS: A total of 143 patients were randomized; 127 completed the study. The change in glycosylated hemoglobin (HbA(1c)) from baseline to end point was significantly greater with Mix75/25 than with glyburide (mean +/- SEM, -1.14% +/- 0.18% vs -0.36% +/- 0.15%, P = 0.001). HbA(1c) changes with preprandial and postprandial Mix75/25 were not significantly different (-1.20% +/- 0.26% vs -1.08% +/- 0.26%, P = 0.748). Fasting blood glucose (BG), 2-hour postprandial BG, and mean daily BG reductions were greater with Mix75/25 than with glyburide (P < 0.001); preprandial and postprandial Mix75/25 administration did not differ significantly with respect to any of these BG variables. The hypoglycemia rate increased with Mix75/25 by 0.17 +/- 0.02 episodes per patient per 30 days, but there was no change with glyburide (P = 0.077). Body weight increased by 1.02 +/- 0.35 kg with Mix75/25 and decreased by 0.85 +/- 0.18 kg with glyburide (P < 0.001). CONCLUSIONS: Compared with glyburide, Mix75/25 significantly improved glycemic control in older patients with type 2 diabetes mellitus, could be administered after meals without compromising glycemic control, and was well tolerated.     

Practical approach for estimation of subcutaneous and visceral adipose tissue

OBJECTIVES: The first objective was to investigate the correlations between anthropometrical measurements and visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in two cohorts differing in age using magnetic resonance imaging (MRI) as reference. A second objective was to investigate the potential usage of abdominal diameters in practical estimation of adipose tissue compartments using these cohorts. METHODS: Measurements of body mass index, waist circumference, sagittal abdominal diameter (sagittal AD) and transverse abdominal diameter (transverse AD) were obtained from 336 volunteers of age 14-70 years. Manual measurements of VAT and SAT from single slice MRI at the L4-L5 level were used as reference. The abdominal diameters were measured from the MR images. Linear correlations between the anthropometrical measurements and the reference were studied. RESULTS: Sagittal AD showed the strongest correlation to VAT (r >or= 0 x 780, P<0 x 0001) and transverse AD was found to give information about the amount of SAT (r >or= 0 x 866, P<0 x 0001). The ellipse spanned by the sagittal AD and the transverse AD was strongly correlated to the total amount of adipose tissue (r >or= 0 x 962, P<0 x 0001). CONCLUSION: Strong correlations were found between sagittal and transverse abdominal diameters, assessed using MRI, and VAT and SAT, respectively. These results suggest the use of abdominal diameters in practical estimations of VAT and SAT depots.     

基于MRI评估的胰腺脂肪沉积及腹部脂肪分布与原发性高血压的相关性研究

目的探讨基于MRI评估的胰腺脂肪沉积、内脏脂肪和皮下脂肪与原发性高血压的相关性。材料与方法纳入54例高血压患者和108例对照者。应用半自动分割对全胰腺进行分割,并测量全胰腺脂肪分数值。应用Image J软件测量内脏脂肪(visceral adipose tissue,VAT)和皮下脂肪(subcutaneous adipose tissue,SAT)面积,并记录VAT和SAT脂肪分数值(fat fraction,FF),计算内脏/皮下脂肪组织的面积比(V/S)。数据由SPSS进行统计学分析。P<0.05被认为差异具有统计学意义。结果高血压患者全胰腺脂肪分数值、VAT和SAT面积、V/S、VAT和SAT脂肪分数值均高于对照者。全胰腺脂肪分数值对高血压的诊断价值最高(AUC=0.816)。全胰腺脂肪分数的阈值为10.15%,对高血压诊断的敏感度为75.9%,特异度为81.5%。全胰腺FF与VAT面积和脂肪分数值呈中等相关性(r=0.541、0.561);与SAT面积、脂肪分数值和V/S的相关性较低(r=0.280、0.324、0.266)。结论高血压者与全胰腺脂肪分数、VAT和SAT增多有关。全胰腺脂肪分数与VAT和SAT的增加相关。     

Adipose Dipeptidyl Peptidase-4 and Obesity: Correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro

OBJECTIVE

To study expression of the recently identified adipokine dipeptidyl peptidase-4 (DPP4) in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) of patients with various BMIs and insulin sensitivities, as well as to assess circulating DPP4 in relation to obesity and insulin sensitivity.

RESEARCH DESIGN AND METHODS

DPP4 expression was measured in SAT and VAT from 196 subjects with a wide range of BMIs and insulin sensitivities. DPP4 release was measured ex vivo in paired biopsies from SAT and VAT as well as in vivo from SAT of lean and obese patients. Circulating DPP4 was measured in insulin-sensitive and insulin-resistant BMI-matched obese patients.

RESULTS

DPP4 expression was positively correlated with BMI in both SAT and VAT, with VAT consistently displaying higher expression than SAT. Ex vivo release of DPP4 from adipose tissue explants was higher in VAT than in SAT in both lean and obese patients, with obese patients displaying higher DPP4 release than lean controls. Net release of DPP4 from adipose tissue was also demonstrated in vivo with greater release in obese subjects than in lean subjects and in women than in men. Insulin-sensitive obese patients had significantly lower circulating DPP4 than did obesity-matched insulin-resistant patients. In this experiment, DPP4 positively correlated with the amount of VAT, adipocyte size, and adipose tissue inflammation.

CONCLUSIONS

DPP4, a novel adipokine, has a higher release from VAT that is particularly pronounced in obese and insulin-resistant patients. Our data suggest that DPP4 may be a marker for visceral obesity, insulin resistance, and the metabolic syndrome.Obesity is an increasing health issue worldwide and an economical burden, and as the hallmark of the metabolic syndrome the obese state is frequently associated with the development of chronic diseases, including type 2 diabetes (1,2). The association between the epidemics of obesity and diabetes has promoted research on the endocrine link between lipid and glucose homeostasis, demonstrating that adipose tissue is an endocrine organ releasing various adipokines. A complex interorgan crosstalk scenario between adipose tissue and other central and peripheral organs underlies the progression of obesity-related metabolic disorders, with adipose tissue being a key player in this scenario (3). The current view of the role of expanded adipose tissue in obesity identifies adipokines as a potential link between obesity and insulin resistance (4). This link has stimulated a further characterization of the adipocyte secretome by means of diverse proteomic profiling approaches, leading to the discovery of such novel adipokines as dipeptidyl peptidase-4 (DPP4) (5).DPP4 is a transmembrane glycoprotein and exoprotease that cleaves N-terminal dipeptides from various substrates (6). Most importantly, DPP4 also cleaves and inactivates the incretins glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide. In this context, DPP4-inhibitors are in clinical use as antidiabetic drugs to improve glycemic control by stimulating pancreatic insulin secretion and suppressing glucagon production (7). We recently demonstrated that adipocytes release DPP4 in a differentiation-dependent manner (5). Circulating DPP4 concentrations are increased in obese subjects and correlate with fasting plasma insulin, leptin, and adipocyte size in subcutaneous adipose tissue (SAT); however, the tissue source of circulating DPP4 is not known. This study aimed to assess DPP4 expression and release in paired biopsies of SAT and visceral adipose tissue (VAT) of lean and obese patients and of patients with or without impaired glucose tolerance, as well as DPP4 release from adipose tissue in vivo. Because circulating DPP4 is increased in obese patients with the metabolic syndrome (5), we hypothesized that DPP4 expression and release in VAT are more prominent than in SAT and that VAT DPP4 could be a marker for insulin sensitivity.     

Improvement in medication compliance and glycemic control with voglibose oral disintegrating tablet

Good compliance with hypoglycemic therapy is important for diabetes treatment, since positive relationship between medication compliance and glycemic control has been reported. To improve medication compliance, the oral disintegrating tablet technology that facilitates drug administration without water has been employed in various drugs, including voglibose, an alpha glucosidase inhibitor. In the present survey, we investigated safety profile of voglibose oral disintegrating tablet (VODT), and whether treatment with VODT results in improvement of medication compliance and glycemic control. Patients with diabetes received VODT 0.6 or 0.9 mg/day for 12 weeks. Among 2,930 eligible patients, adverse drug reactions were observed in 3.6%, with the most common being abdominal distension, flatulence, diarrhea, and increased alanine aminotransferase levels. In 1,067 patients who received conventional voglibose tablet (CVT) prior to VODT, 53.1% reported that taking VODT was easier than taking CVT. Medication compliance was improved after switching to VODT in 28.4% of patients who missed taking tablets more than one time a week during CVT treatment. A significant decrease in HbA(1C) levels was observed in patients whose medication compliance was improved after switching to VODT (P = 0.033), but there was no significant reduction in HbA(1C) levels in patients whose medication compliance did not change. In conclusion, the present survey suggests that the safety profile of VODT is comparable with that of CVT, and switching from CVT to VODT has positive impact on medication compliance which may lead to an improvement in glycemic control.     

Dietary glycemic index and glycemic load, carbohydrate and fiber intake, and measures of insulin sensitivity, secretion, and adiposity in the Insulin Resistance Atherosclerosis Study

OBJECTIVE: We studied the association of digestible carbohydrates, fiber intake, glycemic index, and glycemic load with insulin sensitivity (S(I)), fasting insulin, acute insulin response (AIR), disposition index, BMI, and waist circumference. RESEARCH DESIGN AND METHODS: Data on 979 adults with normal (67%) and impaired (33%) glucose tolerance from the Insulin Resistance Atherosclerosis Study (1992-1994) were analyzed. Usual dietary intake was assessed via a 114-item interviewer-administered food frequency questionnaire from which nutrient intakes were estimated. Published glycemic index values were assigned to food items and average dietary glycemic index and glycemic load calculated per subject. S(I) and AIR were determined by frequently sampled intravenous glucose tolerance test. Disposition index was calculated by multiplying S(I) with AIR. Multiple linear regression modeling was employed. RESULTS: No association was observed between glycemic index and S(I), fasting insulin, AIR, disposition index, BMI, or waist circumference after adjustment for demographic characteristics or family history of diabetes, energy expenditure, and smoking. Associations observed for digestible carbohydrates and glycemic load, respectively, with S(I), insulin secretion, and adiposity (adjusted for demographics and main confounders) were entirely explained by energy intake. In contrast, fiber was associated positively with S(I) and disposition index and inversely with fasting insulin, BMI, and waist circumference but not with AIR. CONCLUSION: Carbohydrates as reflected in glycemic index and glycemic load may not be related to measures of insulin sensitivity, insulin secretion, and adiposity. Fiber intake may not only have beneficial effects on insulin sensitivity and adiposity, but also on pancreatic functionality.     

Maintenance of sulfonylurea responsiveness in NIDDM. Randomized double-blind study of intermittent glyburide therapy.

OBJECTIVE--To assess the effectiveness of intermittent administration of sulfonylurea (glyburide) to patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS--A randomized, double-blind, prospective trial compared daily administration with intermittent administration of glyburide to patients who initially responded to the drug. Twenty-eight of 60 patients with NIDDM achieved the predetermined improvement in plasma glucose concentration on glyburide therapy. These 28 responders were enrolled into a 16-wk trial of daily versus intermittent (2 wk on, 2 wk off) glyburide treatment. Laboratory assessment of glycemic control and insulin secretion in fasting and 2-h postprandial states was done every 2 wk. RESULTS--Patients on continuous glyburide therapy maintained their glycemic control throughout the study. In contrast, patients on the intermittent schedule lost their glycemic control immediately after being placed on placebo. Despite a significant response to each sulfonylurea pulse, these subjects never regained their baseline glycemic levels. Their fructosamine and HbA1c concentrations deteriorated and remained significantly higher than those of the continuously treated subjects. CONCLUSIONS--Results suggest that administration of glyburide on an intermittent basis after a 2-wk drug-free period to patients initially rendered responsive to sulfonylurea therapy is without clinical merit.     

Association of Lifestyle Factors With Abdominal Subcutaneous and Visceral Adiposity: The Framingham Heart Study

OBJECTIVE— The purpose of this study was to assess the relationship between lifestyle factors and abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in a community-based setting.RESEARCH DESIGN AND METHODS— Cross-sectional associations between lifestyle factors (dietary quality, physical activity, smoking, and alcohol consumption) and SAT and VAT volumes were examined in 2,926 Framingham Heart Study participants (48.6% women, aged 50 ± 10 years).RESULTS— Diets consistent with the 2005 Dietary Guidelines Adherence Index and greater physical activity were inversely associated with SAT and VAT (P < 0.0001–0.002). In men, former smoking was associated with higher SAT (2,743 ± 56 cm³) compared with current smokers (2,629 ± 88 cm³) or those who never smoked (2,538 ± 44 cm³; P = 0.02). Both former and current smoking was associated with higher VAT (P = 0.03 [women]; P = 0.005 [men]). Women with high amounts of alcohol intake (>7 drinks/week) had lower SAT (2,869 ± 106 cm³) than those who consumed less alcohol (3,184 ± 44 cm³, P = 0.006); significant differences in VAT were not observed (P = 0.18). In men, high amounts of alcohol intake (>14 drinks/week) were associated with higher VAT (2,272 ± 59 cm³) compared with intake of ≤14 drinks/week (2,139 ± 25 cm³, P = 0.04), whereas SAT did not differ (P = 0.91). An increasing number of healthy lifestyle factors were associated with lower SAT and VAT volumes (all P < 0.003).CONCLUSIONS— Adherence to recommended dietary guidelines and physical activity are associated with lower SAT and VAT volumes. However, both smoking and high alcohol intake are differentially associated with VAT volumes. Further research to uncover the putative mechanisms is warranted.Abdominal adiposity is strongly associated with metabolic and cardiovascular disease (CVD) risk (1) and all-cause mortality (2). Visceral adipose tissue (VAT) in particular may be a pathogenic fat compartment (3). Numerous studies have demonstrated that central obesity is associated with lifestyle factors (4–6). However, the majority of these studies used waist circumference as a proxy for abdominal obesity, which does not allow for the differentiation between subcutaneous adipose tissue (SAT) and VAT. As VAT is more strongly associated with metabolic risk factors than SAT (3), it is important to identify whether VAT is more correlated with lifestyle factors. This information may provide more understanding of the relationship between a healthy lifestyle and VAT and the contribution of individual lifestyle factors to cardiometabolic risk.Thus, the aim of the present study was to examine the relation between lifestyle factors (dietary quality, physical activity, smoking, and alcohol consumption) and SAT and VAT volumes, as assessed by multidetector computed tomography (MDCT), in a large population-based cohort of women and men free of CVD.     

Relation of Abdominal Fat Depots to Systemic Markers of Inflammation in Type 2 Diabetes

OBJECTIVE

Both visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) have been linked to systemic inflammation in nondiabetic cohorts. We examined the relationships between VAT and SAT and systemic inflammatory markers in a large well-characterized cohort of subjects with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Three hundred eighty-two subjects with type 2 diabetes in the CHICAGO (Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone) study cohort underwent abdominal computed tomography to determine SAT and VAT distribution. Fasting blood was obtained for measurement of inflammatory markers. The relationships between inflammatory markers and BMI, SAT, and VAT were examined using regression models adjusted for age, sex, diabetes treatment, duration of diabetes, smoking, statin use, and A1C.

RESULTS

VAT was positively related to CRP, monocyte chemoattractant protein (MCP), intracellular adhesion molecule (ICAM)-1, and plasminogen activator inhibitor type 1 (PAI-1) antigen before adjustment for BMI. After adjustment for BMI, the relationship to CRP was lost but positive associations with MCP (P < 0.01), PAI-1 (P < 0.0001), ICAM-1 (P < 0.01), and vascular cell adhesion molecule (P = 0.01) were evident. BMI was positively related to CRP (P < 0.0001) and IL-6 (P < 0.01) even after adjustment for VAT and SAT. SAT was not related to any inflammatory marker after adjustment for BMI.

CONCLUSIONS

In this large group of subjects with type 2 diabetes, BMI was most strongly associated with CRP and IL-6 levels. SAT was not associated with markers of systemic inflammation. The size of the VAT depot provided information additional to that provided by BMI regarding inflammatory markers that are strongly related to vascular wall remodeling and coagulation. Our findings suggest that adipose tissue distribution remains an important determinant of systemic inflammation in type 2 diabetes.Obesity, especially of the abdominal type, is associated with a proinflammatory state. The association between obesity and inflammation was first reported by Hotamisligil et al. (1), who demonstrated expression of tumor necrosis factor-α (TNF-α) in adipose tissue, an increase in its expression in obesity, and its ability to induce insulin resistance. Since this report, adipose tissue has been recognized as an important source of a number of hormones and cytokines, including TNF-α, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1 (2). While adipokines such as leptin and adiponectin are exclusively produced by adipocytes, inflammatory cytokines can be produced by both adipocytes and adipose tissue macrophages (ATMs) (2). Obesity is associated with an increase in ATM infiltration (3) and activation (4). Epidemiological studies have demonstrated an increase in plasma levels of inflammatory markers such as C-reactive protein (CRP), IL-6, and TNF-α in obesity and a strong association with these levels and risk for type 2 diabetes and cardiovascular disease (2,5). Weight loss in humans has been associated with a reduction in ATM infiltration and levels of systemic inflammatory markers (6). There is also evidence that adipose tissue isolated from specific fat depots, such as visceral fat, may express higher levels of inflammatory markers such as IL-6 (7), MCP-1 (8), and plasminogen activator inhibitor type 1 (PAI-1) (9).For this report, we examined the association between abdominal fat compartments measured by computed tomography (CT) and markers of systemic inflammation in 382 subjects with type 2 diabetes who participated in the Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone (CHICAGO) study (10). To our knowledge, this is the largest cohort in which the relationship between adipose tissue distribution (using abdominal CT) and inflammation in subjects with type 2 diabetes has been examined. A recent study of mostly non-Hispanic whites with low prevalence of diabetes and cardiovascular disease showed that both visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) are associated with inflammatory markers, though the association for VAT was stronger (11). In this analysis, we determined whether adipose tissue distribution and specific adipose tissue depots remain important determinants of systemic inflammation in type 2 diabetes.     

Investigation of the pharmacokinetic and pharmacodynamic interactions between memantine and glyburide/metformin in healthy young subjects: a single-center, multiple-dose, open-label study

BACKGROUND: The high prevalence rates of both Alzheimer's disease (AD) and type 2 diabetes mellitus in the elderly population suggest that concomitant pharmacotherapy is likely. Given the renal tubular transport and extensive urinary excretion of memantine and metformin, it was of interest to assess the pharmacokinetic and pharmacodynamic interaction with glyburide/metformin. OBJECTIVE: The primary goal of this study was to determine whether an in vivo pharmacokinetic or pharmacodynamic interaction exists between memantine (an uncompetitive, moderate-affinity, N-methyl-D-aspartate receptor antagonist with fast blocking/unblocking kinetics that is available in the United States for moderate to severe AD) and glyburide/metformin (a combination pharmacotherapy formulation approved for glycemic control in patients with type 2 diabetes mellitus). METHODS: In this single-center, multiple-dose, open-label study, healthy adult subjects received a single oral dose of memantine hydrochloride (20 mg) on day 1. After a 14-day washout period, subjects were orally administered 1.25-mg glyburide/250-mg metformin BID with food for 6 days. On day 21, subjects were coadministered memantine (20 mg) and glyburide/metformin with food. Assessments included determination of pharmacokinetic parameters for memantine and the antidiabetic agents when administered alone and in combination, pharmacodynamic measurements of blood glucose levels, and analyses of tolerability. RESULTS: The study population consisted of 24 subjects (13 women, 11 men; 79.2% white) with a mean (SD) age of 26.1 (5.6) years and a mean (SD) weight of 69.5 (11.3) kg. Twenty-one subjects completed the study: 2 discontinued due to adverse events judged unrelated to study medication, and 1 withdrew consent. No significant pharmacokinetic or pharmacodynamic interactions were observed between memantine and glyburide/metformin. Adverse events included dizziness (41.7% of patients) with memantine administration and gastrointestinal effects (nausea, 9.1 %; vomiting, 9.1%; abdominal cramps, 13.6%) with glyburide/metformin administration. CONCLUSIONS: No pharmacokinetic interactions between memantine and glyburide/metformin were detected in this study of healthy young volunteers. Memantine had no effect on the pharmacodynamic activities of glyburide and metformin, and the drug combination was well tolerated in this population.     

Abdominal Subcutaneous Adipose Tissue: A Protective Fat Depot?

OBJECTIVE

Obesity is associated with increased metabolic and cardiovascular risk. The ectopic fat hypothesis suggests that subcutaneous fat may be protective, but this theory has yet to be fully explored.

RESEARCH DESIGN AND METHODS

Participants from the Framingham Heart Study (n = 3,001, 48.5% women) were stratified by visceral adipose tissue (VAT) into sex-specific tertiles. Within these tertiles, age-adjusted abdominal subcutaneous adipose tissue (SAT) tertiles were examined in relation to cardiometabolic risk factors.

RESULTS

In the lowest VAT tertile, risk factor prevalence was low, although systolic blood pressure in women and rates of high triglycerides, impaired fasting glucose, hypertension, and the metabolic syndrome in men increased with increasing SAT tertile (all P < 0.04). In contrast, in the top VAT tertile, lower triglycerides were observed in men with increasing SAT (64.4% high triglycerides in SAT tertile 1 vs. 52.7% in SAT tertile 3, P = 0.03). Similar observations were made for women, although results were not statistically significant (50.6% high triglycerides in SAT tertile 1 vs. 41.0% in tertile 3, P = 0.10). Results in the highest VAT tertile were notable for a lack of increase in the prevalence of low HDL in men and women and in rates of impaired fasting glucose in men with increasing subcutaneous fat, despite sizable differences in BMI across SAT tertiles (27.1 to 36.3 kg/m²[women]; 28.1 to 35.7 kg/m²[men]).

CONCLUSIONS

Although adiposity increases the absolute risk of metabolic and cardiovascular disease, abdominal subcutaneous fat is not associated with a linear increase in the prevalence of all risk factors among the obese, most notably, high triglycerides.Obesity is associated with multiple cardiometabolic risk factors, including insulin resistance (1), diabetes (2), hypertension (3), and dyslipidemia (4). Variations in fat distribution may mediate such risks, with visceral adipose tissue (VAT) associated with more adverse risk factor profiles than abdominal subcutaneous adipose tissue (SAT) (5,6). The ectopic fat hypothesis proposes that obesity represents a failure of adipocyte growth and differentiation, resulting in “acquired lipodystrophy” and fat deposition in liver, skeletal muscle, and pancreatic β-cells (7). Such ectopic fat stores are hypothesized to contribute to the pathogenesis of impaired insulin secretion and insulin resistance and to mediate obesity-related cardiovascular disease (8).In addition to the detrimental effects of VAT, human and animal studies have suggested a possible protective role for subcutaneous fat. In humans, increased subcutaneous leg fat is associated with decreased risk of disturbed glucose metabolism and dyslipidemia, independent of abdominal fat (9). Thiazolidinedione treatment, which increases total fat mass, mostly in subcutaneous fat stores, improves insulin sensitivity (10). Removal of VAT by omentectomy results in decreased glucose and insulin levels in humans, (11), whereas removal of SAT by liposuction does not always result in improvements in glucose metabolism or lipid levels (12,13). Transplantation of subcutaneous fat into visceral compartments in mice produces decreases in body weight and total fat mass and improved glucose metabolism, suggesting that subcutaneous fat may be intrinsically different from visceral fat in ways that are beneficial (14).Therefore, the purpose of the present study was to test the hypothesis that abdominal subcutaneous fat is a protective fat depot in terms of cardiometabolic risk factor prevalence. We theorized that among those with similar levels of VAT, increasing SAT might be associated with decreases in cardiometabolic risk factor prevalence despite increasing BMI and total abdominal fat.     

Lipid effects of glyburide/metformin tablets in patients with type 2 diabetes mellitus with poor glycemic control and dyslipidemia in an open-label extension study

BACKGROUND: Because both type 2 diabetes and elevated plasma lipid levels are important independent risk factors for cardiovascular disease and coronary heart disease, the choice of an antihyperglycemic agent for patients with type 2 diabetes--in whom abnormal plasma lipid levels are often seen-should take into account effects on lipids as well as on markers of glycemic control. OBJECTIVE: This study assessed the effects on lipid levels of glyburide/metformin tablets in the treatment of type 2 diabetes, particularly in a group of patients who had poor glycemic control and dyslipidemia at baseline. METHODS: This 52-week, open-label study was an extension of a 32-week, double-blind, placebo-controlled study. The patient population was drawn from 3 groups: those who completed the double-blind study, those who were discontinued from the double-blind study, and those who were ineligible for the double-blind study based on predefined measures of glycemic control (screening fasting plasma glucose > 240 mg/dL and glycosylated hemoglobin [HbA1c] < or = 12%, or HbA1c 11%-12%) and were directly enrolled in the open-label extension study. Patients with an HbA1c of < 9% received glyburide/ metformin tablets 1.25 mg/250 mg BID; those with an HbA1c > or = 9% received glyburide/ metformin tablets 2.5 mg/500 mg BID. Changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels were assessed for 52 weeks. RESULTS: The study population included 828 patients: 515 who completed the double-blind study, 138 who were discontinued from the double-blind study, and 175 who were enrolled directly. Direct enrollees had poor glycemic control and dyslipidemia at baseline. Improvements in plasma lipid levels were seen as early as week 13. At week 52, the mean change in TC from baseline was -8.0 mg/dL for the total population (95% CI, -10.9 to -5.2; P < 0.05) and -23.2 mg/dL for direct enrollees (95% CI, -30.1 to -16.4; P < 0.05). The mean decrease in LDL-C from baseline for the total population was 2.86 mg/dL (95% CI, -5.3 to -0.4; P < 0.05), compared with a reduction of 13.3 mg/dL for direct enrollees (95% CI, -18.5 to -8.1; P < 0.05). Mean HDL-C levels were minimally affected. Mean TG levels decreased by 27.8 mg/dL for the entire population (95% CI, -42.9 to -12.8; P < 0.05) and by 99.7 mg/dL for direct enrollees (95% CI, -152.5 to -46.8; P < 0.05). CONCLUSION: In this open-label extension study, treatment with glyburide/ metformin tablets for type 2 diabetes had a durable, favorable effect on lipid levels, particularly in those with poor glycemic control and dyslipidemia at baseline.     

Treatment of type I diabetes with a combination of glyburide and insulin.

OBJECTIVE: To assess the ability of a combination of insulin and an oral hypoglycemic agent (glyburide) to improve the overall glycemic control in a population of patients with type I diabetes. DESIGN: Randomized, placebo-controlled, double-blind trial. SETTING: Community-based, university-affiliated, family medicine group. PATIENTS: Men and women between 18 and 68 years of age with type I diabetes. INTERVENTIONS: Subjects were observed and titrated on an insulin-only regimen for 12 weeks (phase I). Subjects were then randomized to receive either placebo or glyburide 10 mg/d for an additional 12 weeks (phase II). MAIN OUTCOME MEASURES: Glucose measurements were taken at breakfast, lunch, supper, and bedtime. Each patient also was followed sequentially for serum lipids, glycosylated hemoglobin, (Hb A1c) and daily insulin utilization. RESULTS: Average fasting blood glucose (FBG) measurements were significantly lower in the glyburide-treated group during phase II (9.22 +/- 0.55 mmol/L) compared with baseline (10.27 +/- 0.93 mmol/L) and phase I (10.41 +/- 0.55 mmol/L). A decrease in the average Hb A1c concentration in the glyburide group was evident by week 4 and was sustained for the duration of the study. The average daily insulin dose rose significantly in the glyburide but not the placebo group compared with baseline. Total cholesterol, triglycerides, and low-density lipoprotein cholesterol did not change significantly in either group over the course of the study. High-density lipoprotein cholesterol increased significantly over baseline in the glyburide group during phase II. Several patients experienced dramatic improvements in glycemic parameters after the addition of glyburide to their insulin regimens. CONCLUSIONS: Improvements were observed in the FBG and Hb A1c measurements of this heterogeneous population of patients with type I diabetes after the addition of glyburide to their insulin regimens. The study failed to find consistent trends in glycemic control when evaluating mean changes in FBG measurements.     

Evaluation of glipizide and glyburide in a health maintenance organization.

OBJECTIVE: To determine if there was a difference in the long-term glycemic control, average daily dose, and cost of therapy in patients with noninsulin-dependent diabetes mellitus (NIDDM) treated with glyburide and glipizide in a health maintenance organization (HMO). DESIGN: Retrospective evaluation of medical and pharmacy records. SETTING: Multispecialty group practice HMO. PATIENTS: 140 NIDDM patients being treated with either glyburide (n = 70) or glipizide (n = 70) were randomly selected from the populations of patients receiving either drug using computerized pharmacy records. MAIN OUTCOME MEASURE: Mean daily doses and blood glucose measurements (fasting blood glucose, random blood glucose, hemoglobin A1C) were stratified in 3-month periods from the time the drug therapy was started or the patient first presented to the clinic for a total of 18 months. Long-term glycemic control was defined as fasting blood glucose less than 8.33 mmol/L (150 mg/dL). RESULTS: The groups were comparable with regard to age (53.4 y glyburide, 56.7 y glipizide), gender (43 M:27 F glyburide, 47 M:23 F glipizide), race (38 W/16 B/16 H glyburide, 45 W/16 B/9 H glipizide), concurrent medical conditions, adverse effects, and compliance. Long-term glycemic control was similar in both groups. Although the number of subjects who were controlled (by definition) tended to be greater in the glyburide group, no clinical or statistical difference was found. There was no statistical difference in mean daily dose between the ethnic groups, but the small numbers preclude further analysis. The glipizide group had a larger percentage increase in dose within the first year than did the glyburide group; however, the percentage increase from the 3-month dose was similar after 18 months (22.7 percent glyburide, 27.5 percent glipizide.) Average daily cost of therapy, based on mean daily dose, was slightly lower for glyburide-treated patients. CONCLUSIONS: If glycemic control is similar with glyburide and glipizide, as seen in this study, economic considerations regarding choice of therapy and formulary inclusion may be appropriate.     

Economic assessment of troglitazone as an adjunct to sulfonylurea therapy in the treatment of type 2 diabetes

OBJECTIVE: To assess the economic efficiency of adding troglitazone to sulfonylurea therapy to improve glycemic control. BACKGROUND: Despite the high prevalence of type 2 diabetes, existing treatment strategies often fail. New oral agents give a wider segment of the population with type 2 diabetes hope of achieving near-normal blood-glucose levels. Troglitazone, a novel chemical entity, is one promising new agent. METHODS: We conducted an economic analysis based on glycemic-control data from a randomized clinical trial comparing troglitazone with placebo, each added to glyburide. A patient simulation model was used to translate these data to long-term outcomes associated with diabetes. Patients had poorly controlled type 2 diabetes mellitus despite glyburide therapy. Risk functions of developing and progressing through nephropathy, retinopathy, neuropathy, hypoglycemia, and macrovascular disease were developed from the Diabetes Control and Complications Trial and large epidemiologic studies. Cost estimates were based on data from 5 states, all payor databases, surveys, and literature. The main outcomes of the model were cost-consequences, number of patients developing each type of complication, mean time to development of the complication, cost per life-year gained (LYG), and cost per quality-adjusted life-year. RESULTS: The model predicts that for every 1000 patients treated with troglitazone, the improved glycemic control could mean that 95 to 140 fewer patients would experience one of the most severe diabetic complications (eg, blindness, end-stage renal disease, amputation), which may increase life expectancy by 2.0 years. These benefits are obtained at an additional $2100 per LYG (undiscounted). The ratio remains <$50,000 per LYG for most variations in input. CONCLUSIONS: The clinical trial demonstrated that troglitazone + glyburide improves glycemic control compared with glyburide alone. Based on these results, the model estimates fewer diabetic complications at a cost well below accepted cost-effective thresholds.     

Changes in Adipose Tissue Depots and Metabolic Markers Following a 1-Year Diet and Exercise Intervention in Overweight and Obese Patients With Type 2 Diabetes

OBJECTIVEWe aim to characterize the effects on total body fat and distribution of a 1-year intensive lifestyle intervention (ILI) for weight loss in overweight and obese adults with type 2 diabetes and to examine whether changes in adipose tissue (AT) depots were associated with changes in metabolic biomarkers.RESULTSBody weight changed −0.52 ± 3.62 kg (P = 0.31) in DSE and −7.24 ± 5.40 kg (P < 0.0001) in ILI. Mean ILI changes were different from DSE (P < 0.001 for TAT, SAT, and IMAT and P < 0.01 for VAT in females). Within ILI, SAT and VAT decreased in males and females (P < 0.0001), but IMAT was unchanged (0.00 ± 0.54 kg; P = 0.99). In DSE, SAT and VAT did not change, but IMAT increased by 0.46 ± 0.55 kg (P < 0.001). Controlling for weight loss, reduction of specific AT depots was associated with improvement in metabolic biomarkers.CONCLUSIONSWeight loss of 7–10% from an ILI over 1 year reduced SAT and VAT and prevented an increase in IMAT. Reductions in AT depots were associated with improvements in biomarkers.     

Gender Dimorphism in Central Adiposity May Explain Metabolic Dysfunction After Spinal Cord Injury

Background

Increase in visceral adipose tissue (VAT) is an independent risk for mortality and other health-related comorbidities.

Convergence of adipocyte hypertrophy,telomere shortening and hypoadiponectinemia in obese subjects and in patients with type 2 diabetes

ObjectiveAlthough telomere shortening has been linked with type 2 diabetes and most variables of adiposity, a shortcoming of such studies is the measurement of telomere length in leukocytes. Therefore, we tested the association among adipocyte cell size, telomere length (both subcutaneous and visceral adipose tissue) and systemic levels of adiponectin in obese subjects and patients with type 2 diabetes compared to control subjects.MethodsHuman subcutaneous and visceral adipose tissues were obtained from the subjects who have undergone bariatric surgery or other abdominal surgeries. The study groups comprised: i) control subjects, ii) type 2 diabetes patients, iii) obese subjects without diabetes and iv) obese subjects with diabetes. Adipocyte cell size was measured by histological staining. Adiponectin levels were measured by ELISA. Telomere length was determined by Real-time PCR and lipid peroxidation was assessed by fluorimetry.ResultsCompared to control subjects, adipocyte size (both subcutaneous and visceral) from obese, diabetic and obese–diabetic subjects was significantly larger [p < 0.001]. Individuals with adipose hypertrophy also exhibited shortened telomeres and hypoadiponectinemia. Pearson correlation analysis revealed that both visceral and subcutaneous fat cell size showed a positive correlation with FBS, HbA1c, HOMA-IR, LDL, total cholesterol, triglycerides and negatively correlated with HDL and adiponectin. Regression analysis revealed that the association between shortened telomeres and hypoadiponectinemia was lost when adjusted for adipocyte cell size.ConclusionAdipocyte hypertrophy appears to be strongly associated with shortened telomeres, hypoadiponectinemia and poor glycemic and lipid control. Interestingly, these molecular alterations seen in lean diabetics reflect a state of ‘metabolic obesity’.