Jejunal nutrient sensing is required for duodenal-jejunal bypass surgery to rapidly lower glucose concentrations in uncontrolled diabetes

Gastrointestinal bypass surgeries restore metabolic homeostasis in patients with type 2 diabetes and obesity(1), but the underlying mechanisms remain elusive. Duodenal-jejunal bypass surgery (DJB), an experimental surgical technique that excludes the duodenum and proximal jejunum from nutrient transit(1,2), lowers glucose concentrations in nonobese type 2 diabetic rats(2–5). Given that DJB redirects and enhances nutrient flow into the jejunum and that jejunal nutrient sensing affects feeding(6,7), the repositioned jejunum after DJB represents a junction at which nutrients could regulate glucose homeostasis. Here we found that intrajejunal nutrient administration lowered endogenous glucose production in normal rats through a gut-brain-liver network in the presence of basal plasma insulin concentrations. Inhibition of jejunal glucose uptake or formation of long chain fatty acyl-coA negated the metabolic effects of glucose or lipid, respectively, in normal rats, and altered the rapid (2 d) glucose-lowering effect induced by DJB in streptozotocin (STZ)-induced uncontrolled diabetic rats during refeeding. Lastly, in insulin-deficient autoimmune type 1 diabetic rats and STZ-induced diabetic rats, DJB lowered glucose concentrations in 2 d independently of changes in plasma insulin concentrations, food intake and body weight. These data unveil a glucoregulatory role of jejunal nutrient sensing and its relevance in the early improvement of glycemic control after DJB in rat models of uncontrolled diabetes.     

Bypassing the duodenum does not improve insulin resistance associated with diet-induced obesity in rodents

Roux-en-y gastric bypass (RYGB) surgery rapidly improves glucose tolerance and reverses insulin resistance in obese patients. It has been hypothesized that this effect is mediated by the diversion of nutrients from the proximal small intestine. We utilized duodenal-jejunal bypass (DJB) as a modification of gastric bypass to determine the effect of nutrient diversion from the foregut without gastric restriction on insulin resistance in obese rats. The effects of DJB or Sham surgery on glucose homeostasis were determined in both high-fat-fed Long-Evans and Wistar rats. Body weight and food intake were measured weekly postoperatively, and body composition was monitored before and after surgery. Glucose tolerance was tested before and as early as 1 month postoperation; additionally, in Wistar rats, insulin sensitivity was determined by a hyperinsulinemic-euglycemic clamp (HIEC). DJB did not affect body weight, body composition, glucose tolerance, or insulin concentrations over the period of the study. The average glucose infusion rate (GIR) during the HIEC was 6.2 ± 1.16 mg/kg/min for Sham rats compared to 7.2 ± 1.71 mg/kg/min for DJB rats (P = 0.62), and neither endogenous glucose production (EGP; P = 0.81) nor glucose utilization (glucose disappearance (R(d)), P = 0.59) differed between DJB and Sham rats. DJB does not affect insulin resistance induced by a high-fat diet in Long-Evans and Wistar rats. These data suggest that duodenal bypass alone is an insufficient mechanism to alter insulin sensitivity independent of weight loss in obese, nondiabetic rodents.     

禁食与胰岛素处理对鳜血糖和leptin-A基因表达的影响

为研究硬骨鱼类leptin基因表达与血糖之间的关系, 研究在禁食与胰岛素处理后, 检测鳜血糖和肝脏、肠道和脂肪组织leptin-A基因表达水平。在禁食实验中, 鳜被禁食10d, 并分别于禁食后0、4h、2d、6d和10d取样。禁食后6d鳜血糖开始降低, 禁食后10d鳜血糖显著降低。同时, 禁食后6d鳜肝脏leptin-A基因mRNA表达水平显著升高, 禁食后4h鳜肠道和脂肪组织leptin-A基因mRNA表达水平均显著升高。在胰岛素处理实验中, 分别于注射后12h和36h取样。腹腔注射胰岛素后12h, 鳜血糖显著降低, 而鳜肝脏、肠道和脂肪组织leptin-A基因mRNA表达水平无明显变化。腹腔注射insulin后36h, 鳜肠道leptin-A基因mRNA表达水平显著升高。研究结果表明, 长期禁食或胰岛素处理均能够降低鳜血糖水平, 且影响消化器官和脂肪储存器官leptin-A基因表达。     

The pancreatic beta cell is a key site for mediating the effects of leptin on glucose homeostasis

The hormone leptin plays a crucial role in maintenance of body weight and glucose homeostasis. This occurs through central and peripheral pathways, including regulation of insulin secretion by pancreatic beta cells. To study this further in mice, we disrupted the signaling domain of the leptin receptor gene in beta cells and hypothalamus. These mice develop obesity, fasting hyperinsulinemia, impaired glucose-stimulated insulin release, and glucose intolerance, similar to leptin receptor null mice. However, whereas complete loss of leptin function causes increased food intake, this tissue-specific attenuation of leptin signaling does not alter food intake or satiety responses to leptin. Moreover, unlike other obese models, these mice have reduced fasting blood glucose. These results indicate that leptin regulation of glucose homeostasis extends beyond insulin sensitivity to influence beta cell function, independent of pathways controlling food intake. These data suggest that defects in this adipoinsular axis could contribute to diabetes associated with obesity.     

Oral salmon calcitonin improves fasting and postprandial glycemic control in lean healthy rats

A novel oral form of salmon calcitonin (sCT) was recently demonstrated to improve both fasting and postprandial glycemic control and induce weight loss in diet-induced obese and insulin-resistant rats. To further explore the glucoregulatory efficacy of oral sCT, irrespective of obesity and metabolic dysfunction, the present study investigated the effect of chronic oral sCT treatment on fasting and postprandial glycemic control in male lean healthy rats. 20 male rats were divided equally into a control group receiving oral vehicle or an oral sCT (2?mg/kg) group. All rats were treated twice daily for 5 weeks. Body weight and food intake were monitored during the study period and fasting blood glucose, plasma insulin and insulin sensitivity were determined and an oral glucose tolerance test (OGTT) performed at study end. Compared with the vehicle group, rats receiving oral sCT had improved fasting glucose homeostasis and insulin resistance, as measured by homeostatic model assessment of insulin resistance index (HOMA-IR), with no change in body weight or fasting plasma insulin. In addition, the rats receiving oral sCT had markedly reduced glycemia and insulinemia during OGTT. This is the first report showing that chronic oral sCT treatment exerts a glucoregulatory action in lean healthy rats, irrespective of influencing body weight. Importantly, oral sCT seems to exert a dual treatment effect by improving fasting and postprandial glycemic control and insulin sensitivity. This and previous studies suggest oral sCT is a promising agent for the treatment of obesity-related insulin resistance and type 2 diabetes.     

The effect of massive small bowel resection (MSBR) and small intestinal bypass (JIB) in the rat on the enteroinsular axis

The effect of massive small bowel resection (MSBR) and jejuno-ileal bypass (JIB) on the enteroinsular axis in rats was compared. Glucose levels after an oral glucose tolerance test were determined in MSBR, JIB and control animals. The response of the beta-cell mass to glucose and gastric inhibitory polypeptide (GIP) was established in the same animals using the isolated perfused pancreas model. Immunocytochemical and morphological studies were performed to monitor the adaptive changes seen in the intestine of these animals. The glucose response to the oral glucose load was blunted in both test groups with the fasting GIP levels in the JIB group being elevated and the MSBR group being reduced. The response of the isolated perfused pancreas to GIP showed a marked (70%) reduction of insulin release in the JIB rats and a slight but non-significant reduction in the MSBR rats. In both groups the insulin response to glucose alone appeared normal. The area of the pancreatic islets and the percentage of the total area consisting of the four islet cell types (B, A, D, PP) were unchanged. In the intestine the GIP cells were markedly reduced in number in the jejunum of the functional intestine of the JIB rats and the jejunum from the MSBR rats. The GIP cells in the jejunum of the bypass loop did not differ from the control jejunum. The results indicate that the high basal GIP levels seen in the JIB rats were the result of GIP secreted from the blind loop. This study also confirmed the decreased sensitivity of the beta-cells to GIP after JIB while indicating that MSBR has little if any effect on the response of the beta-cell to GIP. These data presented further evidence that the high basal GIP levels were causally related to the decreased insulin response in the JIB rats.     

The Insulin Tolerance Test in Morbidly Obese Patients Undergoing Bariatric Surgery

Objective: To assess the effect of massive weight loss in relation to insulin resistance and its correlation to changes in glycemic homeostasis and lipid profile in severely obese patients. Research Methods and Procedures: A prospective clinical intervention study was carried out with 31 morbidly obese women (body mass index: 54.2 ± 8.8 kg/m²) divided into three groups according to their glucose tolerance test: 14 normal, 8 impaired glucose tolerance, and 9 type 2 diabetes. All subjects underwent an insulin tolerance test with intravenous bolus of 0.1 U insulin/kg body weight before silastic ring vertical gastroplasty Roux‐en‐Y gastric bypass surgery, and again at 2, 4, 6, and 12 months postoperatively. Fasting plasma glucose, hemoglobin A1c, and lipid profile were also evaluated. Results: A reduction of 68 ± 15% in initial excess body weight was evident within 1 year. Along with weight loss, the following statistically significant changes were found: an increase in the insulin‐sensitivity index (Kitt) and a decrease in fasting plasma glucose and hemoglobin A1c, most notably in the type 2 diabetes group. An overall improvement in lipid profile was observed in all three groups. Discussion: Bariatric surgery was an effective therapeutic approach for these obese patients because it reduced both weight and insulin resistance, along with improving metabolic parameters. Significant correlations were found between insulin resistance and metabolic improvements. Weight loss after bariatric surgery induced an improvement in metabolic fitness, related to the reduction in insulin resistance over a range of glucose tolerance statuses from normal to diabetic.     

Altered dipeptidyl peptidase-4 activity during the progression of hyperinsulinemic obesity and islet atrophy in spontaneously late-stage type 2 diabetic rats

Altered dipeptidyl peptidase-4 (DPP4) activity during the progression of late-stage type 2 diabetes was measured in Otsuka Long-Evans Tokushima fatty (OLETF) rats. Compared with OLETF rats subjected to 30% food restriction, food-satiated OLETF rats exhibited spontaneous hyperphagic obesity, insulin resistance, hyperglycemia, hyperinsulinemia, and increased plasma DPP4 activity during the early phase of the experiment (up to ～30 wk). Subsequently, their plasma DPP4 activity as well as their body weight, body fat, and plasma insulin concentration declined to control levels during the late phase, resulting in excessive polyuria, proteinuria, dyslipidemia, pancreatic islet atrophy, hypoinsulinemia, and diabetes, which changed from insulin-resistant diabetes to hypoinsulinemic diabetes secondary to progressive islet insufficiency, and their fasting blood glucose level remained high. Since plasma DPP4 activity demonstrated significant positive correlations with body weight and the fasting plasma insulin level but not with the fasting blood glucose level during the late stage of diabetes, body fat and fasting plasma insulin levels may be useful factors for predicting the control of plasma DPP4 activity. In contrast, pancreatic DPP4 activity was significantly increased, and the expression of pancreatic insulin was significantly reduced in late-stage diabetic OLETF rats, suggesting that a relationship exists between the activation of pancreatic DPP4 and insulin depletion in pancreatic islet atrophy. In conclusion, it is suggested that plasma DPP4 activity changes in accordance with the progression of hyperinsulinemic obesity and pancreatic islet atrophy. DPP4 activity may play an important role in insulin homeostasis.     

Sterculic Oil,a natural inhibitor of SCD1, improves the metabolic state of obese OLETF rats

Objective:

Abnormal lipid metabolism and excess accumulation of lipid in non‐adipose tissues are defining characteristics of obesity and its comorbidities. Expression and/or activity of stearoyl‐CoA desaturase‐1 (SCD1), a major regulator of lipid metabolism, is increased with obesity and the reduction/ablation of this enzyme is associated with an improved metabolic profile. Sterculic oil (SO), obtained from the seeds of the Sterculia feotida tree, contains a high concentration of cyclopropenoic fatty acids which are known inhibitors of SCD1. The purpose of this study was to determine the effects of SO supplementation on the development of obesity and insulin resistance in hyperphagic, obese Otsuka Long‐Evans Tokushima Fatty (OLETF) rats.

Design & Methods:

Rats received either an AIN‐93G diet (control) or an AIN‐93G diet containing 0.5% SO for 10 weeks.

Results:

SO did not alter body weight or body composition. Importantly, the desaturase indices, a proxy for the activity of SCD1, were reduced in the liver and adipose tissue of SO supplemented animals. This reduction in SCD1 activity was associated with a reduction in fasting blood glucose concentrations and improved glucose tolerance. In addition, SO reduced intra‐abdominal fat mass and adipocyte size and resulted in a ～3‐fold increase in GLUT1 gene expression in intra‐abdominal fat. Liver triglyceride content and lipogenic gene expression were reduced by SO. Consistent with an improved metabolic phenotype, SO also improved plasma cholesterol, LDL‐cholesterol, and triglyceride concentrations.

Conclusion:

Overall, our data demonstrate an improved metabolic phenotype with SO supplementation and suggest further studies are required to better understand the therapeutic potential of SO.     

Differential secretion of satiety hormones with progression of obesity in JCR:LA-corpulent rats

Objective: To characterize the gastrointestinal tract at the onset and in well‐established obesity. Methods and Procedures: Lean (+/?) and obese (cp/cp) male JCR:LA‐cp rats lacking a functional leptin receptor were killed at 3.5 weeks and 9 months of age and plasma concentrations of satiety hormones determined. The small intestine, colon, and stomach were measured, weighed, and mRNA levels of satiety genes quantified. Results: At the onset of obesity, obese rats had greater intestine, colon, and liver mass when adjusted for body weight compared to lean rats. Conversely, adult rats with established obesity had lower intestine and colon mass and length after adjustment for body weight. Early changes in gene expression included decreased ghrelin mRNA levels in stomach and increased peptide YY (PYY) mRNA levels in duodenum of young obese rats. After massive accumulation of adipose tissue had occurred, adult obese rats had increased proglucagon and ghrelin mRNA expression in the proximal intestine. In the distal small intestine, obese rats had lower proglucagon, ghrelin, and PYY mRNA levels. Finally, at the onset and in well‐established obesity, obese rats had higher plasma insulin, amylin, glucagon like peptide‐1 (GLP‐1), and PYY, a finding, with the exception of insulin, unique to this model. Plasma total ghrelin levels were significantly lower at the onset of obesity and established obesity compared to the lean rats. Discussion: Several defects are manifested in the obese gut early on in the disease before the accumulation of large excesses of body fat and represent potential targets for early intervention in obesity.     

Glucose Tolerance and Weight Loss in Obese Women with Obstructive Sleep Apnea

Background

The association of obstructive sleep apnea (OSA) with glucose intolerance and the beneficial effect of lifestyle intervention have been poorly investigated in women particularly before menopausal status. The study explored 1) whether OSA is associated with impaired glucose homeostasis in obese non diabetic premenopausal and menopausal women and 2) the effects of a 3- month lifestyle intervention on glucose homeostasis in OSA women.

Design and Methods

We consecutively recruited 98 obese women (39 premenopausal) from those referred for a weight loss intervention. Ambulatory nocturnal polysomnography, body composition, oral glucose tolerance test, insulin sensitivity and β cell function were assessed before and after intervention.

Results

41% of premenopausal and 64% of menopausal women had OSA which was associated with worse glucose homeostasis before menopausal status. Mean and minimal nocturnal oxygen saturation (SaO₂) was associated with neck/height ratio (NHR), independently of total and central obesity. Mean and minimal nocturnal SaO₂ and NHR were correlated with insulin sensitivity and fasting glucose. In multivariate analyses, nocturnal mean SaO₂ was negatively and independently correlated with fasting glucose (p<0.0001) and NHR with insulin sensitivity (p<0.0001). In OSA women, the intervention induced a 5% weight reduction and a significant increase in minimal nocturnal SaO₂, insulin sensitivity and β cell function. Changes in fasting glucose and insulin sensitivity were associated with those in minimal nocturnal SaO₂ (p<0.05) and not with weight loss.

Conclusions

In obese women, glucose homeostasis worsens due to nocturnal hypoxia and increased neck circumference through mechanisms partially independent of obesity. OSA is more clearly associated with glucose intolerance in premenopausal than in menopausal women. In OSA women, the improvement of nocturnal hypoxia induced by lifestyle modifications is associated with that of glucose homeostasis.     

A Genealogical Study of Essential Hypertension with and without Obesity in French Canadians

Objectives: To investigate genetic homogeneity in a set of hypertensive families and in subsets chosen for high and low prevalence of obesity; and to compare fasting insulin and lipids, ion transport, and water homeostasis in the obese and lean families. Research Methods and Procedures: The study was carried out in a relative population isolate of the Saguenay/Lac St. Jean region in Canada. Genetic homogeneity was evaluated with the mean coeffigcients of kinship (φ) and inbreeding (F) computed with ascending genealogies. Serum insulin and lipids were measured after overnight fasting. Total body water was estimated with bioelectrical impedance. Sodium‐lithium countertransport and sodium‐potassium co‐transport were determined in freshly isolated erythrocytes. Results: F and φ were increased in hypertensive families compared with families selected at random. F and φ were further increased within the subsets of obese and lean families. In addition, fasting insulin, total body water, sodium‐lithium countertransport, and sodium‐potassium co‐transport were higher in the obese than in the lean families. The two subsets of families did not differ by fasting lipids. Discussion: In the Saguenay/Lac St. Jean population, the degree of genetic homogeneity was increased in families selected for hypertension, and it was further increased in subsets of hypertensive families with high and low prevalence of obesity. This suggests that hypertension in lean and obese individuals may represent, at least in part, separate genetic entities. Some of the extra genes shared in common within the subsets may contribute to their differences in body weight, insulin sensitivity, ion transport, and water homeostasis.     

Body adiposity index and other indexes of body composition in the SAPHIR study: Association with cardiovascular risk factors

Objective:

The accuracy of anthropometric surrogate markers such as the body adiposity index (BAI) and other common indexes like the body mass index (BMI), waist‐to‐hip ratio (WHR) and waist‐to‐height ratio (WHtR) to predict metabolic sequelae is essential for its use in clinical practice.

Design and Methods:

Thus, we evaluated the strength of BAI and other indexes to relate with anthropometric parameters, adipocytokines, blood lipids, parameters of glucose‐homeostasis and blood pressure in 1,770 patients from the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) study in a crosssectional design. Measurements were BAI, BMI, WHR, WHtR, abdominal subcutaneous and visceral adipose tissue (aSAT and VAT), total body adipose tissue mass, body weight, waist‐ and hip circumference (WC and HC), leptin, adiponectin, high‐density lipoprotein‐cholesterol (HDL‐C), low‐density lipoprotein‐cholesterol (LDL‐C), triglycerides (TG), fasting plasma glucose, fasting plasma insulin, the homeostasis model assessment of insulin resistance (HOMAIR), systolic and diastolic blood pressure.

Results and Conclusions:

BAI was significantly associated with leptin and HC. We conclude that BAI was the best calculator for leptin. BAI was inferior to BMI to predict anthropometric parameters other than HC, adiponectin, blood lipids, parameters of glucose homeostasis, and blood pressure in this cross‐sectional study.     

Common STAT3 variants are not associated with obesity or insulin resistance in female twins

In animal models, STAT3 action in the hypothalamus and liver appears essential for normal body weight and glucose homeostasis in response to insulin. We hypothesized that variation in the STAT3 gene may be associated with body fat and/or insulin resistance in the general population. Five tagging SNPs spanning the STAT3 gene, rs8074524, rs2293152, rs2306580, rs6503695, and rs7211777 were genotyped in 2776 white female twins (mean age, 47.4+/-12.5 yrs) from the St Thomas' United Kingdom Adult Twin Registry (Twins UK). Minor allele frequencies were as follows: rs8074524 (0.19), rs2293152 (0.37), rs2306580 (0.06), rs6503695 (0.35), and rs7211777 (0.34). The minor allele of rs2293152 was associated with higher homeostasis model assessment index of insulin resistance (p=0.013) in the full cohort and confirmed in sib-transmission/disequilibrium test (TDT): (p=0.015; n=60). However, there were no associations with fasting serum insulin or glucose or with obesity variables. Although defective STAT3 action results in obesity and insulin resistance in animal models, we failed to establish any indicative associations with common SNPs in this human study.     

Fasting Plasma Insulin at 5 Years of Age Predicted Subsequent Weight Increase in Early Childhood over a 5-Year Period—The Da Qing Children Cohort Study

Background

The association between hyperinsulinemia and obesity is well known. However, it is uncertain especially in childhood obesity, if initial fasting hyperinsulinemia predicts obesity, or obesity leads to hyperinsulinemia through insulin resistance.

Objective

To investigate the predictive effect of fasting plasma insulin on subsequent weight change after a 5-year interval in childhood.

Methods

424 Children from Da Qing city, China, were recruited at 5 years of age and followed up for 5 years. Blood pressure, anthropometric measurements, fasting plasma insulin, glucose and triglycerides were measured at baseline and 5 years later.

Results

Fasting plasma insulin at 5 years of age was significantly correlated with change of weight from 5 to 10 years (ΔWeight). Children in the lowest insulin quartile had ΔWeight of 13.08±0.73 kg compare to 18.39±0.86 in the highest insulin quartile (P<0.0001) in boys, and similarly 12.03±0.71 vs 15.80±0.60 kg (P<0.0001) in girls. Multivariate analysis showed that the predictive effect of insulin at 5 years of age on subsequent weight gain over 5 years remained statistically significant even after the adjustment for age, sex, birth weight, TV-viewing time and weight (or body mass index) at baseline. By contrast, the initial weight at 5 years of age did not predict subsequent changes in insulin level 5 years later. Children who had both higher fasting insulin and weight at 5 years of age showed much higher levels of systolic blood pressures, fasting plasma glucose, the homeostasis model assessment for insulin resistance (HOMA-IR) and triglycerides at 10 years of age.

Conclusions

Fasting plasma insulin at 5 years of age predicts weight gain and cardiovascular risk factors 5 year later in Chinese children of early childhood, but the absolute weight at 5 years of age did not predict subsequent change in fasting insulin.     

Gastric bypass does not normalize obesity‐related changes in ghrelin profile and leads to higher acylated ghrelin fraction

Objective:

Gastric bypass (GBP) lowers food intake, body weight, and insulin resistance in severe obesity (SO). Ghrelin is a gastric orexigenic and adipogenic hormone contributing to modulate energy balance and insulin action. Total plasma ghrelin (T‐Ghr) level is low and inversely related to body weight and insulin resistance in moderately obese patients, but these observations may not extend to the orexigenic acylated form (A‐Ghr) whose plasma concentration increase in moderate obesity.

Design and Methods:

We investigated the impact of GBP on plasma T‐, A‐, and A/T‐Ghr in SO patients (n = 28, 20 women), with measurements at baseline and 1, 3, 6, and 12 months after surgery. Additional cross‐sectional comparison was performed between nonobese, moderately obese, and SO individuals before GBP and at the end of the follow‐up period.

Results:

Before GBP, SO had lowest T‐Ghr and highest A/T‐Ghr profile compared with both nonobese and moderately obese individuals. Lack of early (0‐3 months from GBP) T‐Ghr changes masked a sharp increase in A‐Ghr and A/T‐Ghr profile (P < 0.05) that remained elevated following later increments (6‐12 months) of both T‐ and A‐Ghr (P < 0.05). Levels of A‐Ghr and A/T‐Ghr at 12 months of follow‐up remained higher than in matched moderately obese individuals not treated with surgery (P < 0.05).

Conclusions:

The data show that following GBP, early T‐Ghr stability masks elevation of A/T‐Ghr, that is stabilized after later increments of both T‐ and A‐hormones. GBP does not normalize the obesity‐associated elevated A/T‐Ghr ratio, instead resulting in enhanced A‐Ghr excess. Excess A‐Ghr is unlikely to contribute to, and might limit, the common GBP‐induced declines of appetite, body weight, and insulin resistance.     

脂肪细胞型脂肪酸结合蛋白疫苗对高脂喂养雌鼠体重和糖耐量的影响

目的:构建能诱导出针对脂肪细胞型脂肪酸结合蛋白(FABP4)特异性中和抗体的疫苗,为高脂诱导下肥胖和胰岛素抵抗的防治新途径提供理论和实验依据。方法:野生型C57BL/6J雌鼠随机分为疫苗组(n=10,高脂饲养)、佐剂组(n=10,高脂饲养)和空白对照组(n=10,普通饲养),分别予以皮下注射生物合成的FABP4蛋白、佐剂和磷酸盐缓冲液,观察比较各组抗体滴度、安全耐受性和体重、摄食量、空腹血糖、胰岛素抵抗指数(HOMA-IR)、糖耐量实验血糖曲线下面积(AUC)等指标。结果:疫苗组小鼠产生了高滴度的FABP4特异性抗体,并于第3轮加强免疫后达到平衡状态。首次免疫16周后,疫苗组小鼠体重高于空白对照组,但明显低于佐剂组(P<0.05);日平均摄食量高于空白对照组(P<0.05),与佐剂组无差异(P>0.05);空腹血糖、HOMA-IR、腹腔葡萄糖耐量实验AUC均明显低于佐剂组(P<0.05),与对照组无统计学差异(P>0.05)。结论:以FABP4作为抗原免疫小鼠,可产生高滴度特异性抗体IgG,有效降低高脂喂养野生型雌性小鼠体重、空腹血糖、HOMA-IR和血糖AUC等指标,为高脂诱导的肥胖和胰岛素抵抗的治疗提供了新的途径和初步证据,可进行深入研究。     

Lipid Profile in the Severely Obese: Changes with Weight Loss after Lap‐Band Surgery

Objective: To characterize dyslipidemia before and after weight loss in the severely obese. Research Methods and Procedures: Five hundred fifteen subjects who had Lap‐Band surgery were followed with yearly conventional lipid profiles for up to 4 years. Preoperative data were collected from the most recent 381 subjects, and predictors of dyslipidemia were sought. One hundred seventy‐one subjects completed a 1‐year review, providing data to assess predictors of change in lipids. Results: Favorable changes in fasting triglycerides (TG), high‐density lipoprotein‐cholesterol (HDL‐C), and total cholesterol (TC):HDL‐C ratio occurred within 1 year. All improvements were maintained up to 4 years. Male gender, central obesity, elevated fasting glucose, and insulin resistance were associated with less favorable lipid levels. Fasting plasma glucose best predicted TG (r = 0.46, p < 0.001), whereas insulin sensitivity using the homeostatic model assessment (HOMA %S) correlated best with the HDL‐C (r =0.34, p < 0.001). Higher preoperative fasting glucose best predicted the decrease in TG; improved HOMA %S with weight loss correlated best with HDL‐C. The extent of weight loss had limited influence on lipid changes. However, low preoperative HOMA %S was associated with lower weight loss. Greater weight loss was associated with more favorable lipid measures after controlling for preoperative HOMA %S. Discussion: Dyslipidemia of obesity is related to weight distribution, insulin sensitivity, and impaired glucose tolerance. Improvement with weight loss is related to the decrease in fasting glucose, improvement in insulin sensitivity, and the extent of weight lost. Improvement in dyslipidemia is sustained with long‐term weight loss.