Contribution of postprandial insulin and glucose to glucose disposal in normal and insulin-resistant obese subjects

We recently found that postprandial hyperinsulinemia does not compensate for the insulin resistance of obese subjects and proposed that postprandial hyperglycemia might be more important in promoting glucose disposal via the mass action effect of glucose. To test this idea we perform oral glucose tolerance tests (OGTT) in six lean and eight obese subjects, measuring glucose and insulin levels. Afterward two insulin infusion studies were performed. During infusion study I, insulin was infused in a dynamic square wave fashion to mimic the individual post-OGTT insulin levels at content euglycemic glucose levels. During study II, glucose and insulin infusions were varied to mimic post-OGTT levels in each subject. Overall glucose turnover was measured isotopically by infusion of [3-3H] glucose. During the OGTT the obese subjects exhibited significantly higher insulin (P less than 0.005) and glucose levels (P less than 0.002). Insulin-stimulated glucose disposal rates and total incremental glucose disposal (IGD) over 4 h during study I at euglycemia were significantly lower in obese compared to lean subjects (area under the curve, 824 +/- 166 vs. 1222 +/- 161 mmol/L.m2; P less than 0.01) despite higher post-OGTT insulin levels in obese subjects. When insulin plus glucose levels were matched to the individual OGTT levels, IGD was not significantly different between obese and control subjects (1712 +/- 253 vs. 1617 +/- 444 mmol/L.m2; P = NS). A significant inverse correlation (r = -0.73; P less than 0.05) existed between the degree of glucose intolerance (OGTT) and the decrease in IGD during the phasic hyperinsulinemic euglycemic study (infusion study I). These data suggest that with increasing insulin resistance, hyperinsulinemia is less effective in compensating for this decrease in insulin action, and hyperglycemia becomes more important in augmenting overall glucose disposal values.     

Diazoxide-mediated insulin suppression in obese men: a dose-response study

BACKGROUND: It has been suggested that diazoxide (DZX)-mediated insulin suppression may be useful to promote weight loss in obese subjects. AIM: To assess the DZX-dose range that is safe to use in obese hyperinsulinaemic men. METHODS: Assessment of DZX efficacy and safety was based on plasma glucose and insulin responses to a standardized 500-kcal breakfast, taken on the sixth day of treatment. Basic information regarding the potential efficacy of DZX treatment was first evaluated in an open-label study in five non-obese men. Subsequently, a double-blind, randomized, placebo-controlled study was performed in 12 obese but otherwise healthy men, comparing placebo treatment with DZX in doses of 50, 75 and 100 mg three times daily for 6 days. RESULTS: In non-obese subjects, DZX 50 mg decreased peak insulin levels by +/-28% and raised peak glucose concentration from 7.1 +/- 0.6 to 7.8 +/- 0.6 mmol/l (p < 0.05). DZX 100 mg reduced peak insulin levels by 45% and caused a rise in peak glucose levels from 7.1 +/- 0.6 to 9.0 +/- 0.9 mmol/l (p < 0.05). In obese men, the 50 and 75 mg doses had no significant effects on glucose or insulin levels. DZX 100 mg reduced the peak insulin levels and insulin area under the curve by +/-20% (p < 0.05) but did not affect fasting or postprandial glucose levels. The relatively limited insulin-suppressive effects in obese subjects were attributed to the low plasma DZX levels that were achieved in this group. For comparable doses, plasma DZX levels were about 30% lower in obese than in non-obese men. Plasma DZX levels were highly dependent on dose (p < 0.001) and body weight (p < 0.001). Ninety-two percent of the total variability in DZX levels was explained by these two parameters. CONCLUSION: DZX-mediated insulin suppression is dose dependent in normal and in obese men. However, the efficacy of DZX is much less in obese than in non-obese subjects. This is attributed to weight-dependent differences in distribution volume that lead to markedly lower plasma DZX levels in obese subjects. Weight-adjusted doses will be needed to achieve biologically effective plasma DZX levels. Extrapolation of the data suggests that effective insulin suppression in obese men will at least require a daily dose of 3.2-4.2 mg/kg.     

Measurement of muscle insulin sensitivity in obese men

AimsIn 2007, a novel estimate of skeletal muscle insulin sensitivity was derived from the oral glucose tolerance test (OGTT). The aim of this investigation is to assess whether and to what extent the proposed index of skeletal muscle insulin sensitivity derived from the OGTT was associated with muscle insulin sensitivity measured using the hyperinsulinemic-euglycaemic clamp technique.MethodsForty-six middle-aged, abdominally obese men (age 44 ± 8 years, waist circumference 107.4 ± 6.2) were studied. Each participant participated in a 2-hour, 75-g OGTT and a 3-hour hyperinsulinemic-euglycaemic clamp protocol.ResultsThe OGTT-derived index of muscle insulin sensitivity correlated with muscle insulin sensitivity measured with the insulin clamp (r = 0.55, P < 0.01), however, the standard error of estimate (SEE) when predicting muscle insulin sensitivity by the OGTT-derived index was 5.3 (50%).ConclusionOur findings suggest that despite a statistically significant association between the two methods, the OGTT approach lacks precision and is not a useful method for estimating skeletal muscle insulin sensitivity in abdominally obese men.     

Ghrelin, insulin sensitivity and postprandial glucose disposal in overweight and obese children

OBJECTIVE: To explore the changes of ghrelin circulating levels induced by a mixed meal and their relationship with postprandial substrate oxidation rates in overweight and obese children with different levels of insulin sensitivity. METHODS: A group of ten boys (age 9-12 years) with different levels of overweight (standard deviation score of body mass index: 1.6-3.2) was recruited. Body composition was measured by dual-energy X-ray absorptiometry. Insulin sensitivity was assessed by a frequently sampled i.v. glucose tolerance test. Pre-prandial and postprandial (3 h) substrate oxidation was measured by indirect calorimetry. The energy content of the test meal (16% protein, 36% carbohydrate and 48% fat) was 40% of pre-prandial energy expenditure (kJ/day). RESULTS: Pre-prandial serum concentration of total ghrelin was 701.4+/-66.9 pg/ml (S.E.M.). The test meal induced a rapid decrease in ghrelin levels and maximal decrease was 27.3+/-2.7% below baseline. Meal intake induced a progressive increase of the carbohydrate oxidation rate for 45 min after food ingestion, followed by a slow decrease without returning to pre-prandial values. Postprandial cumulative carbohydrate oxidation was 16.9+/-0.8 g/3 h. Insulin sensitivity and postprandial maximal decrease of ghrelin concentration showed a significant correlation (r = 0.803, P < 0.01). Moreover, the postprandial carbohydrate oxidation rate correlated with the area under the curve for both insulin (r = 0.673, P < 0.03) and ghrelin (r = -0.661, P < 0.04). CONCLUSIONS: A relevant association between postprandial insulin-mediated glucose metabolism and ghrelin secretion in children with different levels of overweight was found. It is possible that the maintenance of an adequate level of insulin sensitivity and glucose oxidation may affect appetite regulation by favoring a more efficient postprandial ghrelin reduction.     

Gallbladder emptying stimuli in obese and normal-weight subjects.

Gallbladder stasis may be an important factor in the pathogenesis of cholesterol-gallstone formation in some individuals. We investigated gallbladder function in a group of nondieting, gallstone-free, healthy subjects with normal (22 +/- 1 kg/m2) and high (36 +/- 1 kg/m2) body mass indexes. Fasting gallbladder volume (28.2 +/- 4.4 ml) and residual volume after maximal emptying (8.4 +/- 2.3 ml) in high-body-mass index subjects were not significantly different from those of normal-body-mass index subjects (20.5 +/- 2.5 ml and 4.2 +/- 1.3 ml, respectively). The percentage of gallbladder emptying (71% +/- 5%) and the rate of gallbladder emptying (-1.9 +/- 0.3 x 10(-2) min-1) in high-body-mass index subjects in response to a maximal emptying stimulus was similar to the percentage of emptying (78% +/- 6%) and rate of emptying (-2.3 +/- 0.6 x 10(-2) min-1) in normal-body-mass index subjects. A liquid meal containing less than 1 gm fat, 14 gm protein and 6 gm carbohydrate resulted in both a decreased rate of gallbladder emptying and an increased residual gallbladder emptying and an increased residual gallbladder volume in both groups. The addition of 10 or 20 gm (but not 4 gm) of fat to the liquid meal restored gallbladder emptying to the maximal-stimulus level. These results demonstrate that gallbladder emptying in response to a single liquid meal stimulus is not altered in obesity and that dose-response relationships to fat are similar in obese and normal-weight individuals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationship between altered postprandial lipemia and insulin resistance in normolipidemic and normoglucose tolerant obese patients

OBJECTIVE: Although there are changes in the postprandial lipid responses of obese patients, these are closely associated with high fasting triglycerides (TG). This study of 17 normotriglyceridemic, normoglucose-tolerant android obese subjects (body mass index, BMI = 34.3 +/- 3.1 kg/m2) and 33 normal-weight controls (BMI = 21.8 +/- 1.6 kg/m2) was done to examine their postprandial responses to an oral fat loading test containing retinol (890 calories, 85% fat) and to evaluate the possible association between clinical and biological features of obesity and/or insulin resistance and postprandial lipemia. SUBJECTS AND MEASUREMENTS: Blood samples were taken before giving the fat load and at 2,3,4,5,6 and 8 h after it. Insulin sensitivity was assessed using HOMA, and TG and retinyl palmitate (RP) in the plasma, chylomicrons and non-chylomicron fractions were measured each time. RESULTS: The areas under the curves (AUC) of chylomicron TG for the obese and controls were not different, indicating adequate lipolytic activity. By contrast, the AUC for non-chylomicron TG was significantly greater in the obese than in the controls (512 +/- 135 vs 429 +/- 141 mmol/lmin, P < 0.01). In addition, the AUC for RP in this same fraction was significantly lower in the obese than in the controls (103 +/- 55 vs 157 +/- 88 mg/l min, P < 0.05), suggesting that the TG from endogenous lipoproteins accounted for most of the increase in TG in the non chylomicron fraction. Parameters related to obesity showed no relationship with these postprandial abnormalities, whereas HOMA, which discriminated between the groups, partly explained (r2= 23%, P < 0.01) the significant increase in non-chylomicron TG. CONCLUSIONS: Android obese patients with a fasting TG in the normal range and not different from the fasting TG of lean controls had an abnormal postprandial lipemia response, indicated by a significantly greater TG in the non-chylomicron subfraction than in controls. These alterations may be partly due to postprandial changes in endogenous lipoproteins as a consequence of insulin resistance.     

Relationship between monocyte/macrophage activation marker soluble CD163 and insulin resistance in obese and normal-weight subjects

Context The relationship of monocyte/macrophage activation to insulin resistance in obesity is unknown. Objective To investigate a marker of macrophage activation, soluble CD163 (sCD163), in relationship to insulin resistance and metabolic parameters in obese and normal‐weight subjects. Design and Participants Ninety‐five healthy subjects (65 obese and 30 normal‐weight) were studied. Plasma concentrations of sCD163 were assessed, as well as markers of glucose homeostasis, anthropometrics, cytokines and adipokines. The relationships between sCD163 and these parameters were investigated, and multiple regression modelling assessing the contribution of sCD163 to insulin resistance (HOMA‐IR) was performed. Results Soluble CD163 was significantly increased in obese subjects compared with normal‐weight controls [974 (657, 1272) ng/ml vs 599 (423, 892) ng/ml, median (IQR); P < 0·0001]. sCD163 was strongly associated with HOMA‐IR (Spearman’s ρ = 0·37, P = 0·0003) and other metabolic parameters. In multiple regression modelling for log HOMA‐IR, sCD163 remained significantly associated (P = 0·005) controlling for known mediators of insulin resistance including age, gender, visceral adiposity and inflammatory markers (model R² = 0·54, P < 0·0001). Additional nested multiple regression models for log HOMA‐IR showed that sCD163 added more than other adipokines and inflammatory markers to the prediction of HOMA‐IR. Conclusions Monocyte/macrophage activation, as reflected by sCD163 levels, is strongly associated with HOMA‐IR in normal‐weight and obese subjects after controlling for known mediators of insulin resistance. Moreover, sCD163 adds to standard risk markers for predicting insulin resistance. These data suggest that monocyte/macrophage activation may be an important determinant of insulin resistance in obesity.     

Effect of insulin on plasma norepinephrine and 3,4-dihydroxyphenylalanine in obese men

Increasing evidence relates serum insulin level and blood pressure in obese individuals. Although the connection between these two factors is not established, a common presumption is that the sympathetic nervous system is somehow involved, in part, because laboratory studies demonstrate insulin stimulation of sympathetic and cardiovascular activity. Because the obese may exhibit altered responsiveness to insulin action, the current investigation compared cardiovascular and neurohumoral responses to euglycemic insulin infusion (200 mU/m2/min) in obese and lean men. At baseline, obese men displayed higher glucose and insulin levels, faster pulse rates, and elevated mean arterial pressures (MAP) than lean controls; plasma norepinephrine (NE) and 3,4-dihydroxyphenylalanine (DOPA) concentrations, however, did not differ. During insulin infusion, pulse rate increased equally in obese and lean subjects (from 69 to 78 min-1 in obese and from 56 to 66 min-1 in lean subjects), while MAP remained unchanged in both groups. Elevations in plasma NE (+85 pg/mL in obese and +109 in lean pg/mL) and reductions in plasma DOPA (-233 pg/mL in obese and -376 pg/mL in lean) did not differ between groups. Sodium excretory rate decreased during insulin infusion in lean subjects by 2.2 mEq/h but increased in obese by 5.3 mEq/h (difference in response between groups, P = .024). Thus, in these obese men, cardiovascular and sympathetic responses to insulin persist despite evidence of moderate insulin resistance; increased sympathetic activity, as a cause for the resting tachycardia and borderline hypertension at baseline, seems unlikely.     

Facile fingerstick insulin analysis: Application to monitoring postprandial insulin responses to snack foods

Background: Energy intake from snacks has been increasing in the American diet, but insulin and glucose responses to foods are generally reported for meal‐sized portions (800–1200 kJ). Established methods for insulin determination routinely use indwelling catheters and radioimmunoassay (RIA). The aim of the present study was to develop a more facile method, collecting fingerstick blood samples and measuring insulin with precise ELISA, and then applying this method to determine responses to snack‐sized food portions. Methods: Six healthy, fasting adult volunteers consumed seven different snack foods on separate days, containing approximately 400 kJ/portion. Insulin was measured by ELISA and glucose was measured with the hexokinase procedure in samples collected by fingerstick at 0, 30, and 60 min after consumption of the snack food. Results: A portion of doughnut (half a glazed doughnut) led to marked changes in insulin and glucose; skim milk, an apple, and oatmeal changed insulin significantly; wrinkled peas resulted in a lower glucose response than smooth peas; and walnuts led to non‐significant changes in both insulin and glucose over a 60‐min period. Conclusions: The fingerstick sampling and insulin measurement procedure is simple, economical, and more precise than established RIA. The method can be applied to children and adults to monitor insulin responses following food consumption, as well as during therapeutic assessments or intervention trials. Public health advisories regarding snacks that minimize increases in insulin are desirable for individuals trying to reduce or maintain their weight, because elevated insulin stimulates carbohydrate conversion to fat and suppresses the mobilization of stored triglycerides for energy generation.     

Effects of prior moderate exercise on postprandial metabolism and vascular function in lean and centrally obese men

OBJECTIVES: We investigated whether a session of prior exercise could ameliorate postprandial endothelial dysfunction. BACKGROUND: Endothelial function is impaired after fat ingestion, and this may be related to rises in triglyceride concentrations. Exercise reduces postprandial triglyceride concentrations. METHODS: Ten lean (waist <90 cm) and 10 centrally obese (waist >100 cm) middle-aged men each underwent two oral fat tolerance tests (blood taken fasting and for 8 h after a high-fat meal containing 80 g fat and 70 g carbohydrate). On the afternoon before one test, subjects performed a 90-min treadmill walk (exercise); no exercise was performed before the control test. Endothelium-dependent and -independent microvascular function was assessed using laser Doppler imaging in the fasted state and at two hourly intervals during the 8-h postprandial period. RESULTS: Exercise reduced both fasting and postprandial triglyceride concentrations by 25% in both the lean and centrally obese groups (p < 0.0005). For all subjects taken together, exercise improved fasting endothelium-dependent function by 25% (p < 0.05), and, although there was a significant postprandial decrease in both endothelium-dependent and -independent function in both the control and exercise trials (p < 0.01), postprandial endothelium-dependent and -independent function were 15% and 20% higher, respectively, in the exercise trial than the control trial (both p < 0.05). CONCLUSIONS: A session of prior exercise improves fasting and postprandial vascular function in middle-aged men. This may be one mechanism by which exercise influences cardiovascular risk.     

Orlistat fails to alter postprandial plasma lipid excursions or plasma lipases in normal-weight male volunteers

OBJECTIVES: After 10 d of orlistat administration (120 mg three times/day), the primary objective was to determine the drug's effect on postprandial plasma lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities on day 10 after an oral fat-load. The secondary objectives were to determine the effects of orlistat on 12 h postprandial measures of: (1) preheparin HTGL and LPL; and (2) serum triglycerides, very-low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and free fatty acids. METHODS: Twenty-four normal-weight, healthy male volunteers were randomized to either 120 mg orlistat (n=12) or placebo (n=12) three times a day with meals for 10 d. Preheparin LPL and HTGL activities and LPL specific activity were measured in the fasted state on days 1, 5, and 10. On days 5 and 10 the study medication (orlistat or placebo) was taken at the beginning of a fat-rich breakfast and serum lipid and lipoprotein levels monitored for 12 h postprandially. On day 10, 15 min postheparin HTGL activity was measured 8 h after the fat-rich breakfast. RESULTS: No differences were found between groups in fasting levels of preheparin LPL or HTGL activity or in LPL-specific activity on days 1, 5 and 10. No difference was found between the two treatment groups in postheparin HTGL activity 8 h after the fat-rich breakfast. Also, no differences were found between the two groups in plasma triglycerides or lipoproteins. CONCLUSION: The results indicate that the oral administration of orlistat (120 mg t. i.d.) does not significantly alter plasma triglycerides or lipoproteins, and that the inhibitory effect of orlistat on lipases is limited to the gastrointestinal tract and is not manifested systemically.     

Weight loss in obese men by caloric restriction and high-dose diazoxide-mediated insulin suppression

Objective: To examine the concept whether high‐dose diazoxide (DZX)–mediated insulin suppression, in combination with moderate caloric restriction and increased physical activity, can establish a weight loss of at least 15% in obese hyperinsulinaemic men. Design: Open, uncontrolled, 6‐month pilot study. Energy intake was reduced by 30%, and walking for at least 30 min a day was strongly recommended. DZX treatment was started at 50 mg t.i.d. and increased by 50 mg per dose every 4 weeks to a maximum of 300 mg t.i.d., unless hyperglycaemia or other side‐effects occurred. Subjects and Methods: Eighteen obese hyperinsulinaemic men with a body mass index of 30–35 kg/m². Measurements included body weight, body composition, blood pressure, glycaemic control, insulin response, adiponectin and serum lipids. Results: Body weight decreased by 9.4 kg (95% CI: 5.6–13.2 kg, p < 0.001), waist circumference reduced by 9.2 cm (95% CI: 5.3–12.9 cm, p < 0.001) and total body fat mass decreased by 23.3% (95% CI: 13.7–32.9%, p < 0.001), without a concomitant change in soft tissue lean body mass or bone mass. Fat loss was inversely related to fasting insulin levels achieved at 6 months (r = ?0.76, p < 0.002). Diastolic blood pressure decreased by 10.9 mmHg (95% CI: 6.5–15.4 mmHg, p < 0.002). Fasting and postmeal peak insulin levels were reduced by about 65% (p < 0.001) and decreased to the normal range for non‐obese men. Fasting and postmeal peak glucose levels increased by 0.8 ± 0.3 mmol/l (p = 0.01) and 1.4 ± 0.7 mmol/l (p = 0.06) respectively. Haemoglobin A1c rose by 0.5% to 5.9 ± 0.2%. Conclusion: High‐dose DZX–mediated insulin suppression, in combination with moderate caloric restriction and lifestyle advice, is associated with a clinically relevant degree of weight reduction. A more extensive exploration is warranted to optimize this mode of treatment and to further clarify its risks and benefits.     

Quantitative insulin sensitivity check index is a useful indicator of insulin resistance in Japanese metabolically obese, normal-weight subjects with normal glucose tolerance

To clarify whether quantitative insulin sensitivity check index (QUICKI) is useful as an indicator of insulin resistance in Japanese metabolically obese, normal-weight (MONW, body mass index (BMI) <25 and visceral fat area (VFA) > or = 100 cm2 by abdominal computed tomography scanning) subjects with normal glucose tolerance (NGT). Insulin resistance was measured by QUICKI and euglycemic hyperinsulinemic clamp study (clamp IR) in 27 MONW and 27 normal subjects (BMI <25 and visceral fat area <100 cm2). QUICKI (P<0.01) and clamp IR (p<0.01) were significantly decreased in MONW subjects compared with normal subjects. QUICKI was significantly associated with VFA [MONW subjects: r = -0.459, p<0.02; all (MONW and normal) subjects: r = -0.506, p<0.0001] and with the serum levels of triglycerides (MONW subjects: r = -0.386, p<0.05; all subjects: r = -0.505, p<0.001) in MONW and all subjects. There were significant correlations between clamp IR and VFA (MONW subjects: r = -0.562, p<0.01; all subjects: r = -0.575, p<0.0001), fasting serum levels of insulin (MONW subjects: r = -0.673, p<0.001; all subjects: r = -0.619, p<0.0001) or serum levels of triglycerides (MONW subjects: r = -0.485, p<0.02; all subjects: r = -0.565, p<0.0001) in MONW and all subjects. QUICKI was significantly correlated with clamp IR in MONW (r = 0.754, p<0.0001) and in all subjects (r = 0.568, p<0.0001). QUICKI may be an useful method for assessing insulin resistance in Japanese MONW subjects with NGT.     

20~35岁青年肥胖男性游离睾酮指数与胰岛功能指标的关联性分析

目的分析20~35岁青年肥胖男性游离睾酮指数与胰岛功能之间的关系。方法选取2019年2月至10月于肥胖门诊就诊的82例青年肥胖男性作为研究对象,按照游离睾酮指数三分位数分为3个亚组。对研究对象进行口服葡萄糖耐量试验并测定其血糖和胰岛素水平,以稳态模型评估的胰岛素抵抗指数(HOMA-IR)、稳态模型评估的胰岛β细胞功能指数(HOMA-β)、胰岛素分泌指数及胰岛素敏感指数(Matsuda指数)作为胰岛细胞功能评价指标,分析游离睾酮指数与胰岛功能之间的关系。结果青年肥胖男性人群中,随着游离睾酮指数水平升高,总睾酮、性激素结合球蛋白、Matsuda指数水平均升高,而腰围、体重指数、餐后1 h胰岛素、餐后2 h胰岛素、HOMA-IR水平则降低(均P<0.05);游离睾酮指数与HOMA-IR呈负相关(r=-0.386,P=0.016),且经校正年龄、性别、体重指数、腰围后,相关性仍有线性趋势(P_趋势=0.034);游离睾酮指数与Matsuda指数呈正相关(r=0.280,P=0.004),但经校正上述因素后,关联性消失(P_趋势=0.623)。进一步回归分析显示,经校正后,HOMA-IR每升高1个单位,游离睾酮指数降低14.1%(OR=0.869,95%CI0.767~0.984,P=0.028)。结论游离睾酮指数是青年男性肥胖人群胰岛素抵抗状态的预测指标,但其和胰岛素敏感性之间的关联可能是由肥胖引起。