Dodecanedioic acid overcomes metabolic inflexibility in type 2 diabetic subjects.

Metabolically healthy skeletal muscle possesses the ability to switch easily between glucose and fat oxidation in response to homeostatic signals. In type 2 diabetes mellitus and obesity, the skeletal muscle shows a great reduction in this metabolic flexibility. A substrate like dodecanedioic acid (C-12), able to increase skeletal muscle glycogen stores via succinyl-CoA formation, might both postpone the fatigue and increase fatty acid utilization, since it does not affect insulin secretion. In healthy volunteers and in type 2 diabetic subjects, the effect of an oral C-12 load was compared with a glucose or water load during prolonged, moderate-intensity, physical exercise. C-12 metabolism was analyzed by a mathematical model. After C-12, diabetics were able to complete the 2 h of exercise. Nonesterified fatty acids increased both during and after the exercise in the C-12 session. C-12 oxidation provided 14% of total energy expenditure, and the sum of C-12 plus lipids oxidized after the C-12 meal was significantly greater than lipids oxidized after the glucose meal (P < 0.025). The fraction of C-12 that entered the central compartment was 47% of that ingested. During the first phase of the exercise ( approximately 60 min), the mean C-12 clearance from the central compartment toward tissues was 2.57 and 1.30 l/min during the second phase of the exercise. In conclusion, C-12 seems to be a suitable energy substrate during exercise, since it reduces muscle fatigue, is rapidly oxidized, and does not stimulate insulin secretion, which implies that lipolysis is not inhibited as reported after glucose ingestion.

Predictors of weight loss and reversal of comorbidities in malabsorptive bariatric surgery.

BACKGROUND: Cardiovascular and metabolic comorbidities are dramatically increased in severe obesity, a condition highly resistant to nonsurgical therapy. OBJECTIVE: The objective was to identify predictors of weight loss and reversal of comorbidity in obese patients undergoing malabsorptive bariatric surgery. DESIGN: Morbidly obese men and women (n = 107) were studied before and 2 y after biliopancreatic diversion (BPD). Body composition, serum lipid profile, oral glucose tolerance, and blood pressure were measured. Insulin sensitivity was determined by use of a euglycemic clamp. The length of the small intestine was measured during surgery. RESULTS: Intestinal length was 671 +/- 99 cm, and the residual absorbing intestine after BPD ranged from 54% to 24% of initial length. Patients lost an average of 36% of their initial weight, with approximately 50% of them reaching a body mass index (in kg/m(2)) < 30. Serum cholesterol decreased (from 4.58 +/- 1.11 to 3.34 +/- 0.73 mmol/L; P < 0.0001), as did serum triacylglycerols (from 1.52 +/- 0.59 to 0.88 +/- 0.35 mmol/L; P < 0.0001), whereas insulin sensitivity rose 150% (from 26 +/- 4 to 64 +/- 11 micromol . min(-1) . kg fat-free mass(-1); P < 0.0001). Diabetes (in 23% of patients before surgery) and hypertension (in 83%) were reduced (by 88% and 96%, respectively) after surgery. In a multivariate model (including sex, age, intestinal length, presence of diabetes, insulin sensitivity, and initial fat mass), age and diabetes were independent, negative predictors of weight loss, whereas initial fat mass was a strong positive predictor (r(2) = 0.51). CONCLUSIONS: Two years after BPD in morbidly obese patients, comorbidities are largely corrected and insulin resistance is fully reversed despite persistent obesity. Initial fat mass, but not residual intestinal length, is the strongest predictor of weight loss after BPD.

Ghrelin does not influence gastric emptying in obese subjects.

OBJECTIVE: To evaluate the relationship between fasting plasma concentrations of ghrelin and gastric emptying in obese individuals compared with lean subjects. RESEARCH METHODS AND PROCEDURES: We included 20 obese patients (9 men and 11 women, BMI > 30 kg/m2) and 16 nonobese control subjects (7 men and 9 women, BMI < or = 25 kg/m2). Gastric emptying of solids (egg sandwich labeled with radionuclide) was measured at 120 minutes with (99m)Tc-single photon emission computed tomography imaging. Ghrelin and leptin were analyzed by radioimmunoassay and ELISA methods, respectively. RESULTS: The gastric half-emptying time was similar in obese men and women (67.8 +/- 14.79 vs. 66.6 +/- 13.56 minutes) but significantly shorter (p < 0.001) than in the control population (men: 88.09 +/- 11.72 minutes; women: 97.25 +/- 10.31 minutes). Ghrelin levels were significantly lower in obese subjects (131.37 +/- 47.67 vs. 306.3 +/- 45.52 pg/mL; p < 0.0001 in men and 162.13 +/- 32.95 vs. 272.8 +/- 47.77 pg/mL; p < 0.0001 in women). A negative correlation between gastric emptying and fasting ghrelin levels was observed only in lean subjects (y = -0.2391x + 157.9; R2 = 0.95). Also, in the lean group, ghrelin was the only significant independent determinant of gastric emptying, explaining 98% of the variance (adjusted R2) in a multiple regression analysis. DISCUSSION: This report shows that, in humans, gastric emptying is faster in obese subjects than in lean controls and that, whereas ghrelin is the best determinant of gastric kinetics in healthy controls, this action is lost in obesity.

Changes in fat mass influence SREBP-1c and UCP-2 gene expression in formerly obese subjects.

OBJECTIVE: To investigate the effect of fat mass (FM) reduction on adipose tissue gene expression in terms of lipid synthesis [sterol regulatory binding protein 1c (SREBP-1c)] and lipid oxidation [uncoupling protein 2 (UCP-2)] 2 years after lipid malabsorption and to assess the influence of lipid malabsorption on fat-free mass (FFM) maintenance evaluating the expression of genes related to glycolysis [hexokinase (HKII)] and glucose storage [glycogen synthase (GS)]. RESEARCH METHOD AND PROCEDURES: SREBP-1c, UCP-2, HKII, and GS mRNA expression were studied by reverse transcriptase-competitive polymerase chain reaction in 10 massively obese subjects before and 2 years after bilio-pancreatic diversion (BPD). Body composition was assessed by isotopic dilution method and insulin sensitivity by euglycemic-hyperinsulinemic clamp. RESULTS: FM decrease was approximately 60%, whereas FFM remained at normal physiological levels. In adipose tissue, SREBP-1c mRNA reduction (-39%, p < 0.005) was related only to FM changes after BPD, and UCP-2 decrease (-37%, p < 0.05) was dependent on free fatty acid (FFA) changes. No significant variations were observed in HKII and GS gene expression in skeletal muscle. DISCUSSION: Lipid malabsorption induced by BPD altered the expression of genes involved in glucose and lipid metabolism, with different consequences on FM and FFM. The degree of FM loss seems to interfere with SREBP-1c gene suppression to preserve an adequate amount of fat storage, in accordance with the thrifty genotype hypothesis. The reduction of FFAs induced by BPD acts in inhibiting FFA transportation to the mitochondria (UCP-2), contributing to the decreased lipid oxidation inside the adipose tissue.

The ingestion of saturated fatty acid triacylglycerols acutely affects insulin secretion and insulin sensitivity in human subjects.

To assess the effects of acute dietary saturated fat intake on glucose-induced insulin secretion rate (ISR), measured by the C-peptide deconvolution method, and on insulin clearance and sensitivity, five obese and five normal-weight women (controls) were studied after either a 100 g oral butter load or a 100 ml water load. At 120 min after the oral load a hyperglycaemic clamp was performed over 180 min. A dramatic increase of ISR occurred after butter compared with the water challenge in the controls (1305.6 (SE 124.1) v. 616.1 (SE 52.5) pmol/min; P<0.01) and to a lesser degree in the obese subjects (1975.0 (SE 44.1) v. 1417.5 (se 56.0) pmol/min; P<0.05). Insulin sensitivity was impaired after butter (0.60 x 10(-2) (SE 0.11 x 10(-2)) v. 2.26 x 10(-2) (SE 0.32 x 10(-2)) ml/min per kg FFM per (pmol/l); P<0.01) in the controls but not in the obese group. Insulin clearance during the clamp was reduced after butter compared with after the water load only in the controls (0.89 (SE 0.22) v. 1.70 (SE 0.15) litres/min; P<0.01). The data are consistent with the hypothesis that acute excess lipid availability may lead to a compensatory elevation in glucose-induced insulin secretion as a result of the decline in insulin sensitivity and a reduced insulin clearance.

Insulin clearance in obesity.

Insulin uptake and degradation is a complex and not yet completely understood process involving not only insulin sensitive tissues. The most important degradative system is insulin degrading enzyme which is a highly conserved metalloendopeptidase requiring Zn(++) for its proteolytic action, although protein disulfide isomerase and cathepsin D are also involved in insulin metabolism. The liver and the kidney are the principal sites for insulin clearance. In obese subjects with hyperinsulinemia and high levels of free fatty acids, insulin hepatic clearance is impaired, while the glomerular filtration rate, renal plasma flow and albumin excretion are increased, suggesting a state of renal vasodilatation leading to an abnormally transmitted arterial pressure to the glomerular capillaries through a dilated afferent arteriole. Insulin can be cleared also by muscle, adipocytes, gastrointestinal cells, fibroblasts, monocytes and lymphocytes which contain insulin receptors and internalization and regulation mechanism for insulin metabolism.

Bioimpedance analysis: a useful technique for assessing appendicular lean soft tissue mass and distribution.

The present study was aimed at evaluating the feasibility and reliability of lower limb skeletal muscle (SM) mass estimates obtained by bioimpedance analysis (BIA). BIA estimates were compared with the estimates obtained by dual-energy X-ray absorptiometry (DXA). Ten normal weight and 10 obese women had BIA and DXA evaluations. Lower limb SM mass was then derived from DXA appendicular lean soft tissue estimates. Lower limb SM mass and SM distribution were also estimated from BIA modeling that fits measured resistance values along the leg. SM mass (mean +/- SD) was 5.8 +/- 1.0 kg by BIA vs. 5.8 +/- 1.1 kg by DXA in normal weight subjects and 7.2 +/- 1.4 kg by BIA vs. 7.2 +/- 1.2 kg by DXA in obese subjects. Mean +/- SD of the absolute value of the relative error was 7.0 +/- 3.4 and 5.9 +/- 3.4% in the two groups, respectively. Similar results were obtained by using five resistance values for the analysis. In conclusion, the proposed BIA model provides an adequate means of evaluating appendicular SM mass.