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Objective: To evaluate the effects of diet-induced changes in energy balance and body weight on in vivo colonocyte fractional proliferation rates (FPR) in people with obesity., Methods: In vivo colonocyte FPR was assessed in 31 men and women with obesity (BMI: 35.4 ± 4.0 kg/m 2 , age: 52.6 ± 8.9 years) before and after diet-induced weight loss, weight gain, or weight maintenance. Subjects ingested aliquots of 2 H 2 O (heavy water) daily for 4 to 7 days, followed by flexible sigmoidoscopy with colon biopsies to assess the incorporation of 2 H into the DNA of dividing colonocytes., Results: Colonocyte FPR averaged 12.7% ± 3.8% per day and correlated directly with intra-abdominal adipose tissue (IAAT) volume (r = 0.364, P = 0.044). Colonocyte FPR decreased in the weight loss group, did not change in the weight maintenance group, and increased in the weight gain group. The change in colonocyte FPR correlated directly with the percent change in body weight (r = 0.409, P = 0.028) and IAAT volume (r = 0.598, P = 0.001)., Conclusions: A high-calorie diet and weight gain increase, whereas a low-calorie diet and weight loss decrease, in vivo colonocyte proliferation rate in people with obesity. These results suggest that changes in energy balance influence the risk of developing colon cancer in people with obesity by regulating colonic mucosal growth rates., (© 2017 The Obesity Society.)

Objective: To determine whether upper gastrointestinal tract (UGI) bypass itself has beneficial effects on the factors involved in regulating glucose homeostasis in patients with type 2 diabetes (T2D)., Methods: A 12-month randomized controlled trial was conducted in 17 overweight/obese subjects with T2D, who received standard medical care (SC, n = 7, BMI = 31.7 ± 3.5 kg/m(2) ) or duodenal-jejunal bypass surgery with minimal gastric resection (DJBm) (n = 10; BMI = 29.7 ± 1.9 kg/m(2)). A 5-h modified oral glucose tolerance test was performed at baseline and at 1, 6, and 12 months after surgery or starting SC., Results: Body weight decreased progressively after DJBm (7.9 ± 4.1%, 9.6 ± 4.2%, and 10.2 ± 4.3% at 1, 6, and 12 months, respectively) but remained stable in the SC group (P < 0.001). DJBm, but not SC, improved: (1) oral glucose tolerance (decreased 2-h glucose concentration, P = 0.039), (2) insulin sensitivity (decreased homeostasis model assessment of insulin resistance, P = 0.013), (3) early insulin response to a glucose load (increased insulinogenic index, P = 0.022), and (4) overall glycemic control (reduction in HbA1c with fewer diabetes medications)., Conclusions: DJBm causes moderate weight loss and improves metabolic function in T2D. However, our study cannot separate the benefits of moderate weight loss from the potential therapeutic effect of UGI tract bypass itself on the observed metabolic improvements., (© 2015 The Obesity Society.)

Objectives: An increase in circulating branched-chain amino acids (BCAA) is associated with insulin resistance. Adipose tissue is a potentially important site for BCAA metabolism. It was evaluated whether monomethyl branched-chain fatty acids (mmBCFA) in adipose tissue, which are likely derived from BCAA catabolism, are associated with insulin sensitivity., Methods: Insulin-stimulated glucose disposal was determined by using the hyperinsulinemic-euglycemic clamp procedure with stable isotope glucose tracer infusion in nine lean and nine obese subjects, and in a separate group of nine obese subjects before and 1 year after Roux-en-Y gastric bypass (RYGB) surgery (38% weight loss). Adipose tissue mmBCFA content was measured in tissue biopsies taken in the basal state., Results: Total adipose tissue mmBCFA content was ∼30% lower in obese than lean subjects (P=0.02) and increased by ∼65% after weight loss in the RYGB group (P=0.01). Adipose tissue mmBCFA content correlated positively with skeletal muscle insulin sensitivity (R(2) =35%, P=0.01, n=18)., Conclusions: These results demonstrate a novel association between adipose tissue mmBCFA content and obesity-related insulin resistance. Additional studies are needed to determine whether the association between adipose tissue mmBCFA and muscle insulin sensitivity is causal or a simple association., (© 2014 The Obesity Society.)

Gastric bypass surgery causes resolution of type 2 diabetes (T2DM), which has led to the hypothesis that upper gastrointestinal (UGI) tract diversion, itself, improves glycemic control. The purpose of this study was to determine whether UGI tract bypass without gastric exclusion has therapeutic effects in patients with T2DM. We performed a prospective trial to assess glucose and β-cell response to an oral glucose load before and at 6, 9, and 12 months after duodenal-jejunal bypass (DJB) surgery. Thirty-five overweight or obese adults (BMI: 27.0 ± 4.0 kg/m(2)) with T2DM and 35 sex-, age-, race-, and BMI-matched subjects with normal glucose tolerance (NGT) were studied. Subjects lost weight after surgery, which was greatest at 3 months (6.9 ± 4.9%) with subsequent regain to 4.2 ± 5.3% weight loss at 12 months after surgery. Glycated hemoglobin (HbA(1c)) decreased from 9.3 ± 1.6% before to 7.7 ± 2.0% at 12 months after surgery (P < 0.001), in conjunction with a 20% decrease in the use of diabetes medications (P < 0.05); 7 (20%) subjects achieved remission of diabetes (no medications and HbA(1c) <6.5%). The area under the curve after glucose ingestion was ~20% lower for glucose but doubled for insulin and C-peptide at 12 months, compared with pre-surgery values (all P < 0.01). However, the β-cell response was still 70% lower than subjects with NGT (P < 0.001). DJB surgery improves glycemic control and increases, but does not normalize the β-cell response to glucose ingestion. These findings suggest that altering the intestinal site of delivery of ingested nutrients has moderate therapeutic effects by improving β-cell function and glycemic control.

Aim of this study was to determine whether an increase in adiposity, without a concomitant increase in intrahepatic triglyceride (IHTG) content, is associated with a deterioration in metabolic function. To this end, multiorgan insulin sensitivity, assessed by using a two-stage hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled tracer infusion, and very low-density lipoprotein (VLDL) kinetics, assessed by using stable isotopically labeled tracer infusion and mathematical modeling, were determined in 10 subjects with class I obesity (BMI: 31.6 +/- 0.3 kg/m(2); 37 +/- 2% body fat; visceral adipose tissue (VAT): 1,225 +/- 144 cm(3)) and 10 subjects with class III obesity (BMI: 41.5 +/- 0.5 kg/m(2); 43 +/- 2% body fat; VAT: 2,121 +/- 378 cm(3)), matched on age, sex, and IHTG content (14 +/- 4 and 14 +/- 3%, respectively). No differences between class I and class III obese groups were detected in insulin-mediated suppression of palmitate (67 +/- 3 and 65 +/- 3%, respectively; P = 0.635) and glucose (67 +/- 3 and 73 +/- 5%, respectively; P = 0.348) rates of appearance in plasma, and the insulin-mediated increase in glucose disposal (218 +/- 18 and 193 +/- 30%, respectively; P = 0.489). In addition, no differences between class I and class III obese groups were detected in secretion rates of VLDL-triglyceride (6.5 +/- 1.0 and 6.0 +/- 1.4 micromol/l x min, respectively; P = 0.787) and VLDL-apolipoprotein B-100 (0.40 +/- 0.05 and 0.41 +/- 0.04 nmol/l x min, respectively; P = 0.866), and plasma clearance rates of VLDL-triglyceride (31 (16-59) and 29 (18-46) ml/min, respectively; P = 0.888) and VLDL-apolipoprotein B-100 (15 (11-19) and 17 (11-25) ml/min, respectively; P = 0.608). We conclude that increased adiposity without a concomitant increase in IHTG content does not cause additional abnormalities in adipose tissue, skeletal muscle, and hepatic insulin sensitivity, or VLDL metabolism.

An increased release of free fatty acids (FFAs) into plasma likely contributes to the metabolic complications associated with obesity. However, the relationship between body fat and FFA metabolism is unclear because of conflicting results from different studies. The goal of our study was to determine the inter-relationships between body fat, sex, and plasma FFA kinetics. We determined FFA rate of appearance (Ra) in plasma, by using stable isotopically labeled tracer techniques, during basal conditions in 106 lean, overweight, and obese, nondiabetic subjects (43 men and 63 women who had 7.0-56.0% body fat). Correlation analyses demonstrated: (i) no differences between men and women in the relationship between fat mass (FM) and total FFA Ra (micromol/min); (ii) total FFA Ra increased linearly with increasing FM (r=0.652, P<0.001); (iii) FFA Ra per kg FM decreased in a curvilinear fashion with increasing FM (r=-0.806; P<0.001); (iv) FFA Ra in relationship to fat-free mass (FFM) was greater in obese than lean subjects and greater in women than in men; and (v) abdominal fat itself was not an important determinant of total FFA Ra. We conclude that total body fat, not regional fat distribution or sex, is an important modulator of the rate of FFA release into plasma. Although increased adiposity is associated with a decrease in fatty acid release in relationship to FM, this downregulation is unable to completely compensate for the increase in FM, so total FFA Ra and FFA Ra with respect to FFM are greater in women than in men and in obese than in lean subjects.

Objective: It has been hypothesized that excessive fatty acid availability contributes to steatosis and the metabolic abnormalities associated with nonalcoholic fatty liver disease (NAFLD). The purpose of this study was to evaluate whether adipose tissue lipolytic activity and the rate of fatty acid release into plasma are increased in obese adolescents with NAFLD., Methods: Palmitate kinetics were determined in obese adolescents with normal (n = 9; BMI = 37 +/- 2 kg/m(2); intrahepatic triglyceride (IHTG) or= 10% of liver volume) IHTG content during the basal state (postabsorptive condition) and during physiological hyperinsulinemia (postprandial condition). Both groups were matched on body weight, BMI, percent body fat, age, sex, and Tanner stage. The hyperinsulinemic-euglycemic clamp procedure, in conjunction with a deuterated palmitate tracer infusion, was used to determine free-fatty acid (FFA) kinetics, and magnetic resonance spectroscopy was used to determine IHTG content., Results: The rate of whole-body palmitate release into plasma was greater in subjects with NAFLD than those with normal IHTG content during basal conditions, (87 +/- 7 vs. 127 +/- 13 micromol/min; P < 0.01) and during physiological hyperinsulinemia, (24 +/- 2 vs. 44 +/- 8 micromol/min; P < 0.01)., Discussion: These results demonstrate that adipose tissue lipolytic activity is increased in obese adolescents with NAFLD and results in an increase in the rate of fatty acid release into plasma throughout the day. This continual excess in fatty acid flux supports the hypothesis that adipose insulin resistance is involved in the pathogenesis of steatosis and contributes to the metabolic complications associated with NAFLD.