Metabolic Changes Following a 1-year Diet and Exercise Intervention in Patients with Type 2 Diabetes

Jeanine B. Albu; Leonie K. Heilbronn; David E. Kelley; Steven R. Smith; Koichiro Azuma; Evan S. Berk; F. Xavier Pi-Sunyer; Eric Ravussin; the Look AHEAD Adipose Research Group

Disclosures

Diabetes. 2010;59(3):627-633.

Research Design and Methods

This was an ancillary study of the Look AHEAD (Action For Health in Diabetes) trial at 3 of the 16 participating sites (Pennington Biomedical Research Center, Baton Rouge, LA; the University of Pittsburgh, Pittsburgh, PA; and St. Luke's–Roosevelt Hospital Center, New York, NY). The primary goal of the Look AHEAD trial is to investigate the effects of a lifestyle intervention of weight loss and physical activity (intensive lifestyle intervention [ILI]) versus those of diabetes support and education on cardiovascular morbidity and mortality.^[22–23] One-year results from the Look AHEAD trial and other results of this ancillary study have previously been published.^[24–28]

Research Volunteers

Inclusion and exclusion criteria for Look AHEAD, which include a confirmed diagnosis of type 2 diabetes, have previously been described.^[22–23] This ancillary study included only participants randomized to the ILI arm of the study.^[24–25] To simplify the potential impact of changes in antidiabetes medications during intervention, those with fasting plasma glucose ≥180 mg/dl and those on insulin or thiazolidinedione treatment were excluded from the substudy. Fifty-eight volunteers with type 2 diabetes (43 non-Hispanic whites, 12 African Americans, and 3 Hispanics) were studied at baseline (preintervention) and after 1 year of ILI. Twenty-six men (mean ± SD age 61.6 ± 1.5 years) and 32 women (58.9 ± 1.3 years) completed baseline and 1-year measurements. The sex distribution of volunteers at the three sites was as follows: 12 female and 13 male participants at Pittsburgh, 13 female and 5 male participants at St Luke's–Roosevelt, and 7 female and 8 male at Pennington. At baseline, 6 women were pre- or perimenopausal and 26 were postmenopausal (8 on hormone-replacement therapy). All participants signed informed consent, and the project was approved by the institutional review board of each institution and by the Look-AHEAD Steering Committee.

Lifestyle Intervention and Study Protocol

As described elsewhere,^[22–25] ILI was designed to achieve weight loss through decreased caloric intake (~500 kcal/day) and increased physical activity (≥175 min/week), with an expected 1-year weight loss of ≥7% of initial value. Before and after 1 year of ILI, our participants were admitted to clinical research facilities on the afternoon preceding the metabolic studies and underwent DEXA and CT imaging. After a standardized dinner (50% carbohydrate, 30% fat, and 20% protein), participants were fasted overnight. The next morning, a metabolic weight and a percutaneous adipose tissue biopsy were obtained; 1 h later, a hyperinsulinemic-euglycemic clamp was performed.

Addition or discontinuation of antihyperglycemic medications at the 1-year testing compared with baseline was noted. Medications added were thiazolidinedione and metformin (one man each). Medications discontinued were α-glucosidase inhibitors (one woman), meglitinides and repaglinides (two men and two women), and sulfonylureas (11 men and three women). Metformin was reintroduced for a week prior to the 1-year testing at the same dose as before the study if the patients were on it at baseline and were discontinued during the intervention (six men and two women).

Body Composition

Fat mass and fat-free mass (FFM) (including all nonfat tissue, i.e., lean body mass and bone mineral content) were measured using DEXA (Hologic QDR 4500A) according to the Manual of Procedures of the Look AHEAD trial. All DEXA scans were analyzed using QDR for Windows, version 11.1, software. Fat mass and FFM, gluteo-femoral fat, and trunk and arms fat mass (upper-body fat) were measured by the standard default analysis, in which the commercial computer-based algorithm separates the mass of gluteo-femoral and upper-body fat by two oblique lines that pass through the femoral neck.^[2] The coefficients of variation (CVs) for repeated measures (n = 38; unpublished data) of FFM, fat mass, and percentage of body fat were 0.6, 1.1, and 1.1%, respectively. Three cross-sectional CT scans, 1 cm in width, centered, respectively, on the T₁₂–L₁ and the L₄–L₅ disc space and at the mid-thigh, were obtained to assess hepatic fat as well as abdominal and thigh adipose tissue composition. All CT images were analyzed at the University of Pittsburgh using image analysis software (SliceOmatic; Tomovision, Montreal, Canada). To assess hepatic fat, CT liver and spleen attenuations (Hounsfield units) were determined, and to assess adipose tissue composition, the abdominal and thigh areas for bone, adipose tissue, and skeletal muscle were measured as previously described.^[29] To determine visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT) areas, a separation line was drawn manually on the abdominal CT images along abdominal wall musculature in continuity with the fascia of the paraspinal muscles. Abdominal SAT was further divided into superficial and deep SAT by manually tracing the circumferential superficial fascia as previously described.^[30] On thigh CT images, fascia lata was used to subdivide mid-thigh adipose tissue into SAT and subfascial adipose tissue.^[3]

Abdominal Subcutaneous Adipose Tissue Biopsy and Adipocyte Size

A percutaneous biopsy of superficial abdominal SAT (~500 mg) was performed ~10 cm lateral to the umbilicus using a Bergstrom needle with suction. Adipocyte size and number were determined at the Pennington Biomedical Research Center using a Coulter Counter (Multisizer-3; Beckman Coulter, Fullerton, CA) as previously described.^[26,28] Cell size is presented as the geometric mean.

Hyperinsulinemic-euglycemic Clamp

A primed continuous infusion of insulin (80 mU/m² per min) was used for at least 3 h, with the stipulation that insulin be infused for at least 1 h after reaching a plasma glucose concentration of 100 mg/dl, as previously described.^[27] The mean rate of exogenous glucose infusion during steady-state insulin infusion (last 30 min), glucose disposal rate (GDR), was used to assess peripheral insulin sensitivity.^[31] Oxygen consumption and CO₂ production were measured using metabolic carts (Sensor Medics Corporation, Anaheim CA) over the 40 min just preceding and during the last 40 min of the insulin infusion; fuel oxidation (carbohydrate and fat) was calculated for the last 30 min of each period.^[32] Glucose storage was the difference between total GDR and glucose oxidation. Glucose utilization rates were expressed per kilogram of FFM.

Blood Analyses

Blood samples were immediately centrifuged, aliquoted, and frozen at −70°C. Plasma glucose was analyzed using a glucose oxygen electrode (Synchron CX7 Delta Systems; Beckman, Brea, CA). Plasma insulin was measured by chemiluminescent immunoassays on the Immulite 2000 analyzer (Diagnostic Product, Los Angeles, CA). The intra- and interassay CVs for insulin (at 50 μU/ml) were 1.75 and 3.6%, respectively. Plasma FFA concentrations were measured on a Beckman Synchron CX5 analyzer using a WAKO NEFA C kit (Denver, CO). All samples were analyzed in the Clinical Chemistry Laboratory at the Pennington Biomedical Research Center.

Statistical Analyses

Data were expressed and shown as means ± SEM unless otherwise indicated. For each variable, data were presented for completed, valid measurements both at baseline and after 1 year. Data were missing for men (out of 26) for liver, spleen, and muscle attenuations (1 man each) and for adipose tissue cell size (2 men) and for women (out of 32) for abdominal adipose tissue measurements (1 woman); thigh adipose tissue, liver, spleen, and muscle attenuations (3 women each); and for adipose tissue cell size (1 woman). Variables with significant deviation from normal distribution were log transformed before analyses (insulin, FFAs, and their changes). ANOVA with repeated measures was used to assess significant changes over the 1 year of the intervention; interactions by sex were tested for significance. General linear models were built according to a priori hypotheses. Specifically, we tested the following: 1) whether changes in any of the regional fat measures were predictors of the 1-year changes in metabolic variables independent of the change in overall weight or fat mass; 2) whether the change in clamp FFAs was a predictor of the changes in GDR or fasting glucose, independent of changes in weight, fat mass, or any of the regional fat measures; and 3) whether the change in GDR was a predictor of the change in fasting glucose, independent of changes in weight, fat mass, or any of the regional fat measures. P < 0.05 was considered significant. Statistica, version 6.0 (Statsoft, Tulsa, OK), was used for analyses.

1 2 3 4

Next Section

Cite this: Metabolic Changes Following a 1-year Diet and Exercise Intervention in Patients with Type 2 Diabetes - Medscape - Mar 01, 2010.

Table 1. Weight, adipose tissue mass and distribution, organ fat, and abdominal subcutaneous fat cell size before and after 1-yearlifestyle intervention
	Men (n = 26)*		Women (n = 32)†
	Baseline	1 year	Baseline	1 year
Weight (kg)‡	101.2 ± 1.9	88.8 ± 1.8	91.4 ± 1.7	83.9 ± 1.7
BMI (kg/m²)‡	32.4 ± 0.5	28.4 ± 0.5	34.8 ± 0.6	32.0 ± 0.6
FFM (kg)‡	70.9 ± 1.1	66.9 ± 1.0	54.2 ± 1.0	52.1 ± 0.9
Fat mass (Kg)‡	30.3 ± 1.2	22.0 ± 1.2	37.1 ± 1.1	31.8 ± 1.1
Percent fat mass (of weight)‡	29.8 ± 0.8	24.5 ± 0.9	40.4 ± 0.7	37.5 ± 0.8
Upper-body fat (kg)‡	21.4 ± 0.9	15.1 ± 0.9	24.4 ± 0.9	20.7 ± 0.8
Gluteo-femoral fat (kg)§	8.2 ± 0.3	6.2 ± 0.3	12.1 ± 0.6	10.6 ± 0.5
VAT (cm²)‡	311.7 ± 18.3	216.5 ± 18.3	259.5 ± 16.8	213.3 ± 16.7
Deep abdominal SAT (cm²)‡	170.9 ± 11.6	120.4 ± 10.2	148.2 ± 10.6	130.6 ± 9.3
Superficial abdominal SAT (cm²)§	120.9 ± 11.5	92.0 ± 10.6	237.1 ± 10.6	206.8 ± 9.7
Subfascial thigh AT (cm²)(one leg)§	18.1 ± 1.5	12.9 ± 1.1	22.7 ± 1.5	18.1 ± 1.1
Superficial thigh SAT (cm²) (one leg)§	84.7 ± 7.9	66.8 ± 7.5	156.5 ± 7.5	138.4 ± 7.1
Liver attenuation (HU)§	51.2 ± 2.1	59.7 ± 1.8	46.5 ± 1.9	54.6 ± 1.7
Spleen attenuation (HU)§	50.4 ± 0.8	51.3 ± 0.8	47.6 ± 0.8	48.8 ± 0.7
L/S attenuation ratio§	1.01 ± 0.04	1.17 ± 0.04	0.99 ± 0.04	1.13 ± 0.04
Muscle area (cm²) (both legs)‡	311.5 ± 6.8	292.7 ± 6.9	223.4 ± 6.3	215.2 ± 6.4
Muscle attenuation (HU)	46.8 ± 0.9	47.4 ± 0.8	45.0 ± 0.8	45.1 ± 0.7
Fat cell size§	0.73 ± 0.05	0.50 ± 0.04	0.96 ± 0.04	0.76 ± 0.03
Fat cell number§	3,756 ± 271	4,897 ± 370	2,982 ± 239	3,345 ± 325

Data are unadjusted means ± SE. FFM, FM, upper body fat, and gluteo-femoral fat measured by DEXA; VAT, SAT, abdominal andthigh SAT subcompartments, and organ (liver, spleen, muscle) attenuation measured by CT scan.
*Missing data for men (out of 26) for organ attenuations (1 man each) and fat cell size (2 men).
†Missing data for women (out of 32) for abdominal adipose tissue measurements (1 woman), thigh adipose tissue and organ attenuations(3 women each), and fat cell size (1 woman).
‡Significant change in both men and women (P range <0.05 to 0.00001), with significant interaction by sex (P range <0.05 to 0.001 for the interaction term).
§Significant change in both men and women (P range <0.05 to 0.00001), with no significant interaction by sex.

Table 2. Metabolic parameters during the euglycemic-hyperinsulinemic clamp before and after 1-year lifestyle intervention
	Men (n = 26)		Women (n = 32)
	Baseline	1 year	Baseline	1 year
Postabsorptive state
Glucose (μmol/l)*	8.2 ± 0.4	6.7 ± 0.3	7.8 ± 0.3	7.3 ± 0.3
Insulin (pmol/l)*	71.1 ± 7.2	52.5 ± 8.9	91.5 ± 6.5	80.0 ± 8.0
FFAs (mmol/l)*	0.56 ± 0.02	0.45 ± 0.03	0.79 ± 0.03	0.63 ± 0.02
Steady state during clamp
Glucose (μmol/l)	5.7 ± 0.1	5.7 ± 0.1	5.8 ± 0.1	5.8 ± 0.1
Insulin (pmol/l)†	834.3 ± 49.1	820.1 ± 39.2	982.9 ± 44.2	859.5 ± 35.3
FFAs (mmol/l)*	0.03 ± 0.01	0.01 ± 0.00	0.05 ± 0.06	0.02 ± 0.003
GDR (mg · kg FFM⁻¹ · min⁻¹)*	5.7 ± 0.4	8.9 ± 0.5	6.2 ± 0.4	8.4 ± 0.5
Glucose oxidation (mg · kg FFM⁻¹ · min⁻¹)*‡	2.7 ± 0.1	3.4 ± 0.2	3.1 ± 0.2	3.8 ± 0.2
Glucose storage (mg · kg FFM⁻¹ · min⁻¹)*‡	3.0 ± 0.3	5.5 ± 0.4	2.9 ± 0.4	4.4 ± 0.5

Values are unadjusted means ± SE.
*Significant change in both men and women (P range <0.05 to 0.00001), with no significant interaction by sex.
†Significant change in women only (P < 0.05).
‡Men, n = 26; women, n = 30.

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.