CLA and Metformin Effects on Insulin Sensitivity

In This Article

Abstract and Introduction

Abstract

Context: Insulin resistance precedes metabolic syndrome abnormalities and may promote cardiovascular disease and type 2 diabetes in children with obesity. Results of lifestyle modification programs have been discouraging, and the use of adjuvant strategies has been necessary.

Objective: This study aimed to evaluate the effects of metformin and conjugated linoleic acid (CLA) on insulin sensitivity, measured via euglycemic-hyperinsulinemic clamp technique and insulin pathway expression molecules in muscle biopsies of children with obesity.

Design: A randomized, double-blinded, placebo-controlled clinical trial was conducted.

Setting: Children with obesity were randomly assigned to receive metformin, CLA, or placebo.

Results: Intervention had a positive effect in all groups. For insulin sensitivity Rd value (mg/kg/min), there was a statistically significant difference between the CLA vs placebo (6.53 ± 2.54 vs 5.05 ± 1.46, P = 0.035). Insulinemia and homeostatic model assessment of insulin resistance significantly improved in the CLA group (P = 0.045). After analysis of covariance was performed and the influence of body mass index, age, Tanner stage, prescribed diet, and fitness achievement was controlled, a clinically relevant effect size on insulin sensitivity remained evident in the CLA group (37%) and exceeded lifestyle program benefits. Moreover, upregulated expression of the insulin receptor substrate 2 was evident in muscle biopsies of the CLA group.

Conclusions: Improvement of insulin sensitivity, measured via euglycemic-hyperinsulinemic clamp and IRS2 upregulation, favored patients treated with CLA.

Introduction

Obesity is a multifactorial disease with high prevalence in Mexico. According to the 2012 National Survey of Health and Nutrition, the prevalence of overweight and obese children and adolescents in Mexico is 34%.^[1] Insulin resistance has been recognized as the main physiopathological event preceding metabolic syndrome abnormalities and may promote cardiovascular disease and type 2 diabetes in individuals with obesity.^[2] Lifestyle modification through healthy food selection and consumption, a regular physical activity program, and optimal sleep hygiene have been proposed as the gold standard of care in these individuals. Unfortunately, the compliance and success of these strategies are usually disappointing,^[3,4] making pharmacological approaches somewhat necessary. Metformin (MET) is a biguanide used for the treatment of type 2 diabetes in children and adolescents due to its ability to decrease hepatic glucose production and increase peripheral insulin sensitivity. MET has been proposed as an adjuvant treatment in pediatric obesity efforts, especially in the presence of insulin resistance and its comorbidities. MET has beneficial effects on weight reduction and insulin resistance in obese nondiabetic individuals.^[5,6]

Conjugated linoleic acid (CLA) is a group of isomers of linoleic acid, which are synthesized in the cud of ruminant animals by fermentative bacteria.^[7] CLA is present in dairy products, meat, and fat from beef and lamb. The most common CLA isomer contained in these products is cis-9,trans-11, which can be commercially synthesized from linoleic acid–rich oils and prepared as a 50% mixture with the trans-10,cis-12 isomer.^[8] Several studies have acknowledged the beneficial effects of CLA isomers on body composition,^[9,10] immune response,^[11] bacterial-induced colonic inflammation,^[12,13] as well as improvements in insulin sensitivity and lipid metabolism in experimental animals and humans.^[9] Additionally, CLA purportedly reduces fatty acid synthesis in adipocytes, suggesting that this supplement decreases fat deposition, directly contributing to an improvement in body composition in adults and children.^[14] Nonetheless, the impact of CLA on human health and disease is still controversial and research on this matter continues.

Based on the current obesity frequency in Mexico, and considering the limited and discouraging outcomes of intervention programs, adjuvant strategies must be installed. The objective of the present study was to evaluate the effects of MET and CLA on insulin sensitivity, measured via the euglycemic-hyperinsulinemic clamp technique (EHCT), in children with obesity.

Table 1. Participant Characteristics at Randomization
	MET (n = 14)	Placebo (n = 17)	CLA (n = 17)	P
Age, y	11.43 (2.1)	12.59 (2.62)	11.41 (2.71)	0.31
Weight, kg	63.25 (12.6)	70.15 (13.11)	62.11 (18.47)	0.26
Height, cm	148.4 (10)	153.4 (12)	148.6 (13)	0.42
BMI, kg/m²	28.54 (2.8)	28.79 (2.8)	27.48 (3.7)	0.45
Waist circumference, cm	87.12 (7.6)	89.43 (8.45)	87.17 (11.2)	0.71
Glucose, mg/dL	87 (7)	87 (8.2)	85 (8.1)	0.62
Total cholesterol, mg/dL	167 (27)	167 (28)	162 (23)	0.79
HDL cholesterol, mg/dL	41 (10)	37 (8)	38 (8)	0.42
LDL cholesterol, mg/dL	107 (24)	106 (24)	100 (25)	0.67
Triglycerides, mg/dL	150 (62)	161 (60)	159 (84)	0.89
Physical fitness score (Harvard test)	81 (56)	83 (45)	85 (66)	0.98
Insulin, μU/mL	43.5 (22)	37.1 (17)	42.5 (27)	0.25
HOMA-IR	9.42 (4)	8.07 (4)	9.2 (6)	0.68
QUICKI-IS	0.63 (0.08)	0.64 (0.06)	0.66 (0.15)	0.54

Data are expressed as mean (standard deviation).
Abbreviation: LDL, low-density lipoprotein.

Table 2. Overall Impact of Intervention Regarding Anthropometric, Metabolic, and Insulin Resistance Outcomes in All Patients
	Baseline (n = 48)	4 Months Postintervention (n = 48)	P
Weight, kg	65.29 (2.2)	62.51 (2.15)	<0.001
Height, cm	150.2 (1.75)	151.7 (1.66)	<0.001
BMI, kg/m²	28.25 (0.45)	26.56 (0.51)	<0.001
Waist circumference, cm	87.9 (1.32)	83.8 (1.24)	<0.001
Glucose, mg/dL	87 (1.13)	85 (0.85)	0.28
Total cholesterol, mg/dL	167 (3.75)	161 (4.21)	0.07
HDL cholesterol, mg/dL	39.2 (1.27)	40.4 (1.21)	0.24
LDL cholesterol, mg/dL	105 (3.53)	100 (3.57)	0.056
Triglycerides, mg/dL	154 (9.96)	139 (9.73)	0.22
Insulin, μU/mL	40.9 (3.26)	34.5 (2.95)	0.025
HOMA-IR	8.86 (0.77)	7.27 (0.63)	0.018
QUICKI	0.64 (0.01)	0.68 (0.01)	0.014
Physical fitness score (Harvard test)	83.82 (7.96)	124.0 (5.44)	<0.001

The P values were determined by a paired-samples Student t test. Data are expressed as mean (SEM).
Abbreviation: LDL, low-density lipoprotein.

Table 3. Characteristics of Main Interest Variables After 4 Months of Intervention
	MET (n = 14)	Placebo (n = 17)	CLA (n = 17)	P
Weight, kg	60.85 (3.41)	66.48 (3.19)	59.91 (4.34)	0.39
Height, cm	149.89 (2.45)	154.82 (2.82)	150.27 (3.19)	0.40
BMI, kg/m²	26.17 (0.99)	27.53 (0.78)	25.92 (0.90)	0.37
Waist circumference, cm	82.31 (1.87)	84.96 (1.77)	83.92 (2.68)	0.70
Prescribed diet compliance, %	92.04 (6.15)	83.78 (6.21)	83.09 (3.56)	0.43
Physical fitness score (Harvard test)	103.82 (16)	132.9 (13.09)	132.79 (14.61)	0.29
Rd value, mg/kg/min	5.57 (0.47)^a,b	5.05 (0.35)^b	6.53 (0.61)^a	0.035
Insulin, μU/mL	40.5 (6.37)	32.3 (4.11)	31.6 (5.05)	0.42
HOMA-IR	8.53 (1.36)	6.83 (0.88)	6.68 (1.08)	0.45
QUICKI-IS	0.65 (0.02)	0.69 (0.02)	0.71 (0.02)	0.38
HDL cholesterol	44.86 (2.33)^a	40.00 (2.15)^a,b	36.87± (1.35)^b	0.031
Triglycerides, mg/dL	113.14 (7.26)^b	134.12 (20.36)^a,b	169.80 (15.93)^a	0.027