Insulin Sensitivity, Insulin Secretion, and Abdominal Fat

Lynne E. Wagenknecht, Carl D. Langefeld, Ann L. Scherzinger, Jill M. Norris, Steven M. Haffner, Mohammed F. Saad, Richard N. Bergman

Disclosures

Diabetes. 2003;52(10)

Introduction

The relationship between insulin sensitivity and overall obesity is well established. However, there remains debate as to which of the fat depots, visceral abdominal tissue (VAT) or subcutaneous abdominal tissue (SAT), is of greater importance. Also, the relationship between fat distribution and insulin secretion is largely unknown. We studied S _I, acute insulin response (AIR), and disposition index (DI), as obtained by minimal model analysis, in 999 Hispanic and 458 African-American men and women as part of the Insulin Resistance Atherosclerosis Study (IRAS) Family Study. VAT and SAT were measured from computed tomography scans performed at the L4/L5 vertebral region. A mixed-model approach was used to determine the relationship between each of the glucose homeostasis measures (S _I, AIR, and DI) versus abdominal fat measures. Mean values were as follows: age, 41 years; S _I, 1.98 10^-4 · min^-1 · µU^-1 · ml^-1; AIR, 840 pmol · ml^-1 · min^-1; BMI, 28.5 kg/m²; VAT, 100 cm²; and SAT, 333 cm². SAT, VAT, and their joint interaction were each inversely and significantly associated with S _I, adjusting for age, sex, ethnicity, and BMI. SAT, but not VAT, was positively associated with AIR, except when additionally adjusting for S _I, in which case VAT was inversely associated with AIR. VAT and the joint interaction of VAT and SAT were inversely associated with DI. The fat measures explained 27% of the model R ² for S _I, 16% for AIR, and 16% for DI. Thus, fat distribution is an important determinant of both insulin resistance and insulin secretion.

Insulin resistance is associated with overall obesity and particularly abdominal obesity.^[1] However, simple measures of body size such as BMI or waist circumference do not adequately describe the distribution of adipose tissue, which now appears to be a major determinant of the variation in insulin resistance. Computed tomography has made it possible to discriminate between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT).^[2] However, there is debate regarding which of these fat depots is more important in determining insulin resistance.^[3,4] These fat depots differ morphologically and functionally, suggesting that their metabolic impact may differ as well.^[5]

In normal individuals, as insulin sensitivity declines, the ß-cells of the pancreas compensate by secreting more insulin. An additional compensation is reduced first-pass clearance of insulin by the liver. In individuals at risk for type 2 diabetes, the ability to compensate for insulin resistance is compromised. Thus, it is of interest to clearly determine whether overall obesity or obesity in a specific depot is a more important determinant of insulin resistance, because adipose in that depot would provide a greater stress to the ß-cells and higher risk for type 2 diabetes.

It is possible to assess the ability of the ß-cells to compensate for insulin resistance by exploiting the known hyperbolic relationship between insulin secretion and insulin sensitivity.^[6] As resistance progresses, normal ß-cells will upregulate according to the formula: insulin secretion x insulin sensitivity = constant, where the constant is termed the "disposition index" (DI). It is therefore of interest not only to know the importance of VAT versus SAT vis-à-vis insulin resistance but also the potential for compensation as reflected in the DI.

We sought to examine the relationship between insulin resistance, insulin secretion, DI, and abdominal adiposity in a large epidemiologic cohort in which quantitative assessments of insulin resistance and abdominal fat distribution have been made. Specifically, we wished to determine whether the relationships between abdominal adiposity and glucose homeostasis parameters are independent of overall body mass; whether the relationship differs by ethnicity, sex, or body mass; and whether one or the other fat depot (VAT or SAT) is more strongly associated with these measures.

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Table 1. Descriptive statistics of the IRAS Family Study cohort
	Hispanic (San Antonio)		Hispanic (San Luis Valley)		African American (Los Angeles)
	Men	Women	Men	Women	Men	Women
n	193	301	216	289	197	261
Age (years)	38.4 ± 14.6	41.5 ± 13.7	40.5 ± 13.6	41.7 ± 12.9	42.7 ± 14.4	40.2 ± 13.1
S _I (10^-4 · min^-1 · µU^-1 · ml^-1)	1.89 ± 1.87	2.02 ± 1.83	2.31 ± 1.84	2.33 ± 1.89	1.68 ± 1.20	1.59 ± 1.15
AIR (pmol · ml^-1 · min^-1)	821 ± 728	661 ± 581	793 ± 635	835 ± 689	951 ± 855	1,005 ± 778
DI	1,187 ± 1,106	1,055 ± 848	1,527 ± 1,336	1,642 ± 1,449	1,315 ± 1,199	1,440 ± 1,293
BMI (kg/m²)	29.2 ± 5.2	29.8 ± 6.5	26.9 ± 4.8	27.3 ± 5.4	28.0 ± 4.9	29.7 ± 7.1
SAT (cm²)	274 ± 128	391 ± 154	252 ± 126	359 ± 140	251 ± 137	406 ± 196
VAT (cm²)	124 ± 64	105 ± 55	117 ± 56	90 ± 50	96 ± 60	77 ± 47
VAT/SAT ratio	0.48 ± 0.21	0.28 ± 0.12	0.51 ± 0.22	0.25 ± 0.12	0.42 ± 0.22	0.20 ± 0.10
Overweight (%)	39	30	37	34	45	26
Obese (%)	39	45	25	26	29	43
Impaired fasting glucose (%)	7.3	8.0	6.9	6.9	10.7	8.4

Table 2. Summary of models for S _I, AIR, and DI
	S _I* (model R ² = 43.5)			AIR* (model R ² = 11.6)			DI* (model R ² = 26.3)
	ß ± SE	P	Percent change in R ²	ß ± SE	P	Percent change in R ²	ß ± SE	P	Percent change in R ²
Age
Linear	0.0006 ± 0.0011	<0.0001	10.6	-0.2303 ± 0.0315	<0.0001	41.6	-0.2101 ± 0.0439	<0.0001	16.5
Quadratic	-0.0004 ± 0.0001			0.0013 ± 0.0012			-0.0071 ± 0.0019
Sex (F vs. M)	0.0150 ± 0.0293	0.5839	0.05	-2.4395 ± 0.8883	0.0018	6.1	-1.8651 ± 1.1406	0.0833	0.8
Ethnicity/clinic
African American (Los Angeles)
Hispanic (San Antonio)	0.2052 ± 0.0366	<0.0001	5.7	-5.3888 ± 1.0895	<0.0001	13.8	-1.2041 ± 1.3076	0.0150	2.2
Hispanic (San Luis Valley)	0.2181 ± 0.0387			-3.0265 ± 1.1575			2.4949 ± 1.4139
BMI (kg/m²)	-0.0134 ± 0.0043	0.0002	2.2	-0.0657 ± 0.0968	0.4386	0.4	-0.5349 ± 0.1507	<0.0001	4.0
Log SAT (cm²)	-0.1996 ± 0.0526			5.4969 ± 1.1613	<0.0001	16.3	1.5534 ± 1.8960
Log VAT (cm²)	-0.3456 ± 0.0333		27.0	0.5247 ± 0.9301	0.5271	0.3	-8.7357 ± 1.2202		16.4
SAT by VAT interaction	-0.1334 ± 0.0278	<0.0001					-3.4585 ± 0.9874	0.0009

Table 3. Summary of effect sizes for adipose tissue variables in sex- and obesity-stratified models of S _I, AIR, and DI, adjusted for age, sex, ethnicity/clinic, and BMI
	Sex-stratified models				Obesity-stratified models
	Male		Female		Nonobese (BMI <30 kg/m²)		Obese (BMI ≥30 kg/m²)
	ß ± SE	P	ß ± SE	P	ß ± SE	P	ß ± SE	P
S _I
Log SAT	-0.2353 ± 0.0700		-0.0953 ± 0.0895		-0.3281 ± 0.0510		-0.2316 ± 0.0674
Log VAT	-0.3811 ± 0.0551		-0.3539 ± 0.0395		-0.3580 ± 0.0418		-0.4673 ± 0.0632
Interaction*	-0.1870 ± 0.0359	<0.0001	-0.1167 ± 0.0468	0.01	-0.1653 ± 0.0328	<0.0001	0.0536 ± 0.1083	0.62
AIR
Log SAT	5.1575 ± 1.9600	0.01	3.5354 ± 1.4711	0.02	3.7407 ± 0.9254	<0.0001	5.6776 ± 2.2482	0.01
Log VAT	0.1756 ± 1.7244	0.92	1.2827 ± 1.1378	0.26	1.7151 ± 0.9367	0.07	-1.8919 ± 1.8134	0.30
DI
Log SAT	1.3647 ± 3.0768		0.9500 ± 2.7243		-2.2459 ± 2.0444		0.0189 ± 2.6138
Log VAT	-10.122 ± 1.9501		-8.1781 ± 1.5737		-7.3042 ± 1.4470		-14.260 ± 2.0399
Interaction*	-4.3875 ± 1.6767	0.009	-3.7647 ± 1.2140	0.002	-2.7243 ± 1.4754	0.07	-2.8562 ± 3.9918	0.47

Table 3. Summary of effect sizes for adipose tissue variables in sex- and obesity-stratified models of S _I, AIR, and DI, adjusted for age, sex, ethnicity/clinic, and BMI
	Sex-stratified models				Obesity-stratified models
	Male		Female		Nonobese (BMI <30 kg/m²)		Obese (BMI ≥30 kg/m²)
	ß ± SE	P	ß ± SE	P	ß ± SE	P	ß ± SE	P
S _I
Log SAT	-0.2353 ± 0.0700		-0.0953 ± 0.0895		-0.3281 ± 0.0510		-0.2316 ± 0.0674
Log VAT	-0.3811 ± 0.0551		-0.3539 ± 0.0395		-0.3580 ± 0.0418		-0.4673 ± 0.0632
Interaction*	-0.1870 ± 0.0359	<0.0001	-0.1167 ± 0.0468	0.01	-0.1653 ± 0.0328	<0.0001	0.0536 ± 0.1083	0.62
AIR
Log SAT	5.1575 ± 1.9600	0.01	3.5354 ± 1.4711	0.02	3.7407 ± 0.9254	<0.0001	5.6776 ± 2.2482	0.01
Log VAT	0.1756 ± 1.7244	0.92	1.2827 ± 1.1378	0.26	1.7151 ± 0.9367	0.07	-1.8919 ± 1.8134	0.30
DI
Log SAT	1.3647 ± 3.0768		0.9500 ± 2.7243		-2.2459 ± 2.0444		0.0189 ± 2.6138
Log VAT	-10.122 ± 1.9501		-8.1781 ± 1.5737		-7.3042 ± 1.4470		-14.260 ± 2.0399
Interaction*	-4.3875 ± 1.6767	0.009	-3.7647 ± 1.2140	0.002	-2.7243 ± 1.4754	0.07	-2.8562 ± 3.9918	0.47

Table 3. Summary of effect sizes for adipose tissue variables in sex- and obesity-stratified models of S _I, AIR, and DI, adjusted for age, sex, ethnicity/clinic, and BMI
	Sex-stratified models				Obesity-stratified models
	Male		Female		Nonobese (BMI <30 kg/m²)		Obese (BMI ≥30 kg/m²)
	ß ± SE	P	ß ± SE	P	ß ± SE	P	ß ± SE	P
S _I
Log SAT	-0.2353 ± 0.0700		-0.0953 ± 0.0895		-0.3281 ± 0.0510		-0.2316 ± 0.0674
Log VAT	-0.3811 ± 0.0551		-0.3539 ± 0.0395		-0.3580 ± 0.0418		-0.4673 ± 0.0632
Interaction*	-0.1870 ± 0.0359	<0.0001	-0.1167 ± 0.0468	0.01	-0.1653 ± 0.0328	<0.0001	0.0536 ± 0.1083	0.62
AIR
Log SAT	5.1575 ± 1.9600	0.01	3.5354 ± 1.4711	0.02	3.7407 ± 0.9254	<0.0001	5.6776 ± 2.2482	0.01
Log VAT	0.1756 ± 1.7244	0.92	1.2827 ± 1.1378	0.26	1.7151 ± 0.9367	0.07	-1.8919 ± 1.8134	0.30
DI
Log SAT	1.3647 ± 3.0768		0.9500 ± 2.7243		-2.2459 ± 2.0444		0.0189 ± 2.6138
Log VAT	-10.122 ± 1.9501		-8.1781 ± 1.5737		-7.3042 ± 1.4470		-14.260 ± 2.0399
Interaction*	-4.3875 ± 1.6767	0.009	-3.7647 ± 1.2140	0.002	-2.7243 ± 1.4754	0.07	-2.8562 ± 3.9918	0.47

Table 2. Summary of models for S _I, AIR, and DI
	S _I* (model R ² = 43.5)			AIR* (model R ² = 11.6)			DI* (model R ² = 26.3)
	ß ± SE	P	Percent change in R ²	ß ± SE	P	Percent change in R ²	ß ± SE	P	Percent change in R ²
Age
Linear	0.0006 ± 0.0011	<0.0001	10.6	-0.2303 ± 0.0315	<0.0001	41.6	-0.2101 ± 0.0439	<0.0001	16.5
Quadratic	-0.0004 ± 0.0001			0.0013 ± 0.0012			-0.0071 ± 0.0019
Sex (F vs. M)	0.0150 ± 0.0293	0.5839	0.05	-2.4395 ± 0.8883	0.0018	6.1	-1.8651 ± 1.1406	0.0833	0.8
Ethnicity/clinic
African American (Los Angeles)
Hispanic (San Antonio)	0.2052 ± 0.0366	<0.0001	5.7	-5.3888 ± 1.0895	<0.0001	13.8	-1.2041 ± 1.3076	0.0150	2.2
Hispanic (San Luis Valley)	0.2181 ± 0.0387			-3.0265 ± 1.1575			2.4949 ± 1.4139
BMI (kg/m²)	-0.0134 ± 0.0043	0.0002	2.2	-0.0657 ± 0.0968	0.4386	0.4	-0.5349 ± 0.1507	<0.0001	4.0
Log SAT (cm²)	-0.1996 ± 0.0526			5.4969 ± 1.1613	<0.0001	16.3	1.5534 ± 1.8960
Log VAT (cm²)	-0.3456 ± 0.0333		27.0	0.5247 ± 0.9301	0.5271	0.3	-8.7357 ± 1.2202		16.4
SAT by VAT interaction	-0.1334 ± 0.0278	<0.0001					-3.4585 ± 0.9874	0.0009

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