Reduced insulin secretion: an independent predictor of body weight gain

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1572 SCHWARTZ ET AL. JCE & M . 1995Vol80. No 5

included normal findings from history and physical exa mination and

routine laboratory tests. Informed consent was given by each subject,

and studies were approved by the ethics committees of the NIDDK, the

Indian Health Service, and the Tribal Council of the Gila River India n

Community. Subjects were admitted to the metabolic research ward

annually for 8-16 days, during which time they were fed a weight

maintenance diet (50% of calories as carbohydrate, 30% as fat, and 20%

as protein). Body composition was assessed by underwater weighin g (7),

insulin sensitivity assessed by euglycemic, hyperinsulinemic clamp, and

insulin secretion was determined from the results of an iv glucose

tolerance test, a meal tolerance test (MIT), and a 75-g oral glucose

tolerance test (OGTT). Any subjects who met National Diabetes Data

Group criteria for impaired glucose tolerance (2-h plasma glucose value

of 140-199 mg/dL during the OGTT) were excluded u priori from the

present analysis. Of 135 subjects in whom all studies were performed,

38 were excluded because of impaired glucose tolerance, leaving 97

subjects for the present analysis. Data obtained from some subjects were

included in previous publications (4); however, the requirement for

normal oral glucose tolerance and determination of insulin secretion in

response to 3 different challenges yielded a population whose compo-

sition is unique to the current study. Changes in both weight and body

fat mass (determined from underwater weighing) from the first to the

last admission, with a minim um of 6 months between visits, were used

for all analyses.

Determina tion of insulin secretion and insulin sens itivity

Immunoreactive insulin (IRI) concentrations were determined in

plasma samples by RIA, using the Herbert modification (8) of the

method of Yalow and Berson (91, and glucose levels were determined by

the glucose oxidase method (Beckman Instruments, Fullerton, CA). Af-

ter 8-15 days on the metabolic ward, insulin sensitivity was determined

as the rate of glucose infusion during a euglycemic hyperinsulinemic

clamp (M) (lo), modifie d as previously described (11). Insulin was

infused iv, first at a low dose (40 mLJ/m’ body surface area.min) for 100

min, then at a high dose (400/m’ body surface area.min) for an addi-

tional 100 min while euglycemia was maintain ed by a variable rate iv

20% glucose infusion. Measurement of the rate of endogenous glucose

production using iv infusion of tracer amounts of [3-3H]glucose was

performed before and during the low dose insulin infusion (12). The rate

of glucose infusion during the last 40 min of both low and high dose

insulin infusions and the rate of endogenous glucose production during

the low dose insulin infusions were used to calculate insulin-mediatedglucose disposal rates (referred to as submax M and max M, respec-

tively), as previously described (11,121. Insulin secretion was measured

using three different procedures. Subjects underwent an iv glucose

tolerance test using a 25 g iv glucose infusion over 3.6 min to quantify

insulin secretion. Plasma sam ples were obtained at baseline and 3,4, and

5 min after iv glucose administration, and glucose-stimulated insulin

secretion was assessed as the acute insulin response to glucose (AIRg),

determined as half the incremental area under the curve of plasma IRI

from the third to the fifth minute after the glucose bolus. After an

overnight fast, subjects underwent a 75-g OGTI and, on a separate day,

consumption of a standardized breakfast containing 30% of the weight-

maintain ing caloric requirement, composed of 20% protein, 40% carbo-

hydrate, and 40% fat (13). Insulin levels were determined in plasma

samples obtained at baseline; at 30, 60, 120, and 180 min during the

OGTT; and 0,30,60,90,120,150,180 ,210, and 240 min after the meal.

The insulin secretory response was quantified as the incremental area

under the curve of IRI during the OGTT and M’IT, and was computed

using the trapezoidal approximation (14).

Stat ist ical methods

The percent total weight gain per yr was calculated as final weight

minus initial w eight divided by initial w eight and number of years of

follow-up multip lied by 100. The percent fat mass gain per yr was

calculated as final body fat mass minus initial body fat mass divided by

initial body fat mass and number of years of follow-up multip lied by 100.

For regression analysis, dependent variables of interest were percent

weight change per yr and percent fat mass change per yr. The

relationships between each of these outcomes and independe nt

variables of interest, including the three measures of insulin secretion,

were examined using univariate and multiple linear regression analysis

(15,161. Multip le regression models examined the relationship between

insulin secretion in response to a meal, an OGTT, and the AIRg and each

outcome while adjusting for age in years, sex, submax M or max M, and

initial body weight.

Results

Baseline characteristics

The physical and metabolic characteristics of the subjectsat baseline are shown in Table 1. The subjects (64 males and33 females) were young adults (mean age, -25 yr), withlevels of obesity [mean body mass index (BMI), -34 kg/m’]characteristic of the nondiabetic Pima Indian population.Mean follow-up durations were 3.6 yr for men and 3.0 yr forwomen. Table 1 also shows the rates of increasing bodyweight and fat mass as the yearly percent change from initialvalues. Body weight increased by 2.l%/yr in males and by3.5%/yr in females, whereas body fat mass increased by6.9%/yr in both sexes.

Univariate regression analysis of baseline metabolic

parameters

Significant interrelationships were observed among bodyadiposity, insul in secretion, and insulin sens itivi ty at base-line. As expected, significant univariate correlations existedbetween initial va lues of percent body adipos ity and theinsul in secretory responses to the MTT (r = 0.42; P < 0.0011,the OGTT (r = 0.45; P < O.OOl),and the AIRg (r = 0.21; P =0.044). Each of the three measures of insulin secretion wasnegatively correlated to both the submax M value (r = -0.55,-0.53, and -0.32, respectively; P < 0.005 for each) and maxM (r = -0.46, -0.49, and -0.26, respect ively; P < 0.01 for

each). The insulin responses to both the MTT and OGTT weresignif icantly correlated with in itial body weight (r = 0.30 and0.23, respectively; both P < 0.031, whereas AIRg was not(r = 0.14; P = 0.17). Baseline submax M and max M values

TABLE 1. Mean characteristics by gender amo ng 97 Pima Indian

subjects with normal glucose tolerance

Characteristic Male (n = 64) Female (n = 33)

Age (yr) 25.3 (5.7) 24.6 (5.0)

BMI (kg/m’) 33.8 (8.3) 34.7 (6.4)

MTTmo insulin (pmol/LP 90,156 (56,829) 118,930 (105,340)

OGTT,,, insulin (pmol/L)” 134,500 (69,406) 186,280 (59,382)

AIRg fpmol/L) 1,450 (890) 1,427 (994)

Submax M (mg/kg * min) 3.05 (1.22) 2.82 (0.70)

Max M (mg/kg * min) 9.26 (1.93) 9.53 (1.93)

Initial % body adiposity 27.5 (8.5) 38.9 (5.8)

Final % body adiposity 30.3 (8.2) 40.4 (4.8)

Initial BW (kg) 98.7 (27.6) 88.3 (17.7)

Final BW (kg) 105.3 (31.1) 95.2 (20.3)

Initial fat mass (kg) 29.2 (15.6) 35.2 (11.7)

Final fat mass (kg) 34.2 (18.5) 39.lQ1.7)

Follow-up duration (yr) 3.58 (1.46) 3.02 (1.73)

Yearly % wt change 2.1(3.0) 3.5 (3.6)

Yearly % fat mass change 6.9 (11.9) 6.9 (12.4)

Values are means (23D).

a MTTAUC insulin and OG’M’*uo insulin refer to the incremental

area under the curves of the insulin response during a meal tolerance

test and an oral glucose tolerance test, respectively.

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INSULIN SECRETION PREDICTS WEIGHT GAIN 1573

were significantly correlated with both initial weight (r =

-0.51; P < 0.001 and r = -0.41; P < 0.001, respectively ) andfat mass (r = -0.54; P < 0.001 and r = -0.37; P < 0.001,

respectively). Fasting plasma IRI levels were highly corre-

lated to initial fat mass (r = 0.70; P < O.OOl),submax M (r =-0.62; P < 0.0011, and max M (r = -0.46; P < 0.001) values.

Univariate regression analysis of change s in body weight

and adiposity

The relationship between changes in body weight or bodyfat mass and variables of interest, including AIRg, was ex-amined using linear regression analys is (Table 2). The per-

cent total weight gain per yr was significantly associated

(P < 0.05) with baseline BMI, initial body weight, submax M,and max M values and each of the three measures of insulin

secretion. Higher levels of BMI and insulin secretion by allmeasures at baseline were associated w ith a lower percentincrease in total body weight over the follow-up period, as

reflected by the negative signs of the regression coefficientsfor these variables. Higher submax M and max M, on the

other hand, were associated with a higher percent increasein total body weight over the follow-up period.

Simila r univariate associations were observed for percentbody fat mass change per yr. Initial body fat mass, BMI, and

initial body weight were each significantly associated with

yearly percent change in body fat mass. The regression co-efficients for these associations were negative, indicating thatlower in itial total body weight or BMI predicted a subse-quent increase in body fat (Table 2). A similar negative as-sociation was found for each baseline insulin secretory mea-

sure and increase in body fat. In contrast, both submax M and

max M values were positively associated with yearly percent

body fat mass change.

Multiple linear regression analysis of changes in body

weight and adiposity

Because of the high correlations noted between each mea-sure of insulin secretion and both submax M and max M, a

different regression model was constructed to analyze theassociation between insulin secretion and change in weightwhile adjusting for each measure of insulin sensitivity. Also,

these models were adjusted for age, sex, and initial bodyweight. Model 1 (Table 3) revealed a significant negativecorrelation (P < 0.001) between the insulin secretory re-

sponse during the MTT and yearly percent weight change

even after adjustment for age, sex, init ial body weight, and

submax M. The significant negative association betweenmeal-stimulated insulin secretion and yearly change in bodyweight persisted (P = 0.003) when max M was entered as acovariate instead of the submaximal measure in model 2.

Max M (model 21, but not submax M (model l), approached

statistical significance (P = 0.088) as an independent predic-

tor of yearly percent weight gain over the follow-up period.Simila r results were obtained in the analys is of the relation-ship between meal-related insulin secretion and the yearlyrate of change of body fat content (Table 3). A significant

negative correlation was obtained between insulin secretion

during a test meal and yearly percent change in fat mass aftercontrolling for potential confounders, including submax M(model 3) and max M (model 4). Neither max M nor submax

M, however, was independently identified as a significantpredictor of the rate of fat mass change in this analysis

(models 3 and 4).

TABLE 2. Univariate linear regression analyses of yearly percent weight change a nd yearly percent body fat change by characteristics of

interest

Independent variable Regression coeffk ient Correlation coeffic ient P value

Dependent variable =

yearly % wt change

Age -0.00056 -0.093 0.3653

Sex” 0.01342 0.197 0.0526

BMI -0.0010 -0.235 0.0205

Initial BW -0.00029 -0.221 0.0298

M’IT,,, insulin -0.0000014 -0.352 0.0010

OGTT,,, insulin -0.0000008 -0.297 0.0037

-4W -0.000061 -0.278 0.0058

Submax M 0.00764 0.254 0.0124

MaxM 0.00577 0.342 0.0006


yearly % fat mass

change

Ag e -0.00398 -0.171 0.0938

Sex” 0.00078 0.001 0.9888

BM I -0.00571 -0.364 0.0002

Initial BW -0.00141 -0.297 0.0032

Initial fat mass -0.00285 -0.351 0.0005

!zzC insulinnsulin -0.00000490.0000030 -0.3410.309 0.0015.0025

MRg -0.00243 -0.301 0.0027

Submax M 0.04427 0.397 0.0001

MaxM 0.02126 0.342 0.0006

The regression coefficient is equal to the slope of the regression line between the independen t variable and the variable of interest. Units

are described in Table 1. P values correspond to the significance of the correlation coefficient.

a Sex was coded in this table and in all regression models as M = 1 and F = 2.







SCHWARTZ ET AL. JCE & M . 1995Vol80 . No 5

TABLE 3. Multipl e linear regression analyses of the annual rate

of change of both body weight (models 1 and 2) and fat mass

(models 3 and 4) by characteristics of interest, including the

insulin secretory response to a meal (MTT,,, insulin) as a

measure of insulin secretion

Independent variablesRegression

SE P value

Dependent variable = yearly

% wt change

Model 1

MITAUo insulin

Sex

Ag eInitial BW

Submax M

Model 2

MmAoc insulin

Sex

Ag eInitial BW

MaxM

Dependent variable = yearly

% fat mass change

Model 3

MTTAuc insulinSex

-4sInit ial BW

Submax M

Model 4

M’ITAUc insulin

Sex

Ag eInit ial BW

Max M

-0.0000017 0.00000048 0.0006

0.023741 0.007060 0.0012

-0.000145 0.000603 0.8102

-0.0000951 0.000160 0.5537

0.001299 0.004266 0.7615

-0.0000014 0.00000046 0.0025

0.021616 0.00699 0.0028

-0.000189 0.000589 0.7492

0.000146 0.000146 0.3173

0.003542 0.002053 0.0884

-0.0000358 0.00000182 0.05320.025445 0.027042 0.3496

-0.002888 0.002310 0.2149

-0.000222 0.000613 0.7176

0.021061 0.016339 0.2021

-0.0000038 0.0000018 0.0390

0.016918 0.027305 0.5357

-0.003278 0.002300 0.1581

-0.000390 0.008018 0.2377

0.009542 0.000568 0.0884

Models 5 and 6 (Table 4) analyzed the association betweenyearly percent weight gain and insulin secretion during anOGTT after adjusting for the same covariates as those in

models l-4. In both models, a significant negative associa-tion between the insulin response to oral glucose and theyearly percent change in weight was identified, simi lar to therelationship between meal-related insulin secretion andweight gain (Table 4). In model 6, max M approached sta-tistical sign ificance (P = 0.073) as an independent predictorthat was posit ively correlated with weight gain. Models 7

TABLE 4. Multip le linear regression analysis of yearly percent

weight change by characteristics of interest, including the insulin

secretory response during an OG’IT as a measure of insulin

secretion

Independent variablesRegression

coefficientSE P va lue


yearly % wt change

Model 5

OG!lTAuc insulin

Sex

Ag eInit ial BW

Submax M

Model 6

OG’l’TAUC insulin

Sex

Ag eInit ial BW

MaxM

-0.00000092 0.00000032 0.0058

0.021229 0.007319 0.0047

-0.000229 0.000607 0.7076

-0.0000052 0.000164 0.9749

0.002339 0.004347 0.5919

-0.00000076 0.00000032 0.0183

0.0199 0.007146 0.0066

-0.000303 0.000590 0.6088

0.00000158 0.000141 0.9108

0.003673 0.002023 0.0729

and 8 (Table 5) revealed a negative association between AIRgand weight gain (P = 0.025) comparable to the relationsh ipsdescribed for insulin secretion during the MTT and OGTT.Again, this negative correlation remained significant afteradjusting for age, sex, initial body weight, and either submaxM (model 7) or max M (model 8). Similar to previous models,max M, but not submax M, was significantly positively cor-

related with weight gain (P = 0.016) after controlling forpossible confounders.

Discussion

The principal finding of the current study is that relat ivelyreduced insulin secretion was identified as a significant ris kfactor for an increase in body weight in Pima Indians whowere already moderately obese and had normal glucose tol-erance. The correlations between the change in body weightand the baseline level of insulin secretion, whether deter-mined in response to a standard meal, to an oral glucose load,or to an iv glucose challenge (r = -0.35, -0.30, and -0.28,

respec tively) are simi lar to those reported in previous studiesof Pima Indians between the rate of weight gain and respi-ratory quotient (r = 0.27) (171, basal metabolic rate (r =-0.151, and adjusted 24-h energy expenditure (r = -0.39)(18). The observational nature of these findings precludes theidentification of a causal relationship between insulin secre-tion and weight gain, and an unidentified factor could con-tribute to the association reported here. To minimize thispossibility , we analyzed the relationship between insulinsecretion and weight gain after controlling for potential con-founding variables, including age, body weight, and insulinsensitivity. The results of this analysis indicate that a rela-tively low level of insulin secretion is a strong independentpredictor of weight gain in this population.

Insulin resistance, determined as either a relatively re-duced submax M or max M value, was also predictive ofweight gain in univariate analyses, consistent with a previ-ous study of Pima Indians (4). After controlling for differ-ences in insulin secretion, however, the association betweensubmax M and weight gain was not significant in anyregression model, whereas each of the three measures of

TABLE 5. Multip le linear regression analyses of yearly percent

weight change by characteristics of interest

Independent variables Regression coefficient SE P value


yearly % wt change

Model 7

AR -0.0000515 0.000023 0.0251

Sex 0.012810 0.006967 0.0693

Ag e -0.000417 0.000598 0.4879

Initial BW -0.000012 0.000164 0.9428

Submax M 0.005500 0.003913 0.1633

Model 8

A&z -0.000048 0.000022 0.0302

Sex 0.011245 0.006542 0.0891

Ag e -0.000616 0.000583 0.2940

Initial BW 0.000040 0.000139 0.7752

MaxM 0.004381 0.001789 0.0162

The acute insulin response to glucose (AIRg) is included as the

measure of insulin secretion.







INSULIN SECRETION PREDICTS WEIGHT GAIN 1575

insulin secretion was a significant predictor of weight gaineven after adjusting for differences in submax M. In contrast,

max M was identified as a significant independent predictorof weight gain in some, but not all, regression models, in-dicating that this measure of insulin action may be predictiveof weight gain independent of its association with insulin

secretion. Taken together, these findings suggest that in PimaIndians, the level of insulin secretion may be a stronger

predictor of changes in body adiposity than is the level ofinsulin sensitivity, but that both parameters may have anindependent predictive effect. Further studies are necessary

to clarify the relative contributions of insulin secretion, in-

sulin sensitiv ity, and the interaction between them to the riskof weight gain identified in our study.

The concept that increased insulin secretion protectsagainst weight gain seems, upon initial consideration, to be

counterintuitive. Given insulin ’s potent lipogenic effects andthe major role suggested for hyperinsulinemia in the patho-

genesis of obesity in rodent models (191, increased insulinsecretion might be expected to promote, rather than prevent,

weight gain. A hypothesis that reconciles the lipogenic action

of insulin with a protective effect of increased insulin secre-tion on weight gain is based on evidence that insulin sig-

naling in the brain causes a catabolic response that counter-

balances its anabolic effects in peripheral tissues (6). Supportfor this hypothesis derives from the demonstration that cir-culating insulin gains access to the brain via a specialized

vascular transport mechanism (20-221, and that intracranialinsulin administration lowers food intake and body weight

across mammalian species [including baboons (231, sheep

(24), and rats (25); see Ref. 26 for review]. The neural basisfor this insulin effect includes the regulation of genes en-coding neuropeptides (26) and catecholamine cotransport

proteins (27) in brain areas that control feeding behavior. Theopposing nature of peripheral and central insulin action pro-

vides the foundation for the hypothesis that insulin resis-tance and hyperinsulinemia represent adaptive responses toincreased adiposity, which, by increasing central nervoussystem (CNS) insulin signaling and suppressing food intake,

confer resistance to weight gain. Our finding that the capac-

ity to secrete insulin is inverse ly related to the risk of weightgain in Pima Indians is consistent with this hypothesis.

The mechanism responsible for the protective effect ofincreased insulin secretion on weight gain in Pima Indianscannot be ascertained from the results of this study. Specif-

ically , it is not known whether weight gain associated withrelatively reduced insulin secretion is the result of increased

caloric intake, reduced energy expenditure, or both. How-

ever, as only --lo-12% of the variance in weight gain in thecurrent study was attributable to differences in insulin se-

cretion, the level of insulin secretion is not the only factor

playing a role in the development of obesity in Pima Indians.Moreover, obesity develops in this population despite

marked hyperinsulinemia compared to other ethnic groups.This observation suggests that a reduction in the ability of thebrain to respond to increased circulating insulin levels may

coexist with peripheral tissue insulin resistance in Pima In-dians. Findings of blunted CNS insulin responsiveness in the

genetically obese fa/fa Zucker rat may be relevant to thepresent report. In these animals, marked insulin resistance

and hyperinsulinemia accompany defects in both the trans-

port of insulin into the CNS (28, 29) and the ability of cen-trally administered insulin to regulate neuropeptide expres-sion (30) and inhibit food intake (25). These findings raise the

possibility that a syndrome of generalized insulin resistance(affecting both the periphery and the brain) may play an

etiological role in certain forms of genetic obesity, includingthat conferred by the thrifty genotype. Additional studies to

confirm these results in other populations and in individua lsbefore the onset of obes ity are required to further clarify therole of insulin secretion in long term body weight regulation.

In conclusion, we have identified a significant effect of

reduced insulin secretion to predispose to weight gain in a

prospective study of Pima Indians with normal glucose tol-erance. This effect of reduced insulin secretion was found tobe independent from the previously reported association ofinsulin resistance with a reduced rate of weight gain in this

population. Insulin resistance and hyperinsulinemia, there-

fore, are unlikely to play a primary role in the pathogenesisof obesity in this population. These results are consistent with

the hypothesis that the ability to increase insulin secretion in

parallel with increasing adiposity limits further weight gainand plays an important role in long term body weight reg-

ulation. Moreover, because relatively reduced insulin secre-tion is also an independent predic tor of the development of

NIDDM in Pima Indians (12), our results are consistent withthe hypothesis that relatively reduced insulin secretion con-

tributes to the progression of both obesity and glucose in-tolerance in subjects bearing the thrifty genotype, a progres-

sion that leads to overt B-ce ll failure and NIDDM.

Acknowledgments

Data were collected at the Clinical Research Center of the Clinical

Diabetes and Nutrition Section of the NIDDK and analyzed at the

Department of Medicine, University of Washington and ceterans Af-

fairs Medical Center (Seattle, WA). The authors eratefullv acknowledee

the critical review of this manuscript provided by Drs. Daniel Porte, Jy.,

and Stephen C. Woods.

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Satel lite Symposium of the 15th Congress of the International Federationof Fertility SocietiesUFFS)

WEIGHT, NUTRITION AND HORMONAL EVENTS IN WOMEN

Basic and Clinical Aspects

Impact on Hormonal Therapies

Montpellier (France)

September 15-16,1995

Organizing committee: J. Bringer, A. Basdevant (France).

Cong ress Organization: Soci& le Coru m, Esplanade Charles de Gaulle BP 2200,34027 Montpellier Cede x

1 France. PHON E: (33) 67 61 67 61; FAX: (33) 67 61 66 84.





Documents

Reduced insulin secretion: an independent predictor of body weight gain