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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 9 4232-4238
Copyright © 2003 by The Endocrine Society

Fat Distribution, Lipid Accumulation in the Liver, and Exercise Capacity Do Not Explain the Insulin Resistance in Healthy Males with a Family History for Type 2 Diabetes

Else H. Johanson, Per-Anders Jansson, Lars Lönn, Yuji Matsuzawa, Tohru Funahashi, Marja-Riitta Taskinen, Ulf Smith and Mette Axelsen

Lundberg Laboratory for Diabetes Research (E.H.J., P.-A.J., U.S., M.A.), Departments of Body Composition and Metabolism, Radiology (L.L.), and Internal Medicine, Sahlgrenska Academy at Göteborg University, SE-413 45 Göteborg, Sweden; Department of Internal Medicine and Molecular Science (Y.M., T.F.), Osaka University, 565-0871 Osaka, Japan; and Department of Medicine (M.-R.T.), University of Helsinki, Helsinki, Finland FIN-00029

Address all correspondence and requests for reprints to: Else H. Johanson, The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska Academy at Göteborg University, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. E-mail: else{at}medic.gu.se.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
To explore the mechanisms for the insulin resistance associated with a family history of type 2 diabetes, we studied 16 healthy men with at least two first-degree relatives with type 2 diabetes and 16 control subjects without known heredity. They were pair-wise matched for age, body mass index, and fasting triglycerides and underwent an oral glucose tolerance test, iv glucose infusion to measure the early insulin secretion, euglycemic hyperinsulinemic clamp, computed tomography scan, 7-d food record, and a cardiopulmonary exercise test to measure peak oxygen uptake. Insulin sensitivity index was 30% lower (P = 0.02) in relatives, compared with controls, but fasting and 2-h blood glucose and first-phase insulin secretion were similar. There were no differences in mean fasting free fatty acid levels, amount of sc or visceral adipose tissue, or fat accumulation in the liver. Dietary intake and peak oxygen uptake were also similar. However, multiple regression analysis of both groups showed that fat in the liver and physical capacity were, like known heredity for type 2 diabetes, independent predictors of insulin sensitivity. Thus, lipid accumulation in the liver and physical capacity are related to insulin sensitivity, but neither of these factors nor the amount and distribution of the body fat can explain the insulin resistance associated with a family history for type 2 diabetes.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IMPORTANT FACTORS PRECEDING the development of type 2 diabetes are insulin resistance and ß-cell dysfunction. Insulin resistance is associated with an impaired glucose uptake in the major target organs for insulin action, i.e. muscle, liver, and fat (1). The patients maintain normoglycemia as long as the capacity of the ß-cells is able to compensate for the insulin resistance by an increased insulin secretion. When this compensatory mechanism fails, type 2 diabetes ensues.

First-degree relatives of type 2 diabetic patients have been characterized as being insulin resistant (2, 3, 4), having a reduced first-phase insulin secretion in response to glucose (5, 6) and abdominal obesity (7). In fact, it has been suggested that abdominal obesity is the key link to the development of insulin resistance (8). However, to dissect possible inherent factors for insulin resistance from other confounding associations, it is critical to have carefully matched individuals with or without known predisposition and who are at a very early stage of the development of type 2 diabetes.

Two current working hypotheses may each provide a plausible explanation for how an increased fat mass could be associated with insulin resistance. First, adipose tissue is an endocrinologically active tissue, releasing several hormones/proteins that can influence insulin’s effect on metabolism, such as leptin (9), IL-6 (10), TNF-{alpha} (11), and adiponectin (12). Second, insulin resistance could arise through high rates of free fatty acids (FFAs) released, in part, from an expanded intraabdominal fat mass, the portal vein theory (13), and/or the expanded total adipose tissue mass associated with abdominal obesity (14) because these two factors are closely correlated. Alternatively, these links may only partly explain the insulin resistance, and individuals with genetic predisposition for type 2 diabetes may exhibit insulin resistance also without an expanded fat mass.

To understand the sequence of events leading up to type 2 diabetes, it is critically important to characterize the early prediabetic state. We, therefore, measured insulin sensitivity, insulin secretion, and body composition in nonobese individuals with a family history of type 2 diabetes and compared the results with those seen in control subjects lacking a known family history. The subjects were individually matched for age, body mass index (BMI), and fasting triglycerides to define early phenotypic characteristics associated with a hereditary predisposition for type 2 diabetes.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Healthy male subjects with at least two first-degree relatives with type 2 diabetes (R, n = 16) and control subjects without known relatives with type 2 diabetes (C, n = 16) were recruited through advertisement in local newspapers. The criteria for inclusion were nonsmokers (snuff was allowed), age 25–55 yr, BMI 22–30 kg/m2, normal glucose tolerance during an oral glucose tolerance test (OGTT) (75 g glucose) according to the World Health Organization criteria (15), fasting triglycerides less than 1.7 mmol/liter and no known endocrine or metabolic disease. The two groups were individually matched for age, BMI, and fasting triglycerides. The participants were asked to abstain from alcohol and excessive physical exercise for 2 d before each day of examination. The study was approved by the Ethical Committee of Göteborg University and was consistent with the principles of the Declaration of Helsinki. All participants gave informed consent.

OGTT

The subjects underwent an OGTT (75 g glucose). Blood glucose was measured at 0 and 120 min with a glucose analyzer (Yellow Spring Instruments, Yellow Springs, OH).

Intravenous glucose tolerance test (IVGTT)

An IVGTT was performed to determine the first-phase insulin secretion capacity. After an overnight fast, an iv catheter was placed in the antecubital vein for infusion of glucose. Another cannula for blood sampling was inserted into a hand vein. The underarms were kept in heated pads (~55 C) to arterialize the blood. After baseline blood collection, 300 mg glucose /kg body weight (30% glucose solution) was given within 60 sec to acutely increase the blood glucose level. Samples for plasma glucose were drawn at -5, 0, 2, 4, 6, 8, and 10 min and were analyzed with a glucose analyzer (Yellow Spring Instruments). Plasma samples for insulin were drawn at the same time and were analyzed by the MEIA (Microparticle Enzyme Immunoassay) method (Abbott, Wiesbaden, Germany). The acute insulin secretory response to iv glucose was calculated as the average incremental plasma insulin concentration from the fourth to the sixth minute after glucose bolus (16).

Euglycemic hyperinsulinemic clamp

Insulin sensitivity was measured with the euglycemic hyperinsulinemic clamp technique, essentially as described (17). Briefly, 60 min after the start of the IVGTT, human insulin (Actrapid, Novo Nordisk, Copenhagen, Denmark) was infused as a priming dose for the first 10 min, followed by a continuous infusion (60 mU/m2 body surface/min-1) for 2.5 h. Glucose infusion was also started and the infusion rate adjusted to clamp the blood glucose at 5.0 mmol/liter, assessed at 5-min intervals with a glucose analyzer (Yellow Spring Instruments). Steady-state blood glucose was 5.1 ± 0.03 (coefficient of variation 2.7%) and 5.1 ± 0.07 mmol/liter (coefficient of variation 5.2%) in relatives and controls, respectively. The glucose infusion rate during the last 30 min served as a measure of the subject’s insulin sensitivity and was expressed as glucose disposal rate [milligrams * kilograms lean body mass (LBM)-1 * minute-1], i.e. glucose infusion rate divided by kilogram LBM (M-value). The insulin sensitivity index (ISI) is a measure of the sensitivity in relation to the prevailing plasma insulin concentration and is calculated by dividing the M-value by the steady-state insulin concentration during the last 30 min of the clamp [(100 * milligrams * liter) * kilograms LBM-1 * minutes-1 * picomoles-1]. LBM was calculated from total body 40K determined in a whole-body counter (18). FFA levels were determined with an enzymatic colorimetric method (Wako Chemicals, Neuss, Germany).

Body fat composition and fat distribution

Body composition was determined with a HiSpeed Advantage (HSA) CT system (version RP2, GE Medical Systems, Milwaukee, WI) The scanning was performed with 120 kV, using a slice thickness of 5 mm and fixed filtration. Four scans were obtained from each participant. Scan 1 was obtained in the midthigh region 1 cm below the gluteal fold, scan 2 at the fourth lumbar vertebra level (L4), scan 3 at midliver level, and scan 4 at the fourth cervical vertebra level (C4). From scan 1 the tissue areas of the right leg were reported. The images from the computed tomography (CT) scanner were transferred to a separate UNIX-based analyzing unit. Tissue areas were determined as previously described (19) with the following precision errors calculated from double determinations: sc adipose tissue (0.5%), the sum of visceral adipose tissue (1.2%). The attenuation values of the liver and spleen were determined within three circular regions of interest placed in the dorsal aspects of each organ. Attempts were made to avoid blood vessels, artifacts, and areas of inhomogeneity. The attenuation, i.e. the density of the parenchyme, was measured in Hounsfield units (HU). The attenuation of normal liver, measuring between 45 and 65 HU, is generally 8 HU greater than that of the spleen on noncontrast CT images. In patients with fat infiltration, however, an abnormally decreased density will be demonstrated, typically 10–20 HU less than the spleen (20). This definition was used in the present work to characterize whether a low attenuation of the liver was due to an increased fat content.

Cardiopulmonary exercise test

A cardiopulmonary exercise test was performed with a bicycle ergometer (Rodby Electronic AB, Södertälje, Sweden) in the upright position until exhaustion. A Vmax 29c system (Sensor Medics Corp., Yorba Linda, CA), containing paramagnetic oxygen analyzer and a nondispersive infrared carbon dioxide analyzer, was used. Accuracy for O2 and CO2 was ±0.002%. The initial workload was 70 W with subsequent increments of 20 W/min. Blood pressure, heart rate, a 12-lead electrocardiogram, subjective symptoms, and perceived exertion were recorded during the test. The highest oxygen uptake (VO2) measured during the highest workload was used for peak VO2 level.

Dietary assessment

During 7 consecutive days, the participants recorded all food and drink intake using household measures (cups, spoons, etc.). The food record was completed by looking at photographs showing such factors as portion sizes, amount of spread used on sandwiches, and portion sizes of bread (21). A software package (Diet32, Aivo AB, Spånga, Sweden) was used to calculate the nutrient intake. This package is based on the Swedish National Food Administration’s nutrient database (1997). The statistical power for our possibility to detect differences between the group on intake of energy, macronutrients, dietary fiber, and alcohol was analyzed (22) and was 80% or more for all dietary parameters, except for alcohol, which was around 45%.

Plasma adiponectin concentration

Blood samples were drawn after an overnight fast and plasma samples were kept at -80 C for subsequent assay. The plasma concentration of adiponectin was determined as described elsewhere (23).

Statistical analyses

Data are presented as means ± SEM unless otherwise stated. The incremental area under the curve (IAUC) was calculated according to the trapezium rule (24). Wilcoxon’s signed-rank test was applied for paired comparisons between the relatives and control group. Relationship between insulin sensitivity and eight potential explanatory variables were explored by Spearman rank correlation test and visualized by scatter plots. To examine the major explanatory variables of insulin sensitivity, forward stepwise regression analyses were performed. The parameters that individually were related to insulin sensitivity index (P < 0.07 or less) by simple linear regression analyses were entered, three at a time (25). Heredity was entered as an independent variable in all models. A two-tailed P = 0.05 was used as a criterion to determine statistical significance. Attenuation of liver and adiponectin were not normally distributed and were therefore log transformed before regression analyses. All analyses were done with and without the relative with impaired glucose tolerance (IGT) and the results did not change. The results are, therefore, presented for all subjects.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Anthropometric and biochemical characteristics

As shown in Table 1Go, the two groups were well matched. The relatives had higher fasting insulin levels (55.5 ± 4.2 vs. 42.2 ± 3.3 pmol/liter, P = 0.04), but there were no significant differences in any of the other parameters. One of the relatives had IGT. There were four snuff users among the relatives and three in the control group.


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  		TABLE 1. Anthropometric and biochemical characteristics of the subjects

 
Insulin sensitivity

As shown in Fig. 1Go, the relatives were significantly less insulin sensitive than the control group, in spite of the fact that they reached higher insulin levels during the clamp [insulin level during steady state: 839 ± 33 vs. 717 ± 33 pmol/liter, P = 0.02; M-value: 11.9 ± 0.6 vs. 14.3 ± 0.9 mg * kg LBM-1 * min-1, P = 0.05; ISI: 1.5 ± 0.1 vs. 2.1 ± 0.2 (100 * mg * liter) * kg LBM-1 * min-1 * pmol-1, P = 0.02].



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  		FIG. 1. ISI in relatives and control subjects. Individual and mean values are shown. *, P = 0.02.

 
FFA levels

The fasting FFA levels were similar in the two groups (Table 1Go), and there were no differences between the groups in the suppression during the clamp (R: 0.48 ± 0.04 vs. C: 0.54 ± 0.04 mmol/liter, P = 0.84).

First-phase insulin secretion

For technical reasons, only 12 pairs underwent an IVGTT. The first-phase insulin secretion was similar for both groups (insulin 0–10 min IAUC: 2810 ± 573 vs. 2930 ± 641 pmol/liter * min, P = 0.94) also after adjustment for prevailing glucose concentration (insulin IAUC/glucose IAUC: 252 ± 54 vs. 306 ± 72 pmol * mmol-1, P = 0.88) (Fig. 2Go). The acute insulin secretory response to iv glucose showed the expected curvilinear correlation to ISI in the control group, but this was not seen in the relatives because of the large variation in insulin secretion at low insulin sensitivity (Fig. 3Go). One relative with both low ISI and first-phase insulin secretion was characterized as IGT.



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  		FIG. 2. First-phase insulin secretion expressed as insulin/glucose levels IAUC during 0- to 10-min IVGTT. Data represent means ± SEM (black circles = relatives; white circles = controls). P = 0.94.

 


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  		FIG. 3. Relationship between insulin sensitivity and ß-cell function, defined as early insulin response (4–6 min) in relatives (black circles, dotted line), P = 0.81 and control subjects (white circles, dashed line), P = 0.03.

 
Plasma adiponectin concentration

The fasting plasma adiponectin levels were not different between the two groups (R: 6.75 ± 0.74 vs. C: 6.69 ± 0.74 µg/ml, P = 0.92).

Body composition

Body composition data are presented in Table 1Go. Data presented are from n = 15 pairs because one relative refused to perform the CT investigation. There were no differences between the groups in the amount of visceral adipose tissue, sc adipose tissue at L4 level or the degree of liver attenuation (Table 1Go). The individuals who had the lowest values of liver attenuation (<38 HU) also showed the expected changes in the relationship to the spleen, thus supporting the conclusion that they had increased liver fat ({Delta}liver-spleen: -10 to -19 HU).

Cardiopulmonary exercise test

Data presented are from n = 15 pairs because one relative refused to perform the test. There was no difference in the peak VO2 between the groups (R: 36.2 ± 1.2 vs. C: 37.2 ± 1.5 ml * kg-1 * min-1, P = 0.69), and the values are in the lower part of the normal range (normal range 30–55 ml * kg-1 * min-1). The same result was obtained when expressing peak VO2 in terms of ml * kg LBM-1 * min-1 (47.9 ± 1.6 vs. 49.0 vs. 2.1 ml * kg LBM-1 * min-1, P = 0.61).

Dietary assessment

There was no difference in total energy intake between the groups (R: 2732 ± 128 vs. C: 2613 ± 124 kcal, P = 0.68). The energy-adjusted intake (E%) of fat, carbohydrate, and protein was also similar (E% of fat: 31 ± 1 vs. 32 ± 1, P = 0.78, E% of carbohydrate: 50 ± 1 vs. 49 ± 1, P = 0.46, E% of protein: 16 ± 1 vs. 16 ± 1, P = 0.37). The groups also had similar values of total and energy-adjusted intake of saturated fat (42.9 ± 2.8 vs. 36.8 ± 3.5 g, P = 0.16 and 14 ± 1 vs. 13 ± 1 E%, P = 0.15, respectively) as well as alcohol (14.3 ± 3.6 vs. 9.6 ± 2.4 g, P = 0.31).

Relationship between insulin sensitivity and body measurements, peak VO2, FFAs, triglycerides, and adiponectin

To examine which factors were related to insulin sensitivity for the whole study population, nonparametric correlations as well as scatter plots were performed to visually evaluate the relationship (Fig. 4Go). ISI was significantly negatively correlated to sagittal diameter and sc fat mass and positively correlated to adiponectin and attenuation of the liver, a marker of degree of lipid accumulation. The partial correlation analyses showed that when controlling for heredity for diabetes, the significant correlations among sagittal diameter, attenuation of the liver, adiponectin, and insulin sensitivity persisted, whereas the correlation between insulin sensitivity and sc fat mass did not reach statistical significance (P = 0.11). Fasting FFAs and triglycerides did not correlate with insulin sensitivity. In addition to its association to insulin sensitivity, adiponectin levels were positively correlated to attenuation of the liver (r2 = 0.16, P = 0.03) (Fig. 5Go) and thus inversely related to degree of lipid accumulation.



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  		FIG. 4. Relationship between insulin sensitivity and body measurements, peak VO2, FFAs, triglycerides, and adiponectin in relatives (black squares) and control subjects (white squares). *, P < 0.05; **, P < 0.001.

 


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  		FIG. 5. Linear regression plot of attenuation of the liver and adiponectin (relatives: black circles, control subjects: white circles). Dotted lines show 95% confidence limits. Both parameters were loge transformed because of nonnormal distribution, r2 = 0.16, P = 0.03.

 
Stepwise multiple regression analyses

The individual simple regressions showed that five variables had a relationship to insulin sensitivity with P < 0.07 or less (Table 2Go). The model with log attenuation of liver, peak VO2, and heredity showed the largest explanation of the variation in insulin sensitivity with a total explanatory power of 53% (Table 2Go).


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  		TABLE 2. Linear regression showing independent predictors of insulin sensitivity

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study was designed to allow a comparison between individuals at high risk for type 2 diabetes, i.e. with a strong family history for the disease, compared with those without a known heredity but individually matched for BMI and triglycerides, common markers of the insulin resistance (or metabolic) syndrome as well as age. The salient findings of the study were: 1) impaired insulin sensitivity was seen in the relatives in the absence of any difference in visceral fat mass and fasting FFA levels; 2) liver lipid accumulation and physical capacity (peak VO2) were, like heredity for diabetes, predictors of insulin sensitivity; and 3) adiponectin levels correlated positively with insulin sensitivity and negatively with liver lipids.

A current concept is that an abdominal fat distribution and elevated FFA levels are key factors associated with a family history for type 2 diabetes (7). Increased fasting FFA levels or an impaired suppression of lipolysis by insulin in relatives have been reported by some (26) but not all (27, 28) investigators. The group of relatives in our study was closely similar to the control group with respect to abdominal fat mass and fasting FFA levels. Despite this, the relatives showed a 30% reduction in insulin sensitivity. On the other hand, there was a significant correlation between insulin sensitivity and sagittal diameter, which reflects abdominal fat mass, for the two groups combined and this persisted in the partial correlation analyses. Thus, increased abdominal fat mass or elevated FFA levels are not prerequisites for the insulin resistance associated with a family history for type 2 diabetes, but abdominal fat mass is still a factor that is related to degree of insulin sensitivity.

Diet and nutrition are considered to play an important role in the development of type 2 diabetes, but specific factors have not been clearly defined (29). Generally, a high carbohydrate-low fat diet is recommended and the starchy carbohydrates should be of slow-release origin (i.e. carbohydrates with low glycemic index) and the saturated fat intake should be reduced (29). However, dietary intake was similar in the relatives and controls.

Decreased physical capacity has previously been reported to be a component of the prediabetic state in some (30, 31) but not all (27, 32) reports. In this study, there was no difference between the groups. One reason for this discrepancy might be that the careful matching of the two groups also eliminated differences in physical capacity and dietary intake. However, peak VO2 was a predictor of insulin sensitivity for the whole study population. This finding is in line with the prospective study of Eriksson and Lindgarde (33), showing that poor physical capacity is a predictor for developing type 2 diabetes and negatively associated with insulin sensitivity.

Taken together, the present data suggest that insulin resistance associated with a family history for type 2 diabetes cannot be explained by the factors measured in this study, i.e. body composition, fat distribution, physical capacity, and accumulation of fat in the liver. To what extent an increased accumulation of intramyocellular lipids may contribute (34) was not assessed. However, in animal models of insulin resistance, fat accumulation in the liver is also accompanied by an increased amount of intramyocellular lipids (35).

A recent prospective study concluded that insulin resistance is by itself not a good predictor of risk for type 2 diabetes in the absence of a family history for the disease (36). Interestingly, known heredity for type 2 diabetes was also an independent predictor of insulin sensitivity in this study.

It is a much debated question whether an impaired first-phase insulin secretion (i.e. defect ß-cell function) is an early, independent feature of type 2 diabetes or whether it is secondary to insulin resistance and hyperglycemia. Eriksson et al. (4) and Martin et al. (37) reported that individuals with a normal glucose tolerance (like our group) had normal first-phase insulin secretion, whereas subjects with an IGT also had impaired insulin secretion. Groop et al. (38) reported that the first-phase insulin secretion is decreased only when the 2-h glucose level during an OGTT exceeds 9 mmol/liter. With the exception of one subject, our study population had 2-h glucose levels less than 9 mmol/liter. However, when related to the degree of insulin sensitivity, some of the relatives had a low first-phase insulin secretion, whereas all the control subjects showed the expected curvilinear relationship. When studying the second-phase insulin secretion in the same way, we found a similar curvilinear relationship in both groups. Thus, this does not support the view that also the second phase of insulin secretion is impaired in the early prediabetic state (39). The present data rather support the concept that the development of a reduced glucose tolerance is associated with, and possibly caused by, an impaired early insulin response to glucose in relation to the prevailing degree of insulin sensitivity.

Healthy, first-degree relatives to subjects with type 2 diabetes have also previously been found to have an increased prevalence of biopsy-proven nonalcoholic fatty liver disease (40). Similarly, Marchesini et al. (41) reported that nonalcoholic fatty liver disease is associated with insulin resistance and hyperinsulinemia in lean subjects with a normal glucose tolerance. In the present study, we saw no difference between the groups in degree of liver attenuation. Thus, the decreased insulin sensitivity in the relatives could also not be explained by the degree of lipid accumulation in the liver. However, the present data also show that both liver lipid accumulation, physical capacity, and heredity for type 2 diabetes are important predictors of insulin sensitivity in the combined group. This is consistent with previous studies that have shown that nonalcoholic steatohepatitis and nonalcoholic fatty liver disease are associated with insulin resistance (42) and severe obesity (43). Similarly, Goto et al. (44) found a correlation between insulin sensitivity and fat in the liver in lean Japanese individuals without liver disease. Moreover, an increased inappropriate accumulation of lipids in both the liver and muscles has been found in insulin-resistant states in man (45, 46) and different animal models of lipoatrophy and insulin resistance (35, 47). However, it is not clear whether this is causally related to the insulin resistance or merely another marker or consequence of the insulin resistance. Arguments to support both possibilities can be made. High local FFA levels may inhibit glucose metabolism through the Randle cycle (48) or through malonyl coA as described by Saha et al. (49). However, it is also possible that the hyperinsulinemia per se, which is a consequence of the insulin resistance, may play an important role. Insulin is a powerful activator of the transcription factor sterol regulatory element-binding protein-1c, which, in turn, regulates the expression of key lipogenic enzymes (50, 51). In this scenario, the lipid accumulation is secondary to the hyperinsulinemia and the insulin resistance. Some support for this possibility is the moderate negative correlation found between ambient insulin levels and degree of lipid accumulation in the liver (r2~36%).

Adiponectin, the recently detected adipocyte-derived protein, has previously been reported to be associated to insulin sensitivity (12), and our study supports this finding. Still, the mean adiponectin levels were similar in both groups and thus do not alone explain the decreased insulin sensitivity in the relatives. The increased insulin sensitivity following adiponectin administration is associated with an increased fatty acid oxidation and decreased lipid levels in liver and muscle (52). An important novel observation in the present study was that attenuation of the liver correlated to the circulating adiponectin levels. This relationship could, at least in part, explain the correlation between insulin sensitivity and adiponectin levels. Thus, although the adiponectin levels were not significantly different between the relatives and control subjects, the present data support a role for adiponectin in regulating insulin sensitivity and, possibly, amount of inappropriately stored lipids in the liver.

In conclusion, the present study shows that insulin sensitivity is decreased in nonobese and carefully matched male first-degree relatives to subjects with type 2 diabetes. This seems to be an inherent defect and could not be explained by differences in fat distribution, fat mass, circulating adiponectin levels, attenuation of the liver, dietary intake, or physical capacity. However, degree of insulin sensitivity in all subjects was, in addition to heredity for type 2 diabetes, most strongly related to liver lipids and physical capacity. Thus, these factors, like amount of body fat, can play important roles in the regulation of insulin sensitivity, but they are not necessary for the insulin resistance associated with a family history for type 2 diabetes in men.


   Acknowledgments
 
We thank Margareta Landén, Eva Bergelin, Maria Cedhagen, and Ann-Christin Carlsson for excellent technical assistance.


   Footnotes
 
This work was supported by grants from the Arne and Inga Britt Lundberg Foundation, Swedish Research Council, Swedish Diabetes Association, European Union (QLGI-CT-1999-00674), Novo Nordisk Foundation, Novo Nordisk Pharma AB, Sweden, Swedish Medical Society, Göteborg Medical Society, Sonya Hedenbratt Memorial Fund, and Helsinki University Central Hospital Research Foundation.

Abbreviations: BMI, Body mass index; CT, computerized tomography; E%, energy-adjusted intake; FFA, free fatty acid; HU, Hounsfield unit; IAUC, incremental area under the curve; IGT, impaired glucose tolerance; ISI, insulin sensitivity index; IVGTT, iv glucose tolerance test; LBM, lean body mass; M-value, glucose infusion rate divided by kilogram LBM; OGTT, oral glucose tolerance test; VO2, oxygen uptake.

Received December 13, 2002.

Accepted May 23, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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