Introduction

In the last few years it has been shown that metabolically healthy obese (MHO) individuals comprise roughly 30% of obese people and 10% of the adult general population [1–5]. In addition to having insulin sensitivity that is similar to non-obese individuals, MHO individuals have lower liver fat content and lower intima media thickness (IMT) of the common carotid artery than obese insulin-resistant (OIR) individuals [6].

Current obesity treatment guidelines do not separate MHO and OIR individuals and recommend treatment for all obese individuals, the first-line approach being lifestyle intervention [7]. Data about the effects of lifestyle modifications specifically in MHO and OIR populations are sparse: two small studies implemented energy-restriction diets for 12 weeks and 6 months in women [8, 9], and one a 6 month exercise intervention programme, also in women [10]. All three studies showed an improvement in cardiovascular risk profile in OIR, but not in MHO, women, despite similar weight loss [8–10]. In view of these findings and the limited healthcare resources, the necessity and the benefit of a lifestyle intervention in MHO individuals has been questioned [11, 12]. On the other hand, while OIR individuals clearly benefit from the lifestyle intervention [8–10], it is important to know whether this effect is sufficient to place them in a position where protection from obesity-related metabolic consequences is expected. If not, early pharmacological treatment, in addition to the lifestyle intervention, would be the appropriate strategy for these high-risk individuals in order to reduce incidence rates of type 2 diabetes and cardiovascular disease.

In the present study we addressed this question, using state-of-the-art methods to carefully phenotype 262 non-diabetic individuals who underwent a 9 month structured lifestyle intervention.

Methods

Among the 314 white individuals from southern Germany at risk for type 2 diabetes who were included in our previous report [6], 262 participated in our Tübingen Lifestyle Intervention Program (TULIP) [13]. After the baseline measurements, individuals underwent dietary counselling and had up to ten sessions with a dietitian. During each visit participants presented a 3 day food diary and discussed the results with the dietitians. Counselling was aimed to reduce body weight by ≥5%, to reduce the intake of energy from fat to <30% and particularly the intake of saturated fat to ≤10% of energy consumed and to increase the intake of fibre to at least 15 g/4,184 kJ (1,000 kcal). Individuals were asked to perform at least 3 h of moderate sports per week. All participants completed a standardised self-administered and validated questionnaire to measure physical activity and a habitual physical activity score was calculated. Participants were seen by the staff on a regular basis to ensure that these recommendations were followed [13]. Informed written consent was obtained from all participants and the local medical ethics committee approved the protocol.

All individuals underwent a 75 g OGTT. Insulin sensitivity was calculated from the OGTT as proposed by Matsuda and DeFronzo [14] and with the homeostasis model insulin resistance index [15].

Total body, visceral and subcutaneous abdominal fat were measured with magnetic resonance (MR) tomography (Magnetom Sonata; Siemens Medical Solutions, Erlangen, Germany), and liver fat and intramyocellular lipids in the tibialis anterior muscle (IMCLtibialis) with 1H-MR spectroscopy, as previously described by Kantartzis et al. and Stefan et al. [13, 16].

Blood glucose was determined using a bedside glucose analyser (glucose oxidase method; Yellow Springs Instruments, Yellow Springs, CO, USA). Plasma insulin was determined by microparticle enzyme immunoassay (Abbott Laboratories, Tokyo, Japan). Serum total cholesterol, HDL-cholesterol and LDL-cholesterol concentrations were measured with a standard colorimetric method using a Bayer analyser (Bayer HealthCare, Leverkusen, Germany).

Statistical analyses

Data are given as mean ± SE. Data that were not normally distributed (Shapiro–Wilk W test) were logarithmically transformed. Participants were first divided based on their BMI into three groups: normal weight (BMI < 25 kg/m2), overweight (BMI 25–29.9 kg/m2) and obese (BMI ≥ 30 kg/m2). In the obese group, men and women were further separately divided into quartiles based on their insulin sensitivity estimated from the OGTT. Men and women in the upper quartiles were then combined and represented MHO individuals, while men and women in the other three quartiles represented OIR individuals. Differences between baseline and follow-up were tested by the paired Student’s t test. Differences in group means were tested using the Student’s t test or multiple regression models with the variable of interest set as the dependent variable and sex and duration of follow-up as independent variables. A p value ≤0.05 was considered statistically significant. The statistical software package JMP 5.1 (SAS Institute, Cary, NC, USA) was used.

Results

Baseline characteristics of the participants

Among the 262 participants, 43 were normal weight, 116 were overweight, 26 were found to have MHO and 77 were OIR. The characteristics of the latter two groups at baseline are shown in Table 1. Similarly to the larger cohort [6], the groups differed in insulin sensitivity (all measures p < 0.0001), in liver fat content (p = 0.0008) and in IMCLtibialis (p = 0.001), but not in visceral fat (p = 0.07). Fasting glycaemia (p = 0.0014) and fasting and 2 h insulinaemia (both p < 0.0001) were higher in the OIR group.

Table 1 Participant demographic characteristics, body fat distribution and metabolic characteristics at baseline and after the intervention
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Longitudinal analysis

The mean duration of follow-up was 9.2 ± 0.2 months. Habitual physical activity was similar at baseline (p = 0.48) and increased similarly in both groups (OIR: 27.3%, MHO: 28.4%, p = 0.83), indicating that participants were compliant with the recommendations.

Changes in measurements of adiposity, body fat distribution and insulin sensitivity during the intervention are shown in Table 1. Body weight (OIR: p < 0.0001; MHO: p = 0.036) and waist circumference (both p < 0.0001) decreased in both groups. Visceral adipose tissue decreased in both groups (OIR: p < 0.0001; MHO: p = 0.009), but the decrease in total adipose tissue was significant only in the OIR group (OIR: p < 0.0001; MHO: p = 0.12). The largest decrease was seen in liver fat in the OIR group (35.4%, p < 0.0001), whereas in the MHO group the decrease was not significant (p = 0.47, Fig. 1a–c). A lesser decrease, albeit significant, in the OIR group (p = 0.036) was found for IMCLtibialis. Unexpectedly, there was a small reduction in HDL-cholesterol levels in both groups. However, this was statistically not significant, indicating that these changes are not clinically relevant.

Fig. 1
figure 1

Total body fat (a), visceral fat (b), liver fat (c) and insulin sensitivity (d) in OIR and MHO individuals. White bars, baseline; black bars, follow-up. (a) OIR p < 0.0001, MHO p = 0.12; (b) OIR p < 0.0001, MHO p = 0.0009; (c) OIR p < 0.0001, MHO p = 0.47; and (d) OIR p < 0.0001, MHO p = 0.30; all baseline vs follow-up. AU, arbitrary units

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Similarly to the changes in liver fat, insulin sensitivity, estimated from both the OGTT and the HOMA-IR, increased significantly only in the OIR group (both p < 0.0001), while no change was found in the MHO group (OGTT: p = 0.30; HOMA-IR: p = 0.51). In both groups the change in insulin sensitivity correlated with the change in all measures of adiposity (body weight, waist circumference and total body, visceral and liver fat), except intramyocellular fat (data not shown). However, despite the significant increase in insulin sensitivity in the OIR group, insulin sensitivity at follow-up barely exceeded 50% of the insulin sensitivity in the MHO group (9.30 ± 0.53 vs 16.41 ± 1.05 arbitrary units, p < 0.0001 after adjustment for sex and age, Fig. 1d).

Common carotid artery IMT, which was measured as previously described by Stefan et al. [6], improved, albeit not significantly (from 0.59 ± 0.01 to 0.57 ± 0.01 mm, p = 0.14) during the intervention in OIR individuals. In the MHO group a small increase (from 0.53 ± 0.02 to 0.59 ± 0.02 mm, p = 0.008) was found. However, because IMT is not expected to change very much over such a short period of time and because of the relatively small sample size, we consider this to be a chance finding. Regarding the circulating inflammatory markers C-reactive protein (CRP), IL-6 and TNF-α, significant changes were found only in the OIR group for a decrease in CRP and TNF-α (p = 0.025 and p = 0.005 respectively). The change of IL-6 levels in the OIR group and all changes in the MHO group were not significant.

Discussion

Current obesity treatment guidelines recommend similar treatment strategies for all obese individuals, beginning with a lifestyle intervention [7]. However, elegant studies from the groups of Gerald Reaven and others independently showed that obese individuals constitute an inhomogeneous group, with metabolically healthy obesity and obesity with rather severe metabolic consequences [1–5]. Therefore, and in the light of the limited health resources and the financial, personnel and time costs of a lifestyle intervention programme, it is of the utmost importance to distinguish the effects of a lifestyle intervention in MHO and OIR individuals. Preliminary data showed an improvement in cardiovascular risk profile in OIR, but not in MHO women, although both groups lost similar amounts of body weight [8–10].

In the present study we asked the specific question whether the beneficial effect of a lifestyle intervention in OIR individuals is sufficient to place them in a position where a lower risk for obesity-related metabolic diseases, principally type 2 diabetes and cardiovascular disease, can be expected. As insulin resistance is the most important common background of these disorders, the focus of our study was insulin sensitivity. Despite the significant increase during the lifestyle intervention in the OIR group, insulin sensitivity at follow-up barely exceeded 50% of the insulin sensitivity of the MHO group. When estimated by the HOMA-IR, insulin resistance at follow-up was close to the cut-off of 2.5 that is associated with clamp-measured insulin resistance [5], indicating that OIR individuals remained essentially insulin resistant despite the intervention. The same trend was noted with regards to body fat distribution and ectopic fat deposition, which is a major determinant of the MHO vs the OIR status [6] and of prediabetes [17]. Certainly, it may well be that a longer duration of our relatively intense intervention may have yielded more positive results for the OIR individuals.

In conclusion, our findings underline the potential benefits of differentiating MHO and OIR individuals in clinical practice. This would help to decide the right therapeutic strategy. For MHO individuals, the option of a lifestyle intervention seems to be less effective if the target is to improve insulin sensitivity, although it may positively affect non-metabolic causes of morbidity and mortality in obesity, such as cancer and traumatic incidences. For OIR people, a lifestyle intervention clearly has positive effects. However, their insulin sensitivity remains very low even after the intervention compared with the MHO group, which indicates putative inadequate protection from type 2 diabetes and cardiovascular disease. Thus, an early pharmacological treatment of obese insulin-resistant people, additional to the lifestyle intervention, may be considered as an appropriate therapeutic approach.