Type 2 diabetes is considered one of the greatest health crises of our time. People with PD carry significantly higher risk for diabetes than those with simple obesity (3
), therefore, discerning metabolic differences may prove useful as therapeutic targets in diabetes prevention. This study examined the role of intramuscular lipid concentration and FSR as potentially distinguishing features between simple obesity and PD. Major findings from this study demonstrated higher basal IMTG concentration with synthesis rates that were metabolically “inflexible” in obese people with PD compared to a matched control group with NGT.
Over the past two decades, considerable attention has been paid to the frequent association between high IMTG concentration and insulin resistance (7
). Nonetheless, a direct cause–effect relationship between the two is unlikely for several reasons. First, mounting evidence shows that IMTG concentration and insulin action can be dissociated. Such was the case in trained athletes (10
), and endurance-trained formerly sedentary obese individuals (34
), where insulin sensitivity was maintained in an environment of high IMTG concentration. In addition, transgenic mice overexpressing diacylglycerol acyltransferase-1 display high levels of IMTG with enhanced insulin sensitivity compared to their wild-type littermates (11
). Second, no support is found in the literature for IMTG concentration directly causing insulin resistance. Rather, metabolites involved in the synthesis and/or degradation of IMTG may be more involved in mediating peripheral insulin action (35
). Together, these data have led to speculation about the role of IMTG synthesis, rather than total concentration, as a link to insulin resistance (12
). We believe that our data are the first to examine IMTG FSR in insulin-resistant humans. Our data suggest that obese individuals with PD tended to have lower insulin sensitivity and lower rates of IMTG synthesis than a matched group of obese individuals with NGT. Whether this relationship is a cause or a result of insulin resistance is unclear.
The relevance of IMTG synthesis to insulin action has been highlighted in several recent studies. Schenk et al.
clearly demonstrated the prevention of fatty acid–induced insulin resistance following a single bout of exercise in humans that related to increased IMTG synthesis, decreased DAG and ceramide, but not decreased IMTG concentration (14
). Increased insulin sensitivity has also been reported after exercise training, without changing IMTG concentration in obese individuals (34
), presumably due to enhanced IMTG FSR. In rodents, 1 week of exercise training or diacylglycerol acyltransferase-1 over-expression increased IMTG synthesis and protected against fat-induced insulin resistance, likely from decreased DAG and ceramide concentration (11
). Cell culture studies also suggest protection from lipotoxicity with increased IMTG synthesis (38
). Therefore, high rates of IMTG synthesis may act indirectly by decreasing the concentration of insulin-desensitizing intermediates, such as diacylglycerol (DAG), long-chain Acyl CoA, and/or ceramide (35
), that can modulate insulin action through activation of protein kinase C. Although no differences in PKC-ε were noted in this study, this measure was made in the basal (non-insulin-stimulated state) in two very closely matched groups, likely underestimating the indirect effects of IMTG FSR on insulin signaling and action.
Perhaps more noteworthy than the nonsignificant trend for higher IMTG FSR in NGT vs. PD in the basal state was the failure of IMTG FSR to suppress during exercise in the PD group. Sacchetti et al.
reported a basal IMTG FSR of 3.5%/h that completely suppressed during exercise in a group of healthy, young, lean volunteers (15
). First, basal IMTG FSR was ~0.3%/h in subjects in this study highlighting the dramatic effect of obesity and insulin resistance on this parameter. Second, the suppression of FSR during exercise was only seen in the NGT group, supporting the notion that the IMTG pool is metabolically inflexible in the progression toward diabetes. The latter contention is further supported by examination of palmitate handling. At baseline, palmitate Rd
was higher in NGT. Given that IMTG concentration was lower and FSR trended higher in this group, one would expect palmitate oxidation to be higher in NGT vs. PD, but this was not the case. It is possible, however, that although overall oxidation rates were similar, the source of the palmitate oxidized was different with more coming from muscle in NGT and more from blood in PD. The higher basal palmitate Rd
in NGT is likely a composite of higher oxidative and nonoxidative palmitate disposal into muscle in this group. Palmitate Rd
increased in both groups during exercise, but its fate appeared to reverse from what is observed at baseline. The suppressed FSR and decreased palmitate incorporation into IMTG during exercise in NGT suggests that plasma-derived palmitate comprised the majority of fat oxidation under these conditions. In PD, maintenance of pre-exercise FSR and palmitate incorporation into IMTG implies that Rd
during exercise may be a composite of greater cycling of palmitate through the IMTG pool. Together, failure to suppress IMTG FSR (during exercise or possibly postprandially) in PD may affect substrate trafficking, leading to accumulation of IMTG despite a low IMTG FSR in the basal state.
Known mediators of IMTG concentration (presumably by affecting FSR), such as training status (10
), nutrition (39
), and gender (40
) were controlled for in our study. Similar amount of type 1 and 2 muscle fibers between the groups also makes this an unlikely contributor to differences in IMTG FSR before or during exercise (41
). Furthermore, substrate availability was also not different either at rest or during exercise. Markers of other relevant biologic processes, such as inflammation (MAP4K4), oxidative capacity (succinate dehydrogenase), capacity for mitochondrial lipid transport (CPT-1), lipid peroxidation (4-HNE), and trafficking (peroxisome proliferator–activated receptor-a) implicated by previous investigations, were also unrevealing in this study and may reflect the close matching between groups.
There are several limitations of this study worth noting. In order to focus on metabolic differences between simple obesity and PD, no lean control group was studied. Although this likely diminished finding differences between PD and “normal,” the design was vital in differentiating high- vs. low-risk individuals who are often grouped together. It is also possible that the imbalance in the gender distribution between groups confounded our results. Previous reports of sex differences in lipid metabolism have largely attributed their findings to sex differences in insulin action (42
). Of note, no sex differences in Si
were noted in this study making the group difference in sex distribution less apt to explain our findings. In addition, people with impaired fasting glucose and impaired glucose tolerance were grouped together as “PD”, despite reports that their site of insulin resistance differs (44
). In so doing, differences between NGT and PD may be underestimated. Lastly, a published, nonindividually measured, acetate recovery factor was used in the calculation of palmitate oxidation. This was done because IMTG dynamics, not palmitate oxidation, was the primary outcome of interest.
In conclusion, delineating differences between simple obesity and PD is vital in knowing who will acquire type 2 diabetes and who will not. This study examined the role of intramuscular lipid concentration and synthesis as potentially distinguishing features between simple obesity and PD. Major findings from this study demonstrated higher basal IMTG concentration that was metabolically “inflexible” in people with PD compared to a matched control group with NGT. Longitudinal studies are needed to determine whether alterations in the dynamics of IMTG synthesis can prevent diabetes in this high-risk group.