Adipose tissue content, muscle performance and physical function in obese adults with type 2 diabetes mellitus and peripheral neuropathy
Introduction
The excessive accumulation of intermuscular adipose tissue (IMAT), an ectopic fat deposit developing between skeletal muscle fibers and beneath the deep fascia of muscle, is a morphological maladaptation present in a wide range of clinical conditions, including disuse atrophy, spinal cord injury, human immunodeficiency virus (HIV) infection, chronic obstructive pulmonary diseases (COPD), and diabetes mellitus (DM) (Addison et al., 2014, Mjtahedi et al., 2008, Nardo et al., 2014).
The IMAT infiltration in large muscle groups of the lower extremity is a particularly important etiological factor in the onset and progression of type 2 diabetes (T2DM) and its complications due to its hormonal and structural influence on skeletal muscle – the tissue responsible for 90% of peripheral glucose uptake (DeFronzo & Tripathy, 2009). While it remains uncertain what precipitates the accrual of excessive IMAT accumulation, previous studies have implicated an increased rate of free fatty acid (FFA) release from obese, diabetic adipose tissue stores, leading to inhibition of skeletal muscle glucose uptake (via glucose-fatty acid cycle or Randle cycle competition), amplified gluconeogenesis, beta cell lipotoxicity, and the development of hypertriglyceridemia (DeFronzo, 2004, Jensen, 2008, Randle et al., 1963). The preferential uptake of FFA in skeletal muscle, due to high availability and competitive inhibition of glucose transport, may initiate the accretion of excessive intermuscular lipids. Over time, with increasing resistance to insulin’s action, excessive IMAT accumulation develops and proliferates, particularly in lower extremity musculature, due to concomitant, progressive mitochondrial dysfunction and declining oxidative capacity (Schrauwen & Hesselink, 2004). Proper glycemic control is of paramount importance for the maintenance of neuronal structural integrity and function, with chronic hyperglycemia implicated in peripheral nerve demyelination, decline in nerve conduction velocity, axonal atrophy and degeneration, glial insult, and lipid peroxidation (Obrosova, 2009, Yu et al., 2008)- processes linked to the development of diabetic symmetric peripheral neuropathy.
Since IMAT accumulation has been shown to negatively correlate with insulin sensitivity, it has been hypothesized that IMAT levels in the skeletal muscles of individuals with T2DM and peripheral neuropathy (T2DMPN) would be higher than those with T2DM alone, or age- and BMI-matched controls (Boettcher et al., 2009). However, Tuttle, Sinacore, and Mueller (2012), in a limited sample size, found no differences in total IMAT volume in the calf across these groups.
In addition to the volume of IMAT accumulation, the distribution of adipose tissue deposition may also change with the severity and progression of T2DM complications. The expansion of visceral adipose tissue depots (including IMAT), as opposed to subcutaneous depots (SQAT), has been associated with peripheral insulin resistance, hyperglycemia, and cardiovascular disease in obese populations (Lebovitz & Banerji, 2005). In contrast, higher amounts of SQAT are associated with enhanced glucose metabolism and a reduced risk of dyslipidemia due to its lower lipolytic activity, preferential absorption of plasma FFA, and enhanced secretion of adiponectin (an adipokine associated with increased insulin sensitivity) (Porter et al., 2009, Wronska and Kmiec, 2012).
While many of the previous reports have detailed the protective or deleterious roles of subcutaneous compared to visceral adipose tissue accumulation, the focus has been on the abdomen and abdominal viscera (Klein et al., 2004), with recent evidence suggesting this concept can be extended to lower extremity adipose tissue accumulation. Goodpaster, Thaete, and Kelley (2000), demonstrated that a loss of thigh intramuscular adipose tissue and visceral adipose tissue, but not SQAT, was correlated with higher insulin sensitivity. Goodpaster et al. (2000) did not assess IMAT or SQAT volumes in the leg (calf) and did not examine the association between adipose tissue deposition and physical and functional outcomes. Therefore, the inter-relationships between leg IMAT infiltration, SQAT volume, muscle performance, and physical function across a spectrum of T2DM severity with increasing complications (e.g., the presence of peripheral neuropathy) require further study. Changes in tissue composition in the leg may be particularly important because of its propensity for excess IMAT accumulation (most especially in the gastrocnemius muscle) (Tuttle et al., 2012), and because impairment of calf muscle function may lead to the development of impairments such as foot deformities, ulceration, and impaired gait mobility.
Therefore, the purposes of this study were to: 1) determine leg SQAT, IMAT, and muscle volume, as well as compartmental (anterior, lateral, deep, soleus muscle, gastrocnemius muscle) IMAT, and muscle volumes among obese T2DM, T2DMPN, and non-diabetic obese control groups; 2) determine differences in muscle performance and physical function in groups with different disease and complication severity; and 3) determine the relationship between leg adipose tissue volume and measures of both muscle performance, and physical function.
Section snippets
Methods
Seventy-nine BMI- and age-matched participants were studied (22 obese controls, 10 T2DM participants, and 47 T2DMPN participants). All participants had physical and demographic data and completed tests for body composition (leg muscle and adipose tissue volumes), and muscle performance. Thirty eight of these participants (10 controls, 10 T2DM, 18 T2DMPN) also completed a series of physical performance tests to determine function in simulated activities of daily living (detailed in 2.4.1 9-Item
Group demographics
As shown in Table 1, there were no group differences in sex, age, BMI, weight, height or years of diabetes. Vibration perception threshold (VPT) and monofilament testing confirmed that participants in the T2DMPN group had PN while the other groups did not have PN.
Leg composition
As shown in Fig. 1, there were no differences between groups on total muscle (Fig. 1-A) or total fat volumes in the calf (Fig. 1-B). Lean compartmental muscle volumes were not different between groups. Participants in the T2DMPN group
Leg composition
The results of this study demonstrated that after matching participants for age, weight, height, BMI, and years of diabetes, those with T2DMPN, a more severe complication of diabetes, had higher levels of leg IMAT. Similarly, concurrent with increasing IMAT, participants with T2DMPN had less SQAT volume than T2DM, and obese control participants without diabetes (Fig. 2). In the lower extremity, Snijder et al. (2005) found that larger subcutaneous thigh fat is associated with better glucose and
Conclusion
This study shows group differences in adipose distribution of the leg between obese, T2DM and T2DMPN participants. These groups’ differences suggest that a transition from SQAT to IMAT deposition is a complication that characterizes the progression from obesity, to T2DM, to T2DMPN. IMAT negatively affects muscle performance, which, in turn precipitate reduced physical function – creating a cyclical exacerbation of disease progression that dramatically impairs mobility. %IMAT volume is a strong
Acknowledgements and disclosures
This work was supported by grant funding from NICHD T32 HD007434-19 (PI: Earhart), NSMRC R24HD650837 (PI:R. Lieber), NIH UL1 RR024992, and scholarships from the Foundation for Physical Therapy (to L. J. Tuttle), and NICHD K12 HD055931 (to M. K. Hastings).
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Conflict of Interest:There are no conflicts of interest or significant financial support for this work that could have influenced its outcome.