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Background: Type 2 diabetes mellitus (T2DM) is linked to impaired mitochondrial function. Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is a gadolinium‐contrast‐free 1H method to assess mitochondrial function by measuring low‐concentration metabolites. A CEST MRI‐based technique may serve as a non‐invasive proxy for assessing mitochondrial health. Hypothesis: A 1H CEST MRI technique may detect significant differences in in vivo skeletal muscle phosphocreatine (SMPCr) kinetics between healthy volunteers and T2DM patients undergoing standardized isometric exercise. Study Type: Cross‐sectional study. Subjects: Seven subjects without T2DM (T2DM−) and seven age, sex, and BMI‐matched subjects with T2DM (T2DM+). Field Strength/Sequence: Single‐shot rapid acquisition with refocusing echoes (RARE) and single‐shot gradient‐echo sequences, 3 T. Assessment: Subjects underwent a rest‐exercise‐recovery imaging protocol to dynamically acquire SMPCr maps in calf musculature. Medial gastrocnemius (MG) and soleus SMPCr concentrations were plotted over time, and SMPCr recovery time, τ, was determined. Mitochondrial function index was calculated as the ratio of resting SMPCr to τ. Participants underwent a second exercise protocol for imaging of skeletal muscle blood flow (SMBF), and its association with SMPCr was assessed. Statistical Tests: Unpaired t‐tests and Pearson correlation coefficient. A P value <0.05 was considered statistically significant. Results: SMPCr concentrations in MG and soleus displayed expected declines during exercise and returns to baseline during recovery. τ was significantly longer in the T2DM+ cohort (MG 83.5 ± 25.8 vs. 54.0 ± 21.1, soleus 90.5 ± 18.9 vs. 51.2 ± 14.5). The mitochondrial function index in the soleus was significantly lower in the T2DM+ cohort (0.33 ± 0.08 vs. 0.66 ± 0.19). SMBF was moderately correlated with the SMPCr in T2DM−; this correlation was not significant in T2DM+ (r = −0.23, P = 0.269). Conclusion: The CEST MRI method is feasible for quantifying SMPCr in peripheral muscle tissue. T2DM+ individuals had significantly lower oxidative capacities than T2DM− individuals. In T2DM, skeletal muscle metabolism appeared to be decoupled from perfusion. Level of Evidence: 1 Technical Efficacy: Stage 1 [ABSTRACT FROM AUTHOR]

Chronic limb-threatening ischemia (CLTI) is the most severe form of peripheral artery disease. It is estimated that 60% of all nontraumatic lower-extremity amputations performed annually in the United States are in patients with diabetes and CLTI. The consequences of this condition are extraordinary, with substantial patient morbidity and mortality and high socioeconomic costs. Strategies that optimize the success of arterial revascularization in this unique patient population can have a substantial public health impact and improve patient outcomes. This article provides an up-to-date comprehensive assessment of management strategies for patients afflicted by both diabetes and CLTI. [ABSTRACT FROM AUTHOR]

Patients with diabetes mellitus (DM) are more likely to have densely calcified lesions in the below-the-knee tibial arteries. However, the relationship between peripheral arterial calcification and local skeletal muscle perfusion has not been explored. Thirty subjects were prospectively recruited into three groups in this pilot study: (1) Non-DM: 10 people without DM; (2) DM, ABI < 1.3: 10 people with DM and normal ankle–brachial index (ABI) (0.9–1.3); and (3) DM, ABI ⩾ 1.3: 10 people with DM and ABI ⩾ 1.3. All subjects underwent calf perfusion measurements at rest and during an isometric plantarflexion contraction exercise within the magnetic resonance imaging (MRI) system. The noncontrast MRI techniques were applied to quantitatively assess skeletal muscle blood flow (SMBF) and oxygen extraction fraction (SMOEF) in medial gastrocnemius and soleus muscles. Both SMBF and SMOEF reserves were calculated as the ratio of the exercise value to the resting value. Exercise SMBF and SMOEF values in the medial gastrocnemius muscle were lower in the two DM groups than in the non-DM group (p < 0.05). The SMBF reserve in medial gastrocnemius was significantly lower in the DM, ABI ⩾ 1.3 group compared to the DM, ABI < 1.3 group (p < 0.05). This study demonstrates that people with DM and calcified arteries had lower perfusion in gastrocnemius muscle compared to those without DM and those with DM and a normal ABI. [ABSTRACT FROM AUTHOR]

De novo phospholipogenesis, mediated by choline-ethanolamine phosphotransferase 1 (CEPT1), is essential for phospholipid activation of transcription factors such as peroxisome proliferator-activated receptor α (PPARα) in the liver. Fenofibrate, a PPARα agonist and lipid-lowering agent, decreases amputation incidence in patients with diabetes. Because we previously observed that CEPT1 is elevated in carotid plaque of patients with diabetes, we evaluated the role of CEPT1 in peripheral arteries and PPARα phosphorylation (Ser12). CEPT1 was found to be elevated in diseased lower-extremity arterial intima of individuals with peripheral arterial disease and diabetes. To evaluate the role of Cept1 in the endothelium, we engineered a conditional endothelial cell (EC)-specific deletion of Cept1 via induced VE-cadherin-CreERT2-mediated recombination (Cept1Lp/LpCre+). Cept1Lp/LpCre+ ECs demonstrated decreased proliferation, migration, and tubule formation, and Cept1Lp/LpCre+ mice had reduced perfusion and angiogenesis in ischemic hind limbs. Peripheral ischemic recovery and PPARα signaling were further compromised by streptozotocin-induced diabetes and ameliorated by feeding fenofibrate. Cept1 endoribonuclease-prepared siRNA decreased PPARα phosphorylation in ECs, which was rescued with fenofibrate but not PC16:0/18:1. Unlike Cept1Lp/LpCre+ mice, Cept1Lp/LpCre+Ppara-/- mice did not demonstrate hind-paw perfusion recovery after feeding fenofibrate. Therefore, we demonstrate that CEPT1 is essential for EC function and tissue recovery after ischemia and that fenofibrate rescues CEPT1-mediated activation of PPARα. [ABSTRACT FROM AUTHOR]

Peripheral arterial disease (PAD) is a highly prevalent disease process that afflicts more than 20% of individuals with diabetes. Progression of PAD in the setting of diabetes can lead to critical limb ischemia (CLI), which is associated with increased risk of wounds, gangrene, and limb loss. Prompt noninvasive evaluation of limbs affected by PAD progression and CLI is currently limited. Here, we evaluate the utility of a customdesigned multispectral imaging system for fluorescence-based near-infrared angiography and compare it to the existing gold standard of laser-scanning Doppler perfusion assessments. Due to its higher resolution and fluorescence sensitivity, near-infrared angiography demonstrates a greater capacity to characterize altered dynamic arterial perfusion in a clinically relevant diabetic murine model for CLI. Furthermore, we demonstrate that our imaging system can accurately track arterial perfusion recovery over time following induced ischemia, and reveal unique phenotypic differences in the setting of diabetes. [ABSTRACT FROM AUTHOR]

Diabetes is an independent risk factor for carotid artery stenosis (CAS). Fatty acid synthase (FAS), an essential de novo lipogenesis enzyme, has increased activity in the setting of diabetes that leads to altered lipid metabolism. Circulating FAS (cFAS) was recently observed in the blood of patients with hyperinsulinemia and cancer. We thought to evaluate the origin of cFAS and its role in diabetes-associated CAS. Patients with diabetes and no diabetes, undergoing carotid endarterectomy (CEA) for CAS, were prospectively enrolled for collection of plaque and fasting serum. FPLC was used to purify lipoprotein fractions, and ELISA was used to quantify cFAS content and activity. Immunoprecipitation (IP) was used to evaluate the affinity of cFAS to LDL-ApoB. Patients with CAS had higher cFAS activity (p < 0.01), and patients with diabetes had higher cFAS activity than patients with no diabetes (p < 0.05). cFAS activity correlated with serum glucose (p = 0.03, r2 = 0.35), and cFAS content trended with plaque FAS content (p = 0.06, r2 = 0.69). cFAS was predominantly in LDL cholesterol fractions of patients with CAS (p < 0.001), and IP of cFAS demonstrated pulldown of ApoB. Similar to patients with diabetes, db/db mice had highest levels of serum cFAS (p < 0.01), and fasL −/− (tissue-specific liver knockdown of FAS) mice had the lowest levels of cFAS (p < 0.001). Serum cFAS is higher in patients with diabetes and CAS, appears to originate from the liver, and is LDL cholesterol associated. We postulate that LDL may be serving as a carrier for cFAS that contributes to atheroprogression in carotid arteries of patients with diabetes. • Patients with carotid artery stenosis have higher levels of serum cFAS, and patients with diabetes have even higher levels of serum cFAS activity compared to patients with no diabetes. • Serum cFAS activity correlates with serum glucose and predominantly in LDL cholesterol fractions in patients with carotid artery stenosis. • In LDL cholesterol, cFAS immunoprecipitates with ApoB. • Patients with high serum cFAS also have high carotid plaque FAS and saturated fatty acids. • cFAS appears to originate from the liver as mice with selective knockdown of FAS in the liver tissue have the lowest serum cFAS levels. [ABSTRACT FROM AUTHOR]