Diabetes Clin Research Ctr

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    TIGAR Deficiency Enhances Skeletal Muscle Thermogenesis by Increasing Neuromuscular Junction Cholinergic Signaling
    (2022-03-07) Buddo, Katherine A.; Boykov, Ilya N.; Schmidt, Cameron A.; Lin, Chien-Te; Neufer, P. Darrell
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    Racial Differences in the Limb Skeletal Muscle Transcriptional Programs of Patients with Critical Limb Ischemia
    (2021-06) Terwilliger, Zoe S.; Goldberg, Emma J.; Schmidt, Cameron A.; Karnekar, Reema; Brophy, Patricia; Green, Thomas D.; Zeczycki, Tonya N.; McClung, Joseph M.; Ryan, Terence E.; Yamaguchi, Dean J.; Gabhann, Feilim Mac; Annex, Brian H.
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    Mitochondrial Respiratory Capacity and Content Are Normal in Young Insulin-Resistant Obese Humans
    (2014-01) Fisher-Wellman, Kelsey H.; Weber, Todd M.; Cathey, Brook L.; Brophy, Patricia; Gilliam, Laura A. A.; Kane, Constance L.; Maples, Jill M.; Gavin, Timothy Patrick; Houmard, Joseph A.; Neufer, P. Darrell
    Considerable debate exists about whether alterations in mitochondrial respiratory capacity and/or content play a causal role in the development of insulin resistance during obesity. The current study was undertaken to determine whether such alterations are present during the initial stages of insulin resistance in humans. Young (∼23 years) insulin-sensitive lean and insulin-resistant obese men and women were studied. Insulin resistance was confirmed through an intravenous glucose tolerance test. Measures of mitochondrial respiratory capacity and content as well as H(2)O(2) emitting potential and the cellular redox environment were performed in permeabilized myofibers and primary myotubes prepared from vastus lateralis muscle biopsy specimens. No differences in mitochondrial respiratory function or content were observed between lean and obese subjects, despite elevations in H(2)O(2) emission rates and reductions in cellular glutathione. These findings were apparent in permeabilized myofibers as well as in primary myotubes. The results suggest that reductions in mitochondrial respiratory capacity and content are not required for the initial manifestation of peripheral insulin resistance.
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    Metformin Improves Insulin Signaling in Obese Rats via Reduced IKK Action in a Fiber-Type Specific Manner
    (2010) Bikman, Benjamin Thomas; Zheng, Donghai; Kane, Daniel A.; Anderson, Ethan; Woodlief, Tracey L.; Price, Jesse W.; Dohm, G. Lynis; Neufer, P. Darrell; Cortright, Ronald N.
    Metformin is a widely used insulin-sensitizing drug, though its mechanisms are not fully understood. Metformin has been shown to activate AMPK in skeletal muscle; however, its effects on the inhibitor of κB kinaseβ (IKKβ) in this same tissue are unknown. The aim of this study was to (1) determine the ability of metformin to attenuate IKKβ action, (2) determine whether changes in AMPK activity are associated with changes in IKKβ action in skeletal muscle, and (3) examine whether changes in AMPK and IKKβ function are consistent with improved insulin signaling. Lean and obese male Zuckers received either vehicle or metformin by oral gavage daily for four weeks (four groups of eight). Proteins were measured in white gastrocnemius (WG), red gastrocnemius (RG), and soleus. AMPK phosphorylation increased (P < .05) in WG in both lean (57%) and obese (106%), and this was supported by an increase in phospho-ACC in WG. Further, metformin increased IκBα levels in both WG (150%) and RG (67%) of obese rats, indicative of reduced IKKβ activity (P < .05), and was associated with reduced IRS1-pSer307 (30%) in the WG of obese rats (P < .02). From these data we conclude that metformin treatment appears to exert an inhibitory influence on skeletal muscle IKKβ activity, as evidenced by elevated IκBα levels and reduced IRS1-Ser307 phosphorylation in a fiber-type specific manner.
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    Outcomes of Roux-en-Y gastric bypass surgery for severely obese patients with type 1 diabetes: a case series report
    (2010) Mendez, Carlos E.; Tanenberg, Robert J.; Pories, Walter J.
    Roux-en-Y gastric bypass surgery (RYGB) reverses type 2 diabetes (DM2) in approximately 83% of patients with morbid or severe obesity. This procedure has been performed in small numbers of severely obese patients with type 1 diabetes (DM1), but the impact on glycemic control and insulin requirement in this population has not been widely described. We report three patients with DM1 and severe obesity that underwent RYGB. Weight, glycemic control, and insulin requirements before and one year after the procedure were compared. Significant weight loss was achieved by all three patients but insulin requirements decreased in only 2 patients. In contrast, glycemic control (A1C) remained suboptimal in all three patients up to one year after the surgery. These findings suggest that RYGB leads to important weight loss and positively affects insulin sensitivity. However, reaching optimal glycemic control in patients with DM1 diabetes remains challenging due to persisting insulin deficiency.