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Thabit H.,Wellcome Trust Medical Research Council Institute of Metabolic Science | Kumareswaran K.,Wellcome Trust Medical Research Council Institute of Metabolic Science | Haidar A.,McGill University | Leelarathna L.,Wellcome Trust Medical Research Council Institute of Metabolic Science | And 13 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Discontinuation of anti-hyperglycemic oral agents and initiation of insulin is recommended in certain clinical situations for inpatients with type 2 diabetes (T2D). The effects on glucose turnover when these agents are acutely withdrawn are poorly understood and may be of importance when insulin therapy is initiated. Objective: Our objective was to investigate alterations in glucose turnover after acute withdrawal of noninsulin therapy. Design and Setting: This was a randomized crossover study at a clinical research facility. Participants: Participants included 12 insulin-naive subjects with T2D. Methods: Subjects attended two 24-hour visits. Standard therapy was discontinued and replaced by closed-loop insulin delivery during the intervention visit. Usual anti-hyperglycemic therapy was continued during the control visit. Systemic glucose appearance (Ra)andglucose disposal (Rd)were measured using a tracer dilution technique with iv [6,6-2H2]glucose. Results: Plasma glucose profiles during both visits were comparable (P = .48). Glucose Ra increased during the day (21.4 [19.5, 23.5] vs 18.6 [17.0, 21.6)μmol/kg/min,P=.019)anddecreased overnight (9.7 [8.5, 11.4] vs 11.6 [10.3, 12.9] μmol/kg/min, P = .004) when the usual therapy was discontinued and replaced with insulin. Increased daytime glucose Rd (21.2 [19.4, 23.9] vs 18.8 [18.3, 21.7]μmol/kg/min, P=.002) and decreased overnight Rd (10.4 [9.1, 12.0] vs 11.8 [10.7, 13.7]μmol/kg/min, P=.005) were observedwhenthe usual therapy was discontinued, whereas daytime peripheral insulin sensitivity was reduced (47.8 [24.8, 66.1] vs 62.5 [34.8, 75.8] nmol/kg/min per pmol/L, P = .034). Conclusion: In T2D, acute discontinuation of anti-hyperglycemic therapy and replacement with insulin increases postprandial Ra and reduces peripheral insulin sensitivity. Insulin dose initiation may need to compensate for these alterations. © 2014 by the Endocrine Society.

Bulger D.A.,University of Tennessee Health Science Center | Bulger D.A.,Medicine and Research Services | Bulger D.A.,Wellcome Trust Medical Research Council Institute of Metabolic Science | Bulger D.A.,U.S. National Institutes of Health | And 7 more authors.
Biochemical and Biophysical Research Communications | Year: 2015

Aims/hypothesis PTEN may play a reversible role in TNFα induced insulin resistance, which has been linked to obesity-associated insulin resistance (IR). Methods Western blots for PTEN and p-Akt were performed on H-411E liver cells incubated with insulin, TNFα, and in selected experiments VO-OHpic vanadium complex in the presence and absence of PTEN siRNA. Total PTEN was compared to β-actin loading control and p-Akt was compared to total Akt. Results Western blot and Real Time RT-PCR experiments showed increased PTEN after TNFα treatment (p = 0.04); slightly decreased PTEN after insulin treatment; and slightly increased PTEN after insulin + TNFα treatment. PTEN siRNA markedly inhibited the TNFα-induced increase in PTEN (p < 0.01) without significantly changing the p-Akt levels. The vanadium complex, exhibiting insulin-like effects, also significantly prevented the TNFα-induced increase in PTEN. Combining insulin and VO-OHpic was additive, providing both proof of concept and insight into mechanism. Discussion The PTEN increase due to TNFα treatment was reversible by both PTEN siRNA knockdown and VO-OHpic treatment. Thus, PTEN is identified as a potential new therapeutic target for reducing IR in Type 2 DM.

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