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Effect of phosphodiesterase inhibition on insulin resistance in obese individuals.

ABSTRACT: Obesity is associated with cardiometabolic disease, including insulin resistance (IR) and diabetes. Cyclic guanosine monophosphate (cGMP) signaling affects energy balance, IR, and glucose metabolism in experimental models. We sought to examine effects of phosphodiesterase-5 inhibition with tadalafil on IR in a pilot study of obese nondiabetic individuals.We conducted a randomized, double-blinded, placebo-controlled trial of adults age 18 to 50 years with obesity and elevated fasting insulin levels (?10 ?U/mL). Participants were randomized to tadalafil 20 mg daily or placebo for 3 months. Oral glucose tolerance tests were performed, and the effect of tadalafil on IR was examined. A total of 53 participants (mean age, 33 years; body mass index [BMI], 38 kg/m(2)) were analyzed, 25 randomized to tadalafil and 28 to placebo. In the overall sample, measures of IR did not differ between tadalafil and placebo groups at 3 months. However, in individuals with severe obesity (BMI ?36.2 kg/m(2)), tadalafil use was associated with improved IR (homeostatic model assessment for IR), compared to placebo (P=0.02, respectively). Furthermore, one measure of ?-cell compensation for IR (oral disposition index) improved with tadalafil in the overall sample (P=0.009) and in the subgroup with severe obesity (P=0.01).Results of this pilot study did not show improvements in IR with tadalafil, compared to placebo. However, tadalafil may have favorable effects on ?-cell compensation, particularly in individuals with severe obesity. Future studies evaluating the potential metabolic benefits of cGMP modulation in obesity are warranted.ClinicalTrials.gov. Unique Identifier: NCT01444651.

SUBMITTER: Ho JE

PROVIDER: S-EPMC4323801 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Effect of phosphodiesterase inhibition on insulin resistance in obese individuals.

Ho Jennifer E JE Arora Pankaj P Walford Geoffrey A GA Ghorbani Anahita A Guanaga Derek P DP Dhakal Bishnu P BP Nathan Daniel I DI Buys Emmanuel S ES Florez Jose C JC Newton-Cheh Christopher C Lewis Gregory D GD Wang Thomas J TJ

Journal of the American Heart Association 20140911 5

<h4>Background</h4>Obesity is associated with cardiometabolic disease, including insulin resistance (IR) and diabetes. Cyclic guanosine monophosphate (cGMP) signaling affects energy balance, IR, and glucose metabolism in experimental models. We sought to examine effects of phosphodiesterase-5 inhibition with tadalafil on IR in a pilot study of obese nondiabetic individuals.<h4>Methods and results</h4>We conducted a randomized, double-blinded, placebo-controlled trial of adults age 18 to 50 years ...[more]

PMID: 25213566

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Project description:Both type 2 prediabetes/diabetes (T2DM) and new-onset prediabetes/diabetes after acute pancreatitis (NODAP) are characterized by impaired tissue sensitivity to insulin action. Although the outcomes of NODAP and T2DM are different, it is unknown whether drivers of insulin resistance are different in the two types of diabetes. This study aimed to investigate the associations between abdominal fat phenotypes and indices of insulin sensitivity in non-obese individuals with NODAP, T2DM, and healthy controls. Indices of insulin sensitivity (homeostasis model assessment of insulin sensitivity (HOMA-IS), Raynaud index, triglyceride and glucose (TyG) index, Matsuda index) were calculated in fasting and postprandial states. Fat phenotypes (intra-pancreatic fat, intra-hepatic fat, skeletal muscle fat, visceral fat, and subcutaneous fat) were determined using magnetic resonance imaging and spectroscopy. Linear regression and relative importance analyses were conducted. Age, sex, and glycated hemoglobin A1c were adjusted for. A total of 78 non-obese individuals (26 NODAP, 20 T2DM, and 32 healthy controls) were included. Intra-pancreatic fat was significantly associated with all the indices of insulin sensitivity in the NODAP group, consistently in both the unadjusted and adjusted models. Intra-pancreatic fat was not significantly associated with any index of insulin sensitivity in the T2DM and healthy controls groups. The variance in HOMA-IS was explained the most by intra-pancreatic fat (R2 = 29%) in the NODAP group and by visceral fat (R2 = 21%) in the T2DM group. The variance in the Raynaud index was explained the most by intra-pancreatic fat (R2 = 18%) in the NODAP group and by visceral fat (R2 = 15%) in the T2DM group. The variance in the TyG index was explained the most by visceral fat in both the NODAP group (R2 = 49%) and in the T2DM group (R2 = 25%). The variance in the Matsuda index was explained the most by intra-pancreatic fat (R2 = 48%) in the NODAP group and by visceral fat (R2 = 38%) in the T2DM group. The differing association between intra-pancreatic fat and insulin resistance can be used to differentiate NODAP from T2DM. Insulin resistance in NODAP appears to be predominantly driven by increased intra-pancreatic fat deposition.

Project description:We previously reported that obese individuals with the metabolic syndrome (at risk), compared with obese individuals without the metabolic syndrome (healthy obese), have elevated serum AGEs that strongly correlate with insulin resistance, oxidative stress and inflammation. We hypothesised that a diet low in AGEs (L-AGE) would improve components of the metabolic syndrome in obese individuals, confirming high AGEs as a new risk factor for the metabolic syndrome.A randomised 1 year trial was conducted in obese individuals with the metabolic syndrome in two parallel groups: L-AGE diet vs a regular diet, habitually high in AGEs (Reg-AGE). Participants were allocated to each group by randomisation using random permuted blocks. At baseline and at the end of the trial, we obtained anthropometric variables, blood and urine samples, and performed OGTTs and MRI measurements of visceral and subcutaneous abdominal tissue and carotid artery. Only investigators involved in laboratory determinations were blinded to dietary assignment. Effects on insulin resistance (HOMA-IR) were the primary outcome.Sixty-one individuals were randomised to a Reg-AGE diet and 77 to an L-AGE diet; the data of 49 and 51, respectively, were analysed at the study end in 2014. The L-AGE diet markedly improved insulin resistance; modestly decreased body weight; lowered AGEs, oxidative stress and inflammation; and enhanced the protective factors sirtuin 1, AGE receptor 1 and glyoxalase I. The Reg-AGE diet raised AGEs and markers of insulin resistance, oxidative stress and inflammation. There were no effects on MRI-assessed measurements. No side effects from the intervention were identified. HOMA-IR came down from 3.1?±?1.8 to 1.9?±?1.3 (p?<?0.001) in the L-AGE group, while it increased from 2.9?±?1.2 to 3.6?±?1.7 (p?<?0.002) in the Reg-AGE group.L-AGE ameliorates insulin resistance in obese people with the metabolic syndrome, and may reduce the risk of type 2 diabetes, without necessitating a major reduction in adiposity. Elevated serum AGEs may be used to diagnose and treat 'at-risk' obesity.ClinicalTrials.gov NCT01363141 FUNDING: The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (DK091231).

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Effect of phosphodiesterase inhibition on insulin resistance in obese individuals.

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Effect of phosphodiesterase inhibition on insulin resistance in obese individuals.

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