There is wide variance among individuals in the fraction of insulin cleared by the liver (20% to 80%). Hepatic insulin clearance is 67% lower in African Americans than European Americans. Clearance ...is also lower in African American children 7-13 years of age. Lower hepatic insulin clearance will result in peripheral hyperinsulinemia: this exacerbates insulin resistance, which stresses the β-cells, possibly resulting in their ultimate failure and onset of type 2 diabetes. We hypothesize that lower insulin clearance can be a primary cause of type 2 diabetes in at-risk individuals.
BACKGROUNDMirabegron is a β3-adrenergic receptor (β3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that β3-AR agonists could also improve ...obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODSWe treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by 18F-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test.RESULTSChronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion.CONCLUSIONThese findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of β3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATIONClinicaltrials.gov NCT03049462.FUNDINGThis work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).
Silica and silica-titania based hybrid coatings were prepared through sol–gel process using a fluoropolymer as organic binder and characterized. AFM analysis shows that samples are smooth, ...homogeneous and without any evident phase separation. Upon UV exposure, hybrid coatings containing titania show a significant switch to a superhydrophilic state (contact angle against water down to 6° after UV irradiation) which is only partially recovered after storage in the dark (after two months the contact angle still shows half of its initial value). An efficient UV-induced discoloration of the resazurin ink is also observed on such coatings.
•Titania-fluoropolymer hybrid coatings were prepared through sol–gel chemistry.•Good combination of high scratch hardness, chemical resistance and transparency.•Surfaces are smooth, homogenous and without evident phase segregation (AFM).•Hybrid coatings containing titania show a photoinduced superhydrophilic behavior.•Titania based hybrid surfaces showed a photoinduced discoloration of resazurin ink.
A series of organic–inorganic hybrid coatings was prepared through sol–gel chemistry by combining silanized chlorotrifluoroethylene-vinylether (FEVE) binders with tetraalkoxy silicon and titania sols under acidic conditions. The best compositions to obtain highly transparent and homogeneous coatings after thermal curing were determined. All the hybrid coatings easily pass the MEK test and show high scratch hardness. The atomic force microscopy (AFM) shows the formation of very smooth surfaces (Rrms routinely <1nm) without clear phase separation phenomena. The typical size of the “objects” which may be individuated is in the range of 40–80nm. Wettability through contact angle measurements shows the formation of moderately hydrophobic surfaces with a low contact angle hysteresis (~20°) which is a further indication of very smooth, homogeneous and chemically stable surfaces. After irradiation with UV-B light only hybrid coatings containing titania phases show a significant switch to a superhydrophilic behavior with a contact angle against H2O down to 6°, which is only partially recovered after storage of the material in the dark. Titania based hybrid coatings also showed a fast and efficient UV-induced discoloration of the resazurin ink. The formulation of the coatings with photostabilizers belonging to the class of radical scavengers and UV absorbers does not change the photoinduced surface properties while eliminating the yellowing of the coating after UV exposure. It is concluded that titania-fluoropolymer hybrid coating show photoactivity and UV-induced superhydrophylicity mostly through ionic mechanisms, which could be beneficial to develop high durability and self-cleaning protective coatings.
Background: To compare the functional and anatomical results of two different types of grafts in type 1 tympanoplasty (TPL I). Methods: A retrospective comparative bicentric study was conducted on ...patients treated with TPL I using temporal fascia or tragal cartilage. We evaluated the functional and anatomical results with intergroup and intragroup analyses. Variables predicting long-term success were also evaluated. Results: A total of 142 patients (98 fascia graft vs. 44 cartilage) were initially assessed, with a mean follow-up of 67.1 ± 3.2 months. No significant differences were observed between the two groups on the intergroup analysis of age, gender, ear side, or pre-operative hearing data (all p > 0.05). At the intragroup analysis of auditory outcomes, both groups demonstrated a significant improvement in post-operative air conduction, with greater gain for the fascia group at 6 months follow-up (p < 0.001 for both); however, at long-term follow-up, cartilage demonstrated better stability results (p < 0.001). When comparing the pre-and post-operative air-bone-gap (ABG), both groups showed a significant gain (p < 0.001); the fascia group showed that at 6 months, a greater ABG increase was found, but the difference was not statistically significant (4.9 ± 0.9 dB vs. 5.3 ± 1.2 dB; p = 0.04). On the contrary, the cartilage group at long-term follow-up at 5 years maintained greater outcomes (10 ± 1.6 dB vs. 6.4 ± 2 dB; p < 0.001). Lower age (F = 4.591; p = 0.036) and higher size of perforation (F = 4.820; p = 0.030) were predictors of long-term functional success. Conclusions: The graft material selection should consider several factors influencing the surgical outcome. At long-term follow-up, the use of a cartilage graft could result in more stable audiological outcomes, especially in younger patients or in case of wider perforations.
Recently, we proposed a model describing the suppression of endogenous glucose production (EGP) during a meal. It assumes that EGP suppression depends on glucose concentration and its rate of change ...and on delayed insulin action. Hepatic insulin sensitivity (S(I)(Lmeal)) can be derived from EGP model parameters. This model was shown to adequately describe EGP profiles measured with multiple tracer techniques; however, S(I)(Lmeal) has never been compared directly with its euglycemic hyperinsulinemic clamp counterpart (S(I)(Lclamp)). To do so, 62 subjects with different degrees of glucose tolerance underwent a triple-tracer mixed meal. Fifty-seven subjects also underwent a labeled (3-(3)Hglucose) euglycemic hyperinsulinemic clamp. From the triple-tracer meal data, virtually model-independent estimates of EGP were obtained using the tracer-to-tracee clamp technique, and the EGP model was identified in each subject. Model fit was satisfactory, and S(I)(Lmeal) was estimated with good precision. Correlation between S(I)(Lclamp) and S(I)(Lmeal) was good (r = 0.72, P < 0.001); however, S(I)(Lmeal) was lower than S(I)(Lclamp) (4.60 ± 0.64 vs. 8.73 ± 1.07 10(-4) dl·kg(-1)·min(-1) per μU/ml, P < 0.01). This difference may be due to different ranges of insulin explored during the two tests (ΔI(clamp) = 15.60 ± 1.61 vs. ΔI(meal)= 83.37 ± 10.71 μU/ml) as well as steady- vs. non-steady-state glucose and insulin profiles. In conclusion, the new EGP model provides an estimate of hepatic insulin sensitivity during a meal that is in good agreement with that derived in the same individuals with a hyperinsulinemic clamp. When used in conjunction with the minimal model, the approach potentially enables estimation of hepatic insulin sensitivity from a single-tracer labeled meal or oral glucose tolerance test.
Declining beta-cell function is a key component in the development of type 2 diabetes (T2D). Early in disease progression, first-phase insulin secretion deteriorates, precipitating impaired glucose ...tolerance. Markers for early beta-cell decline could assist in identifying individuals at risk for disease progression, particularly among demographic groups at elevated risk for T2D. This study was designed to test the hypothesis that proinsulin concentrations would be inversely associated with first-phase beta-cell function, as reflected in the Disposition Index (DI), in a diverse cohort of young individuals without T2D. Participants were 117 men and women of African-American and European-American descent aged 19-45 years with normal glucose tolerance. An oral-glucose tolerance test (OGTT) was used to measure proinsulin concentrations and assess beta-cell function. Mathematical modeling was used to estimate insulin sensitivity (Si) and indices of beta-cell function specific to basal, first-phase, second-phase, and total insulin secretion (PhiB, PhiD, PhiS, PhiTot, respectively). First-phase DI (DId) was calculated as Si x PhiD and second-phase DI (DIs) as Si x PhiS. Proinsulin concentrations were normalized for C-peptide. Fasting and 2-h proinsulin concentrations were inversely associated with DId (r=-0.21, p=0.02 and r=-0.22, p=0.01, respectively). Neither fasting nor 2-h proinsulin concentrations were significantly associated with DIs. African-Americans, who as a group have an elevated prevalence of T2D, had 25% higher concentrations of fasting proinsulin and 18% higher concentrations of 2-h proinsulin compared to EA (p=0.001 and p=0.01, respectively). Proinsulin may be a practical biomarker for first-phase beta-cell function that could assist in identification of individuals at risk for T2D who would benefit from interventions to prevent deterioration of glucose metabolism.
Disclosure
C. Couch: None. B. Gower: Advisory Panel; Self; Abbott. F. Piccinini: Employee; Self; Medtronic.
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK096388); Nutrition Obesity Research Center (P30DK056336); Diabetes Research Center (P30DK079626); National Heart, Lung, and Blood Institute (T32HL105349)
In addition to its pivotal role in psychosocial behavior, the hypothalamic neuropeptide oxytocin contributes to metabolic control by suppressing eating behavior. Its involvement in glucose ...homeostasis is less clear, although pilot experiments suggest that oxytocin improves glucose homeostasis. We assessed the effect of intranasal oxytocin (24 IU) administered to 29 healthy, fasted male subjects on glucose homeostasis measured by means of an oral glucose tolerance test. Parameters of glucose metabolism were analyzed according to the oral minimal model. Oxytocin attenuated the peak excursion of plasma glucose and augmented the early increases in insulin and C-peptide concentrations in response to the glucose challenge, while slightly blunting insulin and C-peptide peaks. Oral minimal model analyses revealed that oxytocin compared with placebo induced a pronounced increase in β-cell responsivity (PHI
) that was largely due to an enhanced dynamic response (PHI
), and a more than twofold improvement in glucose tolerance (disposition index). Adrenocorticotropic hormone (ACTH), cortisol, glucagon, and nonesterified fatty acid (NEFA) concentrations were not or were only marginally affected. These results indicate that oxytocin plays a significant role in the acute regulation of glucose metabolism in healthy humans and render the oxytocin system a potential target of antidiabetic treatment.
African Americans (AAs) tend to have higher plasma insulin concentrations than European Americans (EAs); the increased insulin concentrations have been attributed to increased secretion and/or ...decreased insulin clearance by liver or other tissues. This work characterizes the contributions of hepatic versus extrahepatic insulin degradation related to ethnic differences between AAs and EAs. By using a recently developed mathematical model that uses insulin and C-peptide measurements from the insulin-modified, frequently sampled intravenous glucose tolerance test (FSIGT), we estimated hepatic versus extrahepatic insulin clearance in 29 EA and 18 AA healthy women. During the first 20 min of the FSIGT, plasma insulin was approximately twice as high in AAs as in EAs. In contrast, insulin was similar in AAs and EAs after the 20-25 min intravenous insulin infusion. Hepatic insulin first-pass extraction was two-thirds lower in AAs versus EAs in the overnight-fasted state. In contrast, extrahepatic insulin clearance was not lower in AAs than in EAs. The difference in insulin degradation between AAs and EAs can be attributed totally to liver clearance. The mechanism underlying reduced insulin degradation in AAs remains to be clarified, as does the relative importance of reduced liver clearance to increased risk for type 2 diabetes.
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