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PURPOSE OF REVIEW: Episodic hypoglycemia is an almost inevitable consequence of exogenous insulin treatment of type 1 diabetes, and in up to 30% of patients, this can lead to impaired awareness of hypoglycemia. This predisposes to recurrent severe hypoglycemia and has a huge impact on quality of life. Although many patients can get resolution of severe hypoglycemia through novel education and technology, some patients continue to have ongoing life-threatening hypoglycemia. Islet transplantation offers an alternative therapeutic option for these patients, in whom these conventional approaches have been unsuccessful. This review discusses the selection process of identifying suitable candidates based on recent clinical data. RECENT FINDINGS: Results from studies of islet transplantation suggest the optimal recipient characteristics for successful islet transplantation include age >35 years, insulin requirements <1.0/kg, and weight < 85 kg. Islet transplantation can completely resolve hypoglycemia and near-normalize glucose levels, achieving insulin independence for a limited period of time in up to 40% of patients. The selection of appropriate candidates, optimizing donor selection, the use of an optimized protocol for islet cell extraction, and immunosuppression therapy have been proved to be the key criteria for a favorable outcome in islet transplantation.
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Transplante das Ilhotas Pancreáticas , Glicemia/análise , Diabetes Mellitus Tipo 1/tratamento farmacológico , Humanos , Hipoglicemia/terapia , Imunossupressores/uso terapêutico , Insulina/uso terapêutico , Transplante das Ilhotas Pancreáticas/métodos , Qualidade de VidaRESUMO
BACKGROUND AND PURPOSE: 11ß-Hydroxysteroid dehydrogenase-1 (11ß-HSD1) catalyses the oxoreduction of cortisone to cortisol, amplifying levels of active glucocorticoids. It is a pharmaceutical target in metabolic disease and cognitive impairments. 11ß-HSD1 also converts some 7oxo-steroids to their 7ß-hydroxy forms. A recent study in mice described the ratio of tauroursodeoxycholic acid (TUDCA)/tauro-7oxolithocholic acid (T7oxoLCA) as a biomarker for decreased 11ß-HSD1 activity. The present study evaluates the equivalent bile acid ratio of glycoursodeoxycholic acid (GUDCA)/glyco-7oxolithocholic acid (G7oxoLCA) as a biomarker for pharmacological 11ß-HSD1 inhibition in humans and compares it with the currently applied urinary (5α-tetrahydrocortisol + tetrahydrocortisol)/tetrahydrocortisone ((5αTHF + THF)/THE) ratio. EXPERIMENTAL APPROACH: Bile acid profiles were analysed by ultra-HPLC tandem-MS in blood samples from two independent, double-blind placebo-controlled clinical studies of the orally administered selective 11ß-HSD1 inhibitor AZD4017. The blood GUDCA/G7oxoLCA ratio was compared with the urinary tetrahydro-glucocorticoid ratio for ability to detect 11ß-HSD1 inhibition. KEY RESULTS: No significant alterations were observed in bile acid profiles following 11ß-HSD1 inhibition by AZD4017, except for an increase of the secondary bile acid G7oxoLCA. The enzyme product/substrate ratio GUDCA/G7oxoLCA was found to be more reliable to detect 11ß-HSD1 inhibition than the absolute G7oxoLCA concentration in both cohorts. Comparison of the blood GUDCA/G7oxoLCA ratio with the urinary (5αTHF + THF)/THE ratio revealed that both successfully detect 11ß-HSD1 inhibition. CONCLUSIONS AND IMPLICATIONS: 11ß-HSD1 inhibition does not cause major alterations in bile acid homeostasis. The GUDCA/G7oxoLCA ratio represents the first blood biomarker of pharmacological 11ß-HSD1 inhibition and may replace or complement the urinary (5αTHF + THF)/THE ratio biomarker.
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11-beta-Hidroxiesteroide Desidrogenase Tipo 1 , Glucocorticoides , Animais , Humanos , Camundongos , Ácidos e Sais Biliares , Biomarcadores , Glucocorticoides/metabolismo , Hidrocortisona/metabolismo , Tetra-HidrocortisolRESUMO
Glucocorticoids prescribed to limit inflammation, have significant adverse effects. As 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) regenerates active glucocorticoid, we investigated whether 11ß-HSD1 inhibition with AZD4017 could mitigate adverse glucocorticoid effects without compromising their anti-inflammatory actions. We conducted a proof-of-concept, randomized, double-blind, placebo-controlled study at Research Unit, Churchill Hospital, Oxford, UK (NCT03111810). 32 healthy male volunteers were randomized to AZD4017 or placebo, alongside prednisolone treatment. Although the primary endpoint of the study (change in glucose disposal during a two-step hyperinsulinemic, normoglycemic clamp) wasn't met, hepatic insulin sensitivity worsened in the placebo-treated but not in the AZD4017-treated group. Protective effects of AZD4017 on markers of lipid metabolism and bone turnover were observed. Night-time blood pressure was higher in the placebo-treated but not in the AZD4017-treated group. Urinary (5aTHF+THF)/THE ratio was lower in the AZD4017-treated but remained the same in the placebo-treated group. Most anti-inflammatory actions of prednisolone persisted with AZD4017 co-treatment. Four adverse events were reported with AZD4017 and no serious adverse events. Here we show that co-administration of AZD4017 with prednisolone in men is a potential strategy to limit adverse glucocorticoid effects.
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11-beta-Hidroxiesteroide Desidrogenase Tipo 1 , Anti-Inflamatórios , Prednisolona , Humanos , Masculino , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Anti-Inflamatórios/efeitos adversos , Glucocorticoides/efeitos adversos , Inflamação/tratamento farmacológico , Prednisolona/efeitos adversosRESUMO
Background and aims: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition. It is tightly associated with an adverse metabolic phenotype (including obesity and type 2 diabetes) as well as with obstructive sleep apnoea (OSA) of which intermittent hypoxia is a critical component. Hepatic de novo lipogenesis (DNL) is a significant contributor to hepatic lipid content and the pathogenesis of NAFLD and has been proposed as a key pathway to target in the development of pharmacotherapies to treat NAFLD. Our aim is to use experimental models to investigate the impact of hypoxia on hepatic lipid metabolism independent of obesity and metabolic disease. Methods: Human and rodent studies incorporating stable isotopes and hyperinsulinaemic euglycaemic clamp studies were performed to assess the regulation of DNL and broader metabolic phenotype by intermittent hypoxia. Cell-based studies, including pharmacological and genetic manipulation of hypoxia-inducible factors (HIF), were used to examine the underlying mechanisms. Results: Hepatic DNL increased in response to acute intermittent hypoxia in humans, without alteration in glucose production or disposal. These observations were endorsed in a prolonged model of intermittent hypoxia in rodents using stable isotopic assessment of lipid metabolism. Changes in DNL were paralleled by increases in hepatic gene expression of acetyl CoA carboxylase 1 and fatty acid synthase. In human hepatoma cell lines, hypoxia increased both DNL and fatty acid uptake through HIF-1α and -2α dependent mechanisms. Conclusions: These studies provide robust evidence linking intermittent hypoxia and the regulation of DNL in both acute and sustained in vivo models of intermittent hypoxia, providing an important mechanistic link between hypoxia and NAFLD.
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CONTEXT: Glucocorticoids (GCs) are commonly prescribed, but their use is associated with adverse metabolic effects. 5α-reductase inhibitors (5α-RI) are also frequently prescribed, mainly to inhibit testosterone conversion to dihydrotestosterone. However, they also prevent the inactivation of GCs. OBJECTIVE: We hypothesized that 5α-RI may worsen the adverse effects of GCs. DESIGN: Prospective, randomized study. PATIENTS: A total of 19 healthy male volunteers (age 45â ±â 2 years; body mass index 27.1â ±â 0.7kg/m2). INTERVENTIONS: Participants underwent metabolic assessments; 2-step hyperinsulinemic, euglycemic clamp incorporating stable isotopes, adipose tissue microdialysis, and biopsy. Participants were then randomized to either prednisolone (10 mg daily) or prednisolone (10 mg daily) plus a 5α-RI (finasteride 5 mg daily or dutasteride 0.5 mg daily) for 7 days; metabolic assessments were then repeated. MAIN OUTCOME MEASURES: Ra glucose, glucose utilization (M-value), glucose oxidation, and nonesterified fatty acids (NEFA) levels. RESULTS: Co-administration of prednisolone with a 5α-RI increased circulating prednisolone levels (482â ±â 96 vs 761â ±â 57 nmol/L, Pâ =â 0.029). Prednisolone alone did not alter Ra glucose (2.55â ±â 0.34 vs 2.62â ±â 0.19 mg/kg/minute, Pâ =â 0.86), M-value (3.2â ±â 0.5 vs 2.7â ±â 0.7 mg/kg/minute, Pâ =â 0.37), or glucose oxidation (0.042â ±â 0.007 vs 0.040â ±â 0.004 mmol/hr/kg/minute, Pâ =â 0.79). However, co-administration with a 5α-RI increased Ra glucose (2.67â ±â 0.16 vs 3.05â ±â 0.18 mg/kg/minute, Pâ <â 0.05) and decreased M-value (4.0â ±â 0.5 vs 2.6â ±â 0.4 mg/kg/minute, Pâ <â 0.05), and oxidation (0.043â ±â 0.003 vs 0.036â ±â 0.002 mmol/hr/kg, Pâ <â 0.01). Similarly, prednisolone did not impair insulin-mediated suppression of circulating NEFA (43.1â ±â 28.9 vs 36.8â ±â 14.3 µmol/L, Pâ =â 0.81), unless co-administered with a 5α-RI (49.8â ±â 8.6 vs 88.5â ±â 13.5 µmol/L, Pâ <â 0.01). CONCLUSIONS: We have demonstrated that 5α-RIs exacerbate the adverse effects of prednisolone. This study has significant translational implications, including the need to consider GC dose adjustments, but also the necessity for increased vigilance for the development of adverse effects.