11β-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial

Glucocorticoids prescribed to limit inflammation, have significant adverse effects. As 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active glucocorticoid, we investigated whether 11β-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

Who Should Be Considered for Islet Transplantation Alone?

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. SUMMARY: 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

Co-administration of 5α-reductase inhibitors worsens the adverse metabolic effects of prescribed glucocorticoids.

CONTEXT Glucocorticoids (GC) are commonly prescribed, but their use is associated with adverse metabolic effects. 5a-reductase inhibitors (5aRI) are also frequently prescribed, mainly to inhibit testosterone conversion to dihydrotestosterone. However, they also prevent the inactivation of GCs. OBJECTIVE We hypothesised that 5aRIs may worsen the adverse effects of GCs. DESIGN Prospective, randomised study. PATIENTS 19 healthy male volunteers (age; 45±2 years, BMI; 27.1±0.7kg/m2). INTERVENTIONS Participants underwent metabolic assessments; 2-step hyperinsulinemic, euglycemic clamp incorporating stable-isotopes, adipose tissue microdialysis and biopsy. Participants were then randomised to either prednisolone (10mg daily) or prednisolone (10mg daily) plus a 5aRI (finasteride 5mg daily or dutasteride 0.5mg daily) for 7 days; metabolic assessments were then repeated. MAIN OUTCOME MEASURES Ra glucose, glucose utilization (M-value), glucose oxidation, non-esterified fatty acids (NEFA) levels. RESULTS Co-administration of prednisolone with a 5aRI increased circulating prednisolone levels (482±96 vs. 761±57nmol/L, p=0.029). Prednisolone alone did not alter Ra glucose (2.55±0.34 vs 2.62±0.19mg/kg/min, p=0.86), M-value (3.2±0.5 vs 2.7±0.7mg/kg/min, p=0.37), or glucose oxidation (0.042±0.007 vs 0.040±0.004mmol/hr/kg/min, p=0.79). However, co-administration with a 5aRI increased Ra glucose (2.67±0.16 vs. 3.05±0.18mg/kg/min, p<0.05) and decreased M-value (4.0±0.5 vs. 2.6±0.4mg/kg/min, p<0.05), and oxidation (0.043±0.003 vs. 0.036±0.002mmol/hr/kg, p<0.01). Similarly, prednisolone did not impair insulin-mediated suppression of circulating NEFA (43.1±28.9 vs. 36.8±14.3μmol/L, p=0.81), unless co-administered with a 5aRI (49.8±8.6 vs. 88.5±13.5μmol/L, p<0.01). CONCLUSIONS We have demonstrated that 5aRIs 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

Acute intermittent hypoxia drives hepatic de novo lipogenesis in humans and rodents.

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

11β-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial

Glucocorticoids prescribed to limit inflammation, have significant adverse effects. As 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active glucocorticoid, we investigated whether 11β-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