Exenatide twice-daily does not affect renal function or albuminuria compared to titrated insulin glargine in patients with type 2 diabetes mellitus: A post-hoc analysis of a 52-week randomised trial.

AIMS: To compare the effects of long-term treatment with the GLP-1RA exenatide twice-daily versus titrated insulin glargine (iGlar) on renal function and albuminuria in type 2 diabetes (T2DM) patients. METHODS: We post-hoc evaluated renal outcome-data of 54 overweight T2DM patients (mean  ±â€¯SD age 60 ±â€¯8 years, HbA1c 7.5 ±â€¯0.9%, eGFR 86 ±â€¯16 mL/min/1.73 m2, median [IQR] urinary albumin-to-creatinine-ratio (UACR) 0.75 [0.44-1.29] mg/mmol) randomised to exenatide 10 µg twice-daily or titrated iGlar on-top-of metformin for 52-weeks. Renal efficacy endpoints were change in creatinine clearance (CrCl) and albuminuria (urinary albumin-excretion [UAE] and UACR) based on 24-h urines, collected at baseline and Week-52. eGFR and exploratory endpoints were collected throughout the intervention-period, and after a 4-week wash-out. RESULTS: HbA1c-reductions were similar with exenatide (mean ±â€¯SEM -0.80 ±â€¯0.10%) and iGlar (-0.79 ±â€¯0.14%; treatment-difference 0.02%; 95% CI -0.31 to 0.42%). Change from baseline to Week-52 in CrCl, UAE or UACR did not statistically differ; only iGlar reduced albuminuria (P < 0.05; within-group). eGFR decreased from baseline to Week-4 with exenatide (-3.9 ±â€¯2.1 mL/min/1.73 m2; P = 0.069) and iGlar (-2.7 ±â€¯1.2 mL/min/1.73 m2; P = 0.034), without treatment-differences in ensuing trajectory. Exenatide versus iGlar reduced bodyweight (-5.4 kg; 2.9-7.9; P < 0.001), but did not affect blood pressure, lipids or plasma uric acid. CONCLUSIONS: Among T2DM patients without overt nephropathy, one-year treatment with exenatide twice-daily does not affect renal function-decline or onset/progression of albuminuria compared to titrated iGlar. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT00097500.

Influence of prednisolone on parameters of de novo lipogenesis and indices for stearoyl-CoA- and Δ6- desaturase activity in healthy males: A Post-hoc analysis of a randomized, placebo-controlled, double-blind trial.

Glucocorticoid treatment decreases liver insulin sensitivity and may modify fatty acid metabolism. We investigated the influence of oral prednisolone on indices for de novo lipogenesis (DNLi), stearoyl-CoA desaturase (SCDi) and Δ6-desaturase (D6Di) activity in healthy males. In addition, we explored whether the changes may be associated with prednisolone-induced changes in glucose and lipid metabolism and insulin sensitivity. Thirty-two healthy young males (mean ±â€¯SD age 22 ±â€¯3 years, BMI 22.4 ±â€¯1.7 kg/m2) were allocated to receive prednisolone 7.5 mg/day (PRED7.5; n = 12), prednisolone 30 mg/day (PRED30; n = 12), or placebo (n = 8) in a randomized double-blind fashion for 2 weeks. Fatty acid compositions of plasma cholesteryl esters (CE), phospholipids (PL) and triglycerides (TG) were measured at baseline and on day 14. DNLi, SCDi and D6Di were estimated from product/precursor ratios in CE, with DNLi primary deriving from 16:1ω7/18:2ω6, SCDi from 16:1ω7/16:0 and D6Di from 22:6ω3/20:5ω3. Ratios were also assessed in PL and TG. In CE, PRED30 increased DNLi by 51.2 [95%CI 14.8; 87.6]%, increased SCDi by 48.6 [18.7; 78.5]%, and decreased D6Di by 57.7 [-91.8; -23.5]% (p ≤ 0.01 for all, compared to placebo). The prednisolone-induced increases in DNLi and SCDi were positively correlated with insulin sensitivity (r = 0.35 and 0.50, respectively). Similar results were found in PL and TG. Prednisolone dose-dependently increases DNLi and SCDi and decreases D6Di in plasma CE, PL and TG in healthy males after 2 weeks. The observed unfavorable effects on fatty acid metabolism were related to the induction of glucocorticoid-induced insulin resistance.

Gastrointestinal actions of glucagon-like peptide-1-based therapies: glycaemic control beyond the pancreas.

The gastrointestinal hormone glucagon-like peptide-1 (GLP-1) lowers postprandial glucose concentrations by regulating pancreatic islet-cell function, with stimulation of glucose-dependent insulin and suppression of glucagon secretion. In addition to endocrine pancreatic effects, mounting evidence suggests that several gastrointestinal actions of GLP-1 are at least as important for glucose-lowering. GLP-1 reduces gastric emptying rate and small bowel motility, thereby delaying glucose absorption and decreasing postprandial glucose excursions. Furthermore, it has been suggested that GLP-1 directly stimulates hepatic glucose uptake, and suppresses hepatic glucose production, thereby adding to reduction of fasting and postprandial glucose levels. GLP-1 receptor agonists, which mimic the effects of GLP-1, have been developed for the treatment of type 2 diabetes. Based on their pharmacokinetic profile, GLP-1 receptor agonists can be broadly categorized as short- or long-acting, with each having unique islet-cell and gastrointestinal effects that lower glucose levels. Short-acting agonists predominantly lower postprandial glucose excursions, by inhibiting gastric emptying and intestinal glucose uptake, with little effect on insulin secretion. By contrast, long-acting agonists mainly reduce fasting glucose levels, predominantly by increased insulin and reduced glucagon secretion, with potential additional direct inhibitory effects on hepatic glucose production. Understanding these pharmacokinetic and pharmacodynamic differences may allow personalized antihyperglycaemic therapy in type 2 diabetes. In addition, it may provide the rationale to explore treatment in patients with no or little residual ß-cell function.

Acute renal haemodynamic effects of glucagon-like peptide-1 receptor agonist exenatide in healthy overweight men.

AIMS: To determine the acute effect of glucagon-like peptide-1 (GLP-1) receptor agonist exenatide and the involvement of nitric oxide (NO) on renal haemodynamics and tubular function, in healthy overweight men. METHODS: Renal haemodynamics and tubular electrolyte handling were measured in 10 healthy overweight men (aged 20-27 years; BMI 26-31 kg/m(2)) during intravenous administration of placebo (saline 0.9%), exenatide, and exenatide combined with the NO-synthase inhibitor L-N(G)-monomethyl arginine (L-NMMA). Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippurate clearance techniques, respectively, based on timed urine sampling. Glomerular hydrostatic pressure and vascular resistance of afferent and efferent renal arterioles were calculated using the Gomez formulae. Urinary electrolytes, osmolality and pH were also measured. RESULTS: GFR increased by a mean of 18 ± 20 (+20%; p = 0.021) and ERPF increased by a median (interquartile range) of 68 (26; 197) ml/min/1.73 m(2) (+14%; p = 0.015) during exenatide infusion versus placebo. During L-NMMA infusion, exenatide increased GFR by mean 8 ± 12 ml/min/1.73 m(2) (+9%; p = 0.049). Exenatide increased estimated glomerular pressure by +6% (p = 0.015) and reduced afferent renal vascular resistance by -33% (p = 0.038), whereas these effects were blunted during L-NMMA infusion. Exenatide increased absolute and fractional sodium excretion, urinary osmolality and urinary pH. The tubular effects of exenatide were not altered by concomitant L-NMMA infusion. CONCLUSIONS: Exenatide infusion in healthy overweight men acutely increases GFR, ERPF and glomerular pressure, probably by reducing afferent renal vascular resistance, and at least partially in an NO-dependent manner. As baseline renal haemodynamics in patients with type 2 diabetes differ from those in healthy individuals, clinical studies on the renal effects of GLP-1 receptor agonists are warranted.

Glucagon-like peptide-1 receptor agonist exenatide has no acute effect on MRI-measured exocrine pancreatic function in patients with type 2 diabetes: a randomized trial.

AIMS: To investigate the effect of infusion of the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide on exocrine pancreatic function. METHODS: This was a randomized, placebo-controlled, double-blind, crossover study in 12 male patients with type 2 diabetes, treated with oral glucose-lowering agents. On two separate occasions, exenatide or placebo (saline 0.9%) were administered intravenously, in randomized order. Exocrine pancreatic function was measured using secretin-enhanced magnetic resonance cholangiopancreatography. The primary outcome measure was defined as secretin-stimulated pancreatic excretion volume. Secondary outcome measures were maximum secretion speed and the time to reach this maximum. In addition, changes in pancreatic duct (PD) diameter were measured. RESULTS: Exenatide did not change secretin-stimulated pancreatic excretion volume, as compared with placebo (mean ± standard error of the mean 142.2 ± 15.6 ml vs 142.6 ± 8.5 ml, respectively; p = 0.590). Also, exenatide did not change the maximum secretion speed (33.1 ± 1.4 vs 36.9 ± 2.2; p = 0.221), nor the time to reach this maximum (both 4 min 30 s). No differences in PD diameter were observed between the two groups. CONCLUSIONS: Infusion of exenatide did not directly influence MRI-measured exocrine pancreatic excretion in patients with type 2 diabetes. Although long-term studies are warranted, these findings suggest that potential adverse pancreatic effects of GLP-1 receptor agonists are not mediated by changes in exocrine pancreatic secretion.

Saturated fat, carbohydrates and cardiovascular disease.

The dietary intake of saturated fatty acids (SAFA) is associated with a modest increase in serum total cholesterol, but not with cardiovascular disease (CVD). Replacing dietary SAFA with carbohydrates (CHO), notably those with a high glycaemic index, is associated with an increase in CVD risk in observational cohorts, while replacing SAFA with polyunsaturated fatty acids (PUFA) is associated with reduced CVD risk. However, replacing a combination of SAFA and trans-fatty acids with n-6 PUFA (notably linoleic acid) in controlled trials showed no indication of benefit and a signal toward increased coronary heart disease risk, suggesting that n-3 PUFA may be responsible for the protective association between total PUFA and CVD. High CHO intakes stimulate hepatic SAFA synthesis and conservation of dietary SAFA . Hepatic de novo lipogenesis from CHO is also stimulated during eucaloric dietary substitution of SAFA by CHO with high glycaemic index in normo-insulinaemic subjects and during hypocaloric high-CHO/low-fat diets in subjects with the metabolic syndrome. The accumulation of SAFA stimulates chronic systemic low-grade inflammation through its mimicking of bacterial lipopolysaccharides and÷or the induction of other pro-inflammatory stimuli. The resulting systemic low-grade inflammation promotes insulin resistance, reallocation of energy-rich substrates and atherogenic dyslipidaemia that concertedly give rise to increased CVD risk. We conclude that avoidance of SAFA accumulation by reducing the intake of CHO with high glycaemic index is more effective in the prevention of CVD than reducing SAFA intake per se.

Low-dose glucocorticoid treatment affects multiple aspects of intermediary metabolism in healthy humans: a randomised controlled trial.

AIM/HYPOTHESIS: To assess whether low-dose glucocorticoid treatment induces adverse metabolic effects, as is evident for high glucocorticoid doses. METHODS: In a randomised placebo-controlled double-blind (participants and the investigators who performed the studies and assessed the outcomes were blinded) dose-response intervention study, 32 healthy men (age 22 ± 3 years; BMI 22.4 ± 1.7 kg/m(2)) were allocated to prednisolone 7.5 mg once daily (n = 12), prednisolone 30 mg once daily (n = 12), or placebo (n = 8) for 2 weeks using block randomisation. Main outcome measures were glucose, lipid and protein metabolism, measured by stable isotopes, before and at 2 weeks of treatment, in the fasted state and during a two-step hyperinsulinaemic clamp conducted in the Clinical Research Unit of the Academic Medical Centre, Amsterdam, the Netherlands RESULTS: Prednisolone, compared with placebo, dose dependently and significantly increased fasting plasma glucose levels, whereas only prednisolone 30 mg increased fasting insulin levels (29 ± 15 pmol/l). Prednisolone 7.5 mg and prednisolone 30 mg decreased the ability of insulin to suppress endogenous glucose production (by 17 ± 6% and 46 ± 7%, respectively, vs placebo). Peripheral glucose uptake was not reduced by prednisolone 7.5 mg, but was decreased by prednisolone 30 mg by 34 ± 6% (p < 0.0001). Compared with placebo, prednisolone treatment tended to decrease lipolysis in the fasted state (p = 0.062), but both prednisolone 7.5 mg and prednisolone 30 mg decreased insulin-mediated suppression of lipolysis by 11 ± 5% and 34 ± 6%, respectively. Finally, prednisolone treatment increased whole-body proteolysis during hyperinsulinaemia, which tended to be driven by prednisolone 30 mg (5 ± 2%; p = 0.06). No side effects were reported by the study participants. All participants completed the study and were analysed. CONCLUSIONS/INTERPRETATION: Not only at high doses but also at low doses, glucocorticoid therapy impaired intermediary metabolism by interfering with the metabolic actions of insulin on liver and adipose tissue. These data indicate that even low-dose glucocorticoids may impair glucose tolerance when administered chronically. TRIAL REGISTRATION: ISRCTN83991850.

Ectopic fat storage in the pancreas, liver, and abdominal fat depots: impact on ß-cell function in individuals with impaired glucose metabolism.

CONTEXT: Pancreatic fat content (PFC) may have deleterious effects on ß-cell function. OBJECTIVE: We hypothesized that ectopic fat deposition, in particular pancreatic fat accumulation, is related to ß-cell dysfunction in individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). DESIGN, SETTING AND PARTICIPANTS: This was a cross-sectional study in 64 age- and body mass index-matched individuals, with normal glucose tolerance (NGT; n = 16, 60% males), IFG (n = 29, 52% males), or IFG/IGT (n = 19, 63% males) was conducted. INTERVENTION AND MAIN OUTCOME MEASURES: Participants underwent the following: 1) a combined hyperinsulinemic-euglycemic and hyperglycemic clamp, with subsequent arginine stimulation to quantify insulin sensitivity and ß-cell function; 2) proton-magnetic resonance spectroscopy to assess PFC and liver fat content (LFC); and 3) magnetic resonance imaging to quantify visceral (VAT) and sc (SAT) adipose tissue. The disposition index (DI; insulin sensitivity adjusted ß-cell function) was assessed. RESULTS: IFG and IFG/IGT were more insulin resistant (P < 0.001) compared with NGT. Individuals with IFG/IGT had the lowest values of glucose- and arginine-stimulated C-peptide secretion (both P < 0.03) and DI (P < 0.001), relative to IFG and NGT. PFC and LFC gradually increased between NGT, IFG, and IFG/IGT (P = 0.02 and P = 0.01, respectively), whereas VAT and SAT were similar between groups. No direct associations were found between PFC, LFC, VAT, and SAT and C-peptide secretion. The DI was inversely correlated with PFC, LFC, and VAT (all P < 0.05). CONCLUSIONS: PFC was increased in individuals with IFG and/or IGT, without a direct relation with ß-cell function.