Marcel H A Muskiet

Ectopic Fat Storage in the Pancreas, Liver, and Abdominal Fat Depots: Impact on β-Cell Function in Individuals with Impaired Glucose Metabolism

CONTEXTnPancreatic fat content (PFC) may have deleterious effects on β-cell function.nnnOBJECTIVEnWe hypothesized that ectopic fat deposition, in particular pancreatic fat accumulation, is related to β-cell dysfunction in individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT).nnnDESIGN, SETTING AND PARTICIPANTSnThis 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.nnnINTERVENTION AND MAIN OUTCOME MEASURESnParticipants underwent the following: 1) a combined hyperinsulinemic-euglycemic and hyperglycemic clamp, with subsequent arginine stimulation to quantify insulin sensitivity and β-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 β-cell function) was assessed.nnnRESULTSnIFG 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).nnnCONCLUSIONSnPFC was increased in individuals with IFG and/or IGT, without a direct relation with β-cell function.

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

Aim/hypothesisTo assess whether low-dose glucocorticoid treatment induces adverse metabolic effects, as is evident for high glucocorticoid doses.MethodsIn 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 22u2009±u20093xa0years; BMI 22.4u2009±u20091.7xa0kg/m2) were allocated to prednisolone 7.5xa0mg once daily (nu2009=u200912), prednisolone 30xa0mg once daily (nu2009=u200912), or placebo (nu2009=u20098) for 2xa0weeks using block randomisation. Main outcome measures were glucose, lipid and protein metabolism, measured by stable isotopes, before and at 2xa0weeks 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 NetherlandsResultsPrednisolone, compared with placebo, dose dependently and significantly increased fasting plasma glucose levels, whereas only prednisolone 30xa0mg increased fasting insulin levels (29u2009±u200915xa0pmol/l). Prednisolone 7.5xa0mg and prednisolone 30xa0mg decreased the ability of insulin to suppress endogenous glucose production (by 17u2009±u20096% and 46u2009±u20097%, respectively, vs placebo). Peripheral glucose uptake was not reduced by prednisolone 7.5xa0mg, but was decreased by prednisolone 30xa0mg by 34u2009±u20096% (pu2009<u20090.0001). Compared with placebo, prednisolone treatment tended to decrease lipolysis in the fasted state (pu2009=u20090.062), but both prednisolone 7.5xa0mg and prednisolone 30xa0mg decreased insulin-mediated suppression of lipolysis by 11u2009±u20095% and 34u2009±u20096%, respectively. Finally, prednisolone treatment increased whole-body proteolysis during hyperinsulinaemia, which tended to be driven by prednisolone 30xa0mg (5u2009±u20092%; pu2009=u20090.06). No side effects were reported by the study participants. All participants completed the study and were analysed.Conclusions/interpretationNot 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:ISRCTN83991850Funding:The study was funded by the Dutch Top Institute Pharma T1-106.

Pleiotropic effects of type 2 diabetes management strategies on renal risk factors

In parallel with the type 2 diabetes pandemic, diabetic kidney disease has become the leading cause of end-stage renal disease worldwide, and is associated with high cardiovascular morbidity and mortality. As established in landmark randomised trials and recommended in clinical guidelines, prevention and treatment of diabetic kidney disease focuses on control of the two main renal risk factors, hyperglycaemia and systemic hypertension. Treatment of systemic hypertension with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers is advocated because these drugs seem to exert specific renoprotective effects beyond blood pressure lowering. Emerging evidence shows that obesity, glomerular hyperfiltration, albuminuria, and dyslipidaemia might also adversely affect the kidney in diabetes. Control of these risk factors could have additional benefits on renal outcome in patients with type 2 diabetes. However, despite multifactorial treatment approaches, residual risk for the development and progression of diabetic kidney disease in patients with type 2 diabetes remains, and novel strategies or therapies to treat the disease are urgently needed. Several drugs used in the treatment of type 2 diabetes are associated with pleiotropic effects that could favourably or unfavourably change patients renal risk profile. We review the risk factors and treatment of diabetic kidney disease, and describe the pleiotropic effects of widely used drugs in type 2 diabetes management on renal outcomes, with special emphasis on antihyperglycaemic drugs.

Does dipeptidyl peptidase-4 inhibition prevent the diabetogenic effects of glucocorticoids in men with the metabolic syndrome? A randomized controlled trial

OBJECTIVEnAnti-inflammatory glucocorticoid (GC) therapy often induces hyperglycemia due to insulin resistance and islet-cell dysfunction. Incretin-based therapies may preserve glucose tolerance and pancreatic islet-cell function. In this study, we hypothesized that concomitant administration of the dipeptidyl peptidase-4 inhibitor sitagliptin and prednisolone in men at high risk to develop type 2 diabetes could protect against the GC-induced diabetogenic effects.nnnDESIGN AND METHODSnMen with the metabolic syndrome but without diabetes received prednisolone 30 u200amg once daily plus sitagliptin 100u200a mg once daily (n=14), prednisolone (n=12) or sitagliptin alone (n=14) or placebo (n=12) for 14 days in a double-blind 2 × 2 randomized-controlled study. Glucose, insulin, C-peptide, and glucagon were measured in the fasted state and following a standardized mixed-meal test. β-cell function parameters were assessed both from a hyperglycemic-arginine clamp procedure and from the meal test. Insulin sensitivity (M-value) was measured by euglycemic clamp.nnnRESULTSnPrednisolone increased postprandial area under the curve (AUC)-glucose by 17% (P<0.001 vs placebo) and postprandial AUC-glucagon by 50% (P<0.001). Prednisolone reduced 1st and 2nd phase glucose-stimulated- and combined hyperglycemia-arginine-stimulated C-peptide secretion (all P ≤ 0.001). When sitagliptin was added, both clamp-measured β-cell function (P=NS for 1st and 2nd phase vs placebo) and postprandial hyperglucagonemia (P=NS vs placebo) remained unaffected. However, administration of sitagliptin could not prevent prednisolone-induced increment in postprandial glucose concentrations (P<0.001 vs placebo). M-value was not altered by any treatment.nnnCONCLUSIONnFourteen-day treatment with high-dose prednisolone impaired postprandial glucose metabolism in subjects with the metabolic syndrome. Concomitant treatment with sitagliptin improved various aspects of pancreatic islet-cell function, but did not prevent deterioration of glucose tolerance by GC treatment.

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

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.

Biliary effects of liraglutide and sitagliptin, a 12-week randomized placebo-controlled trial in type 2 diabetes patients

Treatment with glucagon‐like peptide (GLP)‐1 receptor agonists or dipeptidyl peptidase (DPP)‐4 inhibitors might increase gallstone formation; however, the mechanisms involved are unknown. We aimed to assess the effects of these drugs on gallbladder volume and bile acid profile.

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

To investigate the effect of infusion of the glucagon‐like peptide‐1 (GLP‐1) receptor agonist exenatide on exocrine pancreatic function.

PS9 - 4. Changes in Circadian Haemodynamics and Autonomic Nervous System Balance in Non- Hypertensive Uncomplicated Type 2 Diabetes

Conflicting results exist regarding circadian haemodynamics in type 2 diabetes mellitus (T2DM). Inasmuch T2DM is associated with an altered cardiac autonomic nervous system (ANS) balance, we investigated circadian haemodynamic and ANS rhythms and their interrelationship in 12 non-hypertensive male patients with uncomplicated T2DM and 15 age- and gender-matched healthy controls.