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See detailAntidiabetic agents: Potential anti-inflammatory activity beyond glucose control.
Scheen, André ULg; Esser, N.; Paquot, Nicolas ULg

in Diabetes & metabolism (2015)

A growing body of evidence is emerging to show that abdominal obesity, the metabolic syndrome, type 2 diabetes, cardiovascular disease and microvascular diabetic complications are intimately related to ... [more ▼]

A growing body of evidence is emerging to show that abdominal obesity, the metabolic syndrome, type 2 diabetes, cardiovascular disease and microvascular diabetic complications are intimately related to chronic inflammation. These observations pave the way to the development of new pharmacological strategies that aim to reduce silent inflammation. However, besides specific anti-inflammatory agents, glucose-lowering medications may also exert anti-inflammatory effects that could contribute to improved outcomes in diabetic patients. Most studies have used metformin, an AMP-activated protein kinase (AMPK) activator, and thiazolidinediones (TZDs), which act as peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists. Both pharmacological classes (considered insulin-sparing agents or insulin sensitizers) appear to have greater anti-inflammatory activity than insulin-secreting agents such as sulphonylureas or glinides. In particular, TZDs have shown the widest range of evidence of lowered tissue (visceral fat and liver) and serum inflammation. In contrast, despite reducing postprandial hyperglycaemia, the effect of alpha-glucosidase inhibitors on inflammatory markers appears rather modest, whereas dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) and glucagon-like peptide-1 (GLP-1) receptor agonists appear more promising in this respect. These incretin-based therapies exert pleiotropic effects, including reports of anti-inflammatory activity. No human data are available so far regarding sodium-glucose cotransporter type 2 (SGLT2) inhibitors. Although they may have indirect effects due to reduced glucotoxicity, their specific mode of action in the kidneys does not suggest systemic anti-inflammatory activity. Also, in spite of the complex relationship between insulin and atherosclerosis, exogenous insulin may also exert anti-inflammatory effects. Nevertheless, for all these glucose-lowering agents, it is essential to distinguish between anti-inflammatory effects resulting from better glucose control and potential anti-inflammatory effects related to intrinsic actions of the pharmacological class. Finally, it would also be of major clinical interest to define what role the anti-inflammatory effects of these glucose-lowering agents may play in the prevention of macrovascular and microvascular diabetic complications. [less ▲]

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See detailIndividualizing treatment of type 2 diabetes by targeting postprandial or fasting hyperglycaemia: Response to a basal vs a premixed insulin regimen by HbA quartiles and ethnicity.
Scheen, André ULg; Schmitt, H.; Jiang, H. H. et al

in Diabetes & metabolism (2015), 41(3), 216-222

AIM: This study evaluated the proportions of prandial (PHG) vs fasting hyperglycaemia (FHG) over 24h in a group of patients with type 2 diabetes (overall and for Caucasian vs Asian patients), and tested ... [more ▼]

AIM: This study evaluated the proportions of prandial (PHG) vs fasting hyperglycaemia (FHG) over 24h in a group of patients with type 2 diabetes (overall and for Caucasian vs Asian patients), and tested the hypothesis that an insulin regimen with a prandial component allows a greater response than basal insulin at low glycated haemoglobin (HbA1c) levels with a higher proportion of PHG than FHG. METHODS: Relative contributions of PHG and FHG to overall hyperglycaemia were analyzed by baseline HbA1c quartiles and by ethnicity at baseline and after 24-week treatment with either insulin glargine or insulin lispro mix 25 in the DURABLE study. RESULTS: With increasing baseline HbA1c, the mean relative contribution of PHG to the total area under the curve decreased (from 41% to 27%) while FHG was increased (from 59% to 73%). Both insulins decreased FHG, but only insulin lispro mix 25 decreased PHG. More patients with baseline HbA1c<9%, where PHG was more relevant, achieved the target HbA1c of<7% at endpoint with insulin lispro mix 25 compared with glargine. On average, Asians had a 10% larger contribution of PHG at all HbA1c quartiles, and a lower proportion of Asians reached the HbA1c target of<7% with either insulin treatment compared with Caucasians. CONCLUSION: At baseline, the contribution of FHG to overall hyperglycaemia predominated at all HbA1c quartiles, whereas PHG was more clinically relevant at lower HbA1c levels and with a greater response to insulin lispro mix 25. Asians had a greater proportion of PHG and a lesser response to either insulins compared with Caucasians. Thus, responses to diabetes drugs by baseline HbA1c and ethnicity are worth investigating to better target and individualize treatment. [less ▲]

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See detailEffects of glucose-lowering agents on vascular outcomes in type 2 diabetes: A critical reappraisal.
Scheen, André ULg; Charbonnel, B.

in Diabetes & metabolism (2014)

Type 2 diabetes mellitus (T2DM) is strongly associated with cardiovascular complications, especially coronary artery disease. Numerous epidemiological studies have shown a close relationship between major ... [more ▼]

Type 2 diabetes mellitus (T2DM) is strongly associated with cardiovascular complications, especially coronary artery disease. Numerous epidemiological studies have shown a close relationship between major cardiovascular events and glycaemia, and several pathophysiological mechanisms have been described that explain how hyperglycaemia induces vascular damage. However, randomized controlled trials investigating either an intensive glucose-lowering strategy vs standard care or the addition of a new glucose-lowering agent vs a placebo have largely failed to demonstrate any clinical benefits in terms of cardiovascular morbidity or mortality. This lack of evidence has led some people to contest the clinical efficacy of lowering blood glucose in patients with T2DM, despite its positive effects on microvascular complications. This article analyzes the various reasons that might explain such discrepancies. There are still strong arguments in favour of targeting hyperglycaemia while avoiding other counterproductive effects, such as hypoglycaemia and weight gain, and of integrating the glucose-lowering approach within a global multi-risk strategy to reduce the burden of cardiovascular disease in T2DM. [less ▲]

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See detailEditorial. SGLT-2 receptor inhibitors: An opportunity to revise our therapeutic strategy for type 2 diabetes?
Bonnet, Fabrice; Scheen, André ULg

in Diabetes & metabolism (2014), 40(6 Suppl 1), 1-3

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See detailMetabolic effects of SGLT-2 inhibitors beyond increased glucosuria: A review of the clinical evidence.
Scheen, André ULg; Paquot, Nicolas ULg

in Diabetes & metabolism (2014), 40(6 Suppl 1), 4-11

Sodium-glucose cotransporter type 2 (SGLT-2) inhibitors (canagliflozin, dapagliflozin, empagliflozin) are new glucose-lowering agents that exert their therapeutic activity independently of insulin by ... [more ▼]

Sodium-glucose cotransporter type 2 (SGLT-2) inhibitors (canagliflozin, dapagliflozin, empagliflozin) are new glucose-lowering agents that exert their therapeutic activity independently of insulin by facilitating glucose excretion through the kidneys. However, this simple renal mechanism that results in sustained glucose urinary loss leads to more complex indirect metabolic effects. First, by reduction of chronic hyperglycaemia and attenuation of glucose toxicity, SGLT-2 inhibitors can improve both insulin secretion by beta cells and peripheraltissue insulin sensitivity. In the case of canagliflozin, because of low-potency SGLT1 inhibition, a non-renal (intestinal) effect may also be considered, which may contribute to better control of postprandial hyperglycaemia, although this contribution remains to be better analyzed in humans. Second, chronic glucose loss most probably leads to compensatory mechanisms. One of them, although not well evidenced in humans, might involve an increase in energy intake, an effect that may limit weight loss in the long run. Another could be an increase in endogenous glucose production, most probably driven by increased glucagon secretion, which may somewhat attenuate the glucoselowering effect. Nevertheless, despite these compensatory mechanisms and most probably because of the positive effects of the reduction in glucotoxicity, SGLT-2 inhibitors exert clinically relevant glucose-lowering activity while promoting weight loss, a unique dual effect among oral antidiabetic agents. Furthermore, the combination of SGLT-2 inhibitors with other drugs that either have anorectic effects (such as incretin-based therapies) or reduce hepatic glucose output (like metformin) and, thus, may dampen these two compensatory mechanisms appears appealing for the management of type 2 diabetes mellitus. [less ▲]

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See detailAnomalies of tolerance in glucose in schizophrenic patients treated with antipsychotics of second generation: 3 months prospective comparative study
Scheen, André ULg; De Hert, M.; Hanssens, L. et al

in Diabetes & Metabolism (2007, March), 33(Sp. Iss. 1), 129

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See detailRimonabant improves glucose tolerance in the overweight or obese non-diabetic patient: analysis of the RIO-Europe and RIO-Lipids studies
Scheen, André ULg; Despres, J. P.; Ziegler, O. et al

in Diabetes & Metabolism (2007, March), 33(Sp. Iss. 1), 68

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