Effect of protein-supplemented fasting on the fuel-hormone response to prolonged exercise in obese subjects

This study aimed at investigating the influence of protein-supplemented fasting (PSF) on the tolerance and the fuel-hormone response to endurance exercise in the severely obese subject. For this purpose, eight obese men (27 +/- 2 yr, 182 +/- 7 per cent of ideal body weight) exercised on a horizontal treadmill (4 km/h) during 3 h before and after 13 d of PSF (Alburone, 70 g protein/day). Because of the 8.9 +/- 0.7 kg weight loss and the corresponding lower energy cost, exercise oxygen consumption decreased from 1.6 +/- 0.1 (before PSF) to 1.4 +/- 0.1 l/min (after PSF). In contrast, mean exercise heart rate was identical (119 +/- 5/min) in both conditions, resulting in a lower oxygen pulse after PSF. The mean respiratory quotient measured during exercise was lower after PSF (0.72 +/- 0.01 vs 0.75 +/- 0.01 2 P less than 0.05), thus demonstrating a higher fat utilization. This was supported by a higher exercise-induced plasma free fatty acid (FFA) mobilization after PSF (delta plasma FFA: + 675 +/- 101 vs + 376 +/- 121 mumol/l, 2 P less than 0.05). This metabolic adaptation mainly results from two mechanisms: a significantly lower plasma IRI at rest and during exercise after PSF (5.7 +/- 0.8 vs 11.4 +/- 1.4 microunits/ml, 2 P less than 0.001); and a lower basal blood glucose (4.2 +/- 0.2 vs 4.6 +/- 0.1 mmol/l) and an earlier decrease of glucose (30th vs 90th min) during exercise after PSF, suggesting a relative depletion of the carbohydrates stores. The lipolytic hormones (glucagon, epinephrine, norepinephrine, cortisol, growth hormone) did not significantly increase during exercise after PSF when compared to exercise before PSF; thus, their role in the enhanced FFA mobilization appears less important. Only two of our eight subjects were unable to achieve the third hour of exercise after PSF; however, no major clinical events or electrocardiographical disturbances were observed in any of the eight subjects. In conclusion, moderate exercise can be tolerated at least for 2 h during PSF when appropriate fluid, mineral and vitamin therapy is given. Under these conditions it induces a preferential utilization of fat-derived substrates and selectively augments fat mobilization which favors weight loss. For these reasons, moderate exercise can be recommended under strict medical supervision as part of all weight reduction therapy.     

Investigational insulin secretagogues for type 2 diabetes

Introduction: Insulin secretory defects are a key feature in the pathophysiology of type 2 diabetes (T2D). Classical insulin-secreting agents such as sulfonlyureas stimulate insulin secretion independent of glucose and cause hypoglycemia. Despite the advantages offered by incretin-based therapies, there is still a medical need for developing new insulin secretagogues for treating T2D.

Area covered: This article discusses: the new advances in the field of incretin-based therapies, glucokinase (GK) activators, free fatty acid receptor (FFAR) or G protein-coupled receptor (GPR) agonists (GPR40, GPR119, GPR120), imeglimin and some other insulin secretagogues with diverse mechanisms of action still in preclinical development.

Expert opinion: New insulin secretagogues should offer major advantages over sulfonylureas and gliptins. The challenge is to avoid uncontrolled insulin secretion and minimize the risk of hypoglycemia, to protect cells from progressive loss of mass and function for a better durability of glucose control, and to offer a good safety profile. Numerous approaches are in development. However, it is too early to decide whether one new pharmacological class will emerge as a clinically useful insulin secretagogue in the near feature.     

Morphologic heterogeneity of malignant lymphomas developing in mycosis fungoides

From an extensive series of patients with mycosis fungoides, we identified 12 in whom subsequently developing extracutaneous (lymph nodal) lymphoma manifested morphologic features other than those of so-called cutaneous T-cell lymphoma. Six patients had features diagnostic of Hodgkin's disease, two had morphologic and cytochemical features consistent with T-cell lymphoma but without the morphologic features ascribed to cutaneous T-cell type, and four had morphologic characteristics most consistent with B-cell lymphoma. Although in most cases of mycosis fungoides the lymphomas exhibit morphologically distinctive features of mycosis cells, we propose that in occasional cases this morphologic correlation is not present.     

The safety of gliptins : updated data in 2018

Introduction: Dipeptidyl peptidase-4 inhibitors (DPP-4is) are generally considered as glucose-lowering agents with a safe profile in type 2 diabetes.

Areas covered: An updated review of recent safety data from randomised controlled trials, observational studies, meta-analyses, pharmacovigilance reports regarding alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin, with a special focus on risks of hypoglycemia, pancreatitis and pancreatic cancer, major cardiovascular events, hospitalisation for heart failure and other new safety issues, such as bone fractures and arthralgia. The safety of DPP-4i use in special populations, elderly patients, patients with renal impairment, liver disease or heart failure, will also be discussed.

Expert opinion: The good tolerance/safety profile of DPP-4is has been largely confirmed, including in more fragile populations, with no gastrointestinal adverse effects and a minimal risk of hypoglycemia. DPP-4is appear to be associated with a small increased incidence of acute pancreatitis in placebo-controlled trials, although most observational studies are reassuring. Most recent studies with DPP-4is do not confirm the increased risk of hospitalisation for heart failure reported with saxagliptin in SAVOR-TIMI 53, but further post-marketing surveillance is still recommended. New adverse events have been reported such as arthralgia, yet a causal relationship remains unclear.     

SGLT2 Inhibitors: Benefit/Risk Balance

Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) reduce hyperglycemia by increasing urinary glucose excretion. They have been evaluated in patients with type 2 diabetes treated with diet/exercise, metformin, dual oral therapy or insulin. Three agents are available in Europe and the USA (canagliflozin, dapagliflozin, empagliflozin) and others are commercialized in Japan or in clinical development. SGLT2 inhibitors reduce glycated hemoglobin, with a minimal risk of hypoglycemia. They exert favorable effects beyond glucose control with consistent body weight, blood pressure, and serum uric acid reductions. Empagliflozin showed remarkable reductions in cardiovascular/all-cause mortality and in hospitalization for heart failure in patients with previous cardiovascular disease. Positive renal outcomes were also shown with empagliflozin. Mostly reported adverse events are genital mycotic infections, while urinary tract infections and events linked to volume depletion are rather rare. Concern about a risk of ketoacidosis and bone fractures has been recently raised, which deserves caution and further evaluation.     

Cardiovascular safety of DPP-4 inhibitors compared with sulphonylureas: Results of randomized controlled trials and observational studies

After failure of metformin monotherapy, another glucose-lowering agent should be added to improve glucose control. The clinician has several pharmacological choices, including the addition of a sulphonylurea (SU) or a dipeptidyl peptidase-4 inhibitor (DPP-4i). While the cardiovascular safety of SUs remains a matter of controversy, DPP-4is have proven their non-inferiority vs placebo in recent cardiovascular (CV) outcome trials. In the absence of a head-to-head CV outcome trial—the CAROLINA, comparing linagliptin with glimepiride, is still ongoing—only indirect information can be found in the literature to compare CV outcomes (major CV events, myocardial infarction, ischaemic stroke, CV death and all-cause mortality) in patients with type 2 diabetes mellitus (T2DM) treated with SUs or DPP-4is. Thus, this comprehensive review summarizes the CV outcomes (excluding heart failure) reported in meta-analyses of randomized controlled trials (RCTs) of SUs vs placebo or other glucose-lowering agents, DPP-4is vs placebo or other glucose-lowering agents and SUs vs DPP-4is in phase-II/III studies. Also, the results of observational studies reporting CV events in patients treated with either SUs or DPP-4is have been carefully examined. Overall, the CV safety of SUs appears to be poorer than that of DPP-4is in both RCTs and cohort studies. However, the results are somewhat disparate, and such heterogeneity may be explained by different patient characteristics across studies, but also perhaps by differences between various molecules in each pharmacological class. In particular, some doubt about a class effect affecting SU CV safety has been raised. The results of CAROLINA are expected to shed more light on SU CV concerns, especially compared with DPP-4is.     

Inhibitors of cannabinoid receptors and glucose metabolism

PURPOSE OF REVIEW: Abdominal obesity is closely related to type 2 diabetes and overactivity of the endocannabinoid system. The present review aims at evaluating the role of endocannabinoid system in glucose dysregulation and the effects of cannabinoid 1 receptor blockade on glucose metabolism in both animal models and overweight/obese humans, especially with type 2 diabetes. RECENT FINDINGS: Cannabinoid 1 receptors have been identified not only in the brain, but also in the adipose tissue, the gut, the liver, the skeletal muscle and even the pancreas, all organs playing a key role in glucose metabolism and type 2 diabetes. Rimonabant, the first selective cannabinoid 1 receptor blocker in clinical use, has been shown to reduce body weight, waist circumference, glycated haemoglobin, triglycerides, insulin resistance index, and to increase HDL cholesterol and adiponectin concentrations in patients with type 2 diabetes, confirming data on nondiabetic overweight/obese patients. Almost half of the metabolic changes, including glycated haemoglobin reduction, could not be explained by weight loss, in agreement with direct peripheral effects. SUMMARY: Cannabinoid 1 blockade reduces food intake and body weight and improves metabolic regulation beyond just weight loss. Because of its positive effect on glucose metabolism, rimonabant deserves consideration in the treatment of overweight/obese patients with type 2 diabetes.