Greater efficacy of pulsatile insulin in type I diabetics critically depends on plasma glucagon levels

The aim of this study was to investigate the role of plasma glucagon levels on the blood glucose response to intravenous insulin administered continuously or in a pulsatile manner. Six type I diabetic patients proven to have no residual insulin secretion were investigated. Endogenous glucagon secretion was inhibited by a continuous intravenous infusion of somatostatin (100 micrograms/h) and replaced by exogenous infusions of the hormone at three different rates (7.5, 4.5, and 2.5 micrograms/h), resulting in three different plasma glucagon steady-state levels (i.e., approximately equal to 200, approximately equal to 130, and approximately equal to 75 pg/ml, respectively). Each subject, in random order and on different days, was infused intravenously with regular human insulin either continuously (0.17 mU X kg-1 X min-1) or with the same amount of insulin infused in a pulsatile manner (0.85 mU X kg-1 X min-1 during 2 min followed by 8 min during which no insulin was infused). At plasma glucagon levels approximately equal to 200 pg/ml, blood glucose rose from approximately 10 to approximately 13 mM without any difference between the two modalities of insulin infusion. For plasma glucagon levels approximately equal to 130 pg/ml, plasma glucose remained steady throughout the experiments, but during the last 40 min, plasma glucose levels were significantly lower when insulin was administered intermittently. This greater blood glucose-lowering effect of pulsatile insulin occurred earlier and was more pronounced for plasma glucagon levels averaging 75 pg/ml. We conclude that the greater hypoglycemic effect of insulin administered intravenously in a pulsatile manner in type I diabetics critically depends on plasma glucagon circulating levels.     

Availability of glucose ingested during muscle exercise performed under acipimox-induced lipolysis blockade

This study investigated the percentage of carbohydrate utilization than can be accounted for by glucose ingested during exercise performed after the ingestion of the potent lipolysis inhibitor Acipimox. Six healthy male volunteers exercised for 3 h on a treadmill at about 45% of their maximal oxygen uptake, 75 min after having ingested 250 mg of Acipimox. After 15-min adaptation to exercise, they ingested either glucose dissolved in water, 50 g at time 0 min and 25 g at time 60 and 120 min (glucose, G) or sweetened water (control, C). Naturally labelled [¹³C]glucose was used to follow the conversion of the ingested glucose to expired-air CO₂. Acipimox inhibited lipolysis in a similar manner in both experimental conditions. This was reflected by an almost complete suppression of the exercise-induced increase in plasma free fatty acid and glycerol and by an almost constant rate of lipid oxidation. Total carbohydrate oxidation evaluated by indirect calorimetry, was similar in both experimental conditions [C, 182, (SEM 21); G, 194 (SEM 16) g · 3 h^–1], as was lipid oxidation [C, 57 (SEM 6); G, 61 (SEM 3) g · 3 h^–1]. Exogenous glucose oxidation during exercise G, calculated by the changes in¹³C:¹²C ratio of expired air CO₂, averaged 66 (SEM 5) g · 3 h^–1 (19% of the total energy requirement). Consequently, endogenous carbohydrate utilization was significantly smaller after glucose than after placebo ingestion: 128 (SEM 18) versus 182 (SEM 21) g · 3 h^–1, respectively (P < 0.05). Symptoms of intense fatigue and leg cramps observed with intake of sweet placebo were absent with glucose ingestion.In conclusion, we found glucose ingestion during 3-h exercise with lipolysis blockade could provide metabolic substrate permitting a significant sparing of endogenous carbohydrate and consequently an improvement in performance.     

Devices for the treatment of diabetes: today

Although single or multiple daily subcutaneous injections of insulin with syringes are the mainstay of insulin delivery techniques for the treatment of diabetes mellitus, several other methods are now available. The present paper will review the main problems occurring with the classical subcutaneous insulin therapy and the possible solutions given by the use of new devices, including more particularly insulin jet injectors, pens, and portable pumps. This review has to be considered as an introduction to the presentations of this symposium devoted to implantable pumps, glucose sensors, and artificial pancreas, respectively.     

Pulsatile insulin delivery has greater metabolic effects than continuous hormone administration in man: importance of pulse frequency

The aim of this study was to see if the greater effect of insulin on hepatic glucose output when insulin is given using 13-min pulses in man remains when the same amount of insulin is delivered using 26-min pulses. The study was performed on nine male healthy volunteers submitted to a 325 min glucose-controlled glucose iv infusion using the Biostator. The endogenous secretion of pancreatic hormones was inhibited by somatostatin. Three experiments were performed in each subject on different days and in random order. In all cases glucagon was replaced (58 ng min-1). The amounts of insulin infused were identical in all instances and were 0.2 mU kg-1 min-1 (continuous), 1.3 mU kg-1 min-1, 2 min on and 11 min off (13-min pulses) or 2.6 mU kg-1 min-1, 2 min on and 24 min off (26-min pulses). Blood glucose levels and glucose infusion rate were monitored continuously by the Biostator, and classic methodology using D-[3-3H] glucose infusion allowed to study glucose turnover. When compared with continuous insulin, 13-min insulin pulses induced a significantly greater inhibition of endogenous glucose production. This effect disappeared when insulin was delivered in 26-min pulses. We conclude that, in man, an adequate pulse frequency is required to allow the appearance of the greater inhibition of pulsatile insulin on endogenous glucose production.     

Anti-inflammatory agents to treat or prevent type 2 diabetes,metabolic syndrome and cardiovascular disease

Introduction: There is a growing body of evidence to suggest that chronic silent inflammation is a key feature in abdominal obesity, metabolic syndrome, type 2 diabetes (T2DM) and cardiovascular disease (CVD). These observations suggest that pharmacological strategies, which reduce inflammation, may be therapeutically useful in treating obesity, type 2 diabetes and associated CVD.

Area covered: The article covers novel strategies, using either small molecules or monoclonal antibodies. These strategies include: approaches targeting IKK-b-NF-kB (salicylates, salsalate), TNF-α (etanercept, infliximab, adalimumab), IL-1β (anakinra, canakinumab) and IL-6 (tocilizumab), AMP-activated protein kinase activators, sirtuin-1 activators, mammalian target of rapamycin inhibitors and C-C motif chemokine receptor 2 antagonists.

Expert opinion: The available data supports the concept that targeting inflammation improves insulin sensitivity and β-cell function; it also ameliorates glucose control in insulin-resistant patients with inflammatory rheumatoid diseases as well in patients with metabolic syndrome or T2DM. Although promising, the observed metabolic effects remain rather modest in most clinical trials. The potential use of combined anti-inflammatory agents targeting both insulin resistance and insulin secretion appears appealing but remains unexplored. Large-scale prospective clinical trials are underway to investigate the safety and efficacy of different anti-inflammatory drugs. Further evidence is needed to support the concept that targeting inflammation pathways may represent a valuable option to tackle the cardiometabolic complications of obesity.     

A Randomized,Double-Blind,Parallel Study to Evaluate the Dose-Response of Three Different Vitamin D Treatment Schemes on the 25-Hydroxyvitamin D Serum Concentration in Patients with Vitamin D Deficiency

Many people worldwide are vitamin D (VTD) deficient or insufficient, and there is still no consensus on the dose of VTD that should be administered to achieve a 25(OH)D concentration of 20 or 30 ng/mL. In this study, we aimed to determine an adapted supplementation of VTD able to quickly and safely increase the vitamin D status of healthy adults with low 25(OH)D. One hundred and fifty (150) subjects were randomized into three groups, each to receive, orally, a loading dose of 50,000, 100,000 or 200,000 IU of VTD3 at Week 0, followed by 25,000, 50,000 or 100,000 IU at Week 4 and Week 8. Whereas 25(OH)D baseline values were not different between groups (p = 0.42), a significant increase was observed at Week 12 (p < 0.0001) with a mean change from baseline of 7.72 ± 5.08, 13.3 ± 5.88 and 20.12 ± 7.79 ng/mL. A plateau was reached after eight weeks. No related adverse event was recorded. This study demonstrated a linear dose-response relationship with an increase in 25(OH)D levels proportional to the dose administered. In conclusion, a loading dose of 200,000 IU VTD3 followed by a monthly dose of 100,000 IU is the best dosing schedule to quickly and safely correct the VTD status.     

Belgian consensus on metabolic problems associated with atypical antipsychotics

A workshop was convened by a panel of psychiatrists, diabetologists and pharmacists from major Belgian hospitals to review the latest information relating to the risks with second-generation antipsychotics (SGA) for the development of metabolic disorders, especially impaired glucose tolerance, diabetes mellitus and dyslipidemia. The panelists sought to formulate recommendations for practising psychiatrists when initiating and maintaining therapy with SGA, and for the switch of SGA or initiation of further treatment if metabolic complications occur. In addition, recommendations for counselling of the patient and for the cooperation between the psychiatrist and the general physician or diabetologist, respectively, were provided.     

Haemodynamic changes during a squat test, pulsatile stress and indices of cardiovascular autonomic neuropathy in patients with long-duration type 1 diabetes

AimCardiovascular autonomic neuropathy (CAN) and pulsatile stress are considered to be independent cardiovascular risk factors. This study compared haemodynamic changes during an active orthostatic test in adult patients with type 1 diabetes (T1DM), using low versus high RR E/I ratios as a marker of CAN.MethodsA total of 20 T1DM patients with low RR E/I ratios were compared with 20 T1DM patients with normal RR E/I ratios, matched for gender (1/1 ratio), age (mean: 46 years) and diabetes duration (22–26 years); 40 matched healthy subjects served as controls. All subjects were evaluated by continuous monitoring of arterial blood pressure (Finapres^®) and heart rate using a standardized posture test (1-min standing, 1-min squatting, 1-min standing), thus allowing calculation of baroreflex gain.ResultsCompared with controls, T1DM patients showed lower RR E/I ratios, reduced baroreflex gains, higher pulsatile stress (pulse pressure × heart rate), greater squatting-induced pulse pressure rises, orthostatic hypotension and reduced reflex tachycardia. Compared with T1DM patients with preserved RR E/I ratios, T1DM patients with low RR E/I ratios showed reduced post-standing reflex tachycardia and baroreflex gain, and delayed blood pressure recovery, but no markers of increased pulsatile stress. Interestingly, decreased baroreflex gain was significantly associated with both pulsatile stress and microalbuminuria.ConclusionThe use of RR E/I ratios to separate T1DM patients allows the detection of other CAN markers during an orthostatic posture test, but with no significant differences in pulsatile stress or microalbuminuria. In this context, squatting-derived baroreflex gain appears to be more informative.     

Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2 diabetes

Free fatty acids (FFAs) are metabolic intermediates that may be obtained through the diet or synthesized endogenously. In addition to serving as an important source of energy, they produce a variety of both beneficial and detrimental effects. They play essential roles as structural components of all cell membranes and as signaling molecules regulating metabolic pathways through binding to nuclear or membrane receptors. However, under conditions of FFAs overload, they become toxic, inducing ROS production, ER stress, apoptosis and inflammation. SFAs (saturated fatty acids), unlike UFAs (unsaturated fatty acids), have recently been proposed as triggers of the NLRP3 inflammasome, a molecular platform mediating the processing of IL-1β in response to infection and stress conditions. Interestingly, UFAs, especially ω-3 FAs, inhibit NLRP3 inflammasome activation in various settings. We focus on emerging models of NLRP3 inflammasome activation with a special emphasis on the molecular mechanisms by which FFAs modulate the activation of this complex. Taking into consideration the current literature and FFA properties, we discuss the putative involvement of mitochondria and the role of cardiolipin, a mitochondrial phospholipid, proposed to be sensed by NLRP3 after release, exposure and/or oxidation. Finally, we review how this SFA-mediated NLRP3 inflammasome activation contributes to the development of both insulin resistance and deficiency associated with obesity/type 2 diabetes. In this context, we highlight the potential clinical use of ω-3 FAs as anti-inflammatory compounds.     

DPP-4 inhibition and COVID-19: From initial concerns to recent expectations

Dipeptidyl peptidase-4 inhibitors (DPP-4is) have gained a key place in the management of type 2 diabetes mellitus (T2DM) essentially because of their good safety profile even in the frail population. DPP-4, originally known as ‘T-cell antigen CD26’, is expressed in many immune cells and regulates their functions, so the initial concern over the use of DPP-4is was the possible increased susceptibility to infections. Furthermore, because of the high affinity between human DPP-4 and the spike (S) receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it was suspected that this virus, responsible for coronavirus disease 2019 (COVID-19), might be able to use the DPP-4 enzyme as a functional receptor to gain entry into the host. However, DPP-4is also exert anti-inflammatory effects, which could be beneficial in patients exposed to cytokine storms due to COVID-19. Yet, when observational (mostly retrospective) studies compared clinical outcomes in DPP-4i users vs non-users among diabetes patients with COVID-19, the overall results regarding the risk of progression towards more severe forms of the disease and mortality were heterogeneous, thereby precluding any definite conclusions. Nevertheless, new expectations have arisen following recent reports of significant reductions in admissions to intensive care units and mortality in DPP-4i users. However, given the limitations inherent in such observational studies, any available results should be considered, at best, as hypothetical and only suggestive of potentially substantial benefits with DPP-4is in diabetes patients with COVID-19. While the safe use of DPP-4is in COVID-19 patients appears to be an acceptable hypothesis, all such positive findings still need to be confirmed in randomized controlled trials (a few of which are currently ongoing) before any recommendations can be made for clinical practice.