Combination of insulin and metformin in the treatment of type 2 diabetes

WSTĘP. Celem pracy była ocena działania metabolicznego metforminy w porównaniu z placebo, u chorych na cukrzycę typu 2, leczonych według schematu intensywnej insulinoterapii. MATERIAŁ I METODY. Metformina poprawia kontrolę glikemii u osób ze źle wyrównaną cukrzycą typu 2. Dotychczas nie zbadano jej wpływu u chorych na cukrzycę typu 2, leczonych metodą intensywnej insulinoterapii. Grupa 390 chorych na cukrzycę typu 2, stosujących insulinę, uczestniczyła w randomizowanym, kontrolowanym, przeprowadzonym metodą podwójnie ślepej próby badaniu z zaplanowaną pośrednią analizą po 16 tygodniach leczenia. Uczestników badania wybrano z 3 przyszpitalnych przychodni i losowo przydzielono do grup, przyjmujących placebo lub metforminę w uzupełnieniu insulinoterapii. Podczas badania prowadzono intensywną kontrolę glikemii z natychmiastowym dostosowaniem dawki insuliny, zgodnie ze ścisłymi wytycznymi. Określano wskaźniki kontroli glikemii, zapotrzebowanie na insulinę, masę ciała, ciśnienie tętnicze, stężenie lipidów, incydenty hipoglikemii i inne działania niepożądane. WYNIKI. Sposród 390 osób 37 nie ukończyło badania (12 w grupie otrzymującej placebo i 25 w grupie leczonej metforminą). U osób, które ukończyły 16-tygodniowy okres leczenia zastosowanie metforminy w porównaniu z placebo powodowało poprawę kontroli glikemii (średnia glikemia podczas 16 tygodni 7,8 vs. 8,8 mmol/l, p = 0,006; średnie stężenie HbA1c 6,9 vs. 7,6%, p < 0,0001), zmniejszone zapotrzebowanie na insulinę (63,8 vs. 71,3 j.; p < 0,0001), mniejszy przyrost masy ciała (-0,4 vs. +1,2 kg; p < 0,01) i zmniejszenie stężenia cholesterolu frakcji LDL (-0,21 vs. -0,02 mmol/l; p < 0,01). Ryzyko wystąpienia hipoglikemii było podobne. WNIOSKI. U chorych na cukrzycę typu 2, leczonych intensywnie insuliną, skojarzenie insuliny z metforminą powoduje lepsze wyrównanie glikemii w porównaniu z monoterapią insuliną, a jednocześnie zmniejsza zapotrzebowanie na insulinę i ogranicza przyrost masy ciała.INTRODUCTION. To investigate the metabolic effects of metformin, as compared with placebo, in type 2 diabetic patients intensively treated with insulin. MATERIAL AND METHODS. Metformin improves glycemic control in poorly controlled type 2 diabetic patients. Its effect in type 2 diabetic patients who are intensively treated with insulin has not been studied. A total of 390 patients whose type 2 diabetes was controlled with insulin therapy completed a randomized controlled double-blind trial with a planned interim analysis after 16 weeks of treatment.The subjects were selected from three outpatient clinics in regional hospitals and were randomly assigned to either the placebo or metformin group, in addition to insulin therapy. Intensive glucose monitoring with immediate insulin adjustments according to strict guidelines was conducted. Indexes of glycemic control, insulin requirements, body weight, blood pressure, plasma lipids, hypoglycemic events, and other adverse events were measured. RESULTS. Of the 390 subjects, 37 dropped out (12 in the placebo and 25 in the metformin group). Of those who completed 16 weeks of treatment, metformin use, as compared with placebo, was associated with improved glycemic control (mean daily glucose at 16 weeks 7.8 vs. 8.8 mmol/l, P = 0.006; mean GHb 6.9 vs. 7.6%, P < 0.0001); reduced insulin requirements (63.8 vs. 71.3 IU, P < 0.0001); reduced weight gain (&#8211;0.4 vs. +1.2 kg, P < 0.01); and decreased plasma LDL cholesterol (&#8211;0.21 vs. &#8211;0.02 mmol/l, P < 0.01). Risk of hypoglycemia was similar in both groups. CONCLUSIONS. In type 2 diabetic patients who are intensively treated with insulin, the combination of insulin and metformin results in superior glycemic control compared with insulin therapy alone, while insulin requirements and weight gain are less

The mind in the middle: Taking stock of affect and cognition research in entrepreneurship.

In spite of substantial advances, entrepreneurship research on affect and cognition remains characterized by a multiplicity of theoretical approaches, methods, variables and measures. Although this multiplicity affords a lot of richness, it also poses potential risks - from the lack of a coherent knowledge base to the dangers of an atomistic evolution, with minimum exchanges between 'siloed' groups of scholars, limited theoretical integration and increased chances of redundant repetitions without real advances in understanding. To help guard against these risks and in order to augment the impact and value-adding contribution of future research, the six papers in this special issue analyse the progress made in entrepreneurship research on (1) situated cognition, (2) fear, (3) how affective dynamics influences entrepreneurship, (4) intuition, (5) opportunity evaluation and (6) entrepreneurial team cognition. This short introductory essay builds on the synthesis of the literature to summarize 'the road travelled so far'. The six papers forming this special issue are then introduced and their respective focus and contributions are detailed. The authors conclude by reflecting on these papers' implications, and offer a number of observations about future research and the 'road ahead'

De Novo Protein Synthesis Mediated by the Eukaryotic Elongation Factor 2 Is Required for the Anxiolytic Effect of Oxytocin.

The neuropeptide oxytocin (OXT) mediates its actions, including anxiolysis, via its G protein-coupled OXT receptor. Within the paraventricular nucleus of the hypothalamus (PVN), OXT-induced anxiolysis is mediated, at least in part, via activation of the mitogen-activated protein kinase pathway following calcium influx through transient receptor potential cation channel subfamily V member 2 channels. In the periphery, OXT activates eukaryotic elongation factor 2 (eEF2), an essential mediator of protein synthesis. In order to study whether OXT activates eEF2 also in neurons to exert its anxiolytic properties in the PVN, we performed in vivo and cell culture experiments. We demonstrate that OXT, in a protein kinase C-dependent manner, activates eEF2 both in a hypothalamic cell line and in vivo within the PVN. Next, we reveal that OXT stimulates de novo protein synthesis, while inhibition of protein synthesis within the PVN prevents the anxiolytic effect of OXT in male rats. Moreover, activation of eEF2 within the PVN conveyed an anxiolytic effect supporting a role of OXT-induced eEF2 activation and protein synthesis for its anxiolysis. Finally, we show that one of the proteins that is upregulated by OXT is the neuropeptide Y receptor 5. Infusion of a specific neuropeptide Y receptor 5 agonist into the PVN consequently led to decreased anxiety-related behavior, while pretreatment with a neuropeptide Y receptor 5 antagonist prevented the anxiolytic effect of OXT. Taken together, these results show that OXT recruits several intracellular signaling cascades to induce protein synthesis, which mediates the anxiolytic effects of OXT within the PVN and suggests that eEF2 represents a novel target for anxiety-related disorders

Tandem substitutions in somatic hypermutation

Upon antigen recognition, activation-induced cytosine deaminase initiates affinity maturation of the B-cell receptor by somatic hypermutation (SHM) through error-prone DNA repair pathways. SHM typically creates single nucleotide substitutions, but tandem substitutions may also occur. We investigated incidence and sequence context of tandem substitutions by massive parallel sequencing of V(D)J repertoires in healthy human donors. Mutation patterns were congruent with SHM-derived single nucleotide mutations, delineating initiation of the tandem substitution by AID. Tandem substitutions comprised 5,7% of AID-induced mutations. The majority of tandem substitutions represents single nucleotide juxtalocations of directly adjacent sequences. These observations were confirmed in an independent cohort of healthy donors. We propose a model where tandem substitutions are predominantly generated by translesion synthesis across an apyramidinic site that is typically created by UNG. During replication, apyrimidinic sites transiently adapt an extruded configuration, causing skipping of the extruded base. Consequent strand decontraction leads to the juxtalocation, after which exonucleases repair the apyramidinic site and any directly adjacent mismatched base pairs. The mismatch repair pathway appears to account for the remainder of tandem substitutions. Tandem substitutions may enhance affinity maturation and expedite the adaptive immune response by overcoming amino acid codon degeneracies or mutating two adjacent amino acid residues simultaneously

Tandem substitutions in somatic hypermutation

Upon antigen recognition, activation-induced cytosine deaminase initiates affinity maturation of the B-cell receptor by somatic hypermutation (SHM) through error-prone DNA repair pathways. SHM typically creates single nucleotide substitutions, but tandem substitutions may also occur. We investigated incidence and sequence context of tandem substitutions by massive parallel sequencing of V(D)J repertoires in healthy human donors. Mutation patterns were congruent with SHM-derived single nucleotide mutations, delineating initiation of the tandem substitution by AID. Tandem substitutions comprised 5,7% of AID-induced mutations. The majority of tandem substitutions represents single nucleotide juxtalocations of directly adjacent sequences. These observations were confirmed in an independent cohort of healthy donors. We propose a model where tandem substitutions are predominantly generated by translesion synthesis across an apyramidinic site that is typically created by UNG. During replication, apyrimidinic sites transiently adapt an extruded configuration, causing skipping of the extruded base. Consequent strand decontraction leads to the juxtalocation, after which exonucleases repair the apyramidinic site and any directly adjacent mismatched base pairs. The mismatch repair pathway appears to account for the remainder of tandem substitutions. Tandem substitutions may enhance affinity maturation and expedite the adaptive immune response by overcoming amino acid codon degeneracies or mutating two adjacent amino acid residues simultaneously.Transplantation and immunomodulatio