A Cross-sectional Survey to Assess Reasons for Therapeutic Inertia in People With Type 2 Diabetes Mellitus and Preferred Strategies to Overcome It From the Perspectives of Persons With Diabetes and General/Family Practitioners: Results From the MOTION Study.

OBJECTIVES: Although multiple causes of therapeutic inertia in type 2 diabetes mellitus (T2DM) have been identified, few studies have addressed the behavioural aspects of treatment-intensification decisions among persons with type 2 diabetes (PwT2DM) and general practitioners/family practitioners (GPFPs). METHODS: A quantitative online survey was developed to capture from 300 PwT2DM and 100 GPFPs the following information: 1) perspectives on shared decision-making (SDM) related to treatment intensification, using the 9-item Shared Decision Making Questionnaire and the Shared Decision Making Questionnaire---physician version; 2) intentions to intensify treatments, using the Theory of Planned Behaviour (TPB); and 3) preferred strategies to overcome causes of therapeutic inertia in T2DM. Regression methods were applied post hoc to examine correlations with SDM scores, behavioural intentions and behaviours. RESULTS: SDM scores showed a significantly lower level of perceived involvement in decision-making related to treatment intensification among PwT2DM compared with GPFPs. The TPB identified that, for PwT2DM, attitudes, perceived behavioural control and age were associated with variation in intention to intensify treatment and, for GPFPs, perceived behavioural control and not being in a shared/group practice were associated with intentions to intensify treatment. PwT2DM behaviour, measured as hesitancy to intensify treatment, was associated with age. PwT2DM want more information to become more comfortable with the treatment decision-making process, whereas GPFPs desired support from other health professionals, and more time to address issues among PwT2DM. CONCLUSIONS: Strategies directed at providing GPFPs with tools/approaches to increase PwT2DM involvement in the decision-making process, such as behavioural coaching, decision aids and goal setting, may increase acceptance of treatment intensification, leading to a reduction in therapeutic inertia in T2DM.

Persons With Diabetes and General/Family Practitioner Perspectives Related to Therapeutic Inertia in Type 2 Diabetes Mellitus Using Qualitative Focus Groups and the Theoretical Domains Framework: Results From the MOTION Study.

OBJECTIVES: Therapeutic inertia in type 2 diabetes (T2DM) is the failure to receive timely treatment intensification as indicated according to T2DM treatment guidelines. Multifactorial causes of therapeutic inertia in T2DM have been documented at the level of persons with diabetes (PwD), health-care providers and health-care systems. METHODS: We developed a 3-part mixed-methods research program, called the Moving to Overcome Therapeutic Inertia Obstacles Now in T2DM (MOTION) study, to inform the development of strategies to address therapeutic inertia in T2DM. We present the results from focus groups with the following objectives: 1) understanding PwD and general practitioner/family practitioner (GPFP) determinants of behaviour related to treatment intensification using the Theoretical Domains Framework (TDF); and 2) identifying the sources of behaviours contributing to therapeutic inertia in T2DM, as proposed by the Behaviour Change Wheel (BCW). Two focus groups with PwD and 4 with GPFPs were conducted. Transcripts from the focus groups were coded independently by 2 investigators to identify themes, then mapped to TDF domains and linked using the BCW. RESULTS: For PwD, the most commonly coded TDF domains were intentions, goals, knowledge, beliefs about consequences and social influences. For GPFPs, the most common domains were intentions, environmental context and resources and social/professional role and identity. The BCW identified that PwD interventions should include reflective motivation, psychological capability and social opportunity; GPFP interventions should include physical opportunity, social opportunity and reflective motivation. CONCLUSIONS: Comprehensive strategies that target both PwD and GPFP barriers would encourage a more collaborative approach toward treatment intensification decisions and reducing therapeutic inertia.

Strategies to Overcome Therapeutic Inertia in Type 2 Diabetes Mellitus: A Scoping Review.

The objectives of this review were to: 1) examine recent strategies and component interventions used to overcome therapeutic inertia in type 2 diabetes mellitus (T2DM), 2) map strategies to the causes of therapeutic inertia they target and 3) identify causes of therapeutic inertia in T2DM that have not been targeted by recent strategies. A systematic search of the literature published from January 2014 to December 2019 was conducted to identify strategies targeting therapeutic inertia in T2DM, and key strategy characteristics were extracted and summarized. The search identified 46 articles, employing a total of 50 strategies aimed at overcoming therapeutic inertia. Strategies were composed of an average of 3.3 interventions (range, 1 to 10) aimed at an average of 3.6 causes (range, 1 to 9); most (78%) included a type of educational strategy. Most strategies targeted causes of inertia at the patient (38%) or health-care professional (26%) levels only and 8% targeted health-care-system-level causes, whereas 28% targeted causes at multiple levels. No strategies focused on patients' attitudes toward disease or lack of trust in health-care professionals; none addressed health-care professionals' concerns over costs or lack of information on side effects/fear of causing harm, or the lack of a health-care-system-level disease registry. Strategies to overcome therapeutic inertia in T2DM commonly employed multiple interventions, but novel strategies with interventions that simultaneously target multiple levels warrant further study. Although educational interventions are commonly used to address therapeutic inertia, future strategies may benefit from addressing a wider range of determinants of behaviour change to overcome therapeutic inertia.

Molecular mechanisms of apoptosis activation by heat shock in multidrug-resistant Chinese hamster cells.

Multidrug resistance (MDR) is a major obstacle to the success of chemotherapy in cancer treatment and is associated with overexpression of P-glycoprotein. MDR cells, aside from resistance to chemotherapy, might also inhibit apoptosis at various levels in the death signaling pathways. Currently, hyperthermia is used in cancer treatment to sensitize tumor cells to radiation and/or chemotherapy. This study investigated the induction of death receptor and mitochondria-mediated signaling pathways of apoptosis by hyperthermia (41-43 degrees C) in MDR CHRC5 cells compared to drug-sensitive AuxB1 Chinese hamster ovary cells. In the receptor-mediated pathway, CHRC5 cells exhibited higher levels of c-FLIP and lower caspase 8 and caspase 10 activation in response to hyperthermia. In the mitochondria-mediated pathway of heat-induced apoptosis, CHRC5 cells showed higher mitochondrial levels of Bax and tBid, more pronounced mitochondrial membrane depolarization, and increased Apaf-1. Similar levels of caspase 3 activation and cleavage of caspase substrates occurred, showing that overall, CHRC5 cells are not resistant to hyperthermia-induced apoptosis compared to AuxB1 cells. This study reveals for the first time the molecular mechanisms of hyperthermia-induced apoptosis in MDR cells overexpressing P-glycoprotein. CHRC5 and AuxB1 cells showed similar clonogenic survival responses to heat, which implies that hyperthermia could be a promising strategy for eradicating MDR tumor cells in the clinic.

Functional interactions between the oxytocin receptor and the ß2-adrenergic receptor: implications for ERK1/2 activation in human myometrial cells.

The Gq-coupled oxytocin receptor (OTR) and the Gs-coupled ß(2)-adrenergic receptor (ß(2)AR) are both expressed in myometrial cells and mediate uterine contraction and relaxation, respectively. The two receptors represent important pharmacological targets as OTR antagonists and ß(2)AR agonists are used to control pre-term uterine contractions. Despite their physiologically antagonistic effects, both receptors activate the MAP kinases ERK1/2, which has been implicated in uterine contraction and the onset of labor. To determine the signalling pathways involved in mediating the ERK1/2 response, we assessed the effect of blockers of specific G protein-associated pathways. In human myometrial hTERT-C3 cells, inhibition of Gαi as well as inhibition of the Gαq/PKC pathway led to a reduction of both OTR- and ß(2)AR-mediated ERK1/2 activation. The involvement of Gαq/PKC in ß(2)AR-mediated ERK1/2 induction was unexpected. To test whether the emergence of this novel signalling mechanism was dependent on OTR expression in the same cell, we conducted experiments in HEK 293 cells that were transfected with the ß(2)AR alone or co-transfected with the OTR. Using this approach, we found that ß(2)AR-mediated ERK1/2 responses became sensitive to PKC inhibition only in cells co-transfected with the OTR. Inhibitor studies indicated the involvement of an atypical PKC isoform in this process. We confirmed the specific involvement of PKCζ in this pathway by assessing PKCζ translocation to the cell membrane. Consistent with our inhibitor studies, we found that ß(2)AR-mediated PKCζ translocation was dependent on co-expression of OTR. The present demonstration of a novel ß(2)AR-coupled signalling pathway that is dependent on OTR co-expression is suggestive of a molecular interaction between the two receptors.

Allosteric interactions between the oxytocin receptor and the ß2-adrenergic receptor in the modulation of ERK1/2 activation are mediated by heterodimerization.

The oxytocin receptor (OTR) and the ß(2)-adrenergic receptor (ß(2)AR) are key regulators of uterine contraction. These two receptors are targets of tocolytic agents used to inhibit pre-term labor. Our recent study on the nature of OTR- and ß(2)AR-mediated ERK1/2 activation in human hTERT-C3 myometrial cells suggested the presence of an OTR/ß(2)AR hetero-oligomeric complex (see companion article). The goal of this study was to investigate potential allosteric interactions between OTR and ß(2)AR and establish the nature of the interactions between these receptors in myometrial cells. We found that OTR-mediated ERK1/2 activation was attenuated significantly when cells were pretreated with the ß(2)AR agonist isoproterenol or two antagonists, propranolol or timolol. In contrast, pretreatment of cells with a third ß(2)AR antagonist, atenolol resulted in an increase in OTR-mediated ERK1/2 activation. Similarly, ß(2)AR-mediated ERK1/2 activation was strongly attenuated by pretreatment with the OTR antagonists, atosiban and OTA. Physical interactions between OTR and ß(2)AR were demonstrated using co-immunoprecipitation, bioluminescence resonance energy transfer (BRET) and protein-fragment complementation (PCA) assays in HEK 293 cells, the latter experiments indicating the interactions between the two receptors were direct. Our analyses suggest physical interactions between OTR and ß(2)AR in the context of a new heterodimer pair lie at the heart of the allosteric effects.