Kaleidoscope model of diabetes care: time for a rethink?

National Audit Data highlight persistent sub-optimum control among increasing numbers of people living with diabetes, with severe consequences for the individual and the NHS. The aim of the present review was to introduce a new cohesive, holistic model of care, tailored to individual needs to support optimum diabetes outcomes. This model of diabetes is necessary in order to understand the driving forces behind behaviour and their impact on diabetes management. Feelings (an emotional state or reaction) and beliefs (an acceptance that something is true or real) are fundamental behavioural drivers and influence diabetes self-management choices. Individually, these explain some of the complexities of behaviour and, collectively, they impact on personal motivation (rationale/desire to act) to achieve a specific outcome. Inevitably, they independently affect diabetes self-management and the environment in which individuals live. A model of care that proposes the encompassing of environment, intrinsic thought and therapy regimens to provide tailored, personalized healthcare should support enhanced diabetes self-management and outcomes from diagnosis. The Kaleidoscope model of care could be deliverable in routine care, incorporating each of the influences on diabetes self-management, and should benefit both individuals with diabetes and healthcare professionals.

Negative allosteric modulation of metabotropic glutamate receptor 5 results in broad spectrum activity relevant to treatment resistant depression.

Evidence suggests that 30-50% of patients suffering from major depressive disorder (MDD) are classified as suffering from treatment resistant depression (TRD) as they have an inadequate response to standard antidepressants. A key feature of this patient population is the increased incidence of co-morbid symptoms like anxiety and pain. Recognizing that current standards of care are largely focused on monoaminergic mechanisms of action (MOAs), innovative approaches to drug discovery for TRD are targeting glutamate hyperfunction. Here we describe the in vitro and in vivo profile of GRN-529, a novel negative allosteric modulator (NAM) of metabotropic glutamate receptor 5 (mGluR5). In cell based pharmacology assays, GRN-529 is a high affinity (Ki 5.4 nM), potent (IC50 3.1 nM) and selective (>1000-fold selective vs mGluR1) mGluR5 NAM. Acute administration of GRN-529 (0.1-30 mg/kg p.o.) had dose-dependent efficacy across a therapeutically relevant battery of animal models, comprising depression (decreased immobility time in tail suspension and forced swim tests) and 2 of the co-morbid symptoms overrepresented in TRD, namely anxiety (attenuation of stress-induced hyperthermia, and increased punished crossings in the four plate test) and pain (reversal of hyperalgesia due to sciatic nerve ligation or inflammation). The potential side effect liability of GRN-529 was also assessed using preclinical models: GRN-529 had no effect on rat sexual behavior or motor co-ordination (rotarod), however it impaired cognition in mice (social odor recognition). Efficacy and side effects of GRN-529 were compared to standard of care agents (antidepressant, anxiolytic or analgesics) and the tool mGluR5 NAM, MTEP. To assess the relationship between target occupancy and efficacy, ex vivo receptor occupancy was measured in parallel with efficacy testing. This revealed a strong correlation between target engagement, exposure and efficacy across behavioral endpoints, which supports the potential translational value of PET imaging to dose selection in patients. Collectively this broad spectrum profile of efficacy of GRN-529 supports our hypothesis that negative allosteric modulation of mGluR5 could represent an innovative therapeutic approach to the treatment of TRD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

Men and osteoporosis.

BACKGROUND: While strict criteria have been developed for defining osteoporosis in women (bone mineral density measurements more than 2.5 standard deviations below the mean for young adult normal women, i.e. t-score value < -2.5), there still remains a controversy regarding the definition in men. Spinal fractures occur in 5% and hip fractures in 6% of men older than 50 years. There are significant differences between men and women with respect to the pathogenesis of osteoporosis, underlying medical conditions and postfracture sequelae. OBJECTIVE: To provide an overview of the pathogenesis, diagnosis and prevention of osteoporosis in men. DISCUSSION: Osteoporosis is increasingly recognised. Data from the Dubbo Osteoporosis Epidemiology Study suggests that 30% of men in Australia aged over 60 years will suffer from an osteoporotic fracture. It is estimated that 30-60% of men presenting with spinal fractures will have another illness contributing to their bone loss. Osteoporotic fractures in men are associated with higher morbidity and mortality than in women. Lifestyle changes together with daily calcium supplementation should be implemented and vitamin D3 should be considered in men with osteopenia.