Loss of 50% of excess weight using a very low energy diet improves insulin-stimulated glucose disposal and skeletal muscle insulin signalling in obese insulin-treated type 2 diabetic patients

Aims/hypothesis Both energy restriction (ER) per se and weight loss improve glucose metabolism in obese insulin-treated type 2 diabetic patients. Short-term ER decreases basal endogenous glucose production (EGP) but not glucose disposal. In contrast the blood glucose-lowering mechanism of long-term ER with substantial weight loss has not been fully elucidated. The aim of this study was to investigate the effect of loss of 50% of excess weight [50% excess weight reduction (EWR)] on EGP, whole-body insulin sensitivity and the disturbed myocellular insulin-signalling pathway in ten obese insulin-treated type 2 diabetic patients. Methods A euglycaemic-hyperinsulinaemic clamp with stable isotopes ([6,6(-2)H(2)]glucose and [H-5]glycerol) combined with skeletal muscle biopsies was performed during a very low energy diet (VLED; 1,883 kJ/day) on day 2 and again after 50% EWR. Oral blood glucose-lowering agents and insulin were discontinued 3 weeks prior to the VLED and at the start of the VLED, respectively. Results Loss of 50% EWR (20.3 +/- 2.2 kg from day 2 to day of 50% EWR) normalised basal EGP and improved insulin sensitivity, especially insulin-stimulated glucose disposal (18.8 +/- 2.0 to 39.1 +/- 2.8 mu mol kg fat-free mass(-1), p=0.001). The latter was accompanied by improved insulin signalling at the level of the recently discovered protein kinase B/Akt substrates AS160 and PRAS40 along with a decrease in intramyocellular lipid (IMCL) content. Conclusions/interpretation Considerable weight loss in obese, insulin-treated type 2 diabetic patients normalises basal EGP and improves insulin sensitivity resulting from an improvement in insulin signal transduction in skeletal muscle. The decrease in IMCL might contribute to this effect

In Pursuit of a Good Death: Managing Changing Sensibilities Toward Death and Dying

This thesis challenges a number of claims that are made in the context of the euthanasia debate: that there is only one version of the good death; that rights discourse is the most appropriate vehicle by which to secure legal recognition of a right to die; that the Netherlands is either a model for reform or the epitome of a slippery slope in its regulation of euthanasia; and that a key argument in the euthanasia debate, the sanctity of life doctrine, is a fixed, immutable concept. In this thesis I use process sociology, developed by Norbert Elias, in order to capture changing sensibilities toward death and dying in the common law jurisdictions (Australia, England, the United States of America, Canada and New Zealand) and in the Netherlands. At the same time I analyse changing attitudes among key groups whose work impacts upon the euthanasia debate namely, parliamentarians, law reform bodies, the judiciary and medical associations. My aim in adopting this approach is threefold. First of all, to examine evolving attitudes to death and dying in order to determine whether the institutions of law and medicine are responding in an adequate manner to changing sensibilities in the common law countries and in the Netherlands. Secondly, to highlight shifting balances of power within the euthanasia debate. Thirdly, to assess whether the various options for reform that I discuss are workable or not. In this thesis I show that there appears to be a sensibility of support in the common law countries for euthanasia to be legally available when an adult is terminally ill, is experiencing pain that he or she cannot bear and has expressed a wish to die (the typical euthanasia scenario). However, the situation is far from clear cut. The methods adopted by one of the ways of measuring sensibilities, opinion polls, suggest that sensibilities may not always be well-informed. Further, attitudes within and between key groups are not uniform or settled. In the context of this unsettled state of affairs, I show that responses to changing sensibilities from law and medicine in the common law jurisdictions are far from satisfactory. So far as legal responses are concerned, case law outcomes in right to die applications suggest a lack of flexibility. Outcomes in prosecutions following active voluntary euthanasia or assisted suicide reveal a non-application of established legal principles and suggest that the courts do not focus, squarely, upon the real issues at stake in the euthanasia debate. Medical responses are similarly less than optimal due to a tendency to de-emphasise existential (emotional) pain which, research shows, is the prime motivating factor in requests to be assisted to die sooner. Responses to changing sensibilities to death and dying in the Netherlands are also unsatisfactory because of the disorganised manner in which euthanasia was legalised and because regulation is inadequate. I come to the conclusion that there are three ways in which we could possibly resolve these problems and increase the flexibility of responses to changing sensibilities toward death and dying. They are as follows: by legalising euthanasia; by permitting a defence of necessity; or, by liberalising the use of terminal sedation in end-of-life care. Of these three, I conclude, in light of shifting sensibilities and overall negative attitudes among key groups to euthanasia, that the last is the most appropriate option at the present time. In closing, I address some of the larger issues at stake in the euthanasia debate. In particular, I deal with the effect that changing sensibilities toward the process of dying have had upon human social life, leading to the problematic situation that Elias referred to as the ‘loneliness of the dying’