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Protein kinase C (PKC) is a family of multifunctional isoenzymes, activated by diacylglycerols (DAGs), which play a central role in signal transduction and intracellular crosstalk by phosphorylating at serine/threonine residues an array of substrates, including cell-surface receptors, enzymes, contractile proteins, transcription factors and other kinases. Individual isozymes vary in their pattern of tissue and subcellular distribution, function and Ca 2+ /phospholipid cofactor requirements, and in diabetes there is widespread activation of the DAG-PKC pathway in metabolic, cardiovascular and renal tissues. In liver, muscle and adipose tissue, PKC isozymes have been implicated both as mediators and inhibitors of insulin action. Activation of DAG-sensitive PKC isoforms, such as PKC-v and PKC-e, down-regulates insulin receptor signalling and could be an important biochemical mechanism linking dysregulated lipid metabolism and insulin resistance in muscle. On the other hand, atypical PKC isozymes, such as PKC-z and PKC-l, have been identified as downstream targets of PI-3-kinase involved in insulin-stimulated glucose uptake, especially in adipocytes.Glucose-induced de novo synthesis of (palmitaterich) DAG and sustained isozyme-selective PKC activation (especially but not exclusively PKC-b) has been strongly implicated in the pathogenesis of diabetic microangiopathy and macroangiopathy through a host of undesirable effects on endothelial function, VSM contractility and growth, angiogenesis, gene transcription (in part by MAP-kinase activation) and vascular permeability. Interventions that increase DAG metabolism (e. g. vitamin E) and/or inhibit PKC isozymes (e. g. the b-selective inhibitor LY333 531) ameliorate the biochemical and functional consequences of DAG-PKC activation in experimental diabetes, for example improving retinal blood flow and albuminuria in parallel with reductions in membrane-associated PKC isozyme activities. Thus, a greater understanding of the functional diversity and pathophysiological regulation of PKC isozymes is likely to have important clinical and therapeutic benefits. [Diabetologia (2001) 44: 659±673]

Aim:The Helping Evaluate Exenatide in overweight patients with diabetes compared with Long-Acting insulin (HEELA) study was designed to examine whether the glucagon-like peptide-1 (GLP-1) receptor agonist, exenatide, could improve HbA1c (≤7.4%) with minimal weight gain (≤1 kg) compared with insulin glargine. 31] kg respectively, p < 0.001) after 26 weeks. There were more treatment-related adverse events with exenatide but a lower incidence of nocturnal hypoglycaemia, with no differences in overall or severe hypoglycaemia. Conclusions: Additional treatment with exenatide resulted in significantly more overweight and obese patients with an elevated cardiovascular risk and type 2 diabetes achieving better glycaemic control with minimal weight gain compared with insulin glargine.

The physiological processes of angiogenesis, vasculogenesis and arteriogenesis contribute to the growth of collateral vessels in response to obstructive arterial disease causing lower limb or myocardial ischaemia, but in clinical practice the endogenous angiogenic response is often suboptimal or impaired, e.g. by factors such as ageing, diabetes or drug therapies. Therapeutic angiogenesis is an application of biotechnology to stimulate new vessel formation via local administration of pro-angiogenic growth factors in the form of recombinant protein or gene therapy, or by implantation of endothelial progenitor cells that will synthesize multiple angiogenic cytokines. Numerous experimental and clinical studies have sought to establish 'proof of concept' for therapeutic angiogenesis in PAD and myocardial ischaemia using different treatment modalities, but the results have been inconsistent. This review summarises the mechanisms of angiogenesis and the results of recent trials evaluating the efficacy and safety of different gene therapy, recombinant protein and cellular-based treatment approaches to enhance collateral vessel formation.

The sodium-glucose co-transporter-2 (SGLT2) is a low-affinity transport system that is specifically expressed in the kidney and plays an important role in renal glucose reabsorption in the proximal tubule. Competitive inhibition of SGLT2 therefore represents an innovative therapeutic strategy for the treatment of hyperglycaemia and/or obesity in patients with type 1 or type 2 diabetes by enhancing glucose and energy loss through the urine. The observation that individuals with familial renal glycosuria maintain normal long-term kidney function provides some reassurance that this mode of action will not adversely affect renal function. Intense research in this therapeutic area has led to the discovery of novel SGLT2 inhibitors, each with different chemical, pharmacodynamic and pharmacokinetic profiles. This review outlines the biology, expression and pleotropic activity of the SGLT system and the pharmacological profile of SGLT2 inhibitors and provides a summary of preclinical and limited clinical data available to characterize the efficacy, safety and potential clinical utility of SGLT2 inhibitors in the management of diabetes.

Background and Purpose— Repeated episodes of limb ischemia and reperfusion (remote ischemic conditioning [RIC]) may improve outcome after acute stroke. Methods— We performed a pilot blinded placebo-controlled trial in patients with acute ischemic stroke, randomized 1:1 to receive 4 cycles of RIC within 24 hours of ictus. The primary outcome was tolerability and feasibility. Secondary outcomes included safety, clinical efficacy (day 90), putative biomarkers (pre- and post-intervention, day 4), and exploratory hemodynamic measures. Results— Twenty-six patients (13 RIC and 13 sham) were recruited 15.8 hours (SD 6.2) post-onset, age 76.2 years (SD 10.5), blood pressure 159/83 mm Hg (SD 25/11), and National Institutes of Health Stroke Scale (NIHSS) score 5 (interquartile range, 3.75–9.25). RIC was well tolerated with 49 out of 52 cycles completed in full. Three patients experienced vascular events in the sham group: 2 ischemic strokes and 2 myocardial infarcts versus none in the RIC group ( P =0.076, log-rank test). Compared with sham, there was a significant decrease in day 90 NIHSS score in the RIC group, median NIHSS score 1 (interquartile range, 0.5–5) versus 3 (interquartile range, 2–9.5; P =0.04); RIC augmented plasma HSP27 (heat shock protein 27; P <0.05, repeated 2-way ANOVA) and phosphorylated HSP27 ( P <0.001) but not plasma S100-β, matrix metalloproteinase-9, endocannabinoids, or arterial compliance. Conclusions— RIC after acute stroke is well tolerated and appears safe and feasible. RIC may improve neurological outcome, and protective mechanisms may be mediated through HSP27. A larger trial is warranted. Clinical Trial Registration— URL: http://www.isrctn.com . Unique identifier: ISRCTN86672015.

SummaryBackgroundIntensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy.MethodsWe did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388.Findings3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p<0·0001).InterpretationAmong patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice.FundingNational Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation.

The mechanisms of insulin resistance in the obese Zucker rat have not been clearly established but increased diacylglycerol-protein kinase C (DAG-PKC) signalling has been associated with decreased glucose utilisation in states of insulin resistance and non-insulin-dependent diabetes mellitus. The purpose of this study was to characterise tissue-and isoform-selective differences in DAG-PKC signalling in insulin-sensitive tissues from obese Zucker rats, and to assess the effects of feeding on DAG-PKC pathways. Groups of male obese (fa/fa, n=24) and lean (fa/-, n=24) Zucker rats were studied after baseline measurements of fasting serum glucose, triglycerides, insulin and oral glucose tolerance tests. Liver, epididymal fat and soleus muscle samples were obtained from fed and overnight-fasted rats for measurements of DAG, PKC activity and individual PKC isoforms in cytosol and membrane fractions. Obese rats were heavier (488 7 vs 315 9 g) with fasting hyperglycaemia (10·5 0·8 vs 7·7 0·1 mM) and hyperinsulinaemia (7167 363 vs 251 62 pM) relative to lean controls. In fasted rats, PKC activity in the membrane fraction of liver was significantly higher in the obese group (174 16 vs 108 12 pmol/ min/mg protein, P<0·05) but there were no differences in muscle and fat. The fed state was associated with increased DAG levels and threefold higher PKC activity in muscle tissue of obese rats, and increased expression of the major muscle isoforms, PKC-and PKC-: e.g. PKC activity in the membrane fraction of muscle from obese animals was 283 42 (fed) vs 107 20 pmol/min/mg protein (fasting) compared with 197 27 (fed) and 154 21 pmol/ min/mg protein (fasting) in lean rats. In conclusion, hepatic PKC activity is higher in obese rats under basal fasting conditions and feeding-induced activation of DAG-PKC signalling occurs selectively in muscle of obese (fa/fa) rats due to increased DAG-mediated activation and/or synthesis of PKC-and PKC-. These changes in PKC are likely to exacerbate the hyperglycaemia and hypertriglyceridaemia associated with obesity-induced diabetes.