Population Health Management in Diabetes Care: Combining Clinical Audit, Risk Stratification, and Multidisciplinary Virtual Clinics in a Community Setting to Improve Diabetes Care in a Geographically Defined Population. An Integrated Diabetes Care Pilot in the North East Locality, Oxfordshire, UK.

BACKGROUND: Disparities in diabetes care are prevalent, with significant inequalities observed in access to, and outcomes of, healthcare. A population health approach offers a solution to improve the quality of care for all with systematic ways of assessing whole population requirements and treating and monitoring sub-groups in need of additional attention. DESCRIPTION OF THE CARE PRACTICE: Collaborative working between primary, secondary and community care was introduced in seven primary care practices in one locality in England, UK, caring for 3560 patients with diabetes and sharing the same community and secondary specialist diabetes care providers. Three elements of the intervention included 1) clinical audit, 2) risk stratification, and 3) the multi-disciplinary virtual clinics in the community. METHODS: This paper evaluates the acceptability, feasibility and short-term impact on primary care of implementing a population approach intervention using direct observations of the clinics and surveys of participating clinicians. RESULTS AND DISCUSSION: Eighteen virtual clinics across seven teams took place over six months between March and July 2017 with organisation, resources, policies, education and approximately 150 individuals discussed. The feedback from primary care was positive with growing knowledge and confidence managing people with complex diabetes in primary care. CONCLUSION: Taking a population health approach helped to identify groups of people in need of additional diabetes care and deliver a collaborative health intervention across traditional organisational boundaries.

Importance of inpatient hypoglycaemia: impact, prediction and prevention.

Hypoglycaemia is a key barrier to achieving euglycaemic control in people who are hospitalized. Inpatient hypoglycaemia has been linked to adverse clinical outcomes, including mortality and longer stay in hospital. A number of studies have applied mathematical tools and statistical models to predict inpatient hypoglycaemia and identify factors that may result in hypoglycaemic events. Several different approaches have been tested to prevent inpatient hypoglycaemia. These can be categorized as human intervention, computerized methods or application of medical devices. In this review we provide an overview of the epidemiology of inpatient hypoglycaemia and its impact on patients and hospitals. We also discuss the existing methodology used to predict inpatient hypoglycaemia and the limited number of trials performed to prevent inpatient hypoglycaemia. The review highlights the urgent need for evidence-based methods to reduce inpatient hypoglycaemia.

Prevalence and severity of non-alcoholic fatty liver disease are underestimated in clinical practice: impact of a dedicated screening approach at a large university teaching hospital.

AIMS: To define the attitudes and current clinical practice of diabetes specialists with regard to non-alcoholic fatty liver disease and, based on the results, implement an evidenced-based pathway for non-alcoholic fatty liver disease assessment. METHODS: An online survey was disseminated to diabetes specialists. Based on findings from this survey, we sought a local solution by launching an awareness campaign and implementing a screening algorithm across all diabetes clinics at a secondary/tertiary referral centre. RESULTS: A total of 133 diabetes specialists responded to the survey. Fewer than 5% of responders correctly assessed the prevalence and severity of advanced fibrotic non-alcoholic fatty liver disease in people with diabetes as 50-75%. Whilst most clinicians performed liver function tests, only 5.7% responded stating that they would use, or had used, a non-invasive algorithm to stage the severity of non-alcoholic fatty liver disease. Implementing a local non-alcoholic fatty liver disease awareness campaign and screening strategy using pre-printed blood request forms, we ensured that 100% (n=395) of all people with Type 1 and Type 2 diabetes mellitus attending secondary/tertiary care diabetes clinics over a 6-month period were appropriately screened for advanced fibrotic non-alcoholic fatty liver disease using the Fib-4 index; 17.9% required further investigation or assessment. CONCLUSIONS: The prevalence and severity of non-alcoholic fatty liver disease are underestimated among diabetes specialists. The Fib-4 index can easily be incorporated into clinical practice in secondary/tertiary care to identify those individuals at risk of advanced fibrosis who require further assessment and who may benefit from a dedicated multidisciplinary approach to their management.

Adipose tissue: a key target for diabetes pathophysiology and treatment?

Excess adipose tissue brings with it a number of adverse consequences, many of which may stem from the development of insulin resistance. An emerging view is that inflammatory changes occurring in expanding adipose tissue are associated with the secretion of peptide and other factors that can adversely affect metabolic processes in other key insulin-target tissues, especially liver and skeletal muscle. However, there is still a commonly-expressed view that the adverse changes in other tissues are ultimately due to an excess of fatty acids, liberated by a metabolically-challenged adipose tissue. Our own studies of adipose tissue metabolism and physiological function (especially blood flow) IN VIVO suggest that these two views of adipose tissue function may be closely linked. Enlarged adipocytes are less dynamic in their responses, just as 'enlarged adipose tissue' is less dynamic in blood flow regulation. Adipocytes seem to be able to sense the appropriate level of fat storage. If the normal mechanisms regulating adipocyte fat storage are interfered with (either in genetically-modified animals or by increasing the size of the adipocytes), then perhaps some sort of cellular stress sets in, leading to the inflammatory and endocrine changes. Some evidence for this comes from the effects of the thiazolidinediones, which improve adipose tissue function and in parallel reduce inflammatory changes.

Validity of simplified protocols to estimate glomerular filtration rate using iohexol clearance.

BACKGROUND: Iohexol clearance is an accurate and precise exogenous marker of glomerular filtration rate (GFR), but protocols are generally lengthy or require multiple sampling. Shorter or simpler protocols would be more practicable. METHODS: Two clearance estimates, two weeks apart, were undertaken in 11 healthy individuals and 26 diabetic patients with minimal to moderate renal impairment (chronic kidney disease stages 1-3). Blood specimens withdrawn at 60, 90, 120, 150, 180 and 240 min post-iohexol were analysed for iohexol. RESULTS: Visit 1 demonstrated excellent correlation with visit 2 (slope 1.00, confidence interval [CI] 0.88 to 1.13, intercept 0.94 mL/min/1.73 m(2), CI -9.9 to 11.8, P=0.43). The within-individual coefficient of variation (CV) of the 240 min reference method was 5.4% at a mean GFR of 84.1 mL/min/1.73 m(2). Single point estimates between 120 and 240 min had CVs of 4.5-7.0%, and did not differ from the reference method CV by more than 2.0 mL/min/1.73 m(2). Two and three point estimates in the interval 60-120 min post iohexol injection offered no advantages over these single-point estimates and overestimated at lower GFRs. CONCLUSIONS: An iohexol clearance estimate of GFR derived from a single sample taken between 2 to 4 h after infusion may provide a suitable tool for routine clinical use.

Removal of triacylglycerols from chylomicrons and VLDL by capillary beds: the basis of lipoprotein remnant formation.

The triacylglycerol content of chylomicrons and VLDL (very-low-density lipoprotein) compete for the same lipolytic pathway in the capillary beds. Although chylomicron triacylglycerols appear to be the favoured substrate for lipoprotein lipase, VLDL particles compete in numbers. Methods to quantify the specific triacylglycerol removal from VLDL and chylomicrons may involve endogenous labelling of the triacylglycerol substrate with stable isotopes in combination with arteriovenous blood sampling in humans. Arteriovenous quantification of remnant lipoproteins suggests that adipose tissue with its high lipoprotein lipase activity is a principal site for generation of remnant lipoproteins. Under circumstances of reduced efficiency in the removal of triacylglycerols from lipoproteins, there is accumulation of remnant lipoproteins, which are potentially atherogenic.

Acute and selective regulation of glyceroneogenesis and cytosolic phosphoenolpyruvate carboxykinase in adipose tissue by thiazolidinediones in type 2 diabetes.

AIMS/HYPOTHESIS: Regulation of glyceroneogenesis and its key enzyme cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) plays a major role in the control of fatty acid release from adipose tissue. Here we investigate the effect of rosiglitazone on the expression of genes involved in fatty acid metabolism and the resulting metabolic consequences. MATERIALS AND METHODS: Rosiglitazone was administered to Zucker fa/fa rats for 4 days and to 24 diabetic patients for 12 weeks, then mRNA expression for the genes encoding PEPCK-C, mitochondrial PEPCK, adipocyte lipid-binding protein, glycerol kinase, lipoprotein lipase and glycerol-3-phosphate dehydrogenase was examined in s.c. adipose tissue by real-time RT-PCR. Glyceroneogenesis was determined using [1-(14)C]pyruvate incorporation into lipids. Cultured adipose tissue explants from overweight women undergoing plastic surgery were incubated with rosiglitazone for various times before mRNA determination and analysis of PEPCK-C protein, activity and glyceroneogenesis. RESULTS: Rosiglitazone administration to rats induced the expression of the gene encoding PEPCK-C mRNA (PCK1) and PEPCK-C activity in adipose tissue with a resulting 2.5-fold increase in glyceroneogenesis. This was accompanied by an improvement in dyslipidaemia as demonstrated by the decrease in plasma NEFAs and triacylglycerol. In rosiglitazone-treated diabetic patients, PCK1 mRNA was raised 2.5-fold in s.c. adipose tissue. Rosiglitazone treatment of adipose tissue explants from overweight women caused a selective augmentation in PCK1 mRNA which reached a maximum of 9-fold at 14 h, while mRNA for other genes remained unaffected. Experiments with inhibitors showed a direct and transcription-only effect, which was followed by an increase in PEPCK-C protein, enzyme activity and glyceroneogenesis. CONCLUSIONS/INTERPRETATION: These results favour adipocyte glyceroneogenesis as the initial thiazolidinedione-responsive pathway leading to improvement in dyslipidaemia.

Insulin sensitisation affects lipoprotein lipase transport in type 2 diabetes: role of adipose tissue and skeletal muscle in response to rosiglitazone.

AIMS/HYPOTHESIS: Lipoprotein lipase (LPL) is produced by adipose tissue and skeletal muscle, but acts on plasma lipoproteins after being transported to endothelial binding sites. Insulin resistance is associated with decreased plasma LPL mass. We investigated the effects of insulin sensitisation on tissue-specific LPL expression and transport in patients with type 2 diabetes. MATERIALS AND METHODS: Arterio-venous gradients of plasma LPL activity and mass across adipose tissue and skeletal muscle were measured in 16 type 2 diabetic patients in a double-blind, placebo-controlled, cross-over randomised trial of rosiglitazone. In vivo LPL rate of action was assessed by tissue-specific arterio-venous triglyceride concentration gradients. LPL mRNA was quantified in adipose tissue and skeletal muscle biopsies. RESULTS: Adipose tissue released large quantities of inactive LPL (p<0.001); skeletal muscle released small amounts of active LPL (p<0.01). Rosiglitazone increased adipose tissue release of LPL mass (+35%, p=0.04) and decreased the release of active LPL from skeletal muscle (-57%, p=0.03). Rosiglitazone increased adipose tissue and skeletal muscle LPL mRNA, but did not affect adipose tissue LPL rate of action or activity. Adipose tissue release of LPL mass correlated with systemic LPL mass concentrations (r=0.47, p=0.007), suggesting that the rate of adipose tissue release of LPL mass is a major determinant of systemic LPL mass concentrations. CONCLUSIONS/INTERPRETATION: LPL transport from adipose tissue and skeletal muscle are regulated differently. In adipose tissue, rosiglitazone increases LPL mRNA abundance and LPL transport rate and possibly increases endothelial binding sites for LPL, but affects neither tissue LPL activity nor LPL rate of action.

The in vivo effects of the Pro12Ala PPARgamma2 polymorphism on adipose tissue NEFA metabolism: the first use of the Oxford Biobank.

AIMS/HYPOTHESIS: To investigate the phenotypic effects of common polymorphisms on adipose tissue metabolism and cardiovascular risk factors, we set out to establish a biobank with the unique feature of allowing a prospective recruit-by-genotype approach. The first use of this biobank investigates the effects of the peroxisome proliferator-activated receptor (PPAR) Pro12Ala polymorphism on integrative tissue-specific physiology. We hypothesised that Ala12 allele carriers demonstrate greater adipose tissue metabolic flexibility and insulin sensitivity. MATERIALS AND METHODS: From a comprehensive population register, subjects were recruited into a biobank, which was genotyped for the Pro12Ala polymorphism. Twelve healthy male Ala12 carriers and 12 matched Pro12 homozygotes underwent detailed physiological phenotyping using stable isotope techniques, and measurements of blood flow and arteriovenous differences in adipose tissue and muscle in response to a mixed meal containing [1,1,1-(13)C]tripalmitin. RESULTS: Of 6,148 invited subjects, 1,072 were suitable for inclusion in the biobank. Among Pro12 homozygotes, insulin sensitivity correlated with HDL-cholesterol concentrations, and inversely correlated with blood pressure, apolipoprotein B, triglyceride and total cholesterol concentrations. Ala12 carriers showed no such correlations. In the meal study, Ala12 carriers had lower plasma NEFA concentrations, higher adipose tissue and muscle blood flow, and greater insulin-mediated postprandial hormone-sensitive lipase suppression along with greater insulin sensitivity than Pro12 homozygotes. CONCLUSIONS/INTERPRETATION: This study shows that a recruit-by-genotype approach is feasible and describes the biobank's first application, providing tissue-specific physiological findings consistent with the epidemiological observation that the PPAR Ala12 allele protects against the development of type 2 diabetes.

Adipose tissue function in the insulin-resistance syndrome.

Insulin resistance is often seen as a consequence of obesity and there are several possible links between adipose tissue function and insulin resistance determined in other organs such as skeletal muscle or liver. One such link is the regulation of NEFA (non-esterified fatty acid) delivery to the rest of the body. Simplistically, an expanded adipose tissue mass delivers more NEFA to the systemic circulation and these fatty acids compete for substrate utilization in skeletal muscle, which in turn reduces glucose utilization. This increases blood glucose concentration and provides the stimulus for increased insulin secretion and hyperinsulinaemia is a key feature of the insulin-resistance syndrome. However, there is abundant evidence that adipose tissue is exquisitely insulin sensitive and hyperinsulinaemia may therefore lead to a constant lipolytic inhibition in adipose tissue. Consequently, the main function of adipose tissue, to rapidly switch between fat uptake and fat release, will be hampered. Adipose tissue blood flow is the conveyor of signals and substrates to and from the adipose tissue. In healthy people adipose tissue blood flow is much enhanced by food intake, whereas in insulin-resistant subjects this response is blunted. This is another facet of unresponsiveness of adipose tissue in the insulin-resistance syndrome.

Changes in adiponectin receptor expression in muscle and adipose tissue of type 2 diabetic patients during rosiglitazone therapy.

AIMS/HYPOTHESIS: Adiponectin is important in the regulation of insulin sensitivity in man. Its receptors, adipoR1 and R2, have recently been identified, but their expression in adipose tissue and their regulation in response to insulin sensitisation of diabetic patients have never been assessed. We therefore explored the regulation of adipoR1/R2 and adiponectin expression in adipose tissue and skeletal muscle, and of adiponectin plasma concentrations in response to insulin sensitisation by rosiglitazone. METHODS: Patients with type 2 diabetes were studied in a double-blind, placebo-controlled crossover study, using in vivo arteriovenous techniques of measuring adipose tissue and muscle blood flow, combined with measurement of adipose tissue and skeletal muscle gene expression. RESULTS: Rosiglitazone treatment increased adiponectin concentrations by 69%. Skeletal muscle adipoR1 expression was down-regulated from 109.0 (70.1-165.7) (median [interquartile range]) to 82.8 (63.6-89.3) relative units (p=0.04), but adipose tissue adipoR1 expression was up-regulated from 5.3 (4.4-9.4) to 11.2 (4.8-15.3) relative units (p=0.02) by rosiglitazone. In contrast to adipoR1 expression, adipoR2 expression was not altered by rosiglitazone in either of the tissues. The increase in adipose tissue adipoR1 expression with rosiglitazone was associated with increased postprandial triglyceride clearance (r=0.67, p=0.05), and increased fasting fatty acid output (r=0.78, p=0.01) measured in subcutaneous adipose tissue. CONCLUSIONS/INTERPRETATION: AdipoR1 expression is up-regulated in adipose tissue but down-regulated in skeletal muscle by rosiglitazone. These data suggest that adipoR1 plays a role in mediating the effects of adiponectin in specific tissues in relation to insulin sensitisation.

The effects of rosiglitazone on fatty acid and triglyceride metabolism in type 2 diabetes.

AIMS/HYPOTHESIS: We investigated the effects of rosiglitazone on NEFA and triglyceride metabolism in type 2 diabetes. METHODS: In a double-blind, placebo-controlled, cross-over study of rosiglitazone in diet-treated type 2 diabetic subjects, we measured arteriovenous differences and tissue blood flow in forearm muscle and subcutaneous abdominal adipose tissue, used stable isotope techniques, and analysed gene expression. Responses to a mixed meal containing [1,1,1-(13)C]tripalmitin were assessed. RESULTS: Rosiglitazone induced insulin sensitisation without altering fasting NEFA concentrations (-6.6%, p=0.16). Postprandial NEFA concentrations were lowered by rosiglitazone compared with placebo (-21%, p=0.04). Adipose tissue NEFA release was not decreased in the fasting state by rosiglitazone treatment (+24%, p=0.17) and was associated with an increased fasting hormone-sensitive lipase rate of action (+118%, p=0.01). Postprandial triglyceride concentrations were decreased by rosiglitazone treatment (-26%, p<0.01) despite unchanged fasting concentrations. Rosiglitazone did not change concentrations of triglyceride-rich lipoprotein remnants. Adipose tissue blood flow increased with rosiglitazone (+32%, p=0.03). Postprandial triglyceride [(13)C]palmitic acid concentrations were unchanged, whilst NEFA [(13)C]palmitic acid concentrations were decreased (p=0.04). In muscle, hexokinase II mRNA expression was increased by rosiglitazone (+166%, p=0.001) whilst the expression of genes involved in insulin signalling was unchanged. Adipose tissue expression of FABP4, LPL and FAT/CD36 was increased. CONCLUSIONS/INTERPRETATION: Rosiglitazone decreases postprandial NEFA and triglyceride concentrations. This may represent decreased spillover of NEFAs from adipose tissue depots. Decreased delivery of NEFAs to the liver may lead to lowered postprandial triglyceride concentrations. Upregulation of hexokinase II expression in muscle may contribute to insulin sensitisation by rosiglitazone.

Clinical usefulness of cystatin C for the estimation of glomerular filtration rate in type 1 diabetes: reproducibility and accuracy compared with standard measures and iohexol clearance.

OBJECTIVE-Assessment and follow-up of early renal dysfunction is important in diabetic nephropathy. Plasma creatinine is insensitive for a glomerular filtration rate (GFR) >50 ml/min and creatinine clearance is unwieldy and subject to collection inaccuracies. We aimed to assess the reproducibility, reliability, and accuracy of plasma cystatin C as a measure of GFR ranging from normal to moderate impairment due to type 1 diabetes in the presence of a normal plasma creatinine concentration. RESEARCH DESIGN AND METHODS-A sensitive immunoturbidimetric cystatin C assay was examined in 29 subjects with type 1 diabetes and 11 nondiabetic subjects. Duplicate measurements of the following were collected from each subject, 2 weeks apart: cystatin C, enzymatic plasma creatinine, 24-h creatinine clearance, GFR estimated from plasma creatinine by the Cockcroft-Gault equation, and iohexol clearance as a gold standard. RESULTS-Iohexol clearance ranged from 35 to 132 ml. min(-1). 1.73 m(-2). Plasma cystatin C compared well with the other clinically used tests. The reliability of cystatin C, as assessed by the discriminant ratio, was superior to creatinine clearance (3.4 vs. 1.5, P < 0.001) and the correlation of cystatin C with iohexol clearance (Rs -0.80) was similar to that of creatinine clearance (Rs -0.74) and superior to that of plasma creatinine and the Cockcroft-Gault estimate (Rs -0.54 and 0.66, respectively). Duplicate estimations were used to provide an unbiased equation to convert plasma cystatin C to GFR. CONCLUSIONS-Based on this study, cystatin C is a more reliable measure of GFR than creatinine clearance, is more highly correlated with iohexol clearance than plasma creatinine, and is worthy of further investigation as a clinical measure of GFR in type 1 diabetes.