How many people inject insulin? UK estimates from 1991 to 2010.

AIMS: We set out to estimate the prevalence rate of insulin use in the UK population, the total number of people in the UK who use insulin, the proportion of users with type 1 and type 2 diabetes and changes between 1991 and 2010. METHODS: Patients receiving prescriptions for insulin were identified in the Clinical Practice Research Datalink and attributed a diagnosis of type 1 or type 2 diabetes. The annual prevalence of insulin use was calculated and applied to population data. RESULTS: The crude prevalence rate of insulin use increased from 2.43 (95% CI 2.38-2.49) per 1000 population in 1991 to 6.71 (6.64-6.77) per 1000 in 2010. The largest change was an increase in the prevalence of insulin users with a diagnosis of type 2 diabetes from 0.67 (0.64-0.70) to 4.34 (4.29-4.39) per 1000 population. The absolute number using insulin increased from 137 000 people (121 000-155 000) in 1991 to 421 000 (400 000-444 000) in 2010. The proportion taking insulin alone (as against combination with oral agents) decreased from 97% in the first decade to 37% in the second. CONCLUSION: The number of people using insulin trebled between 1991 and 2010, largely due to a considerable increase in the number of people with type 2 diabetes using insulin.

The prenatal environment and type 1 diabetes.

There is ample evidence that environmental factors are involved in the aetiology of type 1 diabetes, but the nature and timing of the interactions are poorly understood. The intrauterine environment is known to play a role in the later development of type 2 diabetes, and this review considers a possible role in type 1 diabetes. Autoimmune type 1 diabetes is rare in those diagnosed before 6 months of age, but endogenous autoantibodies predictive of future type 1 diabetes may be detectable by 6-12 months of age, suggesting that environmental factors may operate before this age in some cases. Indirect evidence of a protective effect for the intrauterine environment comes from the observation that mothers with type 1 diabetes are less likely than affected fathers to transmit diabetes to their offspring, although the precise role (if any) is unclear. The risk of childhood-onset type 1 diabetes increases with maternal age at delivery, and with high birthweight, but these associations are weak and heterogeneous, and these factors are unlikely to be directly causally related to type 1 diabetes. No firm conclusion can be drawn from studies of maternal enteroviral infection or from various nutritional exposures. The birth process itself may play a role, as suggested by the slightly increased risk in children born by Caesarean section; lack of contact with maternal bacteria is one suggested mechanism. In sum, there is circumstantial evidence, but no proof of principle, that maternal or intrauterine conditions may modulate genetic risk of type 1 diabetes. The disease process culminating in type 1 diabetes typically begins in early life, but it is not clear whether the trail begins before or after birth.

Diabetes and cancer (2): evaluating the impact of diabetes on mortality in patients with cancer.

In this paper we address methodological aspects of aetiological importance in the link between diabetes and mortality in patients with cancer. We identified nine key points on the cancer pathway at which confounding may arise-cancer screening use, stage at diagnosis, cancer treatment selection, cancer treatment complications and failures, peri-treatment mortality, competing risks for long-term mortality, effects of type 2 diabetes on anti-cancer therapies, effects of glucose-lowering treatments on cancer outcome and differences in tumour biology. Two types of mortality studies were identified: (1) inception cohort studies that evaluate the effect of baseline diabetes on cancer-related mortality in general populations, and (2) cohorts of patients with a cancer diagnosis and pre-existing type 2 diabetes. We demonstrate, with multiple examples from the literature, that pre-existing diabetes affects presentation, cancer treatment, and outcome of several common cancer types, often to varying extents. Diabetes is associated with increased all-cause mortality in cancer patients, but the evidence that it influences cancer-specific mortality is inconsistent. In the absence of data that address the potential biases and confounders outlined in the above framework, we caution against the reporting of cancer-related mortality as a main endpoint in analyses determining the impact of diabetes and glucose-lowering medications on risk of cancer.

Viruses and type 1 diabetes: ignorance acquires a better vocabulary.

The hypothesis that a virus might in some way be involved in the causation of type 1 diabetes has a long history, but decades of research have failed to resolve the issue beyond reasonable doubt. Viruses could potentially play a primary role in the pathogenesis of type 1 diabetes by initiating autoimmunity, a secondary role by promoting established immune responses, or a tertiary role by precipitating the onset of hyperglycaemia. There is currently little evidence to suggest that viruses play a primary role in the causation of type 1 diabetes, let alone a necessary or sufficient role. Secondary or tertiary roles remain possible, but have yet to be confirmed in prospective studies.

Estimation of primary care treatment costs and treatment efficacy for people with Type 1 and Type 2 diabetes in the United Kingdom from 1997 to 2007*.

AIMS: The purpose of this study was to characterize the financial cost and efficacy of primary care treatment for diabetes in the United Kingdom from 1997 to 2007. METHODS: Retrospective data were analysed for people with Type 1 and Type 2 diabetes along with matched control subjects using data from The Health Improvement Network. Costs were attributed from published sources and adjusted for price inflation. Type 2 diabetes was analysed by five commonly used treatment regimens. RESULTS: It was possible to identify 126 052 people for inclusion: 11 300 (8.9%) with Type 1 diabetes and 114 752 (91.1%) with Type 2. The overall mean prescribing costs per person per year (pppy) increased markedly for people with diabetes from 1997 to 2007: for Type 1, from 573 pounds to 1014 pounds pppy (+77%), and for Type 2, from 39 pounds to 740 pounds pppy (+89%). In 2007, diabetes-treatment-specific prescribing represented 57% of prescribing costs in Type 1 diabetes and 28% in Type 2 diabetes. In Type 2 diabetes there was a mean of 5.4 primary care consultations in 1997, increasing to 11.5 pppy in 2007 (+112%). In 1997 the total mean cost of primary care treatment for Type 2 diabetes was 602 pounds pppy, increasing to 1080 pounds in 2007. In Type 1 diabetes, the mean glycated haemoglobin decreased by 0.1% from 8.8% in 2001 to 8.7% in 2007; the corresponding change using insulin in Type 2 diabetes was also 0.1%. Greater improvement in blood pressure and lipids was evident. CONCLUSIONS: Over the 10 year period to 2007, diabetes-related primary care adjusted costs increased considerably, whereas glycated haemoglobin values did not improve at all over the same period.

The metabolic syndrome: useful concept or clinical tool? Report of a WHO Expert Consultation.

This article presents the conclusions of a WHO Expert Consultation that evaluated the utility of the 'metabolic syndrome' concept in relation to four key areas: pathophysiology, epidemiology, clinical work and public health. The metabolic syndrome is a concept that focuses attention on complex multifactorial health problems. While it may be considered useful as an educational concept, it has limited practical utility as a diagnostic or management tool. Further efforts to redefine it are inappropriate in the light of current knowledge and understanding, and there is limited utility in epidemiological studies in which different definitions of the metabolic syndrome are compared. Metabolic syndrome is a pre-morbid condition rather than a clinical diagnosis, and should thus exclude individuals with established diabetes or known cardiovascular disease (CVD). Future research should focus on: (1) further elucidation of common metabolic pathways underlying the development of diabetes and CVD, including those clustering within the metabolic syndrome; (2) early-life determinants of metabolic risk; (3) developing and evaluating context-specific strategies for identifying and reducing CVD and diabetes risk, based on available resources; and (4) developing and evaluating population-based prevention strategies.

The influence of glucose-lowering therapies on cancer risk in type 2 diabetes.

AIMS/HYPOTHESIS: The risk of developing a range of solid tumours is increased in type 2 diabetes, and may be influenced by glucose-lowering therapies. We examined the risk of development of solid tumours in relation to treatment with oral agents, human insulin and insulin analogues. METHODS: This was a retrospective cohort study of people treated in UK general practices. Those included in the analysis developed diabetes >40 years of age, and started treatment with oral agents or insulin after 2000. A total of 62,809 patients were divided into four groups according to whether they received monotherapy with metformin or sulfonylurea, combined therapy (metformin plus sulfonylurea), or insulin. Insulin users were grouped according to treatment with insulin glargine, long-acting human insulin, biphasic analogue and human biphasic insulin. The outcome measures were progression to any solid tumour, or cancer of the breast, colon, pancreas or prostate. Confounding factors were accounted for using Cox proportional hazards models. RESULTS: Metformin monotherapy carried the lowest risk of cancer. In comparison, the adjusted HR was 1.08 (95% CI 0.96-1.21) for metformin plus sulfonylurea, 1.36 (95% CI 1.19-1.54) for sulfonylurea monotherapy, and 1.42 (95% CI 1.27-1.60) for insulin-based regimens. Adding metformin to insulin reduced progression to cancer (HR 0.54, 95% CI 0.43-0.66). The risk for those on basal human insulin alone vs insulin glargine alone was 1.24 (95% CI 0.90-1.70). Compared with metformin, insulin therapy increased the risk of colorectal (HR 1.69, 95% CI 1.23-2.33) or pancreatic cancer (HR 4.63, 95% CI 2.64-8.10), but did not influence the risk of breast or prostate cancer. Sulfonylureas were associated with a similar pattern of risk as insulin. CONCLUSIONS/INTERPRETATION: Those on insulin or insulin secretagogues were more likely to develop solid cancers than those on metformin, and combination with metformin abolished most of this excess risk. Metformin use was associated with lower risk of cancer of the colon or pancreas, but did not affect the risk of breast or prostate cancer. Use of insulin analogues was not associated with increased cancer risk as compared with human insulin.

Glucose control in the UKPDS: what did we learn?

The UK Prospective Diabetes Study (UKPDS) set out to establish whether improved glucose control could alleviate the macrovascular and microvascular complications of diabetes and to compare the relative merits of diet, oral glucose-lowering agents or insulin in achieving this objective. The study broke many of the rules of trial design, not least by constant addition of further interventions and analyses, but this flexibility would, paradoxically, prove to be one of its greatest strengths. The UKPDS taught us that glucose control must be tackled aggressively in Type 2 diabetes. It taught us that treatment must be escalated in parallel with the evolution of pancreatic B-cell failure. It also taught us that glucose control is not enough: the central objective of therapy is to reduce vascular risk by any means available. This commentary looks back along the winding road that led to these conclusions.

Autoantibodies to IA-2beta improve diabetes risk assessment in high-risk relatives.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the prognostic significance of autoantibodies to IA-2beta (IA2betaA) in a large, well-characterised population of islet cell antibody (ICA)-positive relatives followed for 5 years in the European Nicotinamide Diabetes Intervention Trial. METHODS: Autoantibodies to insulin (IAA), glutamate decarboxylase (GADA) and IA-2 (IA2A) were measured in 549 participants at study entry, and IA2A-positive samples tested for IA2betaA. First-phase insulin response (FPIR) and oral glucose tolerance were determined at baseline. RESULTS: Of 212 ICA/IA2A-positive participants (median age 12.1 years; 57% male), 113 developed diabetes (5 year cumulative risk 56%), and 148 were also GADA-positive and IAA-positive (4Ab-positive). IA2betaA were detected in 137 (65%) ICA/IA2A-positive participants and were associated with an increased 5 year diabetes risk (IA2betaA-positive 65 vs 39% in IA2betaA-negative, p=0.0002). The effect was most marked in 4Ab-positive relatives (72% vs 52%, p=0.003). Metabolic testing further refined risk assessment. Among 101 4Ab-positive relatives with IA2betaA, the 5 year risk was 94% in those with a low FPIR (vs 50% in those with a normal FPIR, p<0.0001), and 95% in those with impaired glucose tolerance (IGT) (vs 66% in those with normal glucose tolerance, p<0.0001). The median time to diagnosis of 4Ab/IA2betaA-positive participants with a low FPIR was 1.5 years. Multivariate analysis confirmed IA2betaA status, antibody number, young age, FPIR and IGT as independent determinants of risk. CONCLUSIONS/INTERPRETATION: IA2betaA are associated with a very high risk of diabetes in ICA/IA2A-positive relatives. Testing for IA2A/IA2betaA compares favourably with the IVGTT in identifying a subgroup of autoantibody-positive relatives at increased risk. IA2betaA determination should be added to screening protocols of future intervention trials.