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The introduction of insulin in the treatment of juvenile-onset, now type 1, diabetes mellitus transformed a rapidly fatal disease into a chronic degenerative one. During the insulin-treatment era, long-term microvascular and cardiovascular complications proved to be the bane of existence for people with type 1 diabetes, leading to blindness, kidney failure, amputations, cardiovascular disease (CVD) and premature mortality. The nascent understanding of the link between non-physiologically regulated glucose levels and these complications led to the development of new treatment tools in the 1970s and 1980s that facilitated the delivery of insulin to achieve glucose levels closer to non-diabetic levels. These therapeutic advances set the stage for definitive testing of the glucose hypothesis. The Diabetes Control and Complications Trial (DCCT), supported by the National Institute of Diabetes Digestive and Kidney Diseases, National Institutes of Health (NIH), definitively established the benefits and risks of intensive therapy that substantially lowered mean blood glucose levels, measured by HbA 1c , over a mean 6.5 years of therapy. Intensive therapy in the DCCT, resulting in a mean HbA 1c of ~7% (53 mmol/mol), reduced the development and progression of early microvascular and neurological complications associated with diabetes by 34-76% compared with the conventional-treatment group, which maintained an HbA 1c of ~9% (75 mmol/mol). Intensive therapy was also associated with weight gain and a threefold increased risk for hypoglycaemia. At the end of the DCCT, a long-term observational follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) study, commenced. Despite the convergence of HbA 1c levels between the two groups during EDIC, owing to the adoption of intensive therapy by the original DCCT conventional-treatment group and the return of all participants to their own healthcare providers for diabetes care, the development and progression of complications continued to be substantially less in the original intensive-treatment group vs the conventional-treatment group; this phenomenon was termed 'metabolic memory'. The DCCT demonstrated a major reduction in early-stage complications with intensive therapy and the metabolic memory phenomenon during EDIC contributed to a substantially lower burden of advanced complications over time. These included a 57% lower risk of CVD events and 33% lower rate of mortality in the original intensive-treatment group compared with the conventional-treatment group. DCCT/EDIC has ushered in the intensive-treatment era, which has been universally adopted and includes the goal of achieving HbA 1c levels less than 7% (53 mmol/mol) for most patients. Although the challenge of making intensive therapy (with the aim of achieving normoglycaemia) as widely accessible and safe as possible remains, continuing improvements in insulin therapy 100 years after its introduction promise a brighter future for people with type 1 diabetes.

The global epidemic of type 2 diabetes has prompted numerous studies and public health efforts to reduce its development. A variety of interventions, including lifestyle modifications and pharmacological agents directed at ameliorating the major risk factors for type 2 diabetes, are of proven efficacy in reducing the development of type 2 diabetes in people with impaired glucose tolerance. While prevention of the hyperglycaemia characteristic of diabetes is arguably an important, clinically relevant outcome, a more compelling outcome with greater clinical significance is the prevention or reduction of the relatively diabetes-specific microvascular and less-specific cardiovascular disease (CVD) complications associated with diabetes. These complications cause the majority of morbidity and excess mortality associated with diabetes. Any reduction in diabetes should, logically, also reduce the occurrence of its long-term complications; however, most diabetes prevention trials have not been of sufficient duration to allow such an evaluation. The limited long-term data, largely from the Da Qing Diabetes Prevention Study (DQDPS) and the Diabetes Prevention Program (DPP) and their respective follow-up studies (DQDPOS and DPPOS), suggest a reduction in microvascular complications and amelioration of CVD risk factors. Only the DQDPOS and Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) studies have shown a reduction in CVD events and only DQDPOS has demonstrated a decrease in CVD and overall mortality. While these limited data are promising, whether diabetes prevention directly reduces complication-related morbidity and mortality remains unclear. Longer follow-up of prevention studies is needed to supplement the limited current clinical trial data, to help differentiate the effects of diabetes prevention itself from the means used to reduce diabetes development and to understand the balance among benefits, risks and costs of prevention.

Aims/hypothesis: Chronic hyperglycaemia, as measured by HbA 1c levels, is a major risk factor for atherosclerosis and cardiovascular disease (CVD) in type 1 diabetes. Our aim was to describe the degree to which the effect of HbA 1c on the risk of CVD is mediated by its effect on traditional risk factors over time, and how these mediation pathways change over time., Methods: The DCCT and its observational follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC), followed 1441 participants for a mean of 27 years, with periodic measurement of HbA 1c and risk factors over time. We assessed the proportion of the HbA 1c effect on risk of CVD that was mediated through its effects on systolic BP (SBP), pulse rate, triacylglycerols and LDL-cholesterol (LDLc) levels, and how the proportion mediated changed over time., Results: The association of HbA 1c with CVD outcomes was stable over time, while that of traditional risk factors (SBP, pulse rate, triacylglycerols and LDLc) increased. At 10 years of follow-up, the effect of HbA 1c on 10 year CVD risk was minimally mediated by SBP (2.7%), increasing to 26% at 20 years. Likewise, from 10 year follow-up to 20 year follow-up, the proportion of HbA 1c effect mediated through pulse rate increased from 6.3% to 29.3%, through triacylglycerols from 2.2% to 22.4%, and through LDLc from 9.2% to 30.7%., Conclusions/interpretation: As participants age, the predictive association of mean HbA 1c on subsequent CVD events is increasingly mediated by its effect on standard risk factors. Thus, management of traditional non-glycaemic CVD risk factors may have increasing benefits in an ageing type 1 diabetes population with longstanding hyperglycaemia., Trial Registration: ClinicalTrials.gov NCT00360893 and NCT00360815.

The largest and longest clinical trial of metformin for the prevention of diabetes is the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study (DPP/DPPOS). In this review, we summarise data from the DPP/DPPOS, focusing on metformin for diabetes prevention, as well as its long-term glycaemic and cardiometabolic effects and safety in people at high-risk of developing diabetes. The DPP (1996-2001) was a RCT of 3234 adults who, at baseline, were at high-risk of developing diabetes. Participants were assigned to masked placebo (n = 1082) or metformin (n = 1073) 850 mg twice daily, or intensive lifestyle intervention (n = 1079). The masked metformin/placebo intervention phase ended approximately 1 year ahead of schedule because of demonstrated efficacy. Primary outcome was reported at 2.8 years. At the end of the DPP, all participants were offered lifestyle education and 88% (n = 2776) of the surviving DPP cohort continued follow-up in the DPPOS. Participants originally assigned to metformin continued to receive metformin, unmasked. The DPP/DPPOS cohort has now been followed for over 15 years with prospective assessment of glycaemic, cardiometabolic, health economic and safety outcomes. After an average follow-up of 2.8 years, metformin reduced the incidence of diabetes by 31% compared with placebo, with a greater effect in those who were more obese, had a higher fasting glucose or a history of gestational diabetes. The DPPOS addressed the longer-term effects of metformin, showing a risk reduction of 18% over 10 and 15 years post-randomisation. Metformin treatment for diabetes prevention was estimated to be cost-saving. At 15 years, lack of progression to diabetes was associated with a 28% lower risk of microvascular complications across treatment arms, a reduction that was no different among treatment groups. Recent findings suggest metformin may reduce atherosclerosis development in men. Originally used for the treatment of type 2 diabetes, metformin, now proven to prevent or delay diabetes, may serve as an important tool in battling the growing diabetes epidemic. Long-term follow-up, currently underway in the DPP/DPPOS, is now evaluating metformin's potential role, when started early in the spectrum of dysglycaemia, on later-stage comorbidities, including cardiovascular disease and cancer., Trial Registration: ClinicalTrials.gov NCT00038727 and NCT00004992.

Aims/hypothesis: Lower adiponectin levels are associated with higher risk of incident type 2 diabetes. Most analyses have been adjusted for confounding factors, but few have taken into account insulin resistance per se. We tested the hypothesis that the association of adiponectin levels with incident type 2 diabetes differs between insulin-resistant and insulin-sensitive individuals., Methods: We studied two prospective cohorts: the Framingham Offspring Study (n = 2,023) and the Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 study (n = 887) cohorts. Insulin resistance was estimated by HOMA-insulin resistance (HOMA-IR). We used logistic regression analysis to test the association between adiponectin and incident type 2 diabetes overall and in insulin-resistant vs insulin-sensitive individuals (defined by ≥ vs <75th percentile of HOMA-IR)., Results: At baseline, Framingham's participants were 60 ± 9 years old and 56% were women; KORA's participants were 63 ± 5 years old and 49% were women. Type 2 diabetes incidence was 5.4% over 6.5 years (n = 109) in Framingham and 10.5% over 8 years (n = 93) in KORA. Lower adiponectin levels were associated with type 2 diabetes incidence in both cohorts. In insulin-resistant individuals, lower adiponectin levels were associated with higher risk of type 2 diabetes incidence (OR 1.60 [95% CI 1.10-2.31] per SD decrease in Framingham, p = 0.01; and OR 2.34 [95% CI 1.16-4.73] in KORA, p = 0.02); while this was not observed in insulin-sensitive individuals (OR 1.10 [95% CI 0.73-1.67] in Framingham, p = 0.64; and OR 1.34 [95%CI: 0.88-2.03] in KORA, p = 0.18)., Conclusions/interpretation: We conclude that lower adiponectin levels are associated with higher risk of type 2 diabetes in insulin-resistant but not in insulin-sensitive individuals. This suggests that some level of insulin resistance is needed to see deleterious effects of low adiponectin.

Aims: Increased glucose excursions and postprandial hyperglycaemia have been suggested as unique risk factors for cardiovascular disease (CVD) and mortality in patients with diabetes mellitus. Much of the evidence is based on a single 2 h glucose value after oral glucose tolerance testing in epidemiological studies. We examined the association between various indices of glycaemia measured during everyday activities and metabolic CVD risk factors in the A1C-Derived Average Glucose (ADAG) study., Methods: Participants (268 with type 1 diabetes, 159 with type 2 diabetes) completed 16 weeks of intensive continuous glucose monitoring (CGM) and self-monitoring of blood glucose (SMBG). From these data, common indices of postprandial glycaemia, overall hyperglycaemia, glucose variability and HbA₁(c) were derived. The associations between glycaemic indices and known CVD risk factors (lipids, high-sensitivity C-reactive protein and blood pressure) were explored in linear regression models., Results: For both diabetes types, the overall strongest associations with CVD risk factors were seen for the measures of average glycaemia (mean blood glucose and HbA₁(c)). Associations between self-monitored postprandial and fasting glucose and CVD risk factors were weaker, but significant. Measurements of blood glucose variability showed non-significant associations. Overall, calculations based on CGM were not more informative than those based on frequent SMBG., Conclusions/interpretation: Mean glycaemia and HbA₁(c) show consistent and stronger associations with CVD risk factors than fasting glucose or postprandial glucose levels or measures of glucose variability in patients with diabetes.

Aims/hypothesis: Real-life glycaemic profiles of healthy individuals are poorly studied. Our aim was to analyse to what extent individuals without diabetes exceed OGTT thresholds for impaired glucose tolerance (IGT) and diabetes., Methods: In the A1C-Derived Average Glucose (ADAG) study, 80 participants without diabetes completed an intensive glucose monitoring period of 12 weeks. From these data, we calculated the average 24 h glucose exposure as time spent above different plasma glucose thresholds. We also derived indices of postprandial glucose levels, glucose variability and HbA(1c)., Results: We found that 93% of participants reached glucose concentrations above the IGT threshold of 7.8 mmol/l and spent a median of 26 min/day above this level during continuous glucose monitoring. Eight individuals (10%) spent more than 2 h in the IGT range. They had higher HbA(1c), fasting plasma glucose (FPG), age and BMI than those who did not. Seven participants (9%) reached glucose concentrations above 11.1 mmol/l during monitoring., Conclusions/interpretation: Even though the non-diabetic individuals monitored in the ADAG study were selected on the basis of a very low level of baseline FPG, 10% of these spent a considerable amount of time at glucose levels considered to be 'prediabetic' or indicating IGT. This highlights the fact that exposure to moderately elevated glucose levels remains under-appreciated when individuals are classified on the basis of isolated glucose measurements.

Aims/hypothesis: Advances in type 2 diabetes genetics have raised hopes that genetic testing will improve disease prediction, prevention and treatment. Little is known about current physician and patient views regarding type 2 diabetes genetic testing. We hypothesised that physician and patient views would differ regarding the impact of genetic testing on motivation and adherence., Methods: We surveyed a nationally representative sample of US primary care physicians and endocrinologists (n = 304), a random sample of non-diabetic primary care patients (n = 152) and patients enrolled in a diabetes pharmacogenetics study (n = 89)., Results: Physicians and patients favoured genetic testing for diabetes risk prediction (79% of physicians vs 80% of non-diabetic patients would be somewhat/very likely to order/request testing, p = 0.7). More patients than physicians (71% vs 23%, p < 0.01) indicated that a 'high risk' result would be very likely to improve motivation to adopt preventive lifestyle changes. Patients favoured genetic testing to guide therapy (78% of patients vs 48% of physicians very likely to request/recommend testing, p < 0.01) and reported that genetic testing would make them 'much more motivated' to adhere to medications (72% vs 18% of physicians, p < 0.01). Many physicians (39%) would be somewhat/very likely to order genetic testing before published evidence of clinical efficacy., Conclusions/interpretation: Despite the paucity of current data, physicians and patients reported high expectations that genetic testing would improve patient motivation to adopt key behaviours for the prevention or control of type 2 diabetes. This suggests the testable hypothesis that 'genetic' risk information might have greater value to motivate behaviour change compared with standard risk information.

The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience.

Aims/hypothesis: Abnormalities in retinal haemodynamics have been reported in patients with type 1 diabetes in advance of clinical retinopathy. These abnormalities could therefore be useful as early markers or surrogate endpoints for studying the microangiopathy. Since the DCCT, the increased focus on good glycaemic control is changing the natural history of diabetic retinopathy. Based on this, the aim of this study was to investigate whether patients with type 1 diabetes treated entirely or mostly in the post-DCCT era and tested in the absence of confounding factors show retinal haemodynamic abnormalities., Methods: We measured retinal haemodynamics by laser Doppler flowmetry in 33 type 1 diabetic individuals with no or minimal retinopathy (age 30+/-7 years, duration of diabetes 8.8+/-4.6 years, 9% showing microaneurysms), and 31 age- and sex-matched non-diabetic controls. The study participants were not taking vasoactive medications, and blood glucose at the time of haemodynamic measurements was required to be between 3.8 and 11.1 mmol/l., Results: HbA1c was 7.5+/-1.2% and blood glucose 7.7+/-2.8 mmol/l in these type 1 diabetic individuals, indicating relatively good glycaemic control. Retinal blood speed, arterial diameter and blood flow were not different between the diabetic individuals and the matched controls., Conclusions/interpretation: Type 1 diabetic patients with no or minimal retinopathy who maintain relatively good glycaemic control do not show abnormalities of the retinal circulation at steady state, even after several years of diabetes. In such patients it may be necessary to test the vascular response to challenges to uncover any subtle abnormalities of the retinal vessels.

Aims/hypothesis: HbA(1c), expressed as the percentage of adult haemoglobin that is glycated, is the most widely used measure of chronic glycaemia. Achieving near-normal HbA(1c) levels has been shown to reduce long-term complications and the HbA(1c) assay is recommended to determine whether treatment is adequate and to guide adjustments. However, daily adjustments of therapy are guided by capillary glucose levels (mmol/l). We determined the relationship between an accurate measure of mean glucose levels over time and the HbA(1c) level, and whether HbA(1c) can be expressed in the same units as self-monitoring results., Methods: Twenty-two participants with diabetes and three non-diabetic participants were included in this longitudinal observational study. Mean glucose levels were measured by continuous glucose monitoring (CGM), which measures interstitial glucose levels every 5 min, for 12 weeks. Capillary measurements were obtained four times per day to confirm the accuracy of CGM. HbA(1c) was measured at baseline and every 4 weeks., Results: The HbA(1c) results at weeks 8 and 12 correlated strongly (r = 0.90) with the CGM results during the preceding 8 and 12 weeks. A curvilinear (exponential) relationship and a linear regression captured the relationship with similarly high correlations, which allowed transformation of HbA(1c) values to a calculated mean glucose level., Conclusions and Interpretation: HbA(1c) correlates closely with a complete measure of average glycaemia over the preceding 8-12 weeks. The translation of HbA(1c) to an average glucose level for reporting and management purposes is feasible.