Current Diabetes Reviews - Volume 12, Issue 1, 2016

Diagnosis of type 2 diabetes and prediabetes is mandatory. Chronic hyperglycemia in diabetes is associated with long-term micro- and macrovascular as well as with neurological complications. Prediabetes predisposes patients to develop diabetes and macrovascular disease. Diagnosis of diabetes is established on (at least) one of the following criteria: a fasting plasma glucose ≥ 126 mg/dl (7.0 mmol/l), a casual plasma glucose ≥ 200 mg/dl (11.1 mmol/l) in the presence of symptoms, a 2-h plasma glucose during the 75-g oral glucose tolerance test (OGTT) ≥ 200 mg/dl (11.1 mmol/l) and/or an HbA1c ≥ 6.5%. Prediabetes is defined by the Position Statement of the American Diabetes Association as a fasting plasma glucose between 100 and 125 mg/dl (5.6 - 6.9 mmol/l) [a condition called Impaired Fasting Glucose] and/or by a 2-h plasma glucose during OGTT 140 - 199 mg/dl (7.8 - 11.0 mmol) [Impaired Glucose Tolerance] and/or a HbA1c level 5.7 - 6.4%, with however some potential discordance between tests. The threshold of fasting plasma glucose defining Impaired Fasting Glucose as well as the adequacy of HbA1c as a correct diagnostic tool for prediabetes is still debated.

Glycated haemoglobin (HbA1c) is currently the gold standard for glucose monitoring in patients with diabetes, and has been increasingly adopted as a criteria for diabetes diagnosis. However, conditions that determine alterations in haemoglobin metabolism can interfere with the reliability of HbA1c measurements. Glycated albumin and fructosamine (total glycated serum proteins) are alternative markers of glycaemia, which have been recognised to provide additional information to HbA1c or to provide a reliable measure when HbA1c is observed not to be dependable. Additionally, while HbA1c monitors the exposure to circulating glycaemia in the previous 3 months, glycated albumin and fructosamine represent exposure for a shorter period, which may be beneficial to monitor rapid metabolic alterations or changes in diabetes treatment. The present review further discusses the relative value of HbA1c, glycated albumin, and fructosamine, in prediabetes and diabetes diagnosis, evaluation of glucose variability, and complications risk prediction. Also, a novel molecular role for albumin is presented by which glycated albumin contributes to glucose intolerance development and thus to progression to diabetes, besides the role of glycated albumin as a pro-atherogenic factor.

The rapidly increasing prevalence of type 2 diabetes (T2D) is motivating an intensive search for biomarkers to identify individuals at risk for developing the disease. It has been established that both genetic and environmental factors are influential in the progression to T2D. Currently, the number of genetic loci implicated in T2D susceptibility is more than 65 and together, these factors explain only about 10% of the risk. At this time, prediction models using genetic information do not perform substantially better than models based on routine clinical measures. The search for new biomarkers must integrate new, independent factors beyond the static genome that are influenced by environmental conditions. This search must also recognize the heterogeneity of T2D and seek new biomarkers of potential subtypes and confounding conditions such as obesity. Modulation of gene expression by epigenetic modifications and the action of microRNAs are being recognized as critical processes affecting T2D risk. This review provides an update on the current state of genetic biomarkers of T2D susceptibility and examines how epigenetic modulation of some new and established diabetes susceptibility genes can identify increased risk and provide biomarkers for early detection and therapeutic monitoring.

Type 2 diabetes is a heterogeneous disease with large variation in the relative contributions of insulin resistance and beta cell dysfunction between subgroups and individuals. Some of these differences are reflected in the way people are diagnosed. However, differences in glucose regulation exist among individuals even in those with comparable diagnostic glucose levels. In this review we address the heterogeneity of pre-diabetes and type 2 diabetes with special emphasis on differences in the pathophysiology and treatment responses related to the diagnostic criteria. We also discuss whether novel glycaemic markers of diabetes risk can provide additional information to the established diagnostic criteria. A better understanding of the underlying mechanisms responsible for elevated fasting versus postprandial glucose concentration, as well as knowledge about the expected responsiveness to treatment in individuals with different clinical characteristics at diagnosis, may contribute to optimising strategies for management of hyperglycaemia in both pre-diabetes and type 2 diabetes.

Globally, 382 million adults aged 20-79 years are estimated to have diabetes and 46% are unaware of their condition. Another 316 million adults are at increased risk of developing diabetes. Although there are suggestions that diabetes and related complications can be prevented through early detection, lifestyle intervention and/or treatment, universal screening for diabetes has not been adopted. There are, instead, recommendations for a multi-step screening approach, which include identifying people at risk of diabetes through non-invasive methods such as a risk assessment tool or presence of diabetes risk factors, followed by blood testing for the at risk group and diagnostic blood testing for those screened positive for diabetes. Diabetes screening initiatives have been studied in different medical, health and community settings and some have targeted high risk populations. Most of these screening initiatives, however, have common limitations such as low follow-up rate with primary care providers for those who screen positive, abnormal screening result not communicated to the at risk person’s primary care provider, failure to provide appropriate follow-up for patients with abnormal screening results, time and cost as barriers for both screening providers and people invited for screening, and low acceptance of the oral glucose tolerance test. If these common limitations can be addressed, diabetes screening initiatives have the potential to detect undiagnosed diabetes in most populations.

Morbidity and mortality from diabetes and its complications are increasing in populations globally. Different ethnic groups have varying degrees of risk. The concept of ethnicity encompasses numerous factors relevant to health including genetics, socioeconomics and health behaviours. Ethnicity-related discordance in the glycaemic markers used to diagnose diabetes and to identify those at risk of diabetes has been reported. Furthermore, many ethnicity- and country-specific diabetes risk prediction models have been developed. This review provides a thorough discussion of the impact of ethnicity on how diabetes is detected and the evidence for and against ethnicity-specific approaches to diagnosis.

A personalized approach for prediabetes and diabetes detection is presented, with its rationale and implications. Type 2 diabetes (T2DM) detection is particularly suitable to a personalized approach since the essence of its diagnosis is the identification of individuals who are at most risk of developing complications of the disease and who may benefit from intervention. Thresholds of glucose parameters for T2DM diagnosis have decreased over the years, as levels considered normal have been found to confer risks of complications. A continuum of glucose parameters, rather than universal thresholds, seems to better reflect the risks of diabetes and its complications. Individual trajectories of progression to diabetes suggest the possibility of establishing personalized profiles based on serial measurements. Demographic, clinical, genetic, and environmental factors need also be considered. Different diagnostic criteria are found to identify different phenotypes of T2DM. A personalized approach is needed to apply the accumulating knowledge to the recognition of individual risk for diabetes complications and effective interventions.

Diabetes is a metabolic alteration characterized by a higher than normal blood glucose level. For the experimental study of the metabolic changes that occur during this illness, various animal models have been introduced: alloxan- and streptozotocin-injected animals, as well as depancreatized animals, as models for type 1 diabetes, and high-fat fed diabetic animals and laboratory animals with genetic diabetes as models for type 2 diabetes. All these models have been used to investigate specific events on the cellular and organ levels that occur as a consequence of diabetes. In particular, mitochondrial energy metabolism has been extensively studied using these experimental models for diabetes. The experimental results for the bioenergetics of isolated mitochondria harvested from different animal models for diabetes, with the exception of those obtained with high-fat fed diabetic animals, are conflicting; nevertheless, many researchers now consider mitochondrial energy dysfunction as one of the direct causes of the serious complications, in various organs and tissues, that are exhibited as a result of this illness. For this reason, it is important that future research clarify the true energy functional state of these organelles isolated from diabetic animals. In the present paper, the published data on this controversial but important issue of the energetic functioning of the mitochondria isolated from diabetic animals is reviewed. This paper also includes commentary on the status of current research and makes useful suggestions for the future direction of research on this topic.