Prediabetes: Fatty liver, visceral obesity, production and action of insulin modulate risk

In many countries the prevalence of diabetes and prediabetes has reached epidemic numbers. In the USA and in China more than half of the adult population already has elevated blood glucose levels. Worrisome is that already in the state of prediabetes hyperglycemia is associated with increased risk of type 2 diabetes, cardiovascular disease, dementia and cancer. However, the disease risk considerably varies even in the state of prediabetes. This lead scientists at the Department of Internal Medicine IV of the University Hospital of Tübingen and of the Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, partners of the German Center for Diabetes Research (DZD), to study what parameters may explain this variability in disease risk in prediabetes.

Type 2 diabetes is a very heterogeneous disease

Among scientists it is well established that several pathophysiological mechanisms are involved in the development of type 2 diabetes. However, in a clinical setting it is very difficult to disentangle these mechanisms which may be very useful to implement a personalized prevention and treatment of diabetes. The relevance to account for the major pathophysiological mechanisms of diabetes can be observed that in diabetes diagnosed by elevated fasting or 2 hr glucose levels during a standard oral glucose tolerance test (OGTT) the prevalence and the sequence of appearance of impaired insulin production and impaired insulin secretion differ. This variability in the prevalence of these risk phenotypes can already be observed in the prediabetic states isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT) or IFG+IGT combined.

At-Risk Phenotypes predict prediabetes and cardiovascular risk

In an analysis of data from 1003 subjects of the Tübingen Diabetes Family Study of whom 405 had prediabetes, the 4 at risk phenotypes insulin secretion failure, insulin resistance, fatty liver, and magnetic-resonance imaging (MRI)-determined visceral obesity, but not BMI category (normal weight, overweight, and obese) or visceral obesity based on waist circumference, were independent determinants of prediabetes. Except for visceral obesity, the other 3 at risk-phenotypes also predicted the regression from prediabetes to normal glucose regulation (NGR) during a lifestyle intervention. Among the individuals with prediabetes, fatty liver was the strongest determinant of increased carotid intima-media thickness, an early marker of atherosclerosis, followed by MRI-determined visceral obesity.

Phenotypes of prediabetes

Based on the emerging evidence for the existence of the very interesting extreme metabolic phenotypes metabolically healthy obesity and metabolically unhealthy normal weight the scientist then studied the prevalence of the 4 at-risk phenotypes among the different BMI categories (normal weight, overweight, and obese) in subjects with NGR and prediabetes. They could show that there are distinct signatures of these phenotypes among these BMI categories. For example, while insulin secretion failure is by far the most prevalent at-risk phenotype in normal weight subjects with prediabetes, fatty liver and visceral obesity become more prevalent in overweight and obese subjects.

Conclusion: Phenotypes of prediabetes should be consideration in prevention and treatment of cardiometabolic diseases

Norbert Stefan, the first author of the article, proposes that 'after initial classification of the glucose categories NGR and prediabetes, fatty liver, visceral obesity and impaired production and action of insulin should be included in assessment of cardiometabolic risk. If proven to be effective, this strategy could be included in medical guidelines about the prevention and treatment of diabetes and associated diseases'. Hans Häring, the last author of the study adds 'the application of precise phenotyping strategies in clinical trials will also help to improve understanding of the pathophysiology of cardiometabolic diseases.'