Type 2 diabetes develops slowly, without clinical manifestations, although there are laboratory and anthropometric indications of the existence of prediabetes. Prediabetes is a condition of intermittent hyperglycemia, where glycemic values are neither normal, nor elevated enough to meet the criteria for diabetes. It is a component of metabolic syndrome, often associated with obesity, dyslipidemia and hypertension. It is increasingly accepted that prediabetes is an early stage of type 2 diabetes. However, the current definition of prediabetes does not define different phenotypes which are predictive for developing type 2 diabetes, cardiovascular diseases, liver steatosis, kidney diseases and increased mortality in general.
Prediabetes is not a single entity and neither is type 2 diabetes! To determine the subtype of prediabetes, it is necessary to perform more than just the oral glucose tolerance test (oGTT). Further diagnostics include determination of: insulin sensitivity, insulin secretion, HDL-cholesterol, triglycerides, prevalence of diabetes in the family, abdominal ultrasound and measurement of body composition using bioelectric impedance. Abdominal ultrasound can assess whether there is a fatty liver. Bioelectric impedance can determine the distribution of subcutaneous and visceral fat. In this way, 6 clear subtypes of prediabetes were defined. Subjects from epidemiological studies (TUEF/TULIP, n = 899 and Whitehall II, n = 6810) participated in these trials. Defining subtypes was important to track the results. Subjects were followed 4.1 years in TUEP / TULIP study and 16 years in the Whitehall II study. The goal was to establish the development of morbidity and mortality in each subtype of prediabetes.
The six phenotypes of prediabetes are:
1. Overweight, body mass index (BMI 25-30 kg/m2) with an initial disorder in insulin sensitivity, but normal insulin secretion;
2. Normal BW, body mass index (BMI 18.5 – 25 kg/m2), with almost normal insulin secretion, normal tissues insulin sensitivity, but with increased genetic risk for diabetes;
3. Increased BW or obese with moderately reduced insulin sensitivity, decreased insulin secretion and genetic risk for T2DM;
4. Obese (BMI >30 kg/m2) with preserved insulin sensitivity and normal insulin secretion. In these people, there is an excess of subcutaneous adipose tissue – fat. We used to call them – metabolically healthy fat;
5. Obese with fatty liver, low insulin sensitivity, low insulin secretion and with a genetic risk for T2DM;
6. Obese with large visceral adipose tissue, especially around the kidneys, low insulin sensitivity, moderately low insulin secretion and risk of kidney disease.
Metabolically healthier subtypes of prediabetes are 1, 2 and 4. These subtypes had a minor disorder in tissues insulin sensitivity and low mortality.
Type 2 diabetes occurred least frequently in phenotype 2. Phenotype 4 was characterized by higher amounts of subcutaneous than visceral fat, and rare occurrence of type 2 diabetes. Type 2 diabetes occurred most frequently in subtype 5 and, thereafter, in subtype 3. Subtype 3 was characterized by decreased insulin secretion, and subtype 5 by increased insulin resistance. These two subtypes had high genetic risk. The incidence of diabetes in subtype 6 was moderate.
Cardiovascular risk was assessed in TUEP/TULIP study by measuring the carotid intima – media thickness. Subtypes 3, 5, and 6 had significantly greater intima and media thickness. The Whitehall II study monitored the incidence of coronary and cerebrovascular disease and cardiovascular mortality. The highest cardiovascular risk was in phenotype 5, and the highest mortality was in phenotype 6. The rarest occurrence of CV diseases and mortality was in subjects with phenotype 2.
Subtype 6 – obese with highly increased visceral fat and presence of fat in renal sinuses, most often developed albuminuria and diabetic nephropathy. Their mortality was 40% higher than in subtype 1. Interestingly, the occurrence of type 2 diabetes is not the rule for this subtype, which suggests that hyperglycemia is not the major pathogenetic factor driving increased mortality.
Identification of prediabetes subtypes has preventive and therapeutic potential. Obese people with fatty liver and reduced insulin sensitivity and secretion (phenotype 5) would have to accept a major change in dietary habits and to get seriously engaged in intense physical activity in order to lose fat in liver and reduce total body weight. For obese people with moderately reduced insulin sensitivity and insulin secretion (phenotype 3), standard aerobic physical activity and caloric restriction would be appropriate. Although these types have a strong genetic predisposition, the adoption of these measures could delay the occurrence of type 2 diabetes and slow its progressive course. Insulin resistance with kidney disease and increased mortality in phenotype 6 certainly requires special medical attention.
Medications for preventing T2DM, cardiovascular and kidney diseases are not the same for everyone. Prediabetes is no longer understood as an “easy condition” and a generalized advice, such as “eat less, walk more”, is considered inappropriate. There are many medications which have been shown to be effective in preventing type 2 diabetes in people with prediabetes. The prediabetes phenotype should be considered before deciding on pharmacological intervention during this period.