We describe for the first time betatrophin concentrations in humans, and report that circulating concentrations of betatrophin are increased in type 1 diabetes in contrast with what has recently been described in an insulin-deficient mouse model [3
]. This indicates that there is already a potential stimulus for beta cell proliferation present in type 1 diabetes, but that this is not sufficient to counteract the decline in C-peptide levels in the long run.
The reason for increased betatrophin levels in type 1 diabetes is at present not known. A feedback of insulin or C-peptide deficiency, or increased blood glucose concentrations, to increase beta cell mass by betatrophin secretion would be a favourable physiological mechanism, but the presence of such a mechanism remains to be determined. Expression of the betatrophin gene in mice has been described in several organs including the liver, brown and white adipose tissue, adrenal glands, duodenum and small intestine [3
]. Induced insulin resistance is a known potent stimulator of betatrophin expression in liver and fat tissue. It is possible therefore that the increased betatrophin concentrations in patients with type 1 diabetes can be explained by insulin resistance. Although insulin resistance is not part of the disease as in type 2 diabetes, patients with type 1 diabetes can develop an increasing requirement for insulin [4
]. The characteristics of insulin resistance are hypertension, abdominal obesity, increased triacylglycerol concentrations and low HDL-cholesterol levels [5
]. In the type 1 diabetes group, there was indeed a tendency for a weak correlation between betatrophin level and BMI, but this was negative, and there was no correlation between betatrophin and triacylglycerol level or HDL-cholesterol level. Moreover, although triacylglycerol levels, as a mean, were 32% higher in participants with type 1 diabetes, neither triacylglycerol level, nor BMI, blood pressure, LDL-cholesterol or HDL-cholesterol level differed between the diabetic patients and controls.
Betatrophin belongs to the family of angiopoietin-like proteins. The gene encoding this protein is named C19orf80
, and the nutritionally regulated secreting hormone has been given many different names: lipasin, hepatocellular carcinoma-associated protein-TD26, RIFL, angiopoietin-like protein-8 [6
] and, most recently, betatrophin [3
]. Overexpression of betatrophin in mice leads to an increase in serum triacylglycerol, and variations in the gene have been linked with blood lipid levels in humans by genome-wide association studies [6
]. However, in our work, we observed no changes in blood lipids that correlated with betatrophin levels. It cannot be excluded that the mean increase in triacylglycerol levels observed in the patients with type 1 diabetes would have been statistically significant in a larger study.
In healthy controls, but not in the patients with type 1 diabetes, plasma betatrophin concentrations were, for unknown reasons, higher in older individuals. It will therefore be interesting in future studies to examine betatrophin concentrations in different age groups.
Post-mortem studies show conflicting results with regard to whether beta cell replication occurs in type 1 diabetes [9
]. If present, increased levels of betatrophin may be a contributing factor. However, although betatrophin is increased in plasma in patients with type 1 diabetes, its concentration does not correlate with metabolic parameters. We cannot exclude the possibility that increased betatrophin levels might have had transient positive effects on beta cell mass early in the disease, or that the decline in residual C-peptide may be exaggerated in the absence of betatrophin. However, in the long run, it does not protect from the progressive loss of C-peptide secretion. An intervention in patients with type 1 diabetes with betatrophin treatment might require supraphysiological dosing as well as combination with immune regulatory treatment.