We here describe a direct causal link between impaired telomerase activity and impaired insulin secretion as well as glucose intolerance in Terc-/-
G4 mice. These findings are supported by the fact that shortened telomeres, as found in states of reduced telomerase activity, are associated with type 2 [13
] as well as possibly type 1 diabetes mellitus [21
] in humans. As stated in the introductory section, both disorders exhibit patterns of impaired insulin secretion.
According to our findings, glucose intolerance in Terc-/-
G4 animals is caused by reduced insulin secretion only, whereas insulin sensitivity was found to be unaffected. This latter observation is in conflict with previous reports that shortened telomeres in humans are associated with insulin resistance [14
], a state in which insulin sensitivity is reduced. However and since insulin secretion and insulin sensitivity appear to influence each other primary disturbances in insulin secretion may secondarily affect insulin resistance.
Progressive beta-cell failure and senescence are hallmarks of type 2 diabetes [2
]. More specifically, telomere shortening has been shown to determine the risk of beta-cell growth arrest and cellular senescence in adult human islet cells [26
]. The Tert
gene is moderately expressed in islets from different mouse models, including C57BL/6 (the strain used in the present study), and expression levels interestingly appear to decrease with age [27
]. Moreover, significant telomerase activity can be detected in islet extracts from C57BL/6 mice [27
]. Interestingly, telomerase appears to counteract the senescence-promoting effects of hyperglycemia, at least in vitro
]. Moreover, several of the known downstream targets of telomerase have been identified to affect islet cell growth and regeneration [29
], whereas a link to telomerase deficiency had not been established. Further studies will have to elucidate whether our current findings and these putative downstream effectors converge in deterioration of islet mass and hence development of diabetes mellitus.
Taken together, our findings indicate that reduced telomerase activity may be considered a cause of impaired glucose tolerance and hence diabetes mellitus. In full accordance with the role of this protein in multiple other cell types, telomerase is required to maintain the replicative potential of pancreatic beta-cells. Consistently, lack of telomerase activity causes beta-cell loss and subsequent deterioration of glucose metabolism, reflecting the increasing incidence of diabetes mellitus with increasing age.