Lakhasly

T2DM is characterized by hyperglycaemia, which results from a progressive deterioration of insulin secre-tory β- cell function, typically combined with varying degrees of insulin resistance. These two key pathoge-netic mechanisms are usually accompanied by other glucoregulatory disturbances such as inappropriate hyperglucagonaemia and an impaired incretin response (Fig. 1)14,15. Insulin resistance alone is seldom sufficient to trigger the development of T2DM as the pancreas can initially compensate by proportionally increasing insulin secretion. However, long-term hyperinsulinaemia incurs a stress on β- cells that disrupts the acute (first phase) insulin secretory response to a glycaemic stimulus and eventually impairs the later (second phase) insulin response14,15. Hence, inadequate insulin secretion is an essential pathogenetic component for most patients with T2DM14,15. Ageing contributes to the pathogene-sis of T2DM both directly through the decreased β- cell function that accentuates the lack of insulin secretion and indirectly by increasing insulin resistance through obe-sity and other risk factors (Fig. 1)(16,17). For example, β- cell senescence and reduced β- cell sensitivity to glucose dur-ing ageing increase the susceptibility to T2DM through inadequate compensation for insulin resistance(18,19.)
The detrimental effects of ageing on cellular path-ways of insulin action and glucose metabolism are modest when age-related changes in body composition are considered(20,21). For example, the effects of ageing that lead to increased insulin resistance are primarily asso-ciated with the excess adiposity and decreased muscle mass and function (sarcopenia) that are common in older adults, which can be worsened by a sedentary life-style (Fig. 1)17,22,23. Excess adiposity in older adults typi-cally comprises an absolute or relative increase in visceral adipose tissue depots compared with subcutaneous adipose tissue, which is often reduced24,25. Moreover, age-ing is associated with ectopic deposition of lipids in the liver as well as with intracellular lipids and extra adipose tissue in cardiac and skeletal muscles(25,26). These changes further increase the risk of insulin resistance, with intra-muscular adipose tissue being a key factor contributing to insulin resistance in lean older people23,26. In addition, unfavourable age- related changes in body composition can be aggravated by physical inactivity and poor dietary habits as well as by the effects of comorbidities and their medications(27,28).
Excess visceral and ectopic (intramuscular and hepatic) adiposity decreases insulin sensitivity by producing the adipokines and cytokines that impede the pathways of insulin action downstream of the insulin receptor, such as tumour necrosis factor, and low- grade inflamma-tory factors such as C- reactive protein29. Furthermore, both ageing and obesity are associated with the increased production of pro- inflammatory cytokines from adipose tissue30. In addition, both ageing and obesity are associated with an increased population of macrophages within adipose tissue, a decreased num-ber of regulatory T cells and a reduced self- renewal of mesenchymal progenitor stem cells, thereby promoting metabolic dysregulation and inflammation31. Impaired nutrient metabolism and an age-related decline in mito-chondrial function also link ageing and insulin resis-tance, although the mechanistic details remain to be clarified (Box 1).Age- associated blunting of insulin- mediated glucose uptake is linked with the progressive deterioration of the structure and function of skeletal muscles. Specific age- related changes include a reduced skeletal muscle mass with smaller and fewer type II fibres as well as a decreased density of capillaries in skeletal muscle(33,34).
Underlying mechanisms include mitochondrial dys-function, increased low-grade inflammation, intramyo-cellular lipid accumulation and oxidative stress as well as the accumulation of senescent cells and decreases in autophagic capacity and enzymatic activity During skeletal muscle ageing, pro- inflammatory path-ways become activated. Furthermore, the number of mitochondria is reduced and their oxidative capacity is decreased due to the reduced activity of antioxidant enzymes, which leads to the intracellular accumulation of reactive oxygen species and increased levels of oxi-dative stress in skeletal muscle. Although the com-plete spectrum of the underlying mechanisms has not been fully clarified, all of the processes that characterize skeletal muscle ageing induce insulin resistance and, accordingly, increase the risk of T2DM(23,35).
Evidence suggests that a relationship exists between ageing and T2DM at a biological level: a number of studies in humans have shown that both diabetes melli-tus and ageing shorten telomere length38 (Box 1) and that T2DM induces premature cellular senescence(39)
However, the nature of this relationship requires fur-ther study to understand if the biological processes involved in ageing drive T2DM pathology or if diabetes increases the rate of biological ageing. Ageing can indi-rectly increase insulin resistance and precipitate T2DM through several comorbidities that are prevalent among older adults, notably vascular diseases, chronic stress and poor psychological health16,27,40.