Ageing and diabetes lead to similar organ dysfunction that is driven by parallel molecular mechanisms, one of which is cellular senescence. The abundance of senescent cells in various tissues increases with age, obesity and diabetes. Senescent cells have been directly implicated in the generation of insulin resistance. Recently, drugs that preferentially target senescent cells, known as senolytics, have been described and recently entered clinical trials. In this review, we explore the biological links between ageing and diabetes, specifically focusing on cellular senescence. We summarise the current data on cellular senescence in key target tissues associated with the development and clinical phenotypes of type 2 diabetes and discuss the therapeutic potential of targeting cellular senescence in diabetes.

OBJECTIVE: We examined preadipocyte differentiation in obese and nonobese individuals and the effect of cytokines and wingless-type MMTV (mouse mammary tumor virus) integration site family, member 3A (Wnt3a) protein on preadipocyte differentiation and phenotype.RESEARCH DESIGN AND METHODS: Abdominal subcutaneous adipose tissue biopsies were obtained from a total of 51 donors with varying BMI. After isolation of the adipose and stromalvascular cells, inflammatory cells (CD14- and CD45-positive cells) were removed by immune magnetic separation. CD133-positive cells, containing early progenitor cells, were also isolated and quantified. The CD14- and CD45-negative preadipocytes were cultured with tumor necrosis factor (TNF)-α, interleukin (IL)-6, resistin, or Wnt3a with or without a differentiation cocktail.RESULTS: The number of preadipocytes able to differentiate to adipose cells was negatively correlated with both BMI and adipocyte cell size of the donors, whereas the number of CD133-positive cells was positively correlated with BMI, suggesting an impaired differentiation of preadipocytes in obesity. Cultured preadipocytes, like freshly isolated mature adipocytes, from obese individuals had an increased expression of mitogen-activated protein 4 kinase 4 (MAP4K4), which is known to inhibit peroxisome proliferator–activated receptor-γ induction. TNF-α, but not IL-6 or resistin, increased Wnt10b, completely inhibited the normal differentiation of the preadipocytes, and instead induced a proinflammatory and macrophage-like phenotype of the cells.CONCLUSIONS: The apparent number of preadipocytes in the abdominal subcutaneous tissue that can undergo differentiation is reduced in obesity with enlarged fat cells, possibly because of increased MAP4K4 levels. TNF-α promoted a macrophage-like phenotype of the preadipocytes, including several macrophage markers. These results document the plasticity of human preadipocytes and the inverse relationship between lipid storage and proinflammatory capacity.

In the early 1980s, we analyzed the metabolic profile of 930 men and women and concluded that an abdominal distribution of fat for a given BMI is associated with increased insulin resistance and risk of developing type 2 diabetes and cardiovascular disease. The correlation between abdominal fat and metabolic dysfunction has since been validated in many studies, and waist circumference is now a criterion for the diagnosis of metabolic syndrome. Several mechanisms for this relationship have been postulated; however, we now know that visceral fat is only one of many ectopic fat depots used when the subcutaneous adipose tissue cannot accommodate excess fat because of its limited expandability.

The limited expandability of subcutaneous adipose tissue, due to reduced ability to recruit and differentiate new adipocytes, prevents its buffering effect in obesity and is characterized by expanded adipocytes (hypertrophic obesity). Bone morphogenetic protein-4 (BMP4) plays a key role in regulating adipogenic precursor cell commitment and differentiation. We found BMP4 to be induced and secreted by differentiated (pre)adipocytes, and BMP4 was increased in large adipose cells. However, the precursor cells exhibited a resistance to BMP4 owing to increased secretion of the BMP inhibitor Gremlin-1 (GREM1). GREM1 is secreted by (pre)adipocytes and is an inhibitor of both BMP4 and BMP7. BMP4 alone, and/or silencing GREM1, increased transcriptional activation of peroxisome proliferator–activated receptor γ and promoted the preadipocytes to assume an oxidative beige/brown adipose phenotype including markers of increased mitochondria and PGC1α. Driving white adipose differentiation inhibited the beige/brown markers, suggesting the presence of multipotent adipogenic precursor cells. However, silencing GREM1 and/or adding BMP4 during white adipogenic differentiation reactivated beige/brown markers, suggesting that increased BMP4 preferentially regulates the beige/brown phenotype. Thus, BMP4, secreted by white adipose cells, is an integral feedback regulator of both white and beige adipogenic commitment and differentiation, and resistance to BMP4 by GREM1 characterizes hypertrophic obesity.