Abstract
Obesity-related insulin resistance represents the core component of the metabolic syndrome, promoting glucose intolerance, pancreatic beta cell failure and type 2 diabetes. Efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications Here, we identify transforming growth factor beta-like stimulated clone (TSC) 22 D4 as a molecular determinant of insulin signalling and glucose handling. Hepatic TSC22D4 inhibition both prevents and reverses hyperglycaemia, glucose intolerance and insulin resistance in diabetes mouse models. TSC22D4 exerts its effects on systemic glucose homeostasis—at least in part—through the direct transcriptional regulation of the small secretory protein lipocalin 13 (LCN13). Human diabetic patients display elevated hepatic TSC22D4 expression, which correlates with decreased insulin sensitivity, hyperglycaemia and LCN13 serum levels. Our results establish TSC22D4 as a checkpoint in systemic glucose metabolism in both mice and humans, and propose TSC22D4 inhibition as an insulin sensitizing option in diabetes therapy.
Highlights
Obesity-related insulin resistance represents the core component of the metabolic syndrome, promoting glucose intolerance, pancreatic beta cell failure and type 2 diabetes
We have recently identified transcription factor TSC22D4 as a regulator of hepatic lipid metabolism during cancer cachexia[12]
We identify the hepatic TSC22D4 as a potent regulator of insulin sensitivity in both murine and human diabetes, acting—at least in part—through the secreted factor lipocalin lipocalin 13 (LCN13)
Summary
Obesity-related insulin resistance represents the core component of the metabolic syndrome, promoting glucose intolerance, pancreatic beta cell failure and type 2 diabetes. The inability of key metabolic tissues, including skeletal muscle, adipose tissue and liver to respond to normal circulating concentrations of insulin, that is, insulin resistance, is commonly associated with obesity, ageing and a sedentary lifestyle[8] Under these conditions, systemic glucose and lipid homeostasis are substantially compromised, leading to successive pancreatic beta cell exhaustion and further deterioration of glucose homeostasis. Safe and effective modalities to improve systemic insulin sensitivity are direly needed for counteracting obesity-related type 2 diabetes but may pave the way for novel therapeutic approaches in wasting diseases In this respect, we have recently identified transcription factor TSC22D4 as a regulator of hepatic lipid metabolism during cancer cachexia[12]. TSC22D4 represents a previously unknown checkpoint in inter-organ communication and systemic metabolic control and may serve as an attractive target in insulin sensitizing diabetes therapies
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