Abstract
Type 2 diabetes is characterized by insulin resistance, hyperglycemia, and progressive β cell dysfunction. Excess glucose and lipid impair β cell function in islet cell lines, cultured rodent and human islets, and in vivo rodent models. Here, we examined the mechanistic consequences of glucotoxic and lipotoxic conditions on human islets in vivo and developed and/or used 3 complementary models that allowed comparison of the effects of hyperglycemic and/or insulin-resistant metabolic stress conditions on human and mouse islets, which responded quite differently to these challenges. Hyperglycemia and/or insulin resistance impaired insulin secretion only from human islets in vivo. In human grafts, chronic insulin resistance decreased antioxidant enzyme expression and increased superoxide and amyloid formation. In human islet grafts, expression of transcription factors NKX6.1 and MAFB was decreased by chronic insulin resistance, but only MAFB decreased under chronic hyperglycemia. Knockdown of NKX6.1 or MAFB expression in a human β cell line recapitulated the insulin secretion defect seen in vivo. Contrary to rodent islet studies, neither insulin resistance nor hyperglycemia led to human β cell proliferation or apoptosis. These results demonstrate profound differences in how excess glucose or lipid influence mouse and human insulin secretion and β cell activity and show that reduced expression of key islet-enriched transcription factors is an important mediator of glucotoxicity and lipotoxicity.
Original language | English (US) |
---|---|
Pages (from-to) | 1857-1870 |
Number of pages | 14 |
Journal | Journal of Clinical Investigation |
Volume | 126 |
Issue number | 5 |
DOIs | |
State | Published - May 2 2016 |
Funding
We thank Janice Williams for her expertise and effort in acquiring electron microscopy images. This work was supported by grants from the Department of Veterans Affairs (BX000666, BX002223), the National Institute of Diabetes and Digestive and Kidney Diseases (DK68854, DK66636, DK69603, DK63439, DK62641, DK72473, DK89572, DK89538, DK68764, DK92758, DK97829, DK94199, DK104211, DK050203, DK090570, DK89572, DK104218, DK106755, DK104211, DK108120), JDRF, the Vanderbilt Diabetes Research and Training Center (DK20593), and the Helmsley Charitable Trust (2012PG-T1D018 and 2015PG-T1D057). The EndoC-βH1 cell line was provided by Raphael Scharfmann and Philippe Ravassard and the S961 was provided by Lauge Schäffer. N.S. Kayton was supported by a Vanderbilt Molecular Endocrinology Training Program grant (5T32 DK07563).
ASJC Scopus subject areas
- General Medicine