Abstract
Rodent pancreatic β-cells that naturally lack hypoglycemia/hypoxia inducible mitochondrial protein 1 (HIMP1) are susceptible to hypoglycemia and hypoxia influences. A linkage between the hypoglycemia/hypoxia susceptibility and the lack of HIMP1 is suggested in a recent study using transformed β-cells lines. To further illuminate this linkage, we applied mouse insulin 1 gene promoter (MIP) to control HIMP1-a isoform cDNA and have generated three lines (L1 to L3) of heterozygous HIMP1 transgenic (Tg) mice by breeding of three founders with C57BL/6J mice. In HIMP1-Tg mice/islets, we performed quantitative polymerase chain reaction (PCR), immunoblot, histology, and physiology studies to investigate HIMP1 overexpression and its link to β-cell function/survival and body glucose homeostasis. We found that the HIMP1 level increased steadily in β-cells of L1 to L3 heterozygous HIMP1-Tg mice. HIMP1 overexpression at relatively lower levels in L1 heterozygotes results in a negligible decline in blood glucose concentrations and an insignificant elevation in blood insulin levels, while HIMP1 overexpression at higher levels are toxic, causing hyperglycemia in L2/3 heterozygotes. Follow-up studies in 5–30-week-old L1 heterozygous mice/islets found that HIMP1 overexpression at relatively lower levels in β-cells has enhanced basal insulin biosynthesis, basal insulin secretion, and tolerances to low oxygen/glucose influences. The findings enforced the linkage between the hypoglycemia/hypoxia susceptibility and the lack of HIMP1 in β-cells, and show a potential value of HIMP1 overexpression at relatively lower levels in modulating β-cell function and survival.
Highlights
Pancreatic b-cell failure in diabetes is characterized primarily by progressive loss of insulin production and b-cell mass. b-cell failure has been attributed to autoimmune assault in type 1 diabetes and to glucolipotoxicity, amyloid deposition, insulin resistance, and endoplasmic reticulum (ER) and/or oxidative stress in type 2 diabetes [1,2,3,4,5,6,7]
Three transgenic founders were identified by amplification of a DNA fragment (364 bp) from the mouse insulin gene promoter (MIP)-hypoxia inducible mitochondrial protein 1 (HIMP1) expression cassette rather than natural HIMP1 gene in the genome of mouse as described in the Materials and Methods
The differences in the level of the MIPHIMP1 expression cassette DNA (Fig. 1B) may result from variations in the number of MIP-HIMP1 DNA integrated in genome, which may potentially be responsible for discrepancies in the phenotype of HIMP1-Tg mice between 3 lines
Summary
Pancreatic b-cell failure in diabetes is characterized primarily by progressive loss of insulin production and b-cell mass. b-cell failure has been attributed to autoimmune assault in type 1 diabetes and to glucolipotoxicity, amyloid deposition, insulin resistance, and endoplasmic reticulum (ER) and/or oxidative stress in type 2 diabetes [1,2,3,4,5,6,7]. The lack of regular blood flows in early hours of islet transplantation leads to insufficient supplies of oxygen and nutrients (e.g., glucose) within implanted islets This hypoglycemia/hypoxia influence is implicated in b-cell damages within implanted islets, which limits a long-term success of this technique for patients with type 1 diabetes in clinical practice [8,13,14,15,16]. Proinsulin, the predominant form of insulin precursor in the ER, preserves a low relative folding rate, and bears the greatest burden in the protein folding of b-cells It maintains a homeostatic balance of natively and plentiful non-natively folded states (i.e., proinsulin homeostasis, PIHO) in b-cells as a result of the integration of maturation and disposal processes [18]. The low relative folding rate and plentiful insulin precursor manufactured in b-cells make PIHO susceptible to genetic and environmental influences, and PIHO disorder has been critically linked to defects in b-cells in diabetes [18]
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