My question is related to the C57BL6 HFD-fed, streptozotocin-injected mouse model. Is there evidence indicating that these mice retain their insulin resistance post STZ-injection?
In our model, mice are fed with a 60% HFD from 5wk of age. At 12wks, when mice exhibit hyperinsulinemia and have established insulin resistance, they are injected with low dose streptozotocin (1x75mg/kg followed by 1x50mg/kg). The fasting insulin levels of HFD-STZ mice drops to that of non-diabetic mice and subsequently mice develop hyperglycemia, both features that we desire.
However, between 24-36 wks fasting hyperglycemia begins to normalize and upon performing an insulin tolerance test we observe that, unlike our HFD-mice, the HFD-STZ mice display an insulin-dependent response when provided with exogenous insulin. Our data suggests that the HFD-STZ mice regain insulin sensitivity, a feature we wish to avoid.
Does anyone have experience with these models that could provide suggestions on how we can retain hyperglycemia and insulin resistance in this model?
Thanks,
Phillipe
My work with STZ has shown that insulin sensitivity remains normal in non-HFD mice. By lowering or removing the hyperinsulinemia produced by HFD, STZ is restoring normal insulin sensitivity. The insulin resistance from HFD is almost certainly a result of the hyperinsulinemia.
What is the rationale for doing the STZ after the HFD? Can you induce insulin resistance by giving HFD following the STZ treatment?
If you wish to have insulin resistance after your STZ treatment, you could try a pharmacological approach using the insulin receptor antagonist S961. You can get mini osmotic pumps that would provide chronic insulin blockage.
Hi Derek. Indeed, the decreased hyperinsulinemia, via STZ, is what we consider to be the reason for restoration of insulin sensitivity.
We are attempting to identify a non-genetic mouse model of type 2 diabetes. In the past we have worked on db/db and ob/ob mice and have since moved onto using HFD-fed mice instead so to avoid the caveats associated with leptin models. The problem with HFD-fed C57BL6J mice is that they do not develop as robust a diabetic phenotype as we desire (i.e. they are relatively normoglycemic, GHb% is normal and mice typically have milder diabetic complications).
Several groups have used the HFD-mouse model (to induce pre-diabetes, hyperinsulinemia and insulin resistance; see refs below) followed by an injection with STZ so to try mimic T2D pathophysiology (i.e. eventual failure/death of beta cells to due to 'hypersecretion' of insulin thus resulting in hyperglycemia). It appears that instead of having a pre-diabetic->T2D model that is insulin resistant, our model is actually pre-daibetic->T1D with a HFD that is insulin sensitive.
The pharmalogical approach is something I need to consider so I appreciate your suggestion of using the InsR antagonist.
References:
1. Nongenetic mouse models of non-insulin-dependent diabetes mellitus.
Luo J, Quan J, Tsai J, Hobensack CK, Sullivan C, Hector R, Reaven GM.
Metabolism. 1998 Jun;47(6):663-8.
2. Development of a nongenetic mouse model of type 2 diabetes.
Gilbert ER, Fu Z, Liu D.
Exp Diabetes Res. 2011;2011:416254.
3. Effect of enriching the diet with menhaden oil or daily treatment with resolvin D1 on neuropathy in a mouse model of type 2 diabetes.
Shevalye H, Yorek MS, Coppey LJ, Holmes A, Harper MM, Kardon RH, Yorek MA.
J Neurophysiol. 2015 Jul;114(1):199-208.
I use C57BL/6NTac mice from Taconic for my HFD work. For my purposes they respond quite well to DIO. I have attached some data that compares them to the Jackson Black 6 mice.
Best of Luck.
http://info.taconic.com/hs-fs/hub/355513/file-2452871868-pdf/Technical_Library/DIO_2011_Poster.pdf
Phillipe,
There is a strong indication that sustained hyperinsulinemia itself causes paradoxical upregulation of glucagon secretion, which drives the hyperglycemia. A recent publication in the PNAS (2015) from my mentor's lab (R. Unger) shows that simply blocking the glucagon receptor by an antibody normalized glucose levels. Given this context, by diminishing hyperinsulinemia, you are more than likely interrupting the entire process which involves hyperglucagonemia to sustain hyperglycemia.
If you wish to destroy the native ß-cells by STZ, to keep the rest of the chain intact, you may have to test your hypothesis by continous infusion of glucagon (hyperglucagonnemic clamp) or insulin and glucagon. It will get a little complicated... but possible.
Best,
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