"Cell Metabolism": Major progress in diabetes research!

When it comes to diabetes, the word "insulin" pops up in my mind
.

In 1921, the scientist Frederick Banting (Frederick Banting) teamed up with John Macleod (John Macleod) to successfully extract insulin for the first time
.

In 1922, insulin was put into clinical practice and changed the fate of many diabetics.
From then on, the words "insulin" and "diabetes" were inseparable
.

To this day, insulin is still the only hormone that has been discovered in the body for 100 years to inhibit fat breakdown and lower blood sugar
.

Insulin inhibits lipolysis by activating phosphodiesterase 3B (PDE3B) to limit hepatic glucose (HGP) production, thereby lowering blood glucose levels [1]
.

However, a bug in the human body, insulin resistance, has caused headaches for doctors and scientists
.

In people with insulin resistance, such as those with type 2 diabetes, insulin does not effectively inhibit fat breakdown
.

Once lipolysis is out of control, it will lead to abnormal accumulation of free fatty acids (FFAs) in metabolic tissues such as liver, muscle, and pancreatic islets, causing or aggravating the symptoms of hyperglycemia [2]
.

At the beginning of 2022, just a few days ago, an article published in "Cell Metabolism" broke the situation of insulin "together and defeat" in the field of diabetes treatment
.

Ronald M.
Evans and colleagues from the Salk Institute have identified another hormone that rapidly lowers blood sugar, fibroblast growth factor 1 (FGF1), in adipose tissue
.

Like insulin, FGF1 lowers blood sugar levels by inhibiting lipolysis
.

However, the point is that FGF1 regulates lipolysis by activating phosphodiesterase 4 (PDE4), a new mechanism independent of insulin [3]
.

This means that the FGF1/PDE4 pathway may provide new therapeutic strategies for people with diabetes and insulin resistance
.

In fact, as early as 2014, a paper published in the journal "Nature" proposed that FGF1 can be used as an effective insulin sensitizer to relieve the symptoms of insulin resistance
.

Ronald M.
Evans et al.
injected FGF1 into peripheral blood and successfully normalized the blood glucose level of diabetic mice in a short time without the risk of hypoglycemia [4]
.

Later, Michael Schwartz and others injected FGF1 into the ventricle of diabetic mice, and the mice were in long-term remission.
The research results were published in the journal "Nature Medicine" in 2016 [5]
.

In this way, FGF1 may have become a new weapon against diabetes [6]
.

Comparison of the characteristics of intraventricular injection vs.
peripheral injection of FGF1 [6] So what are scientists not satisfied with? Although it is known that FGF1 effectively lowers glucose in a manner dependent on FGF receptor 1 (FGFR1), its specific mechanism still remains unresolved
.

In the process of excavating the hypoglycemic mechanism of FGF1 this time, Evans and his colleagues actually dug up a treasure! First, the researchers once again confirmed that FGF1 has the effect of lowering blood sugar, and it is dependent on the expression of FGFR1 in adipose tissue [4]
.

They constructed a mouse model (adR1KO) that specifically deleted FGFR1 in mature adipocytes, and injected FGF1 into adR1KO mice and wild-type mice, respectively
.

It was found that blood glucose levels were reduced in wild-type mice, but not improved in adR1KO mice
.

Subsequently, a series of research results showed that the routine of FGF1 to lower blood sugar is exactly the same as that of insulin - firstly, it inhibits lipolysis, thereby reducing the concentration of free fatty acids in serum, to limit the production of HGP, and finally to lower blood sugar levels
.

A: FGF1 hypoglycemic depends on its receptor FGFR1; B: Inhibits lipolysis; C: Reduces the concentration of FFA in serum; D: Limits the production of HGP Then the problem comes
.

Although the hypoglycemic effect of the two hormones can be said to be CTRL C + CTRL V, at the molecular level, does FGF1 really share the same mechanism with insulin? As mentioned at the beginning, after insulin acts on adipocytes, it inhibits lipolysis by activating PDE3B and initiates the hypoglycemic signaling pathway
.

So the researchers put PDE3B to the test to see if the two hormones worked in the same way in inhibiting fat breakdown
.

Who would have thought that the hypoglycemic mechanisms of FGF1 and insulin diverged here
.

In vitro, when the expression of PDE3B was inhibited in the 3T3-L1 adipocyte line, the effect of FGF1 to inhibit lipolysis was not affected
.

In contrast, the inhibitory effect of FGF1 on lipolysis was blocked when PED4 expression was inhibited in either the 3T3-L1 adipocyte line or in mouse or human adipose tissue
.

The results of in vivo experiments are also consistent with this
.

The researchers first gavaged mice with PDE4 inhibitor, and then injected FGF1 1 hour later
.

Analysis of adipose tissue in these mice showed that FGF1's ability to inhibit lipolysis was suppressed
.

The results of both in vivo and in vitro experiments showed that when the expression of PDE4 was inhibited, FGF1 failed.
Further research showed that after FGF1 acts on FGFR1 in adipocytes, it activates PDE4 through the PI3K pathway, and the activated PDE4 inhibits lipolysis through the cAMP/PKA pathway.

.

Among them, among several isoforms of PDE4, PDE4D3 is the most effective isoform for inhibiting lipolysis
.

That is to say, FGF1 and insulin take two distinct paths, respectively, the FGF1/PDE4 and insulin/PDE3B pathways, but the end points of the paths are the inhibition of lipolysis and hypoglycemia
.

This caught the eye of Evans and his colleagues
.

For a long time, FGF1 has been used as an insulin sensitizer [4], which can enhance insulin sensitivity in the human body and promote the full utilization of insulin
.

However, the emergence of the FGF1/PDE4 pathway means that in the hypoglycemic pathway, FGF1 and insulin are not "in series" but "in parallel"
.

To further confirm this conclusion, the researchers found insulin-resistant obese mice (C57/B6, obtained on a high-fat diet)
.

A large number of previous studies have shown that FGF1 can act as an insulin sensitizer and effectively reduce blood sugar in obese mice with insulin resistance [6]
.

This time, however, when these mice were given a PDE4 inhibitor, it was found that the mice's blood sugar, serum free fatty acids, and insulin levels all showed transient and significant increases
.

Even if FGF1 is injected in vitro, it is unable to recover, and FGF1 loses the ability to lower blood sugar
.

A, B: After taking the PDE4 inhibitor, the blood glucose and FFA levels of the mice increased; C: FGF1 also did not work.
In addition, Evans and his colleagues also gave insulin-resistant obese mice a PDE3B inhibitor and found that the inhibition Indeed, PDE3B expression was unable to affect the ability of FGF1 to regulate blood glucose levels
.

It can be concluded that, although from the effect point of view, both FGF1 and insulin are through inhibiting lipolysis → limiting HGP production → lowering blood sugar
.

But at the molecular level, FGF1 and insulin inhibit lipolysis through two independent pathways and initiate a hypoglycemic signaling pathway
.

For insulin-resistant mice, FGF1 and insulin are not "promoting" but "complementary"
.

Subsequently, the researchers refined the mechanism by which the FGF1/PDE4 pathway regulates lipolysis
.

The results showed that the specific phosphorylation of the S44 site is required for the regulation of lipolysis by the FGF1/PDE4 pathway
.

In general, insulin is the only known hormone in the body that inhibits lipolysis and lowers blood sugar for a long time
.

Although FGF1, which is present in human adipose tissue, has long been shown to have a similar effect to insulin, this time Evans and his colleagues found that FGF1 inhibits lipolysis in an insulin-independent mechanism! After acting on FGFR1 on adipocytes, FGF1 activates PDE4 to regulate lipolysis, which is independent of the insulin/PDE3B pathway
.

After inhibiting lipolysis, free fatty acid levels in serum decrease, limiting hepatic glucose production, which in turn lowers blood glucose levels
.

The researchers said that the mechanisms of insulin and FGF1 inhibiting lipolysis and lowering blood sugar can be regarded as two "parallel pathways"
.

"When insulin resistance occurs, the insulin signaling pathway is impaired
.

However, even if the insulin signaling pathway is shut down, the FGF1 signaling pathway can still function
.

This way lipolysis and blood sugar lowering can still be effectively regulated," said Gencer Sancar, one of the authors of the paper.
[7]
.

The discovery of the FGF1/PDE4 pathway may open up a new direction for the study of hyperglycemia and insulin resistance
.

How to improve the activity of PDE4 also needs to be further explored
.

Reference: [1]Kitamura, T.
, et al.
(1999).
Insulininduced phosphorylation and activation of cyclic nucleotide phosphodiesterase 3B by the serine-threonine kinase Akt.
Mol.
Cell.
Biol.
19, 6286–6296.
[2] Saponaro, C.
, Gaggini, M.
, Carli, F.
, and Gastaldelli, A.
(2015).
The Subtle Balance between Lipolysis and Lipogenesis: A Critical Point in Metabolic Homeostasis.
Nutrients 7, 9453–9474.
[3] Sancar G, et al.
FGF1 and insulin control lipolysis by convergent pathways.
Cell Metab.
2022 Jan 4;34(1):171-183.
e6.
doi: 10.
1016/j.
cmet.
2021.
12.
004.
PMID: 34986332.
[4 ]Suh JM, Jonker JW, Ahmadian M, et al.
Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer[J].
Nature, 2014, 513(7518): 436-439.
[5]Gregory J Morton, Michael W Schwartz , et al.
Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents.
nm.
4101.
[6]https://#citeas[7]https:// .
org/news-releases/938927 By Eddie Zhang