INTRODUCCIÓN

Insulin reaches the liver through the portal circulation and then undergo clearance in the
hepatocytes, which regulates the homeostatic insulin level. Receptor-mediated insulin uptake and
its degradation in the hepatocytes is the basic mechanism of insulin clearance. Insulin is cleared
mainly in liver and kidney, however extra-hepatic insulin target tissues and cells such as skeletal
muscle and adipocytes contributes to insulin clearance.

Type 2 Diabetes (T2d) Association: The association between (T2D) and impaired insulin clearance
was reported in 1949. Multiple studies have identified defective insulin clearance as a critical
factor for hyperinsulinemia, insulin resistance and other manifestation of metabolic syndrome.

Insulin Resistance Association: Hyperinsulinemia is a consequence from increased insulin

secretion and a reduced insulin clearance (specially in obese patients) to compensate insulin
resistance. Impaired insulin clearance can also generate hyperinsulinemia-driven systemic insulin
resistance.
Role of CEACAM1 in Receptor-Mediated Insulin Endocytosis

CEACAM1 is a transmembrane glycoprotein from the CEA family of cell adhesion molecules. Is
expressed particularly in the liver and in the kidney main sites of insulin clearance.

Regulation of Insulin Signaling by CEACAM1

1. Insulin binds to IR and activates its tyrosine kinase to catalyze its autophosphorylation and
CEACAM1 phosphorylates.
2. CEACAM1 binds to the SH2 domain, which allows the binding of the PTB domain in IR.
Forming a complex between IR and CEACAM1.
3. CEACAM1 binds to SHP2 to sequester it. This protects IRS against the phosphatase and
prolongs its activation.

CEACAM1 Increases Receptor-Mediated Insulin Endocytosis and Targeting to the Degradation

Process

CEACAM1 phosphorylation plays multiple roles:

- Significant role in the intracellular trafficking of the insulin-IR complex, including lysosomal
exclusion of the receptor.

- Regulation of the receptor mediated insulin uptake followed by its degradation

- Plays a key role in the inward routing of CEACAM1 into endocytosis vesicles.

CEACAM1 Links Insulin Removal with Low Fatty Acid Synthesis in Hepatocytes

This protein is highly expressed in hepatocytes Under non-fasting conditions and the CEACAM1-
dependent pathways contribute to maintaining insulin sensitivity in the liver.

CEACAM1-dependent pathways protect the liver against the physiologically high levels of insulin in
the portal vein by increasing insulin uptake via the IR-A receptor suppressing novo lipogenesis and
regulates the relative distribution of IR-A and IR-B in hepatocytes.
Disturbance in this system leads to impaired insulin clearance with exaggerated hyperinsulinemia
that could lead to downregulation of the insulin receptor and hepatic steatosis.

Insulin Regulates Its Hepatic Clearance

CEACAM1 has a minimal role in the insulin secretion regulation and regulates insulin levels by
promoting insulin clearance in hepatocytes.

By inducing CEACAM1 transcription and phosphorylation, insulin stimulates its own clearance in
hepatocytes, which regulates its homeostatic levels to guarantee the propagation of its multiple
functions in target cells.

Impaired Insulin Clearance,Hyperinsulinemia, and Insulin Resistance

impaired insulin clearance leads to hyperinsulinemia, which in turn, causes insulin resistance
through several mechanisms.

1) Desensitization and lysosomal downregulation of the insulin receptor

2) 2) limiting the pulsatility of insulin release
3) decreasing brown adipogen-
esis and, consequently, energy expenditure (175).
Molecular Mechanism of InsulinDegradation: The Role of Insulin-Degrading Enzyme (IDE)
Revisited

IDE is the most-abundant protease that degrades insulin in the cytosol, particularly in the
kidney. Insulin-degrading enzyme activity has been also reported in lysosomes and
membrane fractions.

IDE and Insulin Clearance

Deletion of ide gene leads to hyperinsulinemia, so a physiological role for IDE in insulin
clearance can be inferred. IDE regulates renal insulin clearance via a non-proteolytical
function.

Role of IDE in Insulin Clearance in Obesity

There is no conclusive information about the impact of obesity on hepatic IDE levels and
insulin clearance.

Role of IDE in Insulin Clearance in Diabetes

There is an existing association between reduced IDE levels and lower insulin clearance in
T2D. Studies have shown lower IDE activity and insulin degradation in fat depots of pre-
diabetics and T2D compared with non-diabetic patients.

IDE inhibitors have been proposed for T2D, however none of them demonstrated valid
therapeutic use due to toxicity, low potency, or selectivity. Also, long-term inhibition of
IDE may cause chronic hyperinsulinemia, resulting in insulin resistance and impaired
insulin secretion.

Proposed Coordination of Insulin Trafficking and Metabolism by CEACAM1 and IDE-

Dependent Pathways
Coordinated regulation of insulin metabolism by CEACAM1 and IDE is a new proposed
model. According to this model, insulin binding to its receptor leads to a conformational
change that induces autophosphorylation of the insulin receptor.

It is possible that cytosolic IDE participates in a conformational change that favors this
step, similar to its interaction with the Type A scavenger receptor A, and with androgen
and glucocorticoid receptors

Concluding Remarks

Insulin secretion and clearance coordinate their

regulation of insulin homeostasis and action. In
this respect, the liver is equipped with multiple
mechanisms that protect it against the high levels

of insulin in the portal vein. This protective reper-

toire is mediated by the pulsatility of insulin re-
lease and by the high level of hepatocytic

CEACAM1 that mediates excess insulin removal

upon its phosphorylation by ligand-activated in-

sulin receptor to maintain normo-insulinemia.

Thus, when hyperin-

sulinemia develops and pulsatility of insulin re-
lease diminishes, CEACAM1 phosphorylation is

compromised to impair insulin clearance, caus-

ing hepatic insulin resistance (downregulation of

the insulin receptor by lysosomal degradation) and

giving way to the lipogenic effect of chronically

elevated levels of insulin.

Mechanistically, hepatic insulin clearance is me-

diated by receptor-mediated insulin uptake and

degradation in hepatocytes, a process that is up-

regulated by CEACAM1. Devoid of enzymatic ac-
tivity, CEACAM1 does not engage in the proteolytic

degradation pathway, per se.

Instead, it acts as a

chaperone that delivers the complex to late endo-

somes where insulin ultimately dissociates from its

receptor to be fully degraded.

Whereas IDE cata-

lyzes insulin degradation in early endosomes, its

proteolytic activity is inhibited in the acidic envi-

ronment of late endosomes, giving way to resident
acidic proteases to degrade insulin.

the therapeutic effect of IDE inhibition

as a strategy to ameliorate insulin resistance. In
light of the undisputed critical role of CEACAM1 in
regulating insulin action by promoting insulin

clearance, we propose that therapy based on in-

ducing CEACAM1 is likely to be more beneficial in

the prevention as well as in the treatment of insulin

resistance and hepatic steatosis.