Diabetes Volume 64, March 2015

715

Bo Ahrn

Hepato-Incretin Function of
GLP-1: Novel Concept and
Target in Type 1 Diabetes
Diabetes 2015;64:715717 | DOI: 10.2337/db14-1671

streptozotocin administration to GLP-1 receptor knockout mice were markedly increased by administration
of a high-afnity glucagon receptor antibody. Thus, loss
of GLP-1 action increases glucose levels and worsens glucose tolerance in insulin-decient mice with no glucagon
action. These results are similar to a recent nding that
glucose levels are elevated by administering the GLP-1
receptor antagonist exendin(9-39) to glucagon receptor
knockout mice that have been rendered insulinopenic by
streptozotocin (13). Jun et al. (10) proceeded further,
however, by examining endogenous glucose production.
This was increased in mice that lacked both glucagon
and GLP-1 receptors after destruction of b-cells with
streptozotocin. Taken together, the results from this interesting study support the idea that the resistance of
glucagon receptor knockout mice to streptozotocininduced diabetes is partially explained by GLP-1. This
occurs through an insulin-independent action of this hormone that inhibits endogenous glucose production.
The strength of this article is the visionary and
innovative use of a double knockout of both glucagon
and GLP-1 receptors. An obvious limitation of the study is
that it is undertaken in animals, highlighting the need for
carefully designed human studies to explore the potential
of such an important action of GLP-1 in humans.
The ndings of this study have three exciting implications. First, direct suppression of endogenous glucose
production by GLP-1 provides a mechanism for a rapid
inhibition of endogenous glucose production after meal
ingestion. The initial shutoff of liver glucose production
after meals may therefore be not only a consequence of
islet hormonal actions but also instituted by GLP-1
reaching the liver after meal ingestion. If so, this would
ensure very tight regulation of hepatic glucose production
after meals, such that meal size, through GLP-1, regulates
inhibition of hepatic glucose production.

Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund,

Sweden

2015 by the American Diabetes Association. Readers may use this article as
long as the work is properly cited, the use is educational and not for prot, and
the work is not altered.

Corresponding author: Bo Ahrn, bo.ahren@med.lu.se.

See accompanying article, p. 819.

COMMENTARY

The liver is a key player in glucose regulation, and several

factors are involved in this regulation (1). Glucagon, autonomic nerves, and the adrenals stimulate hepatic glucose production to allow sufcient brain glucose delivery.
Insulin inhibits hepatic glucose production, preventing
excess hepatic glucose release. This is of particular importance after meals, as is evident from the negative correlation between early insulin response after meals and
postprandial glucose (2). Therefore, low insulin and high
glucagon levelssuch as observed in type 1 and type 2
diabetessustain liver glucose production, thereby resulting in postprandial and fasting hyperglycemia. Thus, reducing hepatic glucose production is an important target
in the treatment of diabetes (3).
The incretin hormone GLP-1 inhibits hepatic glucose
production through its ability to stimulate insulin secretion and inhibit glucagon secretion (4). As GLP-1 is released after meal ingestion in proportion to meal size (5),
this effect allows meal-dependent inhibition of hepatic glucose production. However, GLP-1 may also inhibit endogenous glucose production through an islet-independent
mechanism (69). This allows not only a rapid shutoff of endogenous glucose production after meal ingestion but also
incretin therapy to be potent in insulin-decient diabetes.
A study in the current issue of Diabetes presents convincing evidence for such an islet-independent inhibition
of endogenous glucose production by GLP-1 (10). The
study by Jun et al. (10) leveraged the unique glucagon
receptor mouse knockout model. These mice had low
baseline glucose levels, favorable glucose tolerance, hyperglucagonemia, and a-cell hyperplasia (11). They were also
resistant to induction of insulin-decient diabetes (12).
The new study showed that glucose levels were enhanced
when the b-cells were chemically destroyed by streptozotocin in mice with genetic deletion of both glucagon and
GLP-1 receptors (10). Furthermore, glucose levels after

716

Commentary

Second, the study provides a mechanism for a glucoselowering action of incretin therapy in type 1 diabetes.
GLP-1 receptor agonists, liraglutide and exenatide
(14,15), and the dipeptidyl peptidase-4 inhibitor vildagliptin (16) have demonstrated glucose-reducing effects
in type 1 diabetes, which have been thought to be
mainly due to inhibition of glucagon levels. In fact,
the rst evidence of reduced glucagon levels by GLP-1
in type 1 diabetes was reported more than 20 years ago
(17). However, the results of the current study suggest
that inhibition of endogenous glucose production independent of glucagon may be an additional mechanism
of GLP-1.
Third, and perhaps the most exciting implication of this
study, incretin therapy may be combined with glucagon
antagonism for a powerful glucose-lowering strategy in
type 1 diabetes. This would allow the use of submaximal
doses of the two strategies, resulting in maximal hepatic
glucose production and avoidance of adverse events (3).
However, it is still important to explore the mechanism of the islet-independent action of GLP-1 to inhibit
endogenous glucose production. The mechanism could be
a direct effect on hepatocytes, although this is unlikely as
there is no robust demonstration of GLP-1 receptors in
these cells. It is therefore more likely that the effect is
executed through the autonomic nerves. It has been
shown that GLP-1 receptors are expressed both in the
nodose ganglia and in nerve terminals innervating portal
vein autonomic nerves (18). This may initiate neural
responses, contributing to not only stimulated insulin

Figure 1GLP-1 is released from the gut after meal ingestion and
inhibits hepatic glucose release by the dual islet effects to stimulate insulin secretion and inhibit glucagon secretion (4) and neuroincretin mechanisms (19). Previous suggestions of an additional,
islet-independent, mechanism gained further support in the study
by Jun et al. (10). This islet-independent mechanism of GLP-1 to
restrain endogenous glucose production may be executed by
a direct liver effect and/or an indirect effect through neural afferents passing through the central nervous system.

Diabetes Volume 64, March 2015

secretionthe neuro-incretin effect (19)but also inhibition of hepatic glucose production. Indeed, central activation of GLP-1 receptors inhibits endogenous glucose
production through neural effects (20). Further analyses
of neural contribution to hepatic effects of GLP-1 can be
performed by examining denervated and autonomic
blocking models in humans and animals as well as in
animals with targeted neuronal GLP-1 receptor knockout.
In humans, studies on effects of GLP-1 on hepatic glucose
production during various portal insulin-to-glucagon ratios are also warranted.
In summary, this novel study by Jun et al. (10) shows
important synergistic contributions of GLP-1 receptor
agonism and glucagon receptor antagonism to prevent
hyperglycemia in the setting of insulin deciency. Based
on the new data, it may be proposed that a hepato-incretin
function of GLP-1 exists, as is illustrated in Fig. 1. Such
a potential hepato-incretin function of GLP-1 is of great
interest both for the understanding of the physiology of
GLP-1 and the potential utility of incretin therapy in both
type 1 and type 2 diabetes.
Duality of Interest. B.A. has consulted for Novartis, GlaxoSmithKline,
Merck, Sano, Novo Nordisk, Boehringer Ingelheim, and Takeda and has received lecture fees from Novartis, Merck, Novo Nordisk, Sano, Bristol-Myers
Squibb, AstraZeneca, and GlaxoSmithKline, which all are companies producing
dipeptidyl peptidase-4 inhibitors or GLP-1 receptor agonists. No other potential
conicts of interest relevant to this article were reported.
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