Glucagon-like peptide 1 (GLP-1) is considered to be the primary incretin hormone, released in response to food ingestion and contributing to meal assimilation. GLP-1 is a powerful insulin secretagogue, stimulating insulin secretion and suppressing glucagon secretion in a glucose-dependent manner (1), and indeed, numerous pharmacologic agents use the GLP-1 pathway to produce effective glucose-lowering therapy (2). Given the antidiabetogenic actions of GLP-1, it is a reasonable question to wonder whether defects in GLP-1 secretion contribute to the pathogenesis of type 2 diabetes. Over the years, multiple studies have examined this question. However, the evidence to suggest decreased GLP-1 secretion in prediabetes and diabetes has been mixed at best, with decreased (35), normal (6,7), or increased (8) GLP-1 concentrations reported in subjects with prediabetes or type 2 diabetes.

Subsequently, Nauck et al. (9) undertook a meta-analysis of studies comparing active and total GLP-1 in people with diabetes and weight-matched control subjects and concluded that after an oral glucose challenge or after a mixed meal, the integrated, incremental concentrations of GLP-1 did not differ between patients with type 2 diabetes and control subjects. GLP-1 concentrations were unaffected by weight or age. In addition, we examined active and total GLP-1 concentrations in 165 subjects with varying degrees of glucose tolerance and demonstrated that integrated GLP-1 concentrations were not significantly associated with glucose tolerance or with indices of insulin secretion and action. We concluded that defects in postprandial GLP-1 secretion do not play a significant role in the pathogenesis of prediabetes (10).

This state of affairs has been challenged by the work of Færch et al. (11) who report in this issue of Diabetes that the GLP-1 response to an oral glucose challenge is reduced in a large cohort of subjects who have prediabetes, diabetes, and obesity. The subjects underwent a 75-g oral glucose tolerance test, during which glucose, insulin, and GLP-1 concentrations were measured at three time points. As expected, glucose intolerance and overt type 2 diabetes were associated with decreased insulin and higher glucose concentrations. At 120 min in men, GLP-1 concentrations were decreased in subjects with prediabetes and type 2 diabetes; however, this did not result in differences in integrated GLP-1 concentrations. The other notable findings were an increase in postchallenge concentrations of GLP-1 in women despite adjustment for weight and decreased fasting GLP-1 concentrations in overweight and obese subjects. Other correlations included an inverse relationship between 30-min glucose and GLP-1 concentrations. Contrary to prior reports, GLP-1 was positively associated with insulinogenic, insulin sensitivity, and disposition indices.

There are several caveats associated with these findings (Fig. 1). The temporal course of hormonal concentrations as well as the absolute concentrations at a given time point is the result of two net processes—secretion and clearance. This is especially important with hormones that undergo clearance prior to appearing in the systemic circulation. In the latter category, insulin-based measures of insulin secretion are confounded by first-pass hepatic insulin extraction, which, in part, is affected by glucose tolerance status, thereby introducing a systematic error in the measurement of β-cell function (12). Indeed, although defects in insulin secretion are present in prediabetes and diabetes, it would be a mistake to conclude on the basis of a cross-sectional study that decreased GLP-1 secretion is the cause of decreased insulin secretion.

Figure 1

Defective response to insulin secretagogues may arise from A) decreased concentrations of a given secretagogue, B) loss of β-cell responsiveness to that secretagogue (defective sensing), or C) a partial inability of β-cells to secrete insulin in response to stimulation.

Figure 1

Defective response to insulin secretagogues may arise from A) decreased concentrations of a given secretagogue, B) loss of β-cell responsiveness to that secretagogue (defective sensing), or C) a partial inability of β-cells to secrete insulin in response to stimulation.

Close modal

The other caveat relates to the time course of GLP-1 concentrations in the circulation, which reflect nutrient appearance in the proximal small intestine. Typically, a liquid challenge empties quite rapidly, with the most significant changes in GLP-1 concentrations occurring over the first 45 min after ingestion (13). The sparse sampling schedule used by Færch et al. assumes that GLP-1 concentrations at 30 min are equivalent to GLP-1 secretion. This is clearly subject to the vagaries of gastric emptying and fasting gastric volumes that determine liquid gastric emptying. A more frequent sampling schedule may have provided a better characterization of postchallenge GLP-1 and insulin concentrations.

Undoubtedly, enteroendocrine hormone concentrations can be affected by factors other than intraluminal nutrient. For example, raising active concentrations of GLP-1 and gastric inhibitory polypeptide by inhibiting dipeptidyl peptidase-4 actually decreases the secretion of these hormones by L and K cells, respectively (14). Conversely, blockade of the GLP-1 receptor increases postprandial GLP-1 concentrations (15). Association of fasting GLP-1 concentrations with glucagon concentrations is another observation whose significance remains uncertain (7,10). Similarly, the association of GLP-1 concentrations with obesity and insulin resistance also observed in this cohort but not in others (10) requires further study.

Finally, when examining the role of GLP-1 in the pathogenesis of diabetes, it is important to consider the nature of the β-cell defect present (Fig. 1). Diabetes and prediabetes are characterized by a defective β-cell response to glucose and likely other secretagogues, such as arginine, glucagon, and incretin hormones. Although a mechanistic model to describe the contribution of intravenous GLP-1 infusion to β-cell secretion has been described, it has yet to be applied to an oral challenge where the β-cell is responding to multiple stimuli (16). It remains to be ascertained whether a defective response to one secretagogue is emblematic of a failure of the β-cell or a selective inability to respond to one but not to other secretagogues. Longitudinal prospective studies will be required to determine the contributions of decreased incretin secretion and specific defects in the incretin response (if any) to the pathogenesis of diabetes.

See accompanying article, p. 2513.

Funding. The authors acknowledge the support of the Mayo Clinic Clinical and Translational Science Award grant (RR24150). The authors are supported by grants from the National Institutes of Health (DK78646 and DK82396).

Duality of Interest. A.V. has been the recipient of investigator-initiated grants from Merck, Novartis, Daiichi Sankyo, and GI Dynamics in the past 5 years. He has consulted for XOMA, Sanofi, Bristol-Myers Squibb, Novartis, and Genentech in the past 5 years. No other potential conflicts of interest relevant to this article were reported.

1.
Nauck
MA
,
Kleine
N
,
Orskov
C
,
Holst
JJ
,
Willms
B
,
Creutzfeldt
W
.
Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients
.
Diabetologia
1993
;
36
:
741
744
[PubMed]
2.
Drucker
DJ
,
Nauck
MA
.
The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes
.
Lancet
2006
;
368
:
1696
1705
[PubMed]
3.
Laakso
M
,
Zilinskaite
J
,
Hansen
T
, et al.;
EUGENE2 Consortium
.
Insulin sensitivity, insulin release and glucagon-like peptide-1 levels in persons with impaired fasting glucose and/or impaired glucose tolerance in the EUGENE2 study
.
Diabetologia
2008
;
51
:
502
511
[PubMed]
4.
Muscelli
E
,
Mari
A
,
Natali
A
, et al
.
Impact of incretin hormones on beta-cell function in subjects with normal or impaired glucose tolerance
.
Am J Physiol Endocrinol Metab
2006
;
291
:
E1144
E1150
[PubMed]
5.
Toft-Nielsen
MB
,
Damholt
MB
,
Madsbad
S
, et al
.
Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients
.
J Clin Endocrinol Metab
2001
;
86
:
3717
3723
[PubMed]
6.
Ahrén
B
,
Larsson
H
,
Holst
JJ
.
Reduced gastric inhibitory polypeptide but normal glucagon-like peptide 1 response to oral glucose in postmenopausal women with impaired glucose tolerance
.
Eur J Endocrinol
1997
;
137
:
127
131
[PubMed]
7.
Vollmer
K
,
Holst
JJ
,
Baller
B
, et al
.
Predictors of incretin concentrations in subjects with normal, impaired, and diabetic glucose tolerance
.
Diabetes
2008
;
57
:
678
687
[PubMed]
8.
Faerch
K
,
Vaag
A
,
Holst
JJ
,
Glümer
C
,
Pedersen
O
,
Borch-Johnsen
K
.
Impaired fasting glycaemia vs impaired glucose tolerance: similar impairment of pancreatic alpha and beta cell function but differential roles of incretin hormones and insulin action
.
Diabetologia
2008
;
51
:
853
861
[PubMed]
9.
Nauck
MA
,
Vardarli
I
,
Deacon
CF
,
Holst
JJ
,
Meier
JJ
.
Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down?
Diabetologia
2011
;
54
:
10
18
[PubMed]
10.
Smushkin
G
,
Sathananthan
A
,
Man
CD
, et al
.
Defects in GLP-1 response to an oral challenge do not play a significant role in the pathogenesis of prediabetes
.
J Clin Endocrinol Metab
2012
;
97
:
589
598
[PubMed]
11.
Færch
K
,
Torekov
SS
,
Vistisen
D
, et al
.
GLP-1 response to oral glucose is reduced in prediabetes, screen-detected type 2 diabetes, and obesity and influenced by sex: the ADDITION-PRO study
.
Diabetes
2015
;
64
:
2513
2525
[PubMed]
12.
Sathananthan
A
,
Dalla Man
C
,
Zinsmeister
AR
, et al
.
A concerted decline in insulin secretion and action occurs across the spectrum of fasting and postchallenge glucose concentrations
.
Clin Endocrinol (Oxf)
2012
;
76
:
212
219
[PubMed]
13.
Bredenoord
AJ
,
Chial
HJ
,
Camilleri
M
,
Mullan
BP
,
Murray
JA
.
Gastric accommodation and emptying in evaluation of patients with upper gastrointestinal symptoms
.
Clin Gastroenterol Hepatol
2003
;
1
:
264
272
[PubMed]
14.
Bock
G
,
Dalla Man
C
,
Micheletto
F
, et al
.
The effect of DPP-4 inhibition with sitagliptin on incretin secretion and on fasting and postprandial glucose turnover in subjects with impaired fasting glucose
.
Clin Endocrinol (Oxf)
2010
;
73
:
189
196
[PubMed]
15.
Shah
M
,
Law
JH
,
Micheletto
F
, et al
.
Contribution of endogenous glucagon-like peptide 1 to glucose metabolism after Roux-en-Y gastric bypass
.
Diabetes
2014
;
63
:
483
493
[PubMed]
16.
Dalla Man
C
,
Micheletto
F
,
Sathananthan
A
,
Rizza
RA
,
Vella
A
,
Cobelli
C
.
A model of GLP-1 action on insulin secretion in nondiabetic subjects
.
Am J Physiol Endocrinol Metab
2010
;
298
:
E1115
E1121
[PubMed]