Oskar Minkowski possessed a rare combination of talents: He was an internist with the intuition of a scientist and the dexterity of a surgeon. One day in 1889, he and his colleague Joseph von Mering at the University of Strasbourg performed a total pancreatectomy in a dog to investigate if pancreatic enzymes were necessary to break down fatty acids in the gut. The dog survived the operation but unexpectedly developed polyuria, thirst, hunger, and glycosuria. Minkowski joined the dots to realize the link between the pancreas and diabetes (1).

This story is just one example of how surgical manipulations of anatomy can play a major role in advancing knowledge about physiology and disease. Many lessons about the functioning of the central nervous system, the pituitary gland, and the adrenals have been learned through the help of a scalpel (2), and Minkowski’s observation provided the fundamental clue that lead to the discovery of insulin by Banting and Best in 1921.

More than a century later, surgery may again provide a unique opportunity to improve our understanding of glucose homeostasis, diabetes, and β-cell growth. Readers of Diabetes will know that a number of gastrointestinal (GI) operations used to cause weight loss (bariatric surgery) has also been shown to cause remission of type 2 diabetes (T2D) (3,4) as well as improvement of hypertension and dyslipidemia (5) and reduction of cardiovascular disease and death associated with diabetes and obesity (6). The mechanisms by which these operations control diabetes have become the subject of intense research in recent years, fueled by the experimental evidence that GI bypass surgeries can induce very rapid antidiabetes effects, independent of weight loss (7).

The pathophysiology of T2D is complex but the disease is characterized by a combination of insulin resistance and defective insulin secretion that worsens over time (8); treatments of curative intent would need to address both defects. GI bypass procedures can improve insulin sensitivity and production (9,10), suggesting that the GI tract may be a “sweet spot” for diabetes treatment. In particular, Roux-en-Y gastric bypass (RYGB) restores first-phase insulin response (10) and results in hypersecretion of C-peptide and insulin following nutrient ingestion (11), suggesting enhancement of β-cell function (12). Increased β-cell mass has also been hypothesized following controversial reports of nesidioblastosis complicating RYGB (13). Other hints of an effect of GI surgery on β-cell growth derive from observations of increased PDX1 levels (14) and prevention of β-cell loss after experimental duodenal-jejunal bypass in rodents (15), as well as from case reports of heterotopic pancreatic mass after RYGB in humans (16).

Lindqvist et al. (17) add support to the hypothesis that RYGB can stimulate β-cell growth. In their study, morphometric analysis revealed a doubling of β-cell mass and islet number in four RYGB-treated pigs, studied 20 days after surgery and compared with pair-fed, sham-operated controls. Extraislet β-cells, a surrogate marker of islet neogenesis, also were more frequent after RYGB. There was a greater number of immune-reactive cells per area for both insulin (1.8-fold increase) and glucagon (1.5-fold) in RYGB pigs, although increments in mRNA expression did not achieve significance for either hormone. Immune-reactive cells for GLP-1 receptor were also 3.8-fold higher after RYGB. The authors concluded that increased β-cell mass may explain improved glucose tolerance after RYGB.

The authors acknowledged that their study has limitations. The small sample size and the choice of the porcine model, whose regulation of energy homeostasis is less well characterized than in other animal models, limit the generalizability of the findings. The use of nondiabetic animals and their failure to lose weight after RYGB also prevent the drawing of firm conclusions about the potential to induce β-cell regeneration in human insulin-deficient diabetes and on the relative importance of β-cell growth versus changes in insulin sensitivity in the remission of diabetic glycemia after RYGB. Nevertheless, their results do support the hypothesis that modifications of GI anatomy may influence the regulation of β-cell growth and highlight the importance of further research in this area.

How RYGB exerts its effects on the islets in pigs or humans remains unclear. Enhanced incretin effect after surgery may provide a straightforward explanation. In fact, in both humans and rodents, RYGB causes a three- to fourfold increase in postprandial levels of GLP-1 (11), an incretin hormone that stimulates insulin release from the pancreas and also exerts antiapoptotic effects on the β-cells (18). Increased expression of islet GLP-1 receptor after RYGB as reported by Lindqvist et al. could contribute to increased β-cell mass. However, GLP-1 responses to the intravenous glucose load used in the study are not given and the impact of RYGB on the β-cells and insulin in the islets was mirrored by effects on β-cell and glucagon, at odds with the known glucagon-suppressing effects of GLP-1 (19). Also, recent studies using mice models of functional GLP-1 deficiency, GLP-1 receptor knockout mice (20), and inhibition of GLP-1 receptor by exendin(9–39) in humans (21) call into question the role of GLP-1, suggesting that the mechanisms of action of RYGB are more complex.

RYGB excludes the duodenum and jejunum from the transit of nutrients, which seems to have specific antidiabetes effects (22,23). Given the close anatomic relationship between the duodenum and the pancreas, one cannot exclude that changes in regional/paracrine neuroendocrine mechanisms could also influence β-cell function and growth.

It is important to note that the increase in β-cell mass after RYGB occurred in normal animals and may therefore represent the result of a disruption of the physiologic control of β-cell proliferation that maintains normal β-cell mass. This is consistent with predictions made by the anti-incretin theory (24,25). This theory (Fig. 1) postulates that in addition to the well-known incretin effect (through GLP-1, glucose-dependent insulinotropic polypeptide), nutrient passage in the GI tract could also cause activation of negative feedback mechanisms (anti-incretins) to prevent postprandial hyperinsulinemic hypoglycemia. Given the antiapoptotic effects of incretins, the existence of anti-incretin mechanisms would also be necessary to prevent uncontrolled proliferation of β-cells (Fig. 1A). We note that nesidioblastosis and insulinomas are, in fact, rare. Reduction of anti-incretin signals below thresholds necessary to control incretin-driven responses would expose to the risk of hypoglycemia and uncontrolled β-cell proliferation. Inadequate anti-incretins/incretins balance due to disruption of GI continuity after RYGB might therefore explain the increase in β-cell mass seen in the study by Lindqvist et al. (17), as well as the postprandial hyperinsulinemic hypoglycemia that can complicate RYGB (26) (Fig. 1C).

Preliminary evidence in support of the anti-incretin theory comes from recent experiments showing that protein extracts from the duodenum and/or jejunum of diabetic rodents and humans induce insulin resistance in cell-based assays and in vivo (27).

Whatever the explanation, the findings that RYGB can influence regulation of β-cell growth in pigs contribute to the growing body of evidence that RYGB exerts complex and weight-independent effects on glucose homeostasis. The observation requires confirmation in other animal models and in humans, but it does support further research into GI mechanisms involved in islet regulation, as this may reveal new avenues for the treatment of type 2 and, possibly, type 1 diabetes.

Ten years ago, studies in diabetic rodents (7) provided initial evidence that GI bypass surgery exerts direct effects on glucose metabolism, suggesting that surgical manipulations of the GI tract may be an effective therapeutic approach for T2D as well as a powerful experimental tool to elucidate elusive physiology and pathophysiology of glucose homeostasis (7,24). Since then, several animal and human investigations have shown that RYGB and other procedures can improve T2D through a variety of GI mechanisms, including changes in gut hormones (18,19,21), bile acids metabolism (28), intestinal microbiota, nutrient sensing (29), and reprogramming of intestinal glucose metabolism (30). This demonstrates a critical and previously underappreciated role of the gut in glucose metabolism and underscores the importance of further research on the mechanisms of action of GI surgery. In fact, more than a century after Minkowski’s pancreatectomy, a surgical operation may once again provide a lead for important discoveries in diabetes research.

See accompanying article, Diabetes 2014;63:1665–1671.

Acknowledgments. The authors are grateful to Christin Wismann Rubino for her help with the illustration in the manuscript.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

1.
Luft
R
.
Oskar Minkowski: discovery of the pancreatic origin of diabetes, 1889
.
Diabetologia
1989
;
32
:
399
401
[PubMed]
2.
Welbourn
R
.
The History of Endocrine Surgery
.
New York
,
Praeger Publishers
,
1990
3.
Mingrone
G
,
Panunzi
S
,
De Gaetano
A
, et al
.
Bariatric surgery versus conventional medical therapy for type 2 diabetes
.
N Engl J Med
2012
;
366
:
1577
1585
[PubMed]
4.
Schauer
PR
,
Kashyap
SR
,
Wolski
K
, et al
.
Bariatric surgery versus intensive medical therapy in obese patients with diabetes
.
N Engl J Med
2012
;
366
:
1567
1576
[PubMed]
5.
Ikramuddin
S
,
Korner
J
,
Lee
WJ
, et al
.
Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial
.
JAMA
2013
;
309
:
2240
2249
[PubMed]
6.
Sjöström L, Peltonen M, Jacobson P, et al. Bariatric surgery and long-term cardiovascular events. JAMA 2012;307:56−65
7.
Rubino
F
,
Marescaux
J
.
Effect of duodenal-jejunal exclusion in a non-obese animal model of type 2 diabetes: a new perspective for an old disease
.
Ann Surg
2004
;
239
:
1
11
[PubMed]
8.
Kahn
SE
.
The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes
.
Diabetologia
2003
;
46
:
3
19
[PubMed]
9.
Bojsen-Møller
KN
,
Dirksen
C
,
Jørgensen
NB
, et al
.
Early enhancements of hepatic and later of peripheral insulin sensitivity combined with increased postprandial insulin secretion contribute to improved glycemic control after Roux-en-Y gastric bypass
.
Diabetes
2014
;
63
:
1725
1737
[PubMed]
10.
Salinari
S
,
Bertuzzi
A
,
Guidone
C
,
Previti
E
,
Rubino
F
,
Mingrone
G
.
Insulin sensitivity and secretion changes after gastric bypass in normotolerant and diabetic obese subjects
.
Ann Surg
2013
;
257
:
462
468
[PubMed]
11.
Dirksen
C
,
Bojsen-Møller
KN
,
Jørgensen
NB
, et al
.
Exaggerated release and preserved insulinotropic action of glucagon-like peptide-1 underlie insulin hypersecretion in glucose-tolerant individuals after Roux-en-Y gastric bypass
.
Diabetologia
2013
;
56
:
2679
2687
12.
Kashyap
SR
,
Bhatt
DL
,
Wolski
K
, et al
.
Metabolic effects of bariatric surgery in patients with moderate obesity and type 2 diabetes: analysis of a randomized control trial comparing surgery with intensive medical treatment
.
Diabetes Care
2013
;
36
:
2175
2182
13.
Service
GJ
,
Thompson
GB
,
Service
FJ
,
Andrews
JC
,
Collazo-Clavell
ML
,
Lloyd
RV
.
Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery
.
N Engl J Med
2005
;
353
:
249
254
[PubMed]
14.
Li
Z
,
Zhang
HY
,
Lv
LX
, et al
.
Roux-en-Y gastric bypass promotes expression of PDX-1 and regeneration of beta-cells in Goto-Kakizaki rats
.
World J Gastroenterol
2010
;
16
:
2244
2251
[PubMed]
15.
Speck
M
,
Cho
YM
,
Asadi
A
,
Rubino
F
,
Kieffer
TJ
.
Duodenal-jejunal bypass protects GK rats from beta-cell loss and aggravation of hyperglycemia and increases enteroendocrine cells coexpressing GIP and GLP-1
.
Am J Physiol Endocrinol Metab
2011
;
300
:
E923
E932
[PubMed]
16.
Guimarães
M
,
Rodrigues
P
,
Gonçalves
G
,
Nora
M
,
Monteiro
MP
.
Heterotopic pancreas in excluded stomach diagnosed after gastric bypass surgery
.
BMC Surg
2013
;
13
:
56
[PubMed]
17.
Lindqvist A
,
Spégel P, Ekelund M, et al. Gastric bypass improves β-cell function and increases β-cell mass in a porcine model
.
Diabetes
2014
;
63
:
1665
1671
18.
Lavine
JA
,
Attie
AD
.
Gastrointestinal hormones and the regulation of β-cell mass
.
Ann N Y Acad Sci
2010
;
1212
:
41
58
[PubMed]
19.
Hare
KJ
,
Vilsbøll
T
,
Asmar
M
,
Deacon
CF
,
Knop
FK
,
Holst
JJ
.
The glucagonostatic and insulinotropic effects of glucagon-like peptide 1 contribute equally to its glucose-lowering action
.
Diabetes
2010
;
59
:
1765
1770
20.
Mokadem M, Zechner JF, Margolskee RF, Drucker DJ, Aguirre V. Effects of Roux-en-Y gastric bypass on energy and glucose homeostasis are preserved in two mouse models of functional glucagon-like peptide-1 deficiency. Mol Metab 2013;3:191−201
21.
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]
22.
Salinari
S
,
le Roux
CW
,
Bertuzzi
A
,
Rubino
F
,
Mingrone
G
.
Duodenal-jejunal bypass and jejunectomy improve insulin sensitivity in Goto-Kakizaki diabetic rats without changes in incretins or insulin secretion
.
Diabetes
2014
;
63
:
1069
1078
[PubMed]
23.
Patel
RT
,
Shukla
AP
,
Ahn
SM
,
Moreira
M
,
Rubino
F
.
Surgical control of obesity and diabetes: the role of intestinal vs. gastric mechanisms in the regulation of body weight and glucose homeostasis
.
Obesity (Silver Spring)
2014
;
22
:
159
169
[PubMed]
24.
Rubino
F
,
Gagner
M
.
Potential of surgery for curing type 2 diabetes mellitus
.
Ann Surg
2002
;
236
:
554
559
[PubMed]
25.
Rubino
F
.
Is type 2 diabetes an operable intestinal disease? A provocative yet reasonable hypothesis
.
Diabetes Care
2008
;
31
(
Suppl. 2
):
S290
S296
[PubMed]
26.
Patti
ME
,
Goldfine
AB
.
Hypoglycemia after gastric bypass: the dark side of GLP-1
.
Gastroenterology
2014
;
146
:
605
608
[PubMed]
27.
Salinari
S
,
Debard
C
,
Bertuzzi
A
, et al
.
Jejunal proteins secreted by db/db mice or insulin-resistant humans impair the insulin signaling and determine insulin resistance
.
PLoS One
2013
;
8
:
e56258
[PubMed]
28.
Ryan
KK
,
Tremaroli
V
,
Clemmensen
C
, et al
.
FXR is a molecular target for the effects of vertical sleeve gastrectomy
.
Nature. 26 March
2014 [Epub ahead of print]
[PubMed]
29.
Breen
DM
,
Rasmussen
BA
,
Côté
CD
,
Jackson
VM
,
Lam
TK
.
Nutrient-sensing mechanisms in the gut as therapeutic targets for diabetes
.
Diabetes
2013
;
62
:
3005
3013
30.
Saeidi N1, Meoli L, Nestoridi E, et al. Reprogramming of intestinal glucose metabolism and glycemic control in rats after gastric bypass. Science. 2013;341:406−410
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