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30 Endocrine and metabolic diseases

Figure 1

(a)

(b)

Current Opinion in Pharmacology

(a) For vertical sleeve gastrectomy approximately 75% of the stomach is removed leaving a sleeve-shaped stomach with a capacity ranging from
about 60 to 150 cc. (b) For RYGB, the stomach is divided into a small pouch ( 30 ml), the small intestine is divided 50 cm from the pylorus, and
the distal limb of the small intestine (Roux or alimentary limb) is directly connected to the gastric pouch. The gastric remnant and isolated 50 cm
of small intestine (‘biliopancreatic limb’) is connected to the jejunum 150 cm distal to the gastrojejunal anastomosis. The small intestine distal to
the anastomosis is called the common limb.

procedure, possibly resulting in a similar distal nutrient
exposure as RYGB [7,8].
An additional hypothesis is that a modification of the
number, the location or the sensitivity of enteroendocrine
cells could contribute to the modified hormonal response.
Accordingly, the intestinal adaptation following RYGB is
characterized by a hypertrophy of the Roux limb associated with local increase in the number of several enteroendocrine cells, including CCK-producing, GLP-1-producing, GIP-producing and PYY-producing cells [9–
13,14 ]. Enteroendocrine cell distribution has also been
examined in rats after VSG in two recent reports but
showed conflicting results. In the first study, Mumphrey
et al. reported that GLP-1 cell numbers remained constant three month after VSG surgery [15]. Yet, in the
second study, the number and density of GLP-1 cells
were found to increase 14 days after surgery [14 ].
However, we must note that a change in the number
or density of a specific enteroendocrine cell type is not
necessarily associated with a change in plasma concentrations of the corresponding produced hormones. A recent
study identified two different responses in mice fed a
high-fat diet [16 ]: some maintained normal blood glucose levels and others developed hyperglycemia and
insulin resistance with the same weight gain. The former
had an L-cell density and number comparable to mice
under control diet but an increase in GLP-1 secretion
during a glucose tolerance test. On the contrary, the latter
mice displayed an increase in the number of GLP-1Current Opinion in Pharmacology 2017, 37:29–34

producing cells but secreted less GLP-1 during the glucose tolerance test suggesting a functional alteration of
these cells. In that case, the increase of L-cell numbers
probably constitutes an attempt to compensate for their
functional alteration [17 ,16 ].
These observations raise the question of the existence of
additional signals influencing enteroendocrine cell function beyond nutrients such as glucose or fatty acids that
are known to stimulate hormone production [18,19].
Specific microbiota for instance may be at play. Some
pharmacological treatments today consist in using hormone mimetics as GLP1 receptor agonists or DDPIV
inhibitors that are largely used in patients with type
2 diabetes. GLP-1 receptor agonists appear to lower blood
glucose to a greater extent and promote more weight loss
than DPP-4 inhibitors, which are weight neutral [20] but
GLP-1 receptor agonists are administered by subcutaneous injections, which could potentially reduce compliance among patients. An interesting idea would be to
target the endogenous secretion of GLP1 per
os. Currently, measuring enteroendocrine cells’ sensitivity to nutrients remain a challenge; nevertheless, there is
promise in the development of enteroids from human
biopsies for evaluating nutrient sensitivity [21,22].
Intestinal glucose consumption and metabolism

Recent evidence illustrated an association between
hyperplasia of the alimentary Roux limb after RYGB
and a reprogramming of glucose metabolism in intestinal
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