NATURE REVIEWS | ENDOCRINOLOGY VOLUME 10 | FEBRUARY 2014 | 73

YEAR IN REVIEW

TYPE 2 DIABETES MELLITUS IN 2013

A central role of the gut in glucose homeostasisGeltrude Mingrone and Lidia Castagneto‑Gissey

Metabolic surgery has been proven to be effective in inducing remission of type 2 diabetes mellitus prior to any significant weight reduction. Studies in 2013 have investigated the mechanisms of action of these procedures and have highlighted a central role of the small intestine in the effects on glucose homeostasis.Mingrone, G. & Castagneto-Gissey, L. Nat. Rev. Endocrinol. 10, 73–74 (2014); published online 10 December 2013; doi:10.1038/nrendo.2013.241

A peculiar characteristic of bariatric surgery for the treatment of obesity is that glucose disposal improves before any significant weight loss has occurred. Indeed, random­ized controlled studies have confirmed that bariatric surgery is effective in inducing remission of type 2 diabetes mellitus.1,2 To highlight the metabolic implications, espe­cially on glucose homeostasis, of some of these operations, they are increasingly being referred to as ‘metabolic surgery’. Discerning the mechanisms underlying the metabolic effects of these procedures is crucial, so that a drug might be developed that repro­duces the actions on insulin sensitivity, ob viating the need for invasive surgery.

Clinical studies have highlighted changes in the levels of circulating gastrointestinal hormones, such as glucagon­like peptide 1 (GLP­1) and ghrelin, as possible mecha­nisms of action. GLP­1, which is secreted by the intestinal L cells in response to nutri­ent stimulation, inhibits hepatic glucose production, probably through the inhibi­tion of glucagon secretion. In addition, this hormone increases insulin secretion in a dose­dependent manner. Circulating levels of GLP­1 increase markedly after certain types of metabolic surgery, such as Roux­en­Y gastric bypass (RYGB). Hence, it was proposed that GLP­1 hypersecretion mediate the effects on glucose homeostasis exerted by this procedure. However, studies published in 2013 have disproven this hypothesis, at least in rodents. What these studies do show is a direct effect of the gastrectomy or the exclusion of some tracts of the small intestine on glycaemic control.

In 2013, Wilson­Pérez et al.3 performed vertical sleeve gastrectomy in GLP­1 recep­tor wild­type and knockout mice. After the surgery, the GLP­1 response to a mixed meal administered by gavage was similar in the two groups of animals, that is, GLP­1 secre­tion was not impaired in mice with dis rupted GLP­1 receptor signalling. Subsequently,

wild­type and knockout mice were placed on a high­fat, butter­based diet for 5 weeks, after which researchers measured glucose disposal following a mixed meal. Both mouse strains showed comparable blood glucose levels that were much lower than those of sham­operated mice.3 These results suggest that the effects of meta bolic surgery on glucose disposal are not mediated by GLP­1, as in fact vertical sleeve gastrectomy effectively improved gly­caemic control also in the absence of GLP­1 receptors. Similarly, Chambers et al.4 showed that vertical sleeve gastrectomy is effective in improving glucose tolerance in wild­type and in ghrelin knockout mice exposed to a high­fat diet for 10 weeks before surgery. In other words, the dramatic reduction of circu­lating levels of ghrelin in knockout animals did not translate into the benefits of metabolic surgery on glucose disposal.

The gastric bypass comprises the crea­tion of a gastric pouch anastomosed to the jejunum immediately after the Treitz ligament, which is also known as the sus­pensory muscle of the duodenum. The continuity of biliopancreatic secretions is reconstructed in rats by anastomizing the biliopancreatic limb to the alimentary limb of the small bowel 15 cm distal to the gastrojejunal anastomosis in a Roux­en­Y fashion. This intestinal tract represents the Roux limb. In 2013, Saeidi et al.5 studied the metabolic profile after RYGB in rats with diet­induced obesity, in rats with diabetes mellitus induced by streptozotocin injec­tion and in Goto­Kakizaki rats, a substrain of nonobese Wistar rats that spontaneously develops type 2 diabetes mellitus early in life. The researchers found that the Roux limb showed intense glucose uptake and utiliza­tion, as measured by 18F­FDG­PET–CT in all three animal models.5 In addition, expres­sion of glucose transporter 1 (GLUT­1; also known as SLC2A1) was increased in the Roux limb, which might have contributed to the observed increased glucose uptake and utilization.5 Mucosa cells within the Roux limb showed hypertrophy and hyper­plasia with enhanced aerobic glycolysis to meet the increased energy demand arising from the exposure of the distal jejunum to un digested food.5 In addition, in a separate group of diet­induced obese and nonobese, diabetic rats, a transected loop of the jejunum transposed between the oesophagus and the stomach demonstrated the same morpho­logic and functional adaptations observed after RYGB.5 These findings support a role for reprogramming and remodelling of the small intestine as the cause underlying

Hypothalamus

Jejunum

Hepatic glucose production

Duodenum

Ileum

?

Peripheral glucose uptake

Nutrient sensor

??

Figure 1 | Activation of the gut–brain–liver neuronal axis under glucose and/or lipid stimulation via a nutrient sensor located in the proximal jejunum. By delivering undigested food into the mid-jejunum, the bypass of the duodenum and the proximal jejunum, as performed in the Roux-en-Y gastric bypass, might determine the improvement of hepatic insulin resistance, with subsequent reduction of hepatic glucose production. The bypass of the entire jejunum, by contrast, might abolish or drastically reduce the secretion of intestinal hormones that induce peripheral insulin resistance, thus normalizing insulin sensitivity, as observed after biliopancreatic diversion.

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the improvement of type 2 diabetes mellitus fo llowing metabolic surgery.

In 2013, our group showed that the duode­num and the jejunum of diabetic db/db mice secrete proteins of 10–100 kDa in size that can induce insulin resistance in normal mice and inhibit insulin signalling in vitro in rat skeletal muscle cells.6 Similar results were obtained using human myoblasts incubated with proteins secreted from jejunal biopsy samples from insulin­resistant, but not from insulin­sensitive, individuals.6 These secreted proteins acted by stimulating the mammalian target of rapamycin complex 2 (mTORC2),6 which is a serine/threonine kinase composed of mTOR, the rapamycin­insensitive companion of mTOR (known as RICTOR), the TORC subunit LST8, and the TORC2 subunit MAPKAP1.

mTORC2 catalyses the phosphorylation of AKT, also known as protein kinase B, at the hydrophobic motif site (Ser473). In human myoblasts and in rat myocytes, AKT regulates cellular trafficking of the glucose transporter GLUT­4. Maximal activity of AKT is achieved when the molecule is phosphory lated on both Thr308 and Ser473 residues,7 which enables the translocation of GLUT­4 to the plasma membrane in skeletal muscle and adipose tissue. Muscle­specific Rictor knockout mice exhibit moderately decreased insulin­ stimulated glucose uptake and glucose intol­erance,8 but not overt type 2 diabetes mellitus. In fact, in these animals, the phosphoryla­tion of AKT at Thr308 alone is able to acti­vate GLUT­4 translocation and is sufficient to mediate the phosphorylation of down­stream targets.8 The secreted 10–100 kDa gut proteins enhance AKT phosphoryla­tion of Ser473 whereas they inhibit that of Thr308 in vitro, thereby reducing trafficking

of GLUT­4 to the cell membrane.6 Increased Ser473 AKT phosphorylation is a typical feature of cancer tissues,9 a disease classically associated with insulin resistance. The effect of secreted gut proteins is reversible after washout of the cells,6 which indicates that this process is mediated by membrane receptors. Taken together, these findings suggest that specific secreted jejunal proteins can impair insulin signalling (Figure 1).

Previously, Breen et al. suggested the pres­ence of a jejunal nutrient sensor, which could explain the early improvement of plasma glucose levels after duodenal and proximal jejunal bypass in decompensated diabetes mellitus of nonobese rat models.10 Altogether the reports published in 2013 support this hypothesis. Bypassing the duodenum and a very proximal portion of the jejunum, as is achieved by RYGB, might stimulate a jejunal nutrient sensor, probably via a neuronal pathway, and thereby trigger a reduction in hepatic glucose production. By contrast, exclusion of the duodenum, entire jejunum and the first portion of the ileum from the nutrient transit, for example, by bilio­pancreatic diversion, might inhibit the secre­tion of intestinal hormones that can induce insulin resistance.

The discoveries in 2013 regarding the mec hanisms of action of metabolic surgery on insulin resistance and type 2 dia betes mel­litus should foster further intense research devoted to identifying the neuronal path­way(s) involved and to characterizing the still unidentified intestinal hormones that induce insulin resistance. We are in fact hopeful that a new medical approach will be found in the future that therapeutically mimics the action of metabolic surgery on diabetes remission.

Key advances

■ Diabetes remission after metabolic surgery is not mediated by glucagon-like peptide 1, at least in rodents3

■ Glycaemic control is achieved after metabolic surgery even in the absence of ghrelin4

■ Exposure of the distal jejunum to undigested food results in hypertrophy and hyperplasia of the mucosa and in overexpression of the glucose transporter GLUT-1, which increases glucose uptake and utilization and contributes to the improvement of glucose metabolism after bariatric surgery5

■ Bypass of the duodenum and the whole jejunum may reduce the secretion of proteins able to impair insulin action both in vivo and in vitro6

Department of Internal Medicine, Catholic University of Rome, Largo A. Gemelli 8, 00168 Rome, Italy (G. Mingrone). Department of Surgery, Università La Sapienza, Viale Regina Elena 324, 00195 Rome, Italy (L. Castagneto-Gissey). Correspondence to: G. Mingrone gmingrone@rm.unicatt.it

Competing interestsThe authors declare no competing interests.

1. Mingrone, G. et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N. Engl. J. Med. 366, 1577–1585 (2012).

2. Schauer, P. R. et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N. Engl. J. Med. 366, 1567–1576 (2012).

3. Wilson-Pérez, H. E. et al. Vertical sleeve gastrectomy is effective in two genetic mouse models of glucagon-like peptide 1 receptor deficiency. Diabetes 62, 2380–2385 (2013).

4. Chambers, A. P. et al. The effects of vertical sleeve gastrectomy in rodents are ghrelin independent. Gastroenterology 144, 50–52 (2013).

5. Saeidi, N. et al. Reprogramming of intestinal glucose metabolism and glycemic control in rats after gastric bypass. Science 341, 406–410 (2013).

6. Salinari, S. et al. Jejunal proteins secreted by db/db mice or insulin-resistant humans impair the insulin signaling and determine insulin resistance. PLoS ONE 8, e56258 (2013).

7. Whiteman, E. L., Cho, H. & Birnbaum, M. J. Role of Akt/protein kinase B in metabolism. Trends Endocrinol. Metab. 13, 444–451 (2002).

8. Kumar, A. et al. Muscle-specific deletion of rictor impairs insulin-stimulated glucose transport and enhances basal glycogen synthase activity. Mol. Cell Biol. 28, 61–70 (2008).

9. Godsland, I. F. Insulin resistance and hyperinsulinaemia in the development and progression of cancer. Clin. Sci. (Lond.) 118, 315–332 (2009).

10. Breen, D. M. et al. Jejunal nutrient sensing is required for duodenal–jejunal bypass surgery to rapidly lower glucose concentrations in uncontrolled diabetes. Nat. Med. 18, 950–955 (2012).

METABOLISM IN 2013

The gut microbiota manages host metabolismPatrice D. Cani

In 2013, studies in rodents and humans have reaffirmed the essential role of the gut microbiota in host metabolism. More importantly, several converging results have increased our knowledge regarding the taxa and functions of the gut microbiota that contribute to the management of energy homeostasis, glucose metabolism and metabolic inflammation.Cani, P. D. Nat. Rev. Endocrinol. 10, 74–76 (2014); published online 10 December 2013; doi:10.1038/nrendo.2013.240

Over the past decade, it has become clear that the inhabitants of our gut, the gut micro biota, must be considered as a novel

partner that is involved in the numerous interactions between our own organs.1 A few years ago, an exciting advance in the field

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