David E. Cummings

Central nervous system control of food intake and body weight

The capacity to adjust food intake in response to changing energy requirements is essential for survival. Recent progress has provided an insight into the molecular, cellular and behavioural mechanisms that link changes of body fat stores to adaptive adjustments of feeding behaviour. The physiological importance of this homeostatic control system is highlighted by the severe obesity that results from dysfunction of any of several of its key components. This new information provides a biological context within which to consider the global obesity epidemic and identifies numerous potential avenues for therapeutic intervention and future research.

Gastrointestinal regulation of food intake

Despite substantial fluctuations in daily food intake, animals maintain a remarkably stable body weight, because overall caloric ingestion and expenditure are exquisitely matched over long periods of time, through the process of energy homeostasis. The brain receives hormonal, neural, and metabolic signals pertaining to body-energy status and, in response to these inputs, coordinates adaptive alterations of energy intake and expenditure. To regulate food consumption, the brain must modulate appetite, and the core of appetite regulation lies in the gut-brain axis. This Review summarizes current knowledge regarding the neuroendocrine regulation of food intake by the gastrointestinal system, focusing on gastric distention, intestinal and pancreatic satiation peptides, and the orexigenic gastric hormone ghrelin. We highlight mechanisms governing nutrient sensing and peptide secretion by enteroendocrine cells, including novel taste-like pathways. The increasingly nuanced understanding of the mechanisms mediating gut-peptide regulation and action provides promising targets for new strategies to combat obesity and diabetes.

The Mechanism of Diabetes Control After Gastrointestinal Bypass Surgery Reveals a Role of the Proximal Small Intestine in the Pathophysiology of Type 2 Diabetes

Summary Background Data:Most patients who undergo Roux-en-Y gastric bypass (RYGB) experience rapid resolution of type 2 diabetes. Prior studies indicate that this results from more than gastric restriction and weight loss, implicating the rearranged intestine as a primary mediator. It is unclear, however, if diabetes improves because of enhanced delivery of nutrients to the distal intestine and increased secretion of hindgut signals that improve glucose homeostasis, or because of altered signals from the excluded segment of proximal intestine. We sought to distinguish between these two mechanisms. Methods:Goto-Kakizaki (GK) type 2 diabetic rats underwent duodenal-jejunal bypass (DJB), a stomach-preserving RYGB that excludes the proximal intestine, or a gastrojejunostomy (GJ), which creates a shortcut for ingested nutrients without bypassing any intestine. Controls were pair-fed (PF) sham-operated and untreated GK rats. Rats that had undergone GJ were then reoperated to exclude the proximal intestine; and conversely, duodenal passage was restored in rats that had undergone DJB. Oral glucose tolerance (OGTT), food intake, body weight, and intestinal nutrient absorption were measured. Results:There were no differences in food intake, body weight, or nutrient absorption among surgical groups. DJB-treated rats had markedly better oral glucose tolerance compared with all control groups as shown by lower peak and area-under-the-curve glucose values (P < 0.001 for both). GJ did not affect glucose homeostasis, but exclusion of duodenal nutrient passage in reoperated GJ rats significantly improved glucose tolerance. Conversely, restoration of duodenal passage in DJB rats reestablished impaired glucose tolerance. Conclusions:This study shows that bypassing a short segment of proximal intestine directly ameliorates type 2 diabetes, independently of effects on food intake, body weight, malabsorption, or nutrient delivery to the hindgut. These findings suggest that a proximal intestinal bypass could be considered for diabetes treatment and that potentially undiscovered factors from the proximal bowel might contribute to the pathophysiology of type 2 diabetes.

Ghrelin and the short- and long-term regulation of appetite and body weight.

Ghrelin, an acylated upper gastrointestinal peptide, is the only known orexigenic hormone. Considerable evidence implicates ghrelin in mealtime hunger and meal initiation. Circulating levels decrease with feeding and increase before meals, achieving concentrations sufficient to stimulate hunger and food intake. Preprandial ghrelin surges occur before every meal on various fixed feeding schedules and also among individuals initiating meals voluntarily without time- or food-related cues. Ghrelin injections stimulate food intake rapidly and transiently, primarily by increasing appetitive feeding behaviors and the number of meals. Preprandial ghrelin surges are probably triggered by sympathetic nervous output. Postprandial suppression is not mediated by nutrients in the stomach or duodenum, where most ghrelin is produced. Rather, it results from post-ingestive increases in lower intestinal osmolarity (information probably relayed to the foregut via enteric nervous signaling), as well as from insulin surges. Consequently, ingested lipids suppress ghrelin poorly compared with other macronutrients. Beyond a probable role in meal initiation, ghrelin also fulfills established criteria for an adiposity-related hormone involved in long-term body-weight regulation. Ghrelin levels circulate in relation to energy stores and manifest compensatory changes in response to body-weight alterations. Ghrelin crosses the blood-brain barrier and stimulates food intake by acting on several classical body-weight regulatory centers, including the hypothalamus, hindbrain, and mesolimbic reward system. Chronic ghrelin administration increases body weight via diverse, concerted actions on food intake, energy expenditure, and fuel utilization. Congenital ablation of the ghrelin or ghrelin-receptor gene causes resistance to diet-induced obesity, and pharmacologic ghrelin blockade reduces food intake and body weight. Ghrelin levels are high in Prader-Willi syndrome and low after gastric bypass surgery, possibly contributing to body-weight alterations in these settings. Extant evidence favors roles for ghrelin in both short-term meal initiation and long-term energy homeostasis, making it an attractive target for drugs to treat obesity and/or wasting disorders.

Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens

Ghrelin, a powerful orexigenic peptide released from the gut, stimulates feeding when injected centrally and has thus far been implicated in regulation of metabolic, rather than hedonic, feeding behavior. Although ghrelins effects are partially mediated at the hypothalamic arcuate nucleus, via activation of neurons that co-express neuropeptide Y and agouti-related protein (NPY/Agrp neurons), the ghrelin receptor is expressed also in other brain sites. One of these is the ventral tegmental area (VTA), a primary node of the mesolimbic reward pathway, which sends dopaminergic projections to the nucleus accumbens (Acb), among other sites. We injected saline or three doses of ghrelin (0, 0.003, 0.03, or 0.3 nmol) into the VTA or Acb of rats. We found a robust feeding response with VTA injection of ghrelin, and a more moderate response with Acb injection. Because opioids modulate feeding in the VTA and Acb, we hypothesized that ghrelins effects in one site were dependent on opioid signaling in the opposite site. The general opioid antagonist, naltrexone (NTX), injected into the Acb did not affect feeding elicited by ghrelin injection into the VTA, and NTX in the VTA did not affect feeding elicited by ghrelin injected into the Acb. These results suggest interaction of a metabolic factor with the reward system in feeding behavior, indicating that hedonic responses can be modulated by homeostatic factors.

Elevated Free Fatty Acids Induce Uncoupling Protein 3 Expression in Muscle: A Potential Explanation for the Effect of Fasting

The newly described uncoupling protein 3 (UCP3) may make an important contribution to thermogenesis in humans because of its high level of expression in skeletal muscle. Contrary to expectations, fasting, a condition that reduces resting energy expenditure, has been reported to increase UCP3 expression in muscle. We have confirmed that a 10-fold increase in UCP3 mRNA levels occurs in rat quadriceps muscle between 12 and 24 h of food removal. A less consistent twofold increase in muscle UCP2 mRNA levels was observed in animals fasted for up to 72 h. Administration of recombinant leptin to prevent a fall in circulating leptin levels did not eliminate the fasting-induced increase in quadriceps UCP3 expression. Administration of a high dose of glucocorticoid to fed animals to mimic the increase in corticosterone induced by fasting did not reproduce the increase in UCP3 expression observed in fasted animals. In contrast, elevation of circulating free fatty acid levels in fed animals by Intralipid plus heparin infusion caused significant increases in the UCP3/actin mRNA ratio compared with saline-infused fed controls in both extensor digitorum longus (2.01 ± 0.34 vs. 0.68 ± 0.11, P = 0.002) and soleus muscles (0.31 ± 0.07 vs. 0.09 ± 0.02, P = 0.014). We conclude that free fatty acids are a potential mediator of the increase in muscle UCP3 expression that occurs during fasting. This seemingly paradoxical induction of UCP3 may be linked to the use of free fatty acid as a fuel rather than an increased need of the organism to dissipate energy.

Hormonal and Metabolic Mechanisms of Diabetes Remission after Gastrointestinal Surgery

Bariatric surgery is the most effective available treatment for obesity. The most frequently performed operation, Roux-en-Y gastric bypass (RYGB), causes profound weight loss and ameliorates obesity-related comorbid conditions, especially type 2 diabetes mellitus (T2DM). Approximately 84% of diabetic patients experience complete remission of T2DM after undergoing RYGB, often before significant weight reduction. The rapid time course and disproportional degree of T2DM improvement after RYGB compared with equivalent weight loss from other interventions suggest surgery-specific, weight-independent effects on glucose homeostasis. Potential mechanisms underlying the direct antidiabetic impact of RYGB include enhanced nutrient stimulation of lower intestinal hormones (e.g. glucagon-like peptide-1), altered physiology from excluding ingested nutrients from the upper intestine, compromised ghrelin secretion, modulations of intestinal nutrient sensing and regulation of insulin sensitivity, and other changes yet to be fully characterized. Research aimed at determining the relative importance of these effects and identifying additional mechanisms promises not only to improve surgical design but also to identify novel targets for diabetes medications.

Metabolic Surgery to Treat Type 2 Diabetes: Clinical Outcomes and Mechanisms of Action

Several gastrointestinal (GI) operations that were designed to promote weight loss can powerfully ameliorate type 2 diabetes mellitus (T2DM). Although T2DM is traditionally viewed as a chronic, relentless disease in which delay of end-organ complications is the major treatment goal, GI surgery offers a novel endpoint: complete disease remission. Ample data confirm the excellent safety and efficacy of conventional bariatric operations-especially Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding-to treat T2DM in severely obese patients. Use of experimental procedures as well as conventional bariatric operations is increasingly being explored in less obese diabetic patients, with generally favorable results, although further assessment of risk:benefit profiles is needed. Mounting evidence indicates that certain operations involving intestinal diversions improve glucose homeostasis through varied mechanisms beyond reduced food intake and body weight, for example by modulating gut hormones. Research to elucidate such mechanisms should facilitate the design of novel pharmacotherapeutics and dedicated antidiabetes GI manipulations. Here we review evidence regarding the use and study of GI surgery to treat T2DM, focusing on available published reports as well as results from the Diabetes Surgery Summit (DSS) in Rome and the World Congress on Interventional Therapies for T2DM in New York City.

The Diabetes Surgery Summit consensus conference: recommendations for the evaluation and use of gastrointestinal surgery to treat type 2 diabetes mellitus.

Objectives:To develop guidelines for the use of gastrointestinal surgery to treat type 2 diabetes and to craft an agenda for further research. Background:Increasing evidence demonstrates that bariatric surgery can dramatically ameliorate type 2 diabetes. Not surprisingly, gastrointestinal operations are now being used throughout the world to treat diabetes in association with obesity, and increasingly, for diabetes alone. However, the role for surgery in diabetes treatment is not clearly defined and there are neither clear guidelines for these practices nor sufficient plans for clinical trials to evaluate the risks and benefits of such “diabetes surgery.” Methods:A multidisciplinary group of 50 voting delegates from around the world gathered in Rome, Italy for the first International Conference on Gastrointestinal Surgery to Treat Type 2 Diabetes–(the “Diabetes Surgery Summit”). During the meeting, available scientific evidence was examined and critiqued by the entire group to assess the strength of evidence and to draft consensus statements. Through an iterative process, draft statements were then serially discussed, debated, edited, reassessed, and finally presented for formal voting. After the Rome meeting, statements that achieved consensus were summarized and distributed to all voting delegates for further input and final approval. These statements were then formally critiqued by representatives of several sientific societies at the 1st World Congress on Interventional Therapies for T2DM (New York, Sept 2008). Input from this discussion was used to generate the current position statement. Results:A Diabetes Surgery Summit (DSS) Position Statement consists of recommendations for clinical and research issues, as well as general concepts and definitions in diabetes surgery. The DSS recognizes the legitimacy of surgical approaches to treat diabetes in carefully selected patients. For example, gastric bypass was deemed a reasonable treatment option for patients with poorly controlled diabetes and a body mass index ≥30 kg/m2. Clinical trials to investigate the exact role of surgery in patients with less severe obesity and diabetes are considered a priority. Furthermore, investigations on the mechanisms of surgical control of diabetes are strongly encouraged, as they may help advance the understanding of diabetes pathophysiology. Conclusions:The DSS consensus document embodies the foundations of “diabetes surgery,” and represents a timely attempt by leading scholars to improve access to surgical options supported by sound evidence, while also preventing harm from inappropriate use of unproven procedures.

Metabolic Surgery in the Treatment Algorithm for Type 2 Diabetes: A Joint Statement by International Diabetes Organizations

BACKGROUND Despite growing evidence that bariatric/metabolic surgery powerfully improves type 2 diabetes (T2D), existing diabetes treatment algorithms do not include surgical options. AIM The 2nd Diabetes Surgery Summit (DSS-II), an international consensus conference, was convened in collaboration with leading diabetes organizations to develop global guidelines to inform clinicians and policymakers about benefits and limitations of metabolic surgery for T2D. METHODS A multidisciplinary group of 48 international clinicians/scholars (75% nonsurgeons), including representatives of leading diabetes organizations, participated in DSS-II. After evidence appraisal (MEDLINE [1 January 2005–30 September 2015]), three rounds of Delphi-like questionnaires were used to measure consensus for 32 data-based conclusions. These drafts were presented at the combined DSS-II and 3rd World Congress on Interventional Therapies for Type 2 Diabetes (London, U.K., 28–30 September 2015), where they were open to public comment by other professionals and amended face-to-face by the Expert Committee. RESULTS Given its role in metabolic regulation, the gastrointestinal tract constitutes a meaningful target to manage T2D. Numerous randomized clinical trials, albeit mostly short/midterm, demonstrate that metabolic surgery achieves excellent glycemic control and reduces cardiovascular risk factors. On the basis of such evidence, metabolic surgery should be recommended to treat T2D in patients with class III obesity (BMI ≥40 kg/m2) and in those with class II obesity (BMI 35.0–39.9 kg/m2) when hyperglycemia is inadequately controlled by lifestyle and optimal medical therapy. Surgery should also be considered for patients with T2D and BMI 30.0–34.9 kg/m2 if hyperglycemia is inadequately controlled despite optimal treatment with either oral or injectable medications. These BMI thresholds should be reduced by 2.5 kg/m2 for Asian patients. CONCLUSIONS Although additional studies are needed to further demonstrate long-term benefits, there is sufficient clinical and mechanistic evidence to support inclusion of metabolic surgery among antidiabetes interventions for people with T2D and obesity. To date, the DSS-II guidelines have been formally endorsed by 45 worldwide medical and scientific societies. Health care regulators should introduce appropriate reimbursement policies.