Our Research: Faculty/Research Laboratories

David Cummings, MD

Professor, Department of Medicine, Division of Metabolism, Endocrinology and Nutrition

Email Address: davidec@u.washington.edu

Division of Metabolism, Endocrinology and Nutrition Website:  http://depts.washington.edu/metab/

David Cummings, MD

Background:

Dr. Cummings received his AB in Biochemistry from Dartmouth College, and his MD from Harvard Medical School and the Massachusetts Institute of Technology. He performed his residency and chief residency in Medicine at UW. As a fellow at UW, he was mentored by Stan McKnight in Pharmacology and William Bremner in Endocrinology. In addition to teaching at UW and seeing patients at the VA Hospital, he has maintained continuous NIH funding for >20 years, studying body weight regulation, obesity, and diabetes, and he has >120 publications in this field. Dr. Cummings is a member of the American Society for Clinical Investigation. He received the U.S. Presidential Early Career Award for Scientists and Engineers, the highest award conferred by the US government to researchers in their early independent careers. Given at the White House by President George W. Bush, it was accompanied by 5 years of funding.

Focus:

Dr. Cummings’ research focuses on regulation of food intake, body weight, and glucose homeostasis, with particular focus on the gut-brain axis.

Mechanisms Mediating Resolution of Diabetes Following Gastrointestinal Surgery

Our earlier work implicated impaired ghrelin secretion in the effects of Roux-en-Y gastric bypass (RYGB) on food intake, body weight, and glucose homeostasis. We now seek to examine additional mechanisms by which RYGB rapidly and dramatically resolves type 2 diabetes, through actions beyond just reduced food intake and body weight. We study animals with a gastric-sparing bypass of the amount of proximal small intestine that is bypassed in a typical RYGB. This duodenal-jejunal bypass operation (DJB) markedly improves or resolves type 2 diabetes in rodents and humans, independent of changes in food intake or body weight, and without causing malabsorption. Our work implicates the exclusion of nutrients from the duodenum as an important component of the anti-diabetes effects of DJB, rather than just increased GLP-1 secretion from expedited delivery of ingested nutrients to the distal intestine. Glucose tolerance also improves in animals and humans following implantation of a plastic endoluminal sleeve into the proximal small intestine, preventing contact between ingested food and the duodenal lumen.

Our current and proposed studies seek to elucidate the anti-diabetes mechanisms of duodenal bypass with experiments in rats, pigs, and humans. We have worked with Dr. David Flum to develop and characterize porcine models of gastric bypass and DJB, which we employ for studies requiring large animals. Using insulin-resistant Ossabaw pigs, we are characterizing the effects of various surgical manipulations of the gastrointestinal tract on the details glucose homeostasis. We will perform complementary studies in rats, collaborating with Mike Schwartz, Greg Morton, and the Animal Physiology Core, to determine whether proximal intestinal bypass (achieved with a DJB or duodenal sleeve) ameliorates diabetes by increasing insulin secretion, insulin sensitivity, or both. These experiments involve frequently sampled IV glucose tolerance tests and hyperinsulinemic-euglycemic clamps in various rat models of diabetes. We also have an NIH RO1 grant that funds complementary human studies.

Determining the Clinical Roles for Bariatric/Metabolic Surgery in Diabetes Care Using Randomized Controlled Trials

Because certain “bariatric” operations cause rapid, complete remission of type 2 diabetes, through mechanisms additional to the effects of reduced food intake and body weight, they are increasingly viewed as “metabolic surgery” and are being considered for the treatment of diabetes per se, including among less obese or even non-obese patients. The proper place for metabolic surgery in diabetes care, however, has not been fully determined. We seek to shed light on this issue with several ongoing clinical studies. For example, funded by an NIH RO1 grant, we are conducting a randomized controlled trial (the CROSSROADS trial) of gastric bypass surgery vs. an intensive medical and lifestyle intervention to treat diabetes among patients with a BMI of 30-40 kg/m2, which includes individuals not obese enough to qualify for conventional bariatric surgery. This trial is notable for its focus on methods to recruit, educate, and retain the rare individuals who are willing to be randomized into such diverse interventions as surgery vs. medicines/lifestyle. Wee use an unbiased, population-based strategy and a unique, Shared Decision Making instrument that members of our group developed. Another distinctive feature of this trial is that the medical/lifestyle intervention of is far more intensive than any other in similar studies.

Dr. Cummings is also Principal Investigator on another RCT comparing gastric bypass surgery with medical/lifestyle care to treat type 2 diabetes among Asian Indian patients with a BMI of 25-35 kg/m2. The concept of using surgery to treat diabetes in less obese patients with diabetes is particularly logical in this population because of their extraordinary susceptibility to developing diabetes at very low levels of adiposity. Dr. Cummings is also involved in very longstanding non-randomized clinical investigations of bariatric/metabolic surgery in Brazil. He is senior and contributing author on a 2012 paper from that work published in Diabetes Care and recognized by the American Diabetes Association as one of the most noteworthy six papers published during the prior year in that journal.

Roles and Mechanisms of Action of Ghrelin in the Regulation of Food Intake, Body Weight, and Glucose Homeostasis

For several years we have studied the actions and regulation of ghrelin, a relatively recently discovered orexigenic (appetite-stimulating) peptide hormone that is produced primarily by the stomach and proximal small intestine, with lesser expression in pancreatic islets.  Our areas of study are as follows.

Regulation of Circulating Ghrelin Levels

The following is summarizes some of the findings from our ongoing studies to clarify mechanisms of ghrelin regulation.  We demonstrated that plasma ghrelin levels surge shortly before each meal, implicating this orexigenic hormone in mealtime hunger and meal initiation.  We have since focused in rats and humans on mechanisms mediating mealtime ghrelin fluxes.  We find that the preprandial ghrelin surge is entrainable to the timing of habitual meals and is triggered by the sympathetic nervous system.  During meals, ghrelin levels are suppressed dose-dependently by the number of calories ingested.  For a given number of calories, proteins suppress ghrelin levels the most, and lipids the least.  Carbohydrate ingestion initially suppresses ghrelin, followed by a rebound to above the pre-meal baseline.  These findings have implications for some of the mechanisms by which popular diets influence appetite.

Ghrelin levels are not affected by gastric, duodenal, or jejunal distention, nor by direct contact between enteral nutrients and gastric or duodenal ghrelin cells.  Meal-related ghrelin suppression results initially from increased intestinal osmolarity, with later contributions from postprandial insulin, both of which are minimal following fat ingestion.  Part of meal-related ghrelin suppression is mediated by the enteric nervous system, but not the vagus nerve.  Gastrointestinal neural transmission involving both nicotinic cholinergic receptors and 5-hydroxytriptamine-3 receptors appears to be involved in the relevant enteric nervous signaling.

Ghrelin levels respond adaptively to changes in body weight from various interventions, increasing in proportion to weight loss and decreasing with weight gain, consistent with a role in long-term body-weight regulation.  However, humans who have undergone gastric bypass surgery (but not gastric banding) have reduced 24-h ghrelin profiles, which may contribute to weight loss.  Humans with Prader-Willi syndrome have markedly increased ghrelin levels, possibly contributing to their hyperphagic obesity.  This elevation is not observed during the first few years of life, i.e., before hyperphagia and obesity develop.  Ghrelin levels are also elevated in restrained eaters, including among those who are at their lifetime maximal weight.

Interactions of ghrelin and anorexigenic hormones in hypothalamic intracellular signaling.  Ghrelin exerts opposite effects on feeding behavior, energy homeostasis, and hypothalamic neuronal activity compared with the anorexigenic hormones insulin and leptin.  Hence, we have tested whether ghrelin antagonizes hypothalamic intracellular signaling events triggered by insulin and leptin, and vice versa.  Our studies show that modulation of hypothalamic PI3K signaling is not required for ghrelin’s orexigenic effects, and that insulin and ghrelin do not oppose one another’s actions in the hypothalamus through this pathway.  In contrast, intracellular signaling events triggered by ghrelin and insulin within the hypothalamus converge competitively along PKA pathways, and PKA activation is necessary for ghrelin’s full orexigenic effects.

Effects of Ghrelin on Reward-Related Feeding Behaviors

We have shown that ghrelin acts at the hypothalamus and hindbrain, sites that regulate homeostatic feeding behavior.  In collaboration with Allen Levine, we helped show that ghrelin also increases food intake by acting on mesolimbic reward sites – the ventral tegmental area and nucleus accumbens.  Reward feeding involves processes that affect the “liking” of food (palatability), in which endogenous opioids are primary mediators, and those that affect the “wanting” of food (motivation), in which dopamine is a primary mediator.  We seek to determine which of these primarily explains ghrelin’s orexigenic effects.  We find that ghrelin does not increase food palatability, as measured using lickometry, and pharmacologic blockade of mesolimbic opioid signaling does not affect feeding induced by VTA ghrelin injections.  In contrast, working with Dianne Lattemann we found that ghrelin administration markedly increases the work (bar pressing) that animals will perform to obtain food, and blockade of brain dopamine signaling attenuates ghrelin-induced feeding.  Our results indicate that although ghrelin does not increase food palatability, it does increase animals’ motivation to obtain food.

Roles of Ghrelin in Meal Initiation

Our data implicate ghrelin in mealtime hunger and meal initiation, in part because circulating levels surge before meals.  To clarify the physiologic significance of this, we seek to determine whether genetic or pharmacologic ablation of ghrelin signaling impairs meal initiation and food intake under various feeding conditions.  In ghrelin-receptor knockout mice, we have studied the details of meal initiation, meal termination, the microstructure of eating (lickometry), overall food intake, and body weight.  Because of initial negative results using a mixed genetic background, we have back-crossed the mutants for 10 generations against C57BL/6 and plan to use those animals to complete these studies.

Mechanisms by Which Ghrelin Suppresses Insulin Secretion

We and others have found that ghrelin administration suppresses insulin secretion in vivo.  In collaboration with Ian Sweet, we have investigated the mechanisms for this action in isolated, perifused rat islets.  We find that ghrelin suppresses insulin secretion by mechanisms analogous but opposite to those of the incretins, GLP-1 and GIP.  These observations suggest that ghrelin acts as an “anti-incretin” hormone.

Characterize the Effects of Multiple Cycles of Weight Loss and Regain on the Body-Weight Regulatory System

We are characterizing the effects on energy homeostasis of repeated cycles of weight loss and regain.  We serially subject rats to 50% caloric restriction until they lose 20% of body weight, followed by ad libitum feeding until they regain a stable weight.  Relevant hormones (e.g., ghrelin, leptin, insulin) are measured throughout.  We find that following each cycle of weight loss and recovery, weight-cycled rats return to a stable body weight that is progressively lower than that of ad-lib-fed controls.  The time taken to reach a 20% weight loss, and the time to recover a stable body weight, both increase with each successive dieting cycle.  When rats that had been subjected to serial weight-loss/regain cycles for a year were subsequently fed ad libitum for many months, they durably defended lower body weights and adiposity (especially visceral fat), with better glucose tolerance, compared with rats never subjected to caloric restriction.

Our data indicate that repeated bouts of diet-induced weight loss followed by weight recovery confers long-lasting metabolic benefits, causing rats to defend a lower level of body weight and adiposity, with improved glucose homeostasis, even long after dieting ceases.  We hypothesize that weight-cycled rats are spared some of the toxic effects of nutrient excess compared with continuously ad-lib-fed rats, rendering them more sensitive to leptin and/or insulin.  We plan to examine this hypothesis in future experiments, starting with a study of hypothalamic neuropeptide expression in previously weight-cycled vs. control rats.  These findings have clinical implications regarding the utility of repeated dietary weight-loss attempts, which may be beneficial in the long run, even if they are not individually successful in the short run.

Representative Publications:

Cummings DE, Brandon EP, Planas J, Idzerda R, McKnight GS. Genetically lean mice derived by targeted disruption of the RII subunit of protein kinase A. Nature 382:622-626 (1996).

Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ. Human plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. New Engl J Med 346:1623-1630 (2002).

Foster-Schubert KE, Overduin J, Prudom CE, Liu J, Callahan HS, Gaylinn BD, Thorner MO, Cummings DE. Acyl and total ghrelin are suppressed strongly by ingested proteins, weakly by lipids, and biphasically by carbohydrates. J Clin Endocrinol Metab 93:1971-1979 (2008).

Overduin J, Figlewicz DP, Bennett-Jay J, Kittleson SA, Cummings DE. Ghrelin increases the motivation to eat, but does not alter food palatability. Am J Physiol Regul Integr Comp Physiol 303:R259-269 (2012).

Cohen RV, Pinheiro JC, Schiavon CA, Salles JE, Wajchenberg BL, Cummings DE. Effects of gastric bypass surgery in patients with type 2 diabetes and only mild obesity. Diabetes Care 35:1420-1428 (2012).

Cummings DE, Rubino F. Mechanistic insights into obesity and type 2 diabetes from bariatric/metabolic surgery. Nature Medicine (in press, 2013).

  • Papers in Refereed Journals

    Beck BN, Frelinger JG, Shigeta M, Infante AJ, Cummings DE, Hammerling G, Fathman CG. T cell clones specific for hybrid I-A molecules. Discrimination with monoclonal anti-I-Ak antibodies. J Exp Med 156:1186-94 (1982).

    Ceredig R, Cummings DE. Phenotypic and functional properties of murine thymocytes. III. Kinetic analysis of the recovery of intrathymic cytolytic T lymphocyte precursors after in vivo administration of hydrocortisone acetate. J Immunol 130:33-37 (1983).

    Fornace AJ, Cummings DE, Comeau CM, Kant JA, Crabtree GR. Single-copy inverted repeats associated with regional genetic duplications in gamma fibrinogen and immunoglobulin genes. Science 224:161-164 (1984).

    Fornace AJ, Cummings DE, Comeau CM, Kant JA, Crabtree GR. Structure of the human gamma-fibrinogen gene. Alternate mRNA splicing near the 3′ end of the gene produces gamma A and gamma B forms of gamma-fibrinogen. J Biol Chem 259:12826-12830 (1984).

    Galvin K, Krishna S, Ponchel F, Frohlich M, Cummings DE, Carlson R, Wands JR, Isselbacher KJ, Pillai S, Ozturk M. The major histocompatibility complex class I antigen-binding protein p88 is the product of the calnexin gene. Proc Natl Acad Sci USA 89:8452-8456 (1992).

    Cummings DE, Edelhoff S, Disteche CM, McKnight GS. Cloning of a mouse protein kinase A catalytic subunit pseudogene and chromosomal mapping of C subunit isoforms. Mamm Genome 5:701-706 (1994).

    Cummings DE, Bremner WJ. Prospects for new hormonal male contraceptives. Endocrinol Metab Clin North Am 23:893-922 (1994).

    Cummings DE, Brandon EP, Planas J, Idzerda R, McKnight GS. Genetically lean mice derived by targeted disruption of the RIIβ subunit of protein kinase A. Nature 382:622-626 (1996).

    Amieux PS, Cummings DE, Motamed K, Brandon EP, Wailes L, Le K, Idzerda RL, McKnight GS. Compensatory regulation of RIα protein levels in protein kinase A mutant mice. J Biol Chem 272:3993-3998 (1997).

    McKnight GS, Cummings DE, Amieux PS, Sikorski MA, Brandon EP, Planas JV, Motamed K, Idzerda RL. Cyclic AMP, PKA, and the physiological regulation of adiposity. Rec Prog Horm Res 53:139-161 (1998).

    Weigle D.S, Selfridge LE, Schwartz MW, Seeley RJ, Cummings DE, Havel PJ, Kuijper JL. Elevated free fatty acids induce uncoupling protein 3 expression in muscle: A potential explanation for the effect of fasting. Diabetes 47:298-302 (1998).

    Cummings DE, Kumar N, Bardin CW, Sundaram K, Bremner WJ. Prostate-sparing effects in primates of the potent androgen 7α-methyl-19-nortestosterone: A potential alternative to testosterone for androgen replacement and male contraception. J Clin Endocrinol Metab 83:4212-4219 (1998).

    Cummings DE. Insights into the genetics of obesity from transgenic and knockout mice. J Nutr 129:791-795 (1999).

    Cummings DE, Planas JV, Idzerda RL, McKnight GS. Mutation of the RIIβ subunit of protein kinase A differentially affects lipolysis but not gene induction in white adipose tissue. J Biol Chem 274:36281-36287 (1999).

    Wu JY, Ribar TJ, Cummings DE, Burton KA, McKnight GS, Means AR. Spermiogenesis and exchange of basic nuclear proteins are impaired in male germ cells lacking Camk4. Nature Genetics 25:448-452 (2000).

    Cummings DE, Schwartz MW. Melanocortins and body weight: a tale of two receptors. Nature Genetics 26:8-9 (2000).

    Mystkowski P, Shankland E, Schreyer SA, LeBoeuf RC, Schwartz RS, Cummings DE, Kushmerick M, Schwartz MW. Validation of whole-body magnetic resonance spectroscopy as a tool to assess murine body composition. Int J Obes Relat Metab Disord 24:719-724 (2000).

    Cummings DE, Merriam GR. Age-related changes in growth hormone secretion: Should the somatopause be treated? Semin Reprod Endocrinol 17:311-325 (2000).

    Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50:1714-1719 (2001).

    Wisse B, Frayo S, Schwartz, MS, Cummings DE. Reversal of cancer anorexia by blockade of central melanocortin receptors in rats. Endocrinology 142:3292-3301 (2001).

    Schreyer SA, Cummings DE, McKnight GS, LeBoeuf RC. Mutation of the PKA RIIβ subunit prevents diet-induced insulin resistance and dyslipidemia. Diabetes 50:2555-2562 (2001).

    Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ. Human plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. New Engl J Med 346:1623-1630 (2002).

    Cummings DE, Clement K, Purnell JQ, Vaisse C, Foster KE, Frayo RS, Schwartz MW, Basdevant A, Weigle DS. Elevated plasma ghrelin levels in Prader-Willi syndrome. Nature Medicine 8:643-644 (2002).

    Cummings DE, Purnell JQ, Weigle DS. Weight loss and plasma ghrelin levels. New Engl J Med 347:1379-1381 (2002).

    Weigle DS, Cummings DE, Newby PD, Breen PA, Frayo RS, Matthys CC, Callahan HS, Purnell JQ. Roles of leptin and ghrelin in the loss of body weight caused by a low fat, high carbohydrate diet. J Clin Endocrinol Metab 88:1577-1586 (2003).

    Williams DL, Cummings DE, Grill HJ, Kaplan JM. Meal-related ghrelin suppression requires post-gastric feedback. Endocrinology 144:2765-2767 (2003).

    Cummings DE, Merriam GR. Growth hormone therapy in adults. Annual Review of Medicine 54:513-533 (2003).

    Cummings DE, Schwartz MW. Genetics and pathophysiology of human obesity. Annual Review of Medicine 54:453-471 (2003).

    Levin BE, Dunn-Meynell AA, Ricci MR, Cummings DE. Abnormalities of ghrelin and leptin regulation in obesity-prone juvenile rats. Am J Physiol Endocrinol Metab 285:E949-957 (2003).

    Cummings DE. The stomach and weight reduction: the role of ghrelin. Gastroenterology 124:575-577 (2003).

    Faulconbridge LF, Cummings DE, Kaplan JM, Grill HJ. Hyperphagic effects of brainstem ghrelin administration. Diabetes 52:2260-2265 (2003).

    Haqq AM, Stadler DD, Rosenfeld R, Pratt K, Weigle DS, Frayo RS, LaFranchi SH, Cummings DE, Purnell JQ. Circulating ghrelin levels are suppressed by meals and octreotide therapy in children with Prader-Willi syndrome. J Clin Endocrinol Metab 88:3573-3576 (2003).

    Williams DL, Grill HJ, Cummings DE, Kaplan JM. Vagotomy dissociates short- and long-term controls of circulating ghrelin. Endocrinology 144:5184-5187 (2003).

    Cummings DE, Shannon MH. Roles for ghrelin in the regulation of appetite and body weight. Archives of Surgery 138:389-396 (2003).

    Cummings DE, Foster KE. Ghrelin-leptin Tango in body-weight regulation. Gastroenterology 124:1532-1535 (2003).

    Purnell JQ, Weigle DS, Breen P, Cummings DE. Ghrelin levels correlate with insulin levels, insulin resistance, and high-density lipoprotein cholesterol, but not with gender, menopausal status, or cortisol levels in humans. J Clin Endocrinol Metab 88:5747-5752 (2003).

    Wisse BE, Schwartz MW, Cummings DE. Melanocortin signaling and anorexia in chronic disease states. Proc NY Acad Sci 994:275-282 (2003).

    Cummings DE, Shannon MH. Ghrelin and gastric bypass: Is there a hormonal contribution to surgical weight loss? J Clin Endocrinol Metab 88:2999-3002 (2003).

    Callahan HS, Cummings DE, Pepe MS, Breen PA, Matthys CC, Weigle DS. Postprandial suppression of plasma ghrelin level is proportional to ingested caloric load but does not predict inter-meal interval in humans. J Clin Endocrinol Metab 89:1319-1324 (2004).

    McLaughlin T, Abbasi F, Lamendola C, Frayo RS, Cummings DE. Plasma ghrelin concentrations are decreased in insulin-resistant obese adults relative to equally obese insulin-sensitive controls. J Clin Endocrinol Metab 89:1630-1635 (2004).

    Cummings DE, Overduin J, Foster-Schubert KE. Gastric bypass for obesity: mechanisms of weight loss and diabetes resolution. J Clin Endocrinol Metab 89:2608-2615 (2004).

    Gelling RW, Overduin J, Morrison CD, Morton GJ, Frayo RS, Cummings DE, Schwartz MW. Effect of uncontrolled diabetes on plasma ghrelin concentrations and ghrelin-induced feeding. Endocrinology 145:4575-4582 (2004).

    Cummings DE, Frayo RS, Marmonier C, Aubert R, Chapelot D. Plasma ghrelin levels and hunger scores among humans initiating meals voluntarily in the absence of time- and food-related cues. Am J Physiol Endocrinol Metab 287:E297-304 (2004).

    Cummings DE. Helicobacter pylori and ghrelin: inter-related players in body-weight regulation? Amer J Med 117:436-439 (2004).

    Wisse BE, Ogimoto K, Morton GJ, Wilkinson CW, Frayo RS, Cummings DE, Schwartz MW. Physiological regulation of hypothalamic interleukin-1beta (IL-1) gene expression by leptin and glucocorticoids: implications for energy homeostasis. Am J Physiol Endocrinol Metab 287:E1107-1113 (2004).

    Newhall KJ, Cummings DE, Nolan MA, McKnight GS. Deletion of the RII subunit of protein kinase A decreases body weight and increases energy expenditure in the obese, leptin-deficient ob/ob mouse. Molecular Endocrinology 19:982-991 (2005).

    Himmerich H, Fulda S, Kunzel HE, Pfennig A, Dzaja A, Cummings DE, Pollmacher T. Ghrelin plasma levels during psychopharmacological treatment. Neuropsychobiology 52:11-16 (2005).

    Williams DL, Cummings DE. Regulation of ghrelin in physiologic and pathophysiologic states. J Nutrition 135:1320-1325 (2005).

    Hirsh D, Heinrichs C, Leenders B, Wong AC, Cummings DE, Chanoine JP. Ghrelin is suppressed by glucagon and does not mediate glucagon-related growth hormone release. Horm Res 63:111-118 (2005).

    Cummings DE, Overduin J, Foster-Schubert KE. Roles for ghrelin in the regulation of appetite and body weight. Curr Opin Endo Diabetes 12:72-79 (2005).

    Foster-Schubert KE, McTiernan A, Frayo RS, Rajan KB, Yasui Y, Tworoger SS, Cummings DE. Human plasma ghrelin levels increase during a one-year exercise program. J Clin Endocrinol Metab 90:820-825 (2005).

    Cummings DE, Foster-Schubert KE, Overduin J. Ghrelin and energy balance: focus on current controversies. Curr Drug Targets 6:153-169 (2005).

    Overduin J, Frayo RS, Grill HJ, Kaplan JM, Cummings DE. Role of the duodenum and macronutrient type in ghrelin regulation. Endocrinology 146:845-850 (2005).

    Cummings DE, Carlson MJ, Shannon MH. The obesity pandemic and research horizons. Endo News 30:20-22 (2005).

    Stefan M, Ji H, Simmons RA, Cummings DE, Ahima RS, Friedman MI, Nicholls RD. Hormonal and metabolic defects in a Prader-Willi syndrome mouse model with neonatal failure to thrive. Endocrinology 146:4377-4385 (2005).

    Cummings DE, Overduin J, Shannon MH, Foster-Schubert KE. Hormonal mechanisms of weight loss and diabetes resolution after bariatric surgery. Surg Obes Relat Dis 1:358-388 (2005).

    Consensus Conference Panel. Consensus conference statement on bariatric surgery for morbid obesity: health implications for patients, health professionals, and third-party payers. Surg Obes Rel Dis 1:371-381 (2005).

    Cummings DE. Gastric bypass and nesidioblastosis – too much of a good thing for islets? New Engl J Med 353:300-302 (2005).

    Allison KC, Ahima RS, O’Reardon JP, Dinges DF, Sharma V, Cummings DE, Heo M, Martino NS, Stunkard AJ. Neuroendocrine profiles associated with energy intake, sleep, and stress in the night eating syndrome. J Clin Endocrinol Metab 90:6214-6217 (2005).

    Naleid AM, Grace MK, Cummings DE, Levine AS. Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens. Peptides 26:2274-2279 (2005).

    Cummings DE, Shannon MH, Carlson MJ. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. New Engl J Med 353:2192-2194 (2005).

    Griffen S, Oostema K, Stanhope K, Graham J, Styne D, Glaser N, Cummings DE, Connors MH, Havel PJ. Administration of Lispro insulin with meals improves glycemic control, increases circulating leptin, and suppresses ghrelin compared with regular/NPH insulin in female patients with type-1 diabetes. J Clin Endocrinol Metab 91:485-491 (2006).

    Cummings DE. Ghrelin and the short- and long-term regulation of appetite and body weight. Physiol Behav 89:71-84 (2006).

    Yukawa M, Cummings DE, Matthys CC, Callahan HS, Frayo RS, Spiekerman CF, Weigle DS. Effect of aging on the response of ghrelin to acute weight loss. J Am Geriatr Soc 54:648-653 (2006).

    Shannon MH, Cummings DE. Hunger and memory: Can ghrelin help us remember where to find dinner? Cell Science 3:1 (2006).

    Rubino F, Forgione A, Cummings DE, Vix M, Gnuli D, Mingrone G, Castagneto M, Marescaux J. The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes. Ann Surg 244:741-749 (2006).

    Carlson MJ, Cummings DE. Prospects for an anti-ghrelin vaccine to treat obesity. Molec Interv 6:249-252 (2006).

    Mundinger TO, Cummings DE, Taborsky GJ Jr. Direct stimulation of ghrelin secretion by sympathetic nerves. Endocrinology 147:2893-2901 (2006).

    Littman AJ, Vitiello MV, Foster-Schubert K, Ulrich CM, Tworoger SS, Potter JD, Weigle DS, Cummings DE, McTiernan A. Sleep, ghrelin, leptin, and changes in body weight during a 1-year moderate-intensity physical activity intervention. Int J Obes (Epub ahead of print).

    Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature 443:289-295 (2006).

    Foster-Schubert KE, Cummings DE. Emerging therapeutic strategies for obesity. Endocr Reviews 27:779-793 (2006).

    Patel JV, Cummings DE, Girod JP, Mascarenhas AV, Hughes EA, Gupta M, Lip GY, Reddy S, Brotman DJ. Role of metabolically active hormones in the insulin resistance associated with short-term glucocorticoid treatment. J Neg Res Biomed 5:14-21 (2006).

    Williams DL, Grill HJ, Cummings DE, Kaplan JM. Overfeeding-induced weight gain suppresses plasma ghrelin levels in rats. J Endocrinol Invest 29:863-868 (2006).

    Erdie-Lalena CR, Holm VA, Kelly PC, Frayo RS, Cummings DE. Ghrelin levels in young children with Prader-Willi syndrome. J Pediatr 149:199-204 (2006).

    Purnell JQ, Cummings DE, Weigle DS. Changes in 24-hour area-under-the-curve ghrelin values following diet-induced weight loss are associated with loss of fat-free mass, but not with changes in fat mass, insulin levels or insulin sensitivity. Int J Obes 31:385-389 (2007).

    Cummings DE, Overduin J, Foster-Schubert KE, Carlson MJ. Role of the bypassed proximal intestine in the anti-diabetic effects of bariatric surgery. Surg Obes Relat Dis 3:109-115 (2007).

    Cummings DE, Naleid AM, Figlewicz Lattemann DP. Ghrelin: a link between energy homeostasis and drug abuse? Addict Biol 12:1-5 (2007).

    Cummings DE. Hormonal mechanisms underlying the anti-diabetic and weight-reducing effects of gastrointestinal surgery. JPEN J Parenter Enteral Nutr (2007).

    Cummings DE, Overduin J. Gastrointestinal regulation of food intake. J Clin Invest 117:13-23 (2007).

    Flum DR, Devlin A, Wright AS, Figueredo E, Alyea E, Hanley PW, Lucas MK, Cummings DE. Development of a porcine Roux-en-Y gastric bypass survival model for the study of post-surgical physiology. Obes Surg 17:1332-1339 (2007).

    Lasseter KC, Shaughnessy L, Cummings D, Pezzullo JC, Wargin W, Gagnon R, Oliva J, Kosutic G. Ghrelin agonist (TZP-101): Safety, pharmacokinetics, and pharmacodynamic evaluation in healthy volunteers: A phase I, first-in-man study. J Clin Pharmacol 48:193-202 (2008).

    Taleban S, Carew HT, Dichek HL, Deeb SS, Hollenback D, Weigle DS, Cummings DE, Brunzell JD. Energy balance in congenital generalized lipodystrophy type I. Metabolism 57:1155-1161 (2008).

    LABS Writing Group for the LABS Consortium. Relationship of body mass index with demographic and clinical characteristics in the Longitudinal Assessment of Bariatric Surgery (LABS). Surg Obes Relat Dis 4:474-480 (2008).

    Longitudinal Assessment of Bariatric Surgery Study group. Physical activity levels of patients undergoing bariatic surgery in the Longitudinal Assessment of Bariatric Surgery study. Surg Obes Relat Dis 4:721-728 (2008).

    Schur EA, Cummings DE, Callahan HS, Foster-Schubert KE. Association of cognitive restraint with ghrelin, leptin, and insulin levels in subjects who are not weight-reduced. Physiol Behav 93:706-712 (2008).

    Cummings DE, Flum DR. Gastrointestinal surgery as a treatment for diabetes. JAMA 299:341-343 (2008).

    Heap AJ, Cummings DE. A novel weight-reducing operation: lateral subtotal gastrectomy with silastic ring plus small bowel reduction with omentectomy. Obes Surg 8:819-828 (2008).

    Thaler JP, Cummings DE. Metabolism: food alert. Nature 452:941-942 (2008).

    Foster-Schubert KE, Overduin J, Prudom CE, Liu J, Callahan HS, Gaylinn BD, Thorner MO, Cummings DE. Acyl and total ghrelin are suppressed strongly by ingested proteins, weakly by lipids, and biphasically by carbohydrates. J Clin Endocrinol Metab 93:1971-1979 (2008).

    *** Winner of the Endocrine Society’s 2009 Pfizer International Award (for 1 of 4 best papers published per year in J Clin Endocinol Metab)

    Karaoglu A, Aydin S, Dagli AF, Cummings DE, Ozercan IH, Canatan H, Ozkan Y. Expression of obestatin and ghrelin in papillary thyroid carcinoma. Mol Cell Biochem 323:113-118 (2009).

    Brethauer SA, Goncalves CG, Cummings DE, Rubino F, Kaplan LM, Kashyap S, Schauer PR. Bariatric surgery as a treatment for type 2 diabetes mellitus in obese patients. Obes Manag 6/09:112-118 (2009).

    Cummings DE. Endocrine mechanisms mediating remission of diabetes after gastric bypass surgery. Int J Obes 33 Suppl 1:S33-40 (2009).

    Goel N, Stunkard AJ, Rogers NL, van Dongen HP, Allison KC, O’Reardon JP, Ahima RS, Cummings DE, Heo M, Dinges DF. Circadian rhythm profiles in women with night eating syndrome. J Biol Rhythms 24:85-94 (2009).

    Blevins JE, Overduin J, Fuller JM, Cummings DE, Matsumoto K, Moralego DH. Normal feeding and body weight in Fischer 344 rats lacking the cholecystokinin-1 receptor gene. Brain Research 1255:98-112 (2009).

    Thaler JP, Cummings DE. Hormonal and metabolic mechanisms of diabetes remission after gastrointestinal surgery. Endocrinology 150:2518-25 (2009).

    Longitudinal Assessment of Bariatric Surgery (LABS) Consortium. Perioperative safety in the longitudinal assessment of bariatric surgery. N Engl J Med 361:445-454 (2009).

    Cummings DE. Gastrointestinal regulation of insulin secretion and sensitivity: implications for bariatric and metabolic surgery mechanisms. Nature Medicine (in press).

    Prudom C, Liu J, Patrie J, Gaylinn BD, Foster-Schubert KE, Cummings DE, Thorner MO, Geysen HM. Comparison of competitive radioimmunoassays and two-site sandwich assays for the measurement and interpretation of plasma ghrelin levels. J Clin Endocrinol Metab 95:2351-2358 (2010).

    Rubino F, Schauer PR, Kaplan LM, Cummings DE. Metabolic surgery to treat type 2 diabetes: clinical outcomes and mechanisms of action. Annu Rev Med 61:393-411 (2010).

    Rubino F, Kaplan LM, Schauer PR, Cummings DE. The Diabetes Surgery Summit consensus conference: recommendations for the evaluation and use of gastrointestinal surgery to treat type 2 diabetes mellitus. Ann Surg 251:399-405 (2010).

    Tong J, Prigeon RL, Davis HW, Bidlingmaier M, Kahn SE, Cummings DE, Tschöp MH, D’Alessio D. Ghrelin suppresses glucose-stimulated insulin secretion and deteriorates glucose tolerance in healthy humans. Diabetes 59:2145-2151 (2010).

    Shah SS, Todkar JS, Shah PS, Cummings DE. Diabetes remission and reduced cardiovascular risk after gastric bypass in Asian Indians with body mass index <35 kg/m2. Surg Obes Relat Dis 6:332-338 (2010).

    Cohen RV, Rubino F, Schiavon C, Cummings DE. Diabetes remission without weight loss after duodenal bypass surgery. Surg Obes Relat Dis 8:66-68 (2012).

    Overduin J, Figlewicz DP, Bennett-Jay J, Kittleson SA, Cummings DE. Ghrelin increases the motivation to eat, but does not alter food palatability. Am J Physiol Regul Integr Comp Physiol 303:R259-269 (2012).

    Cohen RV, Pinheiro JC, Schiavon CA, Salles JE, Wajchenberg BL, Cummings DE. Effects of gastric bypass surgery in patients with type 2 diabetes and only mild obesity. Diabetes Care 35:1420-1428 (2012).

    * Selected as an honorary Diabetes Care Symposium paper for the 2012 annual ADA meeting, recognizing the 6 most notable papers in that journal from the prior year.

    Cummings DE, Bloom SR, Rubino F. At the heart of the benefits of bariatric surgery. Nature Medicine 18:358-359 (2012).

    Cummings DE. Metabolic surgery for type 2 diabetes. Nature Medicine 18:656-658 (2012).

    Rubino F, Cummings DE. The coming of age of metabolic surgery. Nature Rev Endocrinol 8:702-704 (2012).

    Cummings DE, Rubino F. Mechanisms mediating weight loss and diabetes remission after bariatric/metabolic surgery. Transl Endocrinol Metab 3:63-92 (2012).

    Arterburn D, Flum DR, Westbrook EO, Fuller S, Shea M, Bock SN, Landers J, Kowalski K, Turnbull E, Cummings DE. A population-based, shared decision making approach to recruit for a randomized trial of bariatric surgery vs. lifestyle for type 2 diabetes. Surg Obes Relat Dis (in press 2013).

    Cummings DE, Cohen RV. Gastric bypass for type 2 diabetes. Diabetes Care (in press, 2013).

    Cummings DE, Cohen RV, Rubino F. Metabolic surgery reveals novel roles for the proximal intestine in the regulation of insulin sensitivity. Cell Metabolism (in press, 2013).

    Cummings DE, Rubino F. Mechanistic insights into obesity and type 2 diabetes from bariatric/metabolic surgery. Nature Medicine (in press, 2013).

    Books and Book Chapters

    Cummings DE, Bremner WJ. Male contraception: Ideas for the future. In Bardin, C.W. (ed.), Current Therapy in Endocrinology and Metabolism, 6th edition, pp. 300-304, Mosby, St. Louis (1997).

    McKnight GS, Idzerda RL, Kandel ER, Brandon EP, Zhuo M, Qi M, Bourtchouladze R, Huang Y, Burton KA, Skalhegg BS, Cummings DE, Varshavsky L, Planas J, Motamed K, Gerhold KA, Amieux PS, Guthrie CR, Millett KM, Belyamani M, Su T. Targeted disruption of the protein kinase A system in mice. In Hansson V, Levy FO, Tasken K (eds.), Signal transduction in testicular cells, pp. 95-122, Springer-Verlag, Heidelberg, Germany (1997).

    Cummings DE, Merriam GR. Growth hormone and growth hormone secretagogues in adults. In Meikle AW (ed.), Contemporary Endocrinology: Hormone Replacement Therapy, pp. 61-88, Humana Press, Totowa, NJ (1998).

    Merriam GR, Cummings DE. Growth hormone and growth hormone secretagogues in adults. In Meikle AW (ed.), Endocrine Replacement Therapy in Clinical Practice, pp. 63-94, Humana Press, Totowa, NJ (2003).

    Nicholls RD, Stefan M, Ji H, Qi Y, Frayo RS, Wharton RH, Dhar MS, Cummings DE, Friedman MI, Ahima RS. Mouse models for Prader-Willi and Angelman syndromes offer insights into novel obesity mechanisms. In Medeiros-Neto G, Halpern A, Bouchard C (eds.) Progress in Obesity Research, pp. 313-319, John Libbey Eurotext Ltd. (2003).

    Cummings DE, Overduin J. Circulating ghrelin levels in pathophysiological conditions. In Ghigo E (ed.), Ghrelin, Kluwer Academic Publishers, Boston, p. 207-224 (2004).

    Cummings DE, Foster-Schubert KE, Carlson MJ, Shannon MH, Overduin J. Possible hormonal mechanisms mediating the effects of bariatric surgery. In Pitombo C (ed.), Obesity Surgery: Principles and Practice, McGraw-Hill, New York, NY (2007).

    Cummings DE. Hormonal and metabolic mechanisms of diabetes remission following intestinal bypass surgery. Oxford Textbook of Endocrinology & Diabetes (2011).

    Cummings DE, Rubino F. Mechanisms mediating weight loss and diabetes remission after bariatric/metabolic surgery. In Cummings DE & Rubino F (eds.), Translational Endocrinology & Metabolism: Metabolic Surgery, The Endocrine Society, Chevy Chase, MD (2012).

    Cummings DE, Rubino F (book editors). Translational Endocrinology & Metabolism: Metabolic Surgery, The Endocrine Society, Chevy Chase, MD (2012).

Current Collaborations:

Within the Diabetes and Obesity Center of Excellence, The Diabetes and Endocrinology Research Center, and Their Affiliated Members
Denis Baskin, PhD
Ernie Blevins, PhD
Dianne Figlewicz-Lattemann, PhD
David Flum, MD, MPH
Steven Kahn, MB, ChB
Bob Knopp, MD
Mario Kratz, PhD, MSc
Anne McTiernan, MD, PhD
Greg Morton, PhD
Michael Schwartz, MD
Ian Sweet, PhD
Jay Taborsky, PhD
Michi Yukawa, MD, MPH