Reviews/Commentaries/ADA Statements PERSPECTIVES ON THE NEWS

Gut and Adipocyte Peptides

ZACHARY T. BLOOMGARDEN, MD sented information pertaining to effects of GLP-1 on insulin action, noting that a ma- jor confounding factor is the increase in his is the third in a series of articles els are increased. The perfused pancreas portal insulin levels and the decrease in Ϫ Ϫ on presentations at the American isolated from GLP-1R / animals shows glycemia with GLP-1, both indirectly im- T Association Annual Meet- normal insulin response to glucose, proving the glucose-lowering effect of insu- ing, San Diego, California, 10–14 June although without response to GLP-1. GLP- lin. GLP-1 concentrations are somewhat Ϫ Ϫ 2005. 1R / ␤-cells appear to have increased sen- lower in persons with diabetes and, to a sitivity to the incretin glucose-dependent lesser extent, with impaired glucose toler- Glucagon-like peptide-1 (and related insulinotropic polypeptide (GIP), perhaps ance, and GLP-1R activation is increased hormones) representing an adaptive upregulation of well beyond the physiologic range both Daniel Drucker (Toronto, Canada) re- GIP and/or of GIP response, and mice nei- with agonists and with administration of viewed evidence that the incretin effect, ther expressing the GLP-1 nor the GIP re- DPP-IV inhibitors. In vitro, GLP-1 increases the phenomenon of enteral glucose load- ceptor show glucose intolerance with adipocyte 2-deoxy-glucose uptake, rat so- ing increasing the insulin secretory re- decreased insulin response to glucose, and leus muscle glycogen synthesis, and hep- sponse to an increase in blood glucose, is fail to show a glucose-lowering response taocyte glycogen synthase A levels. In reduced in type 2 diabetes, and that the with administration of DPP-IV inhibitors, mouse models, the effect of insulin in in- incretin glucagon-like peptide (GLP)-1 suggesting that the mechanism of DPP-IV creasing glucose uptake is enhanced with- may ameliorate this defect. The major inhibition involves both peptides. GLP- out change in glucose effectiveness by Ϫ Ϫ limitation to use of GLP-1 in clinical treat- 1R / mice have increased ␤-cell suscepti- administration of GLP-1. In obese hyper- ment is its rapid clearance by the enzyme bility to apoptotic streptozotocin injury. In glycemic Zucker rats, administration of ex- Ϫ Ϫ dipeptidyl peptidase (DPP)-IV. GLP-1 the ob/ob (-deficient) GLP-1R / enatide increases the glucose infusion rate stimulates insulin secretion, inhibits glu- mouse, insulin gene levels are upregulated required to maintain euglycemia, suggest- cagon secretion, and delays gastric emp- and there is islet hyperplasia to the same ing increased insulin action. In nondiabetic tying. Loss-of-function studies with a extent as seen in the ob/ob mouse with nor- humans, however, the glucose dis- mouse model not expressing the GLP-1 mal GLP-1R function. With partial pancre- appearance rate with peripheral infusion of Ϫ Ϫ receptor (GLP-1R / ), and with the atectomy, however, although exendin-(9- GLP-1 is equal to that with insulin infusion GLP-1R antagonist exendin-(9-39), show 39) does not block ␤-cell hyperplasia, the to produce similar insulin levels. A measure Ϫ Ϫ effects of GLP-1 on the hypothalamic- GLP-1R / mouse has reduced ␤-cell re- of “glucose effectiveness” appears to be in- pituitary-adrenal (HPA) axis, the repro- generation and is hyperglycemic. Taken to- creased in persons without diabetes admin- ductive system, the portal glucose gether, these studies suggest that trophic istered GLP-1, but Rizza showed another receptor, gastric motility, and a number of effects of GLP-1 on the ␤-cell occur physi- study of persons with type 2 diabetes, in Ϫ Ϫ other potential targets. GLP-1R / mice ologically. There are areas with high density which GLP-1 increased insulin and reduced have normal insulin sensitivity, arguing of GLP-1R binding sites in the hypothala- glucose levels modestly, without change in against an effect of the system on insulin mus, but their role is uncertain. The GLP- glucose effectiveness with insulin clamped. Ϫ Ϫ action, but have glucose intolerance, and 1R / mouse has normal body weight and In a 6-week study of persons with type 2 administration of exendin-(9-39) simi- minimal perturbation in food ingestion on a diabetes undergoing continuous GLP-1 in- larly is associated with glucose intoler- standard diet, although showing lesser de- fusion, the glucose infusion requirement ance in mice, in primates, and in humans. grees of on a high-fat diet. Gastric was increased during a hyperinsulinemic- Ϫ Ϫ Drucker noted that there is controversy as emptying is not changed in the GLP-1R / euglycemic clamp, although with some- to whether the product of DPP-IV degra- mouse, which shows a response to chole- what lower glucose levels, potentially dation may act at a second GLP-1R, per- cystokinin although not to exendin. Studies explaining improved insulin sensitivity (1). haps having additional effects on in these mice also suggest that there is a Rizza showed an interesting study in per- metabolism, but that GLP-1 does not neural portal vein and/or liver glucose sen- Ϫ Ϫ sons with type 1 diabetes, with glucose in- lower glucose levels in GLP-1R / mice, sor, which may be in part activated by fusion rates during a euglycemic clamp arguing against such a receptor. In the GLP-1 to enhance the response to ingested modestly increased by GLP-1, again sug- model, pancreatic insulin mRNA levels food. gesting possible effect on insulin action. are reduced and somatostatin mRNA lev- Robert Rizza (Rochester, MN) pre- David D’Alessio (Cincinnati, OH) dis-

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● cussed the effect of GLP-1 on body weight. Central administration of GLP-1 Zachary T. Bloomgarden, MD, is a practicing endocrinologist in New York, New York, and is affiliated with decreases, whereas that of exendin-(9-39) the Division of , Mount Sinai School of Medicine, New York, New York. Abbreviations: AGRP, agouti-related peptide; ARIC, Atherosclerosis Risk in Communities; BBB, blood- increases food intake (2). There is a taste- brain barrier; CART, cocaine-amphetamine–regulated transcript; CNTF, ciliary neurotrophic factor; DPP, aversive effect of central GLP-1, not seen dipeptidyl peptidase; FFA, free fatty acid; GIP, glucose-dependent insulinotropic polypeptide; GLP, gluca- with leptin in doses similarly decreasing gon-like peptide; GLP-1R, GLP-1 receptor; MCH, melanin-concentrating hormone; NPY, neuropeptide Y; food intake (3). Furthermore, central ad- NTS, nucleus of the solitary tract; POMC, proopiomelanocortin; PPAR, peroxisome proliferator–activated receptor; REE, resting energy expenditure; SOCS, suppressor of cytokine signaling; STAT, signal transducers ministration of GLP-1 induces neuronal and activators of transcription; TLR, toll-like receptor; TNF, tumor necrosis factor. growth in central emetic areas. Thus, © 2006 by the American Diabetes Association. GLP-1 may suppress food intake by acting

450 DIABETES CARE, VOLUME 29, NUMBER 2, FEBRUARY 2006 Bloomgarden as a satiety factor, as a regulator of energy ministration of central GLP-1R agonists, sion, glucose levels are reduced, with balance like leptin or insulin, or intrigu- so that ongoing suppression of appetite suggestion of improvement in insulin ingly, as a mediator of a “visceral illness” and weight loss can be expected to occur, sensitivity. As GLP-1 is rapidly inacti- response. Examining the brain GLP-1 sys- although the mechanisms of these vated by DPP-IV, which cleaves alanine or tem, the nucleus of the solitary tract chronic effects may differ from those of proline at the second amino acid of the (NTS) receives signals from gut visceral GLP-1 administered acutely. NH2-terminal of the peptide, the two afferents and contains a small number of Peripheral infusions of supraphysi- strategies that have been employed have GLP-1–staining neurons. Central GLP-1 ologic levels of GLP-1 in humans decrease been to use GLP-1 R agonists, including synthesis occurs almost exclusively in the food intake with increased fullness and exenatide, liraglutide, and CJC-1131, and NTS, but GLP-1Rs are widespread, found satiety in a dose-dependent fashion. DPP-IV inhibitors, those in development in the amygdala, the hypothalamic para- These effects may be mediated by delay in being vildagliptin (Novartis), sitagliptin ventricular nucleus, the NTS itself, and gastric emptying, but the relationship be- (Merck), and saxagliptin (Bristol-Myers circumventricular areas where the blood- tween gastric emptying and the appetite- Squibb). brain barrier (BBB) is attenuated with regulating functions of central GLP-1 is Exenatide, the pharmaceutical name greater potential effect of circulating not known. There is evidence that visceral given to the peptide exendin-4, has GLP-1. A number of stimuli increase cen- signals are mediated through the vagus Ͼ50% homology to GLP-1, acting as a tral GLP-1, including leptin and balloon nerve. The GLP-1-R is expressed in the GLP-1 agonist, but with glycine as the distension of the stomach, although in- vagus nerve, so that signals originating in second NH2-terminal amino acid, so that gestion of a large meal does not increase the gastrointestinal tract or portal vein it is not inactivated by DPP-IV. In three central GLP-1 levels. Acting in a fashion may be responsible for some of central 30-week studies, combination therapy similar to that of lithium chloride, GLP-1 effects of peripheral GLP-1. The extent to with sulfonylureas, with metformin, and decreases food intake, causes taste aver- which intestinal GLP-1 plays a role in sa- with both was associated with decrease in ϳ sion, decreases water intake, decreases tiety is uncertain, with D’Alessio com- HbA1c (A1C) by 1% from starting levels locomotor activity, decreases body tem- menting that DPP-IV inhibitors, which of ϳ8.5%. The proinsulin-to-insulin ratio perature, reduces gastric emptying, and may be considered to increase GLP-1 decreases with exenatide administration, activates sympathetic outflow and the hy- within the upper physiologic range, have suggesting improvement in ␤-cell func- pothalamic-pituitary-adrenal axis. The much less weight loss effect than GLP-1-R tion. In open-label extension studies with GLP-1 antagonist exendin-9, when in- agonists. 392 persons, A1C decreased 1.2% and fused in the fourth ventricle, decreases the Bo Ahre´n (Lund, Sweden) presented body weight decreased progressively by anorexic response to other stimuli, sug- a perspective on the potential of GLP-1 4–5 kg from ϳ100 kg, with A1C remain- gesting that central GLP-1 may mediate a analogs and of DPP-IV inhibitors in the ing suppressed over 82 weeks in 265 per- number of food aversion responses. In treatment of diabetes. GLP-1 has multiple sons. HDL cholesterol and triglyceride neonatal rats treated with monosodium desirable effects and targets key defects in levels also decreased, presumably at least gluconate, which induces lesions in the type 2 diabetes, stimulating insulin secre- in part related to the reduction in body arcuate nucleus, GLP-1–mediated an- tion in a glucose-dependent manner, re- weight. Preliminary 2-year data suggest orexia is prevented under a variety of cir- ducing the likelihood of hypoglycemia, ongoing benefit with 5.5-kg weight loss cumstances. increasing ␤-cell mass in animal models and stable A1C lowering. Nausea occurs Thus, central food intake, aversion, with the potential to modify long-term in approximately half of patients on initi- and stress responses are mediated by the disease progression, decreasing gluca- ation of treatment, but treatment discon- GLP-1R, presumably with different re- gons secretion, leading to reduction in he- tinuation is required in only ϳ4%. sponses mediated in different areas of the patic glucose output, delaying gastric Hypoglycemia was seen in combination brain, leading D’Alessio to comment, emptying with consequent inhibition of with sulfonylurea. Low-titer antibodies “GLP-1 sits right in the middle of an ill- glucose influx from the gastrointestinal are found but do not affect the efficacy of ness- and stress-integrative system.” Cen- tract, possibly increasing insulin sensitiv- the agent. tral GLP-1R activation may be indirect, ity after chronic administration, and de- Liraglutide is a GLP-1 analog contain- via activation of hindbrain GLP-1 neu- creasing food intake. The stimulation of ing a fatty acid moiety, not degraded by rons, as seen following psychogenic insulin in a glucose-dependent fashion, DPP-IV, leading to slower absorption and stress, may involve GLP-1R activation in the inhibition of glucagon, and the ability prolongation of action. Ahre´n described a the circumventricular organs, may in- to increase ␤-cell mass are functions not 5-week study with or without metformin volve GLP-1 transport across the BBB, or achievable by other existing diabetes showing reduction in fasting glucose and may occur via activation of peripheral af- treatments. 1% decrease in A1C (despite the short du- ferent nerves. A GLP-1–albumin conju- Studies more than a decade ago ration of study) with reduction in body gate, which does not cross the BBB, does showed that GLP-1 reduces the meal- weight by 1–2 kg. Usually, this agent also activate central GLP-1 response when ad- related exogenous insulin requirement in causes transient nausea in approximately ministered to the circumventricular or- type 2 diabetes, presumably related to ef- one-quarter of patients and does not lead gans, suggesting their importance. fects on glucagon and on gastric emptying to antibody formation. CJC-1131 is a Exenatide may be transported across the (4). Infusion of GLP-1 over a several-hour GLP-1 analog covalently bound to albu- BBB and therefore may act at a number of period to persons with type 2 diabetes de- min, leading to a 10-day half-life, with central nervous system sites. An addi- creases glucose and increases C-peptide evidence of therapeutic benefit in persons tional aspect of GLP-1 action is that the levels during hyperglycemia, but not with type 2 diabetes. adaptive responses seen with many other when the glucose level is normal (5). Fol- Reviewing studies of DPP-IV inhibi- factors do not occur with long-term ad- lowing a 6-week period of GLP-1 infu- tors, which appear to be weight-neutral

DIABETES CARE, VOLUME 29, NUMBER 2, FEBRUARY 2006 451 Perpsectives on the News rather than causing weight loss, but caused 25–30% lowering of adult body (abstract 482) reported that analysis of which are administered orally and do not weight, suggesting that glucagon sup- metformin and metformin- plus sulfonyl- cause nausea, Ahre´n noted that vildaglip- pression may contribute to the weight loss urea-treated persons given exenatide tin binds with high affinity to DPP-IV, in- occurring with GLP-1 agonist treatment. showed that the agent improved insulin creasing GLP-1 levels approximately Duttaroy et al. (abstract 267) adminis- secretion. Maggs et al. (abstract 485) re- threefold. In patients with baseline A1C tered the DPP-IV inhibitor vildagliptin ported no correlation of the reduction in 7.2%, the GLP-1 response to a standard orally or exendin-4 parenterally begin- A1C or weight loss on exenatide with ei- meal increased with an 18-mg/dl reduc- ning 5 days before streptozotocin admin- ther early or late experience of gastroin- tion in fasting glucose levels and with im- istration in mice, showing similar testinal side effects. Ratner et al. (abstract provement in the 24-h glucose profile improvement in glycemia, with evidence 10) administered the albumin-bound following a 4-week treatment period, of enhanced differentiation of pancreatic GLP-1 conjugate CJC-1131 at two doses with lower glucagon and without change progenitor cells after both treatments. versus placebo for 12 weeks to 81 persons in circulating insulin levels. In a 52-week Duttaroy et al. (abstract 572) reported treated with metformin, with baseline study of 107 persons receiving met- that vildagliptin increased islet cell mass A1C 7.9% decreasing 0.6 and 1.1% vs. formin, with baseline A1C 7.7%, the fast- 50% and increased islet insulin content placebo with lower and higher dosages. ing glucose decreased 10 mg/dl and A1C 23% in a 3-week neonatal mouse model, Karl et al. (abstract 48) administered decreased 0.5%, while the A1C levels in- with ␤-cell mass continuing to be 43% 120 ␮g pramlintide two to three times creased 0.6% with placebo, without above baseline 1 week following discon- daily to 166 insulin-treated type 2 dia- change in body weight. Ahre´n showed tinuation of treatment. Carter et. al (ab- betic persons, showing that weight de- similar effect of the other DPP-IV inhibi- stract 270) administered exenatide and/or creased 2.8 kg and that A1C decreased tors being developed, with sitagliptin lisofylline, an anti-inflammatory com- 0.6% from the initial level of 8.3%, with a (MK-0431) the best studied. In studies of pound, in a type 1 diabetic mouse model, 10% dose-related decrease in prandial in- this agent reported at the meeting, Brazg showing that with the combination of sulin requirement. Guthrie et al. (abstract et al. (abstract 11) administered 50 mg both agents diabetes could be reversed, 478) reported an open-label study of per- MK-0431 twice daily versus placebo to 28 with histology showing development of sons with type 1 diabetes receiving 30 or patients in a 4-week cross-over study, new islet-like groups of insulin-producing 60 ␮g pramlintide three to four times with 24-h glucose 125 vs. 158 mg/dl and cells. daily, with a decrease in A1C from 8 to fasting glucose decreasing 24 vs. 3 mg/dl. Heine et al. (abstract 9) compared ex- 7.8%, a 3-kg decrease in body weight, and Herman et al. (abstract 541) treated 552 enatide versus insulin glargine in a 26- a 22% reduction in rapid-acting insulin persons with placebo, or MK-0431 25, week study of 283 vs. 268 persons treated doses after 26 weeks. Nausea and vomit- 50, or 100 mg daily, or 50 mg twice daily, with metformin and/or a sulfonylurea, ing occurred in 40 and 8% of patients, finding a modest dose-response effect showing fall in A1C from 8.2 and 8.3% to respectively, and 23% experienced at with placebo-adjusted decrease in A1C 7.2 vs. 7.1%, with a 2.3-kg weight loss vs. least one episode of severe hypoglycemia from baseline 7.6–7.8% by 0.4–0.7%, a 1.8-kg weight gain. Exenatide reduced during the study period. and with decrease in fasting glucose by postprandial glucose excursions follow- 11–17 mg/dl. The fall in A1C in the ing breakfast and dinner, while glargine Leptin and adiponectin 100-mg daily group was 0.4, 0.6, and predominantly reduced fasting glucose, Several presentations at the meeting 0.8% for baseline A1C Ͻ7, 7–8.5, and suggesting that the two agents may offer based on the Atherosclerosis Risk in Com- 8.5–10%, respectively. Scott et al. (ab- complementary approaches to treatment. munities (ARIC) study suggested that stract 41) reported a 12-week study of Kendall et al. (abstract 16) and Blonde et substances produced by adipocytes are monotherapy with the agent in 743 per- al. (abstract 477) reported 82-week, relevant to the development of diabetes. sons, with placebo-corrected A1C de- open-label, extension study results with Duncan et al. (abstract 364) studied com- crease from 7.9 by 0.8%, without change exenatide in 256 persons, as well as effects plement C3, which is produced by adipo- in body weight as opposed to a 1.1-kg in 128 persons receiving placebo for the cytes, and which, in addition to its weight gain with 5–20 mg glipizide daily. first 30 weeks, showing weight loss aver- immune actions, is a precursor to acyla- Two vs. 21 patients treated with MK- aging 4.6 kg, sustained A1C reduction of tion-stimulating protein, stimulating tri- 0431 vs. glipizide experienced one or 1.2%, and weight loss–related decreased glyceride synthesis. In 581 persons more hypoglycemic event. triglyceride, diastolic blood pressure, and developing diabetes and 572 control sub- A number of studies presented at the LDL cholesterol, as well as increase in jects in the ARIC study, the risk of diabe- ADA meeting illustrated further aspects of HDL cholesterol. Linnebjerg et al. (ab- tes in the second through fourth C3 GLP-1 physiology and its therapeutic po- stract 469) reported that exenatide, which quartiles was 1.6- to 2-fold greater than tential. Parsons et al. (abstract 589) re- is cleared by the kidneys, has half-life av- that in the lowest quartile, adjusting for ported that in a type 2 diabetes animal eraging 1.5 h in persons with normal re- age, sex, ethnicity, study center, parental model, overexpression of GLP-1 was as- nal function, 2.1 h in those with history of diabetes, hypertension, BMI, sociated with evidence of improvement in creatinine clearance 60–80 ml/min, 3.2 h waist-to-hip ratio, fasting glucose, and in- islet cell function as well as in glucose lev- in those with clearance 35–50 ml/min, sulin at baseline. Schmidt et al. (abstract els. Bodvarsdottir et al. (abstract 500) ad- and6hinthose with clearance Ͻ30 ml/ 1052) similarly presented a case-control ministered the GLP-1 analog liraglutide in min, with worse gastrointestinal side ef- analysis from ARIC participants, showing a type 2 diabetes animal model, showing fects in the latter group, leading to the that there was an association between lep- dose-related normalization of glycemia. suggestion that the agent can be adminis- tin and diabetes risk, with the second, Mu et al. (abstract 53) found that gluca- tered without dose adjustment to persons third, and fourth sex-specific quartiles of gon receptor deletion in ob/ob mice with clearance Ͼ35 ml/min. Mari et al. leptin having 1.6-, 2.3-, and 4-fold

452 DIABETES CARE, VOLUME 29, NUMBER 2, FEBRUARY 2006 Bloomgarden greater risk than the lowest quartile. After tumor necrosis factor (TNF)-␣, angio- against high-fat diet–induced obesity, at adjustment for BMI, waist, inflammation tensinogen, and adipokines including least in part due to increased hypotha- score, hypertension, triglycerides, insu- adiponectin and resistin. An additional lamic leptin-mediated STAT3 activation. lin, and fasting glucose, leptin was seen to adipocyte process is the intracellular pro- SOCS3, then, appears to be rate limiting, be protective, with the second through duction of active glucocorticoids, as seen with mice having neuron-specific dele- fourth quartiles having 7, 42, and 61% in the action of 11-␤ hydroxysteroid de- tion of SOCS3, despite reduced leptin lev- lower risk of diabetes, respectively, sug- hydrogenase-1 on cortisone to increase els, more sensitive to leptin and protected gesting that leptin resistance is the risk levels of cortisol. An important adipocyte against diet-induced obesity, showing im- factor, with leptin itself having antidia- secretory product is leptin, which rises as proved glucose homeostasis. betic effects. The implications of these adipocyte mass increases and signals the Flier speculated that SOCS3 may also studies and of much related research were brain to decrease food intake and increase play a role in insulin action, as its overex- the topic of a number of fascinating pre- energy expenditure. It is likely that reduc- pression decreases insulin signal trans- sentations. tion in the level of leptin with starvation duction and as adipocytes with SOCS3 Jeffrey Flier (, MA) gave the serves as a starvation signal (7), causing deletion showed increased insulin- Banting Lecture on the interrelationship hunger, suppression of energy expendi- stimulated glucose uptake and reduced between fat and the brain, as well the reg- ture, and changes in thyroid and repro- ability of TNF-␣ to suppress insulin ac- ulation of energy balance. He noted the ductive hormones (8,9), leading to weight tion. SOCS3 appears, then, to be induced interaction of obesity and diabetes and regain. both by leptin and by insulin in some of the rising prevalence of obesity in the U.S. Most obese humans have increased their target cells and to antagonize their and worldwide, with consequent increase levels of leptin but are resistant to its cen- actions. SOCS3 is induced by FFAs and in cardiovascular disease and malignancy. tral actions. Flier explored the mechanism by resistin and appears to be necessary for In the Nurses Health Study, the risk of of this phenomenon. There is no evidence resistin-induced . The diabetes increased nearly 100-fold com- of circulating antagonists. The blood- mechanism of FFA-induced insulin resis- paring a BMI of 20 with that of 35 kg/m2 brain leptin barrier may play a role in lep- tance is more complex, with SOCS3, pro- (6). From an evolutionary perspective, tin resistance. Leptin resistance may also tein kinase C ␪, Janus kinase, peroxisome starvation is a greater threat to survival be a function of decreased postreceptor proliferator–activated receptors (PPARs), than obesity, resulting in the growing ep- response. The hormone acts at two neu- and the inhibitor of nerve factor-␬B ki- idemic of obesity with excess food avail- ronal systems, one producing proopio- nase all involved. FFA uptake interacts ability. Obesity results both from genes melanocortin (POMC) and cocaine- with toll-like receptor (TLR)4, the oblig- and from the environment. The most amphetamine–regulated transcript atory receptor for lipopolysaccharide (en- common monogenic abnormality associ- (CART), causing catabolic effects and dotoxin), and activates the macrophage ated with obesity is the loss-of-function weight loss and activated by leptin, and innate immune response. TLR4 may be mutation in the melanocortin (MC)-4 the other producing agouti-related pep- present on adipocytes and mediate FFA gene, accounting for 3–4% of severe obe- tide (AGRP) and neuropeptide Y (NPY), effects, with evidence that mice not ex- sity. There are likely to be many polygenic causing food intake and inhibited by lep- pressing TLR4 show reduced response to abnormalities, most of which have not tin. POMC stimulates and AGRP inhibits high-fat diets and to lipid infusion, sug- been identified. Environmental factors in- the MC-4 receptor in the paraventricular gesting TLR4 to be a link between the in- clude the easy and inexpensive availabil- nucleus and ventromedial hypothalamus. nate immune system and the ity of food in much of the world, Other circulating factors related to central inflammatory signals contributing to in- particularly that of foods increasing the control of food intake and energy balance sulin resistance. development of obesity, in the setting of include insulin, gastrointestinal peptides Returning to the response of central reduced activity. such as ghrelin and peptide YY, serotonin, circuits regulating energy balance to pe- The brain controls many aspects of cannabinoids, glucose, and FFAs. Multi- ripheral signals such as leptin, Flier appetite, food intake, physical activity, ple sites in the hypothalamus and else- pointed out the important concept of thermogenesis, metabolic fluxes, repro- where in the brain are involved in the neural plasticity, so that, for example, the duction, growth, and thyroid activity, process. number and direction of neural projec- with the hypothalamus particularly in- Leptin receptor activation leads to tions at hypothalamic sites can be regu- volved in regulation of energy balance, its tyrosine phosphorylation via Janus lated by leptin, the number of synaptic with multiple brain signaling mecha- kinase 2, leading to signal transducers inputs can be regulated by ghrelin, and nisms both increasing and limiting food and activators of transcription (STAT)3 the number of functional neurons can be intake, involving olfaction, taste, visual activation, with subsequent nuclear tran- modified by ciliary neurotrophic factor signals, and the more complex memories scription effects essential for appetite/ (CNTF). CNTF is a 22,000–molecular and associations involved in central re- metabolism regulation. In a negative weight protein expressed in astrocytes, ward circuitry. The challenge, Flier sug- feedback loop, STAT3 activates the sup- acting as a trophic factor for motor neu- gested, is to understand the integration of pressor of cytokine signaling (SOCS)3 in rons in the ciliary ganglion and stimulat- these diverse signals. both POMC/CART and in NPY/AGRP ing cell survival. CNTF ameliorates Adipose tissue acts not only as a site of neurons, leading to inhibition of leptin obesity in leptin-deficient and diet- energy storage but also as an endocrine action, and likely responsible for the lep- induced models, activating STAT3 signal- gland, producing substances including tin resistance associated with obesity. ing, with clinical studies suggesting free fatty acids (FFAs), estrogen, adipsin Heterozygotes with partial lack of SOCS3 weight loss that persists after completion (a complement-related protein that is expression have reduced fat mass and in- of treatment, perhaps because of stimula- suppressed in obesity), cytokines such as creased leptin sensitivity, with protection tion of hypothalamic neurogenesis. Neu-

DIABETES CARE, VOLUME 29, NUMBER 2, FEBRUARY 2006 453 Perpsectives on the News ral stem cells do give rise to new neurons a number of adiponectin polymorphisms tal adiponectin and to high portal FFAs, throughout life, as has particularly been associated with diabetes, and the suscep- both of which have important effects on found in the dentate gyrus of the hip- tibility locus for type 2 diabetes and the hepatic metabolism. pocampus, playing a role in memory, and metabolic syndrome on chromosome A novel family of cytokines includes in the subventricular zone, having effect 3q27, where the adiponectin gene is lo- resistin and resistin-like molecules, on olefaction. Direct central administra- cated, appears to act by decreasing circu- which have effects opposite to those of tion of CNTF causes neurogenesis with lating adiponectin levels. adiponectin on hepatic insulin sensitivity. expression of neuropeptides including Adiponectin circulates in forms made Resistin has highly exposed disulfide NPY and POMC, potentially both activat- up of different numbers of adiponectin bonds, with forms of resistin not able to ing neural signaling and causing growth monomers, making it difficult to deter- form disulfide bonds having decreased of new leptin-responsive cells. Flier com- mine the circulating biologically relevant activity, a phenomenon also seen with mented on another peptide, melanin- level. The higher levels in females appear adiponectin. The redox potential of the concentrating hormone (MCH), which due to higher–molecular weight forms, endoplasmic reticulum is determined by stimulates food intake, with MCH antag- which appear to be metabolically active, cellular glutathione, which has important onists having potential benefit in the with PPAR␥ agonists primarily increasing effects on the formation of these disulfide treatment of obesity. these forms of adiponectin (10). Con- bonds. As adipocyte glucose uptake does Philipp Scherer (Bronx, NY) received versely, type 2 diabetes is associated with not decrease with increasing glucose ex- the ADA Outstanding Scientific Achieve- particular reduction in the high– posure, hyperglycemia leads to increased ment Award for his research on adipose molecular weight forms, with levels de- adipocyte reactive oxygen species pro- tissue, which he placed in clinical context creasing progressively as glycemia duction, contributing to inflammatory by reviewing the increasing prevalence of worsens. The ratio of low-to-high molec- adipocyte changes, with activation of obesity in the U.S. and worldwide. He ad- ular weight forms appears to show partic- nerve factor-␬B triggering the inflamma- dressed new understanding of the adipo- ularly close correlation with insulin tory cascade and worsening insulin sensi- cyte based on a series of mouse models resistance (11). tivity, as well as lowering glutathione with relevance to clinical disease. Excess In transgenic mouse models overex- levels. The insulin resistance further adipose tissue, but also lipoatrophy and pressing adiponectin, insulin sensitivity is worsens adipocyte oxidative stress, pro- lipodystrophy, are associated with insulin increased, lipids improved, and the ad- ducing a positive feedback cycle. PPAR␥ resistance. The absence of adipose tissue verse effect of high-fat diet is lessened, agonists decrease glutathione molecular leads to dysregulation of triglyceride and with increased brown adipose tissue de- chaperones in addition to having direct fatty acids and fat deposition in muscle pots, perhaps increasing the metabolic antioxidant effects. and liver, and to abnormalities of adipo- rate. In leptin-deficient ob/ob mice, over- Examining a lipodystrophic fat model kines, suggesting the importance of this expression of adiponectin improves gly- termed FAT-ATTAC (fat apoptosis tissue in maintaining normal insulin sen- cemia, islet morphology, and ␤-cell through triggered activation of caspase 8), sitivity. Adipose tissue also has effects on function, with more efficient triglyceride leading to the ability to induce acute com- inflammation, leading to effects on energy clearance due in part to higher levels of plete fat loss after maturation, with the metabolism, metabolic syndrome, cardio- adipocyte lipoprotein lipase. Smaller adi- ob/ob mutation, FAT-ATTAC mice have vascular disease, and malignancy. Adi- pocytes are seen, concordant with im- low insulin levels, loss of ␤3 agonist insu- pose tissue is the only organ with proved metabolism. Administration of lin response, and dramatically increased unlimited growth potential at every stage neutralizing adiponectin antibodies re- food intake. The mice have increased of life, producing factors with effects on verses these improvements. However, body core temperature and decreased in- the vasculature, liver, muscle, brain, re- adiponectin overxpression in these mice flammatory markers, with reduction in productive tract, and ␤-cells. increases their fat mass despite the im- response to endotoxin. There is evidence Adiponectin, Scherer noted, strongly proved metabolic health, suggesting po- that macrophages present in adipose tis- resembles the proinflammatory cytokine tential adverse effects of increased sue mediate much of the increase in cir- TNF-␣. Adiponectin infusion decreases adiponectin, although depositing lipids culating inflammatory markers in obesity, hepatic glucose production by increasing in adipocytes appears far more desirable perhaps in response to paracrine signals the hepatocyte response to insulin, sug- than that in sites such as muscle and liver, from adipocytes. Thus, a number of ques- gesting that it acts as an endogenous in- which worsen insulin sensitivity. The ef- tions remain to be addressed in under- sulin sensitizer. Despite its exclusive fects of adiponectin are remarkably simi- standing adipocyte physiology, including production in adipocytes, adiponectin lar, then, to those of the PPAR␥ agonists. fuller characterization of adipocyte secre- levels are lowest in persons with high fat In mice not expressing adiponectin, the tory factors and receptors, in particular mass, and levels also tend to be low in response to PPAR␥ agonists is reduced, those for resistin and resistin-like mole- persons with evidence of inflammation or and the agents fail to improve glucose tol- cule. Scherer also touched on the impor- of atherosclerosis. Adiponectin has anti- erance or to increase hepatic AMP- tance of determining the mechanism of atherosclerotic effects in suppressing the activated protein kinase activity. Scherer leptin action, and the role of the macro- endothelial inflammatory response and pointed out that visceral fat stores are ma- phage in adipose tissue. He noted that an- inhibiting vascular smooth muscle cell jor sites of adiponectin production, so giogenesis inhibitors have marked effects proliferation. Adiponectin levels are that hepatic exposure to adiponectin may on adipocytes, suggesting a future direc- higher in women than in men, lower in be particularly high because of higher tion for the treatment of obesity. lipodystrophy and in type 2 diabetes, portal venous levels. Visceral obesity may Streamson Chua (New York, NY) dis- higher in type 1 diabetes, and increase therefore be particularly damaging in in- cussed additive and synergistic interac- with PPAR␥ agonist treatment. There are sulin-resistant states, leading to low por- tions of leptin-sensitive neurons,

454 DIABETES CARE, VOLUME 29, NUMBER 2, FEBRUARY 2006 Bloomgarden beginning with an overview of the neural There is a relatively linear relationship of cose utilization and increase in FFA utili- connections from leptin-sensitive neu- 24-h energy expenditure to body mass zation also returning to baseline. Weight rons. Leptin is produced by white and across all mammalian species (12), and loss decreases thyroxin and triiodothyro- brown fat, signaling both orexigenic neu- Rosenbaum described a linear relation- nine, with both normalized by leptin, al- rons (NPY, AGRP, MCH, and hypocretin), ship between fat-free mass and 24-h en- though the decrease in thyroid-stimulating and anorexogenic neurons (melanocyte- ergy expenditure in human studies. hormone with weight loss is not restored stimulating hormone, CART, corticotrop- During 6- to 8-week periods of fixed com- by leptin. Urinary catecholamine excre- in-releasing hormone, and thyrotropin- position liquid diets at basal, 90%, and tion and sympathetic nervous system ac- releasing hormone), in the arcuate 80% weight, however, weight loss re- tivity were decreased by weight loss and nucleus, NPY/AGRP and POMC/CART duces the expected energy expenditure, increased by leptin replacement. These neurons, in the paraventricular nucleus with persons who lose 10% of body actions of leptin are concordant with its corticotropin-releasing hormone and thy- weight having ϳ20% lower fat-free mass– known effects, then, and suggest that the rotropin-releasing hormone neurons, and adjusted caloric requirement, a phenom- hormone may have therapeutic benefit in the lateral hypothalamic area MCH and enon that persists over years. Energy following weight loss in obese persons. hypocretin neurons. These neurons in expenditure includes the resting energy Christos Mantzoros (Boston, MA) ex- turn have multiple interconnections, sug- expenditure (REE), the non-REE, caloric tended these observations, discussing po- gesting both direct and indirect effects of expenditure required for physical activ- tential therapeutic uses of leptin in low- leptin on these and other neurons. ity, and the thermic effect of feeding. With leptin states. He noted that leptin acts in The leptin receptor is a class I cyto- 10% weight loss, Rosenbaum described muscle, brown and white adipose tissue, kine receptor of the interleukin-6 family. reductions not only in REE but also a 40% liver, and macophages, as well as in brain. Animals with a defective leptin receptor decrease in non-REE, together accounting Leptin administration to children with develop hyperphagia, obesity, insulin re- for 89% of the change in total energy ex- leptin deficiency restores normal weight. sistance, glucose intolerance, brown fat penditure. Thus, after weight is lost, skel- In a study of leptin administration to 73 atrophy, cold intolerance, hypothalamic etal muscle work efficiency at low levels of leptin-deficient heterozygotes, there was hypogonadism, and adrenal hyperfunc- activity increases by 15–20%, associated a dose-response weight loss effect, sug- tion. Chua described studies utilizing with preferential use of fatty acids as fuel, gesting potential benefit for these individ- three different receptor alleles, Lepr-neo, and accounting for 35% of the reduction uals as well. This is not, however, a Lepr-flox, and Lepr-d17, the latter lack- in nonresting nervous expenditure. common cause of severe obesity in hu- ing the STAT3 activation site, allowing Rosenbaum noted that these changes are mans. Leptin has a direct relationship to study of the effects of defective leptin re- similar to those occurring with leptin de- body fat, so that in the vast majority of ceptors at the POMC/CART, NPY/AGRP, ficiency, with both weight–reduced and persons’ obesity is associated with leptin or both sets of neurons. Body weight was leptin-deficient persons being hypometa- resistance rather than deficiency, while increased in the mice lacking receptors at bolic and hyperphagic, and showing de- low leptin “is the signal . . . that there are both sites and to a lesser extent in those creased sympathetic and increased not enough calories, ” and is associated lacking receptor at one site, particularly parasympathetic tone. He suggested that with energy deficiency, with low leptin in without leptin receptors at AGRP neu- leptin is a negative regulator defending turn reducing levels of reproductive hor- rons. Lean tissue mass particularly in- body fatness rather than increasing with mones, thyroid hormone, and IGF-1. creased in females, due to increased linear weight gain to preserve thinness, noting Leptin-deficient mice and humans have growth, while fat mass tripled in females that from an evolutionary perspective the not only extreme obesity but also delayed and doubled in males with the dual recep- imperative is to decrease energy expendi- pubertal development, with replacement tor deletion. Adrenal hyperfunction and ture and fertility during periods of under- increasing gonadotropins and leading to hyperinsulinemia were seen with the dual nutrition, so that leptin exhibits puberty onset in leptin-deficient persons. receptor defect, although insulin levels “asymmetric regulation, ” with reduction Leptin plays a role in the initiation of nor- are higher in db/db mice completely lack- in levels causing hyperphagia, hypome- mal puberty (13). Women with hypotha- ing the leptin receptor, and fasting glu- tabolism, infertility, hypothyroidism, and lamic amenorrhea have low estrogen, low cose was not increased, suggesting that hypercortisolemia. The weight-reduced or normal gonadotropins, low thyroid other leptin-sensitive neurons, presum- state, then, is perceived by the brain as hormone, increased growth hormone but ably in the ventral hypothalamic nucleus one of relative leptin insufficiency, lead- decreased IGF-1, increased cortisol, and and the lateral hypothalamic area, also ing to adaptations aimed at preservation infertility and bone loss with increased contribute to the actions of leptin on body of fat mass. This concept predicts that lep- risk for stress fracture. This occurs in composition, insulin sensitivity, and fer- tin administration will have little or no women during stress, weight loss, low tility. effect in states of leptin sufficiency, but weight for height, and/or strenuous exer- Michael Rosenbaum (New York, NY) might have significant impact following cise, with the set of abnormalities seen in discussed aspects of regulation of body weight loss. To study this, leptin was ad- ϳ5% of college-age women. These weight, reviewing the concept that “the ministered to restore baseline levels in women have low leptin levels and absence brain knows how many calories ” to store persons who had had 10% weight loss. of the normal diurnal leptin pattern. Ad- and suggesting that leptin constitutes the Energy expenditure in skeletal muscle de- ministration of leptin to six such women signal and that relative leptin deficiency creased with weight loss and was restored for 2 months led to increase in leptin lev- must be present in obesity. Body fatness is almost to baseline with leptin administra- els, with associated ovulation and im- more strongly heritable than schizophre- tion. The work efficiency of skeletal mus- provement in ovarian and endometrial nia, hypertension, seizure disorders, cor- cle increased with weight loss, and this morphology and improvement of hypo- onary artery disease, or breast cancer. reversed with leptin, the decrease in glu- thalamic function. Increased bone forma-

DIABETES CARE, VOLUME 29, NUMBER 2, FEBRUARY 2006 455 Perpsectives on the News tion was suggested by increased osteocalcin tract, the adipocyte, and the brain. The type 2 (non-insulin-dependent) diabetic and bone alkaline phosphatase (9). knowledge gained may have important patients. Diabetologia 36:741–744, 1993 Lipoatrophy, both the spontaneous benefits in a number of states related to 6. Colditz GA, Willett WC, Rotnitzky A, form and that caused by antiretroviral diabetes and insulin resistance, as well as Manson JE: Weight gain as a risk factor for treatment of HIV, is associated with insu- having potential applicability in under- clinical diabetes mellitus in women. Ann lin resistance. In persons with congenital standing and treatment of adverse effects Intern Med 122:481–486, 1995 lipoatrophy and diabetes, leptin treat- of hypocaloric states. It is intriguing to 7. Ahima RS, Prabakaran D, Mantzoros C, ment lowered triglyceride, A1C (by speculate that some of the mechanisms of Qu D, Lowell B, Maratos-Flier E, Flier JS: ϳ3%), and liver fat. In a controlled trial of benefit of agents acting at the level of Role of leptin in the neuroendocrine re- HIV-infected persons with lipoatrophy GLP-1 may be better understood with un- sponse to fasting. Nature 382:250–252, 1996 and insulin resistance, leptin replacement derstanding of the effects of leptin and of 8. Chan JL, Heist K, DePaoli AM, Veldhuis improved insulin resistance and hyperlip- adiponectin, and that the discovery of ad- JD, Mantzoros CS: The role of falling lep- idemia. Two studies addressing leptin ditional signaling processes derived from tin levels in the neuroendocrine and met- treatment of lipodystrophy were pre- these three tissues will have profound ef- abolic adaptation to short-term starvation sented at the ADA meeting. Javor et al. fects on future therapy of metabolic dis- in healthy men. J Clin Invest 111:1409– (abstract 47) administered twice-daily re- orders. 1421, 2003 combinant methionyl human leptin for 9. Welt CK, Chan JL, Bullen J, Murphy R, 12 months to 15 persons with generalized Smith P, DePaoli AM, Karalis A, Mantzo- References lipodystrophy, showing decrease in fast- ros CS: Recombinant human leptin in ing glucose from 205 to 126 mg/dl, in 1. Zander M, Madsbad S, Madsen JL, Holst JJ: Effect of 6-week course of glucagon- women with hypothalamic amenorrhea. A1C from 9 to 7.1%, in triglycerides from like peptide 1 on glycaemic control, insu- N Engl J Med 351:987–997, 2004 1,380 to 516 mg/dl, and in LDL choles- lin sensitivity, and beta-cell function in 10. Tonelli J, Li W, Kishore P, Pajvani UB, terol from 139 to 85 mg/dl, with a 40% type 2 diabetes: a parallel-group study. Kwon E, Weaver C, Scherer PE, Hawkins reduction in liver volume and a 4-kg Lancet 359:824–830, 2002 M: Mechanisms of early insulin-sensitiz- weight loss. In a similar study with this 2. Turton MD, O’Shea D, Gunn I, Beak SA, ing effects of thiazolidinediones in type 2 treatment for up to 30 months, Kusakabe Edwards CM, Meeran K, Choi SJ, Taylor diabetes. Diabetes 53:1621–1629, 2004 et al. (abstract 610) showed early reduc- GM, Heath MM, Lambert PD, Wilding JP, 11. Pajvani UB, Hawkins M, Combs TP, Ra- tion in glycemia and reduction of urinary Smith DM, Ghatei MA, Herbert J, Bloom jala MW, Doebber T, Berger JP, Wagner albumin excretion in patients with overt SR: A role for glucagon-like peptide-1 in JA, Wu M, Knopps A, Xiang AH, albuminuria. the central regulation of feeding. Nature Utzschneider KM, Kahn SE, Olefsky JM, 379:69–72, 1996 Thus, leptin is the peripheral signal of Buchanan TA, Scherer PE: Complex dis- 3. Thiele TE, Van Dijk G, Campfield LA, tribution, not absolute amount of adi- adequate energy stores required for nor- Smith FJ, Burn P, Woods SC, Bernstein IL, mal body weight regulation, insulin sen- ponectin, correlates with thiazolidinedione- Seeley RJ: Central infusion of GLP-1, but mediated improvement in insulin sen- sitivity, and immune, reproductive, and not leptin, produces conditioned taste sitivity. J Biol Chem 279:12152–12162, aversions in rats. Am J Physiol 272:R726– neuroendocrine function. It may repre- 2004 R730, 1997 sent a better treatment for hypothalamic 12. Kleiber M: Metabolic turnover rate: a 4. Gutniak M, Orskov C, Holst JJ, Ahren B, amenorrhea than estrogen, with other physiological meaning of the metabolic disease states potentially responding to Efendic S: Antidiabetogenic effect of glu- cagon-like peptide-1 (7–36)amide in nor- rate per unit body weight. J Theor Biol 53: leptin including anorexia nervosa, de- 199–204, 1975 layed puberty, and a variety of related mal subjects and patients with diabetes mellitus. N Engl J Med 326:1316–1322, 13. Mantzoros CS, Flier JS, Rogol AD: A lon- conditions. We appear ready to enter a 1992 gitudinal assessment of hormonal and new stage in the therapy of obesity and 5. Nauck MA, Kleine N, Orskov C, Holst JJ, physical alterations during normal pu- related conditions, applying seemingly Willms B, Creutzfeldt W: Normalization berty in boys. V. Rising leptin levels may disparate areas of research regarding pep- of fasting hyperglycaemia by exogenous signal the onset of puberty. J Clin Endocri- tides derived from the gastrointestinal glucagon-like peptide 1 (7–36 amide) in nol Metab 82:1066–1070, 1997

456 DIABETES CARE, VOLUME 29, NUMBER 2, FEBRUARY 2006