Case SAUL M. GENI A patient with obesity and diabetes mellitus had insulin secretion studies done during a 3.year yc of weight loss and regain inthe course of which she progressed from frank. diabetes to a normal state of carbohydrate tolerance and then back to her original diabetic state. The results suggest that therapeutic weight reduction not only reverses insulin resistance but also restores beta cell sensitivity and ‘ennances beta cell capacity. The eventual reestablishment of a degree of obesity, hyperinsulinemia, and carbohydrate intolerance virtually igentical to that originally seenis, ‘compatible with a primary disorder involving hypothalamic control of adipose stores and insulin secretion. Qnese_sworwimuars display _byperinsulinism (1), TWith weight loss (5-7) anc eight individuals by overfeet: isi Which can be Fevers which ‘ean be induced mn normal ng that leads to adiposity (8). They also ex! ‘Tesibiance (O-LI.Waich Fas been sssochuted reased numbers of insulin receptors on cell membranes individuals are characterized by insulin Brassed to Tasting hyperglycemia (3, 16); before that time they may also exhibit a degree of insulin resistance (17) ‘Therefore, patterns of insulin secretion seen in indivihu- als with both obesity and diabetes reflect the contradictory influence of each state (2, 14, U8 30). We have studied insulin secretion over a 3-year net fod ih at obese diabetic worsan during four consecutive Res trst- whey she-was both qussively_obese and ‘Frankly alabetic, second, afer weight loss wMin she was” esi O6SSE Snag lonaee Gubetie third, when © ‘complex ans may Tinally, when she 0 ne both massive ‘and frankly diabet “FERITIS OF THIS BATTY “Tstrate The aymamctinterplay among hyperslimenta: tion, obesity, beta cell function, and glucose metabolism. ase Report TA 29-yearold white whman was admitted to the Saltzman Institute for Chical Investigation, Mt. Sinai Hospital, in No- vember 1972, with a 4secgk history of polyuria, nocturia, poly Uipsia, blurred vision, vaginal prustus, and a recent episode of oral thrash: During hospitalization 2 yeats before, she had fed a fasting blood glucosg of 100 mg/dl and a 2-h postprandial blood glucore of 188 mg/al, Because of mildly abnordhat liver demons therapy for diabetes in the interim: Obesity began in hihi She weighed 727 kg at age 18, 1.8 kg. at age 20, and betwen 86-4 and 100 kg from age 24 to age 29. The lower weights engl the result of short-term attempts at dieting during which wg¥ 0 loss never eacceded 112 kg, Past history included pneamaq’ find atelesta veal cord paralysis; repeated eye, inary ab ions 2 lgementous back injury, and ae 4 ‘war postive for dlabeten, coro 5 2 Piya exominaton showed a highs of 155 em, weight | sg (1755 of eal body weigh; blood presre, 120/803 puke, 38 The patents obsty was gnetalieed. A scot Mig’ ‘opal discharge and eythematows peres! skin were 26 ‘The Teale the remander ofthe exumnaton were cb ‘Fasting plasma glucose was 282 mg/d urinalysis shows o sia ghcose, lage acetone, 2, pron, seciment nei danceulture wis nepave, vaginal core showed Jest ow 2 24h urine glucose excretion was 66 g, complete blood soil chetistnes yee Tanetion fxs, an pam cota) aera teanetisenesupesion waa Soma risa oq cheatin wine a cd tistng (i) wan begun shortly afer semision. By 3 we fSsnnynlasna glucose had deoreased 10 98 m/l BSAA hd Wstppence and weight had droppes to 88 hy. TAS {Fram an coinued on an outpatient bass unt her sat“ feached 59 kg and fasting plasma glucose 68 mg/dl ia Ma S75, The patient was then started on a conventional. wei fintenance diet, Despite intensive follow-up anc efor? Conteo! her intake, ineluding two more trials of ae fasting, she ate excessively and regained her orginal week June 1974, Diabetes remained in clinical remission, hoveag Ghul November 1978'when glycosuria and fasting plas Be 4% Lose of 272 mg/dl recurred, whereupon she was placed ov fy 1 fin treatment, Studies of insulin secretion were carried AP, previously described (3) by measuring plasma glucose an 6 EM tevels hourly from 0800 to 2300 while the patent ae Nandurd €00-alorie meals at 0800, 1500, and 1800. ila Studies were done after periods of caloric suficiency or ea 13 Ses re shown (800 to 1300) because they ae repre Sf the results observed throughout each testing day Th ose and insulin responses to cach lunch and dinner (eh i {eailable on request Ato fime throughout the study nage patient taking diuretics, oral contraceptives, aa h norenigenics, or other Grugs knowin to sect carbohydig gow abolism 2s Results and Discussion ‘, The results of the six consecutive studies of plaial _. —- , Sreakfast are shown in Figore 1. At the time the i first presented in November 1972, her weight wai 5 fasting plasma glucose was 252 mg/dl, and post plasma glucose reached 367 mg/dl. Fasting pasne i2s 42 t/t and rosé only threfold 16 pstpran Jal peg 116 Um, Tins, nally she showed sea foe Ot oss ihe ares os leas lass Teel Soneenratont i ist of those usually. seen iv otal weight Mae USlong with fisting and ponpraadiat aes an alteration in eta cll revopriiorrot ar vesponse to {ulating alco levels G2) so at a Tsing slecone OF 199 me/dl was permifted even though additional insulin [ha8 available for secretion with the further stimulus of ie meal (3), The next study was carried out when the ‘vient had seduced her weight to 39 kg by supplemented ‘{ssing and then—after resuming eatinng=had regained 10 ‘M.kz Guly 1973) AL this Time diabetes had disappeared evidenced by a fasting plasma ghicose of OT mg/al and {fk postprandial glucose of only 150 mg/l, Fasting in ia had decreased, 10 normal (17 U/ml), and post= jahinsutin-mow rose tVefoId¢9 a peak of 86 U/l ign this study oe well the next one 79 hg (Octo ¥F 1973), it is noteworthy that normal plasma glucose jeS.maintained by insulin levels equal t0 or even lower {fan those exhibited by the patient. when-she presented al Fossly diabetic State, This dramatic remis- in her diabetes. was thus largely attr sed Sei i@ inlin. An adi ‘ell responsiveness To meal Fae ee as penk poutprandal Titahowel + Oc: Tncrease over fasting insulin concentrations. Despite ited ein scose values oF 130 me? ising and 209 and 8¢'m/ch at 1 and 2 ae / Gas: Posing plasma sun once aga become He fate #9 n/m al er Gauberan poatpronal ns Lr ————™— Fesndiabetie of minimally diabetiéccbece individuals PV This marked ypecosnemi ed the dees ot Jesprancal hypergigcema and even atsed the pawn “Hucose to fall 50 mg/dl below the morning fasting level The Anh postprandial hour’ At hi key stage in rhe hee tee eof obesity vet ao Hyper Bes vee et lucose metabo as Jock Better cegulated [he importimee-of this beta-cell Sornsvty_was"shown -Honihs ter Ciarche 1973) "ered to be’ a_harbinger”of Beta’ cell d ion. ‘Ge months Turther on (November1975), still ata sught of 95 kp, a frankly diabetic state identical to that 3 years before spontaneously re-emerged, coincident Bits steep decline in postprandial, plasma insulin re- Syrses to the levels originally observed.,The full eyele fom diabetes to normal and back to' diabetes had been the patient. studies emphasizes ine aynamic relations Posrse time, Pitherageutic efforts, weight gain continued and the pa jie “Os shortly after returning to her original pe W's ke June 1974). At this time she was only nimatly a Tabet. Sringent calorie dep minimal weight loss) Tiselt sufficed to lower plasnia Biv ‘cose levels from 252 fo 98 mg/dl and concurrent plasma insulin Tans 327 19 U/ml. This inital improvement in Pepetvecmia may pt be arte oa ete inn cena eng ante ype se 2) 4). However subsequent innuln secttion sted were tried out when the palient was at a markedly reduced wight But ingesting sufcent calories to have alresdy Begun a sgmicant reaccumlaion ef adipoxe seco ‘These studies show that alleviation of obesity also clearly ameliorated inslis resistance and improsed the zespon- siveness of the beta cells as vell, This was seenaa-8 ors te ATE Tien [vels appropriate to the lessened adiposity and to the lover fasting lucose levee, vwheress mich smaller postprandial set in plasma gl one prodvced& prompt and brisk increase in innlin oe centration, suggesting jenprovement in beta cell sensitive 42.25). Furthermore, weight reduction resulted ina ree {oration of beta cell capacity (25) so that the subsequent Challenge of recurrent obesity could be metyat least for a y greatly enhanced total insulin eutput. With the continuation of the stress of hyperalimentation and obesi- tatoorwennr” 9588 "79 95" 98” 9s oeat weg (75%) (250 (458) 75H) (80x) GSR) Figure 1. Plsuna glucose ewer nae and piss insuln (upper Bare ae setts Roun trom O860 to 1500 ater gestion othe "enti! 6D0~slorin meal a 0800 ({_). The month and yer of the study iy ineiened ove each wus Curve and he Body seceht a sr ume is shown tbe doses ng an os borcon, Idea! weient. Kiran s0 for normal weight subjects given toe ert fal moots are: gucose (rg/ay 6800, 87 © 10; 0900, 114 £13, Yooo, 84 = 1.1300, 83 = 7. 1200, a8 £4, 1300. 84+ 3 inguin “u/m: “0800. 11% 0900, 106.2 62; 1000, 524 14!1400. 2047; 1200, 1345; 190010 & Gents © Oveniyana Dabwtes 715,{yy however, beta ell“funetion eventually deteriorated, ‘Thus, the development of frank diabetes in such patie appears 10 be dependent on the duration as well as the degree of obesity. The period of relative beta cell compen- sation produced by weight reduction may be influenced by the extent of subsequent hyperalimentation (19) and ‘may even end abruptly in ketoacidosis (26): This case, therefore, re-emphasizes the imperative need to develop reliable methods of weight mainteasnee after successful weight reduction in the obese diabetic Its also noteworthy that this obese patient eventwally returned precisely to her original weight and stabilized there spontaneously, This phenomenon has also been no!- ed in animals with experimentally induced obesity due to hypothalamic injury in whom surgical lipectomy is fol- lowed by further enlargement of the remaining adipos tissue Gill the original obese weight is exactly regained (27). This has suggested the existence of a hypothala lipostat which regulates caloric storage, The patient ex hibited almost identical fasting and postprandial insulin levels on two occasions 3 years apart when her weight and her plasma glucose levels were virtually the same. Evidence for hypothalamic regulation of beta cell fune- tion has also been adduced in animal studies (28-30). One may therefore speculate that both the patient's weight and her insulin response to glucose or other stimuli may be simultaneously determined by a primary hypothalar: ic abnormality ACKNOWLEDGMENTS: The casingng operation ofthe patient nd theanistance of the nursing and schol sta of the Sloman et or ‘Cnsea! Investigation, Me Sint Hostal are gattly ackowiegee 59 > Resuons for reprint should be arate 9 Saul Gena, MLD, 160 Esa 18 Surat Chevsnd, O8 44108 References 1. KaKass JH, Gxonsky GM, Fonswas: PM: Encaieiaatinryponse {0 glocotefa-abwe sdjens Ae measured by immunocherieat Bator 12199204, 163 2 Vauow RS, Glick SM, Kors J, gasow SA Phsms ipa and 3. Gist SM: Plana inal and lucos rote ia orn, bet, and ‘Sabo penons Ara ines Mod 9 sia-822. 1973 4, Raamourte B, Mraisice 1), Nruaos JK, Sewuure RB, Rios Ls 26 {The hormonal pro in obey. Trane Aso sin Phin 80 190 iv oer n 5, RALSNOVe RK, Kis HY, Coster J. PenKoU, CA: Metabo lets (oF wcght losin obee satjecrs Change tm pas subst eve Stoslimand growth hormane rapemses Disbets20829' 1971 2 6: Guererekeavrs Go ian JW Es ni rebut Ejgelpopratcncnne sot J Cho Inver 339635 178 ». 7, Beconbe Jb, Ponte D Jk, bnuwettt JD, Bisasas El: Basal 2nd tiated hypeninatinen seversle mctole nowcle of obst7 Tob Chin Maunss-363, 17 »0 Sieg EAH, DawrontitE, HORTON ES, Bkay GA, GLENNON 28 n6 Sa.ans Lit Eadwinc an mea ot teen foi Ree Pog Hn Re STR Rants Bednarsn Re For meen ‘Sn iret ae hae eon und ene or apne hye’ d hn ioe $1 hiss Um Bay GA, Clan sw, Danroun in TAL Iitas t8 foe catt Chen mbt soe it eee iy ianen tee ee apne sd epee fies ay eon ed scp cl 4 Sieantsense oe ae od n uunmll'n bend Soko am fd vo a celina hn ova 000 90 Kucyur A: Conor F, Rot) Deas ac ng Ba Aan Amann ih coe eaneion toons ns ea 4 Kat Sin DM a Rom Ine ag : Scie mg At nin eg nit Sees Seg ont species Beh adn beng Mo, Rvs DM Pama es Yoon tr ep iGreftivce wer Ribdes Rovunroow RP, Porre JK: THe gem wir A Sten ent ‘Shiny cede fom ete sare cg Eien Oe ee a = Secsmes ia tao RP, Leama RL:Hnzeaee YE Se one pe ISSUING deka’ Loe D nc Reatoge sed GRAB pr Sl oe Distt tou ha Ennio ss, once Sas H Kamat Gr Osrocs kt Reaves OM SRE tients Son fen! n we as ont dab SERRE ‘Sta tpereomas 7h lnc Soaseas te a ecu Am? Gia Nuratieae ian ivete eee 2 peimeliie rates follwing ery econ so Ua ‘mentation, Am J Clin Nutr 25:746-755, 1972. ae a te Shvace Pi Dives Sey Beever PH GoabEN P, ROP "ono Nb Shun Hypemaieni aed ype ‘Shino a uty nt 4 ide pcm ps Be Disease Drs Grsu SM, Casnro Jt, Vente V- Wei rection ‘Snuicnathsarctlon iAata nosetas Schone Ch, Conny Ml, Weanacn JH: Conta i Son dung tg pegged dae thin and concenration ili receptors occult Biotest of aren rc a a Haksisox LC, Mantin FIR, MELiCk RA: Correlation betwect ‘captor bing lt cl and ili esti Jey Chin ner SE Tastes IO Kanan 3 Onapens GM, Gnine KN, Sova Fu Foveay PH *Starcase” puso stilton of ins Shen Meosire ef ua el tent an cacy, Diet Datsnok Ed, sow D:Entton of dete Lena hcp Ase Cin Narr 28ae-272, 1975. sa, nino’ Nenousow N Repl intdeacadd Fronnrss LA, Deusen LE Sownare 1D, Buus L Pses In-and inven levels ater bypass 9 wea ‘in Pha 2689651901 1909 ee ‘ihiin , Kowe oie We BoUsias PR: Isai and goth "Hone sretion oh foe ith settromedia hypo le That on ests fod intake Diattes 23:308-208, 1974 8 Ges pa Be jneres