Acta Clinica Belgica International Journal of Clinical and Laboratory Medicine
ISSN: 1784-3286 (Print) 2295-3337 (Online) Journal homepage: http://www.tandfonline.com/loi/yacb20
From Obesity to Type 2 Diabetes A.J. Scheen* To cite this article: A.J. Scheen* (1992) From Obesity to Type 2 Diabetes, Acta Clinica Belgica, 47:sup14, 30-36, DOI: 10.1080/17843286.1992.11718274 To link to this article: https://doi.org/10.1080/17843286.1992.11718274
Published online: 16 May 2016.
Submit your article to this journal
Article views: 1
View related articles
Citing articles: 2 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=yacb20
30
FROM OBESITY TO TYPE 2 DIABETES A.J. SCHEEN *
SUMMA RY Obes ity is a we ll -known ri sk fac tor for the deve lopmen t of non-in ulin -depend ent di abetes mellitus (N IDDM). Both insulin resistance and concomitant B-cell dys fun ction are necessary for the development of NIDDM. In ulin resistance, probably geneti ca lly determined but worsened by obesity, appears to be the primary defect that lead to impaired glucose tolerance. However, B-cell dy function pl ays a critical role during progre ive deterioration from mild impaired glucose t lerance to severe NIDDM.
INTR DUCTION Type 2 or non-in ulin-dependent di abetes mell itus (N IDDM) i apopulartopic in biomedica l cience becau e of it high preva lence (2-4 % of our popul ation), its important morbidity (both mi cro- and macroangiopathy), and its till undefin ed pathophy iology ( I). Besides a we ll -known geneti c bac kground , obe it y probably play an important role in the deve lopmen t of NIDDM as most type 2 di abeti c patient have indeed a ignifi cant we ight excess. Thus, NIDDM is considered by many as an inherit ed di sease which is expres ed late in life but whose progress ion can be accelerated by overeating and obe ity.
*Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medici ne, CHU Li ~ge , Sart Tilman, 4000 Liege I. Ac/a Clinica Be/Rica 47. suppl. 14 ( 1992)
The reason why obe ity and type 2 di abetes mellitus are often associated are not fully known, but it is hypothesized th at insulin resistance, wh ich is a common findin g in NIDDM and obe ity, is involved (2). Jean Vague reported 35 years ago (3) that subjec ts wi th NIDDM have a more centra li ze d di stributi on of body fa t compared to non-di abetic subjects and recent papers howed that ubjects with trunca l or upperbody di stributi on of body fat («android ») are more in ulin-resistant than equally obese subjects w ith predomin antl y lower -body obes ity ( «gynoid») (rev iew in 4)(see paper of Yan Gaal in thi s is ue of Acta Clinica Belgica)). The reaso n(s) for the assoc iation of central obesity with reduced in ulin ac tion is (are) still unknown. In partic ul ar, it is not establi shed whether they arc causa lly related to each other or are only both econdary to a pathogeni c third factor (4). As both obesity and NIDDM are characteri zed by variou s abnorm alit ies in insulin secretion and acti on, it is interesting to consider both aspects of the «g lucose- insulin » feedback loop in order to appreciate the interrelati onships between the e two metabolic di orders.
INSULIN SECRETION We have measured the plasma insulin response during ora l glucose (I 00 g) tolerance test (OGTT) 1 in evera l groups of obese subjects. The mean body mass index was similar in all groups (about , 33 kg/m2) . The subjects were separated according to either their glucose tolerance (norma l or
FROM OBESITY TO TYP E 2 DIABETES
impaired) or the severit y of fa stin g hyperglycaemi a in those fulfillin g th e revi sed Nati onal Diabetes Data Group crit eria for the di agnosis of diabetes mellitus (5).
3t
Because thi s inverted-U shaped curve relating the insulin response to the fasting bl ood glucose co nce ntration so stron g ly resse mbl es th e Starling's curve of the heart, DeFronzo (I) called it the «Starling'scurveofthe pancreas». However, it is noteworth y that, when viewed in absolute term s, onl y the most hyperglycae mic obese subj ects (g roup 8) arc in ulinopeni c wh en compared to the lean cont rols (group I) (Fig la).
The relati onship between the pl asma insulin response and the severity of di abetes is complex, the two parameters being linked in a charac teri stic in vert ed-.U-s haped curve (Fi g la). The pl asma insulin response increased from the lea n cont ro ls (group I) to the obese subjects with norm al glucose tolerance (group 2), and even more in the obese subjects with impaired glucose tol erance (group ( 3). We have rece ntl y re po rt ed th at th e hyperinsulini sm assoc iated with obes ity not onl y results from an increased insulin secreti on by the pancreas (despite a nonn al feedback inhibition of in sul in ccretion by insulin itself), but also coul d be parti ally attributed to a decreased metabolic clearance rate (M R) of the hormone, presu mabl y at the hepati c itc (6). When the obese subjects started to become diabeti c (gro up 4), the pl asma insulin response further increased to reach a max imum when fasting bl ood glu cose levels averaged 5.8 mmol/l . Beyond th is lim it, further increments in fasting blood glucose levels were associated with a progressive dec line in the insulin respon e (from group 5 to group 8).
Due to the stri ct int errelationship between glucose and insulin , the insulin response has to be interpreted regarding the simultaneous glucose response during the OGTT (8). The latter of course increased progre sive ly from the obese subjects with normal glucose tolerance (group 2) to the obese ubj ects with the highest fas ting blood glucose leve ls (group 8). When the pl asma insul in response was corrected fortheconcomitant glucose stimulu s (Fig lb), the inverted-U-shaped curve still persi. ted but the defec t in insulin sec retion is more apparent. All the di abetic obc e patient s (from group 4 to group 8) had lower in sulin/glucose rati o than the non-diabeti c obese subjects (group 2) and all obese diabeti c subjects with a fasting bl ood glucose level above 6 mmol/ I (from group 5 to group 8) had a lower insulin/ glucose rati o th an the lea n control s (group 1).
Our results, as tho eof others ( I), were obtai ned in cross-sectional studies using different groups of subjects bu t they were confirm ed recentl y in a long itudina l study perfonned in Pima indians (7). These results can be interpreted as fo llows {I): as the obese subject starts to become glucose{ intolera nt and later on diabeti c, the B-cc ll «recog ni zes» th at th e glu cose homeos tati c mechani sm has been disru pted, and it augments r its in sulin sec retory capac ity in an attempt to overcome the disturbance in gluco c metaboli sm. However, once the fasting glucose levels exceed about 6 mmol/l , the B-cell can no longer maintain 1 its accelerated rate of insulin secretion, and further , increments in the blood glucose concentration s 1 areas ociatedwith a progress ive decline ininsulin secretion.
The data pre cntcd in fi gure I document that the plasma insulin levels, when viewed in absolute terms, are normal or increased in most obese diabeti c patients with mild-to-moderate fa sting hyperglycaemi a. Therefore. insulin resistance app ea rs to pl ay an import ant rol e in the . uevelopment of the glucose intolerance ( 1,2). However, the insul in secretion can be overestimated in obese type 2 di abetic patients due to either a reduced MCR of insulin by the liver (6) or an interference in the radioimmunoassay by intact proinsulin or split proinsulin products (9). Moreover, when the insulin response is corrected for the simultaneous hyperglycaemic stimulus, the defect in insulin secretion is obvious in all diabeti c patients when all groups are adequately matched for body mass index (I 0). Acta Clinica Belgica 47, suppl. 14 ( 1992)
FROM OBESITY TO TYPE 2 DIABETF,S
32
INSULIN /GLUCOSE RATIO
PLASMA INSULIN A . U . C .
U . 1- 1
m U . mmoi-1
X 180 min
22 14
20
14 oet:Sl
10
.J 2I
2~
SUBJECTS
4
16
12
OllCSl
12
18
I
8
.\ ~
S
SUllJCCTS
16
6
10
8 COHTllOl.S
2
4
PATl(NT1i
.
~
4
6
_,
OIAllCTIC
C~
0+--t--+---t-~~+--+--t--+--+--i~~
2 2
J
4
5
6
7
8
9
10 11 12 1J 14
FASTING BLOOD GLUCOSE mmol . I - l
2
J
4
5
6
7
8
9
10 11 12 1J 14
FASTING BLOOD GLUCOSE mmol . I - 1
Fig. I : hanges in plasma insulin response expressed ei1h er in abso/u1e Jerms (figure la : lefl panel) or re/a1i vely 10 !h e concomi1a111 hyperglycaemic slimulus (figure lb: righl pane/) during an oral glucose 1olera11ce 1es1 in eight groups of subjec1s: I ) lean controls: 2) obese subjec1s wi1h normal glucose IOI era nee; 3) obese subjec1s wiih impaired gluco e 10/erance; and 4 10 8) ohese subjects wi1h NIDDM of various severity according 10 the fas1ing blood glucose concen1ra1io11s. Th e response is determined by 1he area under 1he curve (A .U.C.) of plasma insulin levels measured at 0, 60, 120 and 180 min after an oral load of JOOg glucose. Each point corresponds to th e mean ± SEM of 12 to 30 subjects.
INSULIN ACTIO The increa ed fat ma in obe e individual is a soc iated wi th an enhanced rate of lipoly i , which lead to a ri e in the pla ma free fa tty acid circu lating level s. By a ma s-action, this promotes lipid oxid ati on in the mu sc le (and consequently inhibits in ulin -medi ated glu co e di posa l)(l, 11 ) and timulate. gluconeogenes i in the liver (and thu s increases hepati c glu cose producti on des pite normal or increa ed plasma in ulin leve ls) ( I). The mo t conclusive documentati on of insulin re istance in obesi ty and NIDDM has come from tudi es th at have employed the euglycaemi c hyperinsulinaemic glu cose clamp tec hnique (review in I and 8). Thi s technique all ows to prec i ely mea ure the insulin - ti mu lated gluco e di posa l in conditions where more than 90 o/t of gluco e uptake occurs in ex trahepatic ti ss ues (mainly the skel etal muscle ). Moreover, when it is used together wi th a priming-constant infu sion of tritiated gluco e, it allow to tudy the insulinAc1a
linica Belgica 47. suppl. 14 ( 1992)
mediated inhibition in endogeno us (mai nl y hepatic) gluco e production .
I
W e measured the glucose di sposa l and the endogeno u s g lu cose produ c ti o n durin g euglycaemic gl ucoseclamps performed at various pl asma insulin levels in order to study the charac teri stics of the dose-re pon se curves in non- , diabeti c obese ubjects and in type 2 di abeti c pati ents (Fi g 2) ( 12, 13). The insulin -mediated gluco e dispo al curve wa sli ghtly but significantl y shifted to the ri ght in the non-di abetic obese subject ; however, in the di abeti c patients, the ri ght shift wa more obvious and the max i rn al res pon se was markedl y redu ced even when supraphys iologica l plasma in sulin levels (above 700 mU/l) were tested.
Basa l hepatic glucose output wa simil ar in Jean and obe e non-diabeti c subject (around 2 mg. kg·1.min- 1). However, a complete inhibition , by in ulin required signifi cantly hi gher plasma in ulin concentration s in obese th an in lean
33
FROM OBESITY TO TYPE 2 DIABETES
ENDOGENO US GLUCOSE PRODUCTION
GLUCO SE MCA
ml . kg - 1 .
mg . kg - 1 .
min - 1
8
3
6
2
min- 1
4
2
0
5 10 20
50100
500 1000
5 10 20
50100
PLASMA INSULIN LEVELS
500 1000
mu .
I- 1
Fig. 2: Dose-response cun•es ofeither the metabolic clearance rate (MCR ) of11 /urose (le/I panel) or the endo11eno11s glucose production {right panel) versus the plasma i11su/i11 levels measured i11 1he basal Slate and during e11g/ycaemic hyperi11.m/i11aemic glucose clamps in th ree groups ofs11bjec1s: lean con1rols (n = 8), no11-diabe1icobese s11bjec1s (n = 10) and obese patie111s with NIDDM (n = 10) .
subjects, suggesting the presence of reduced insu lin sensitivity at the hepati c site in pre ence of obesity. In the type 2 di abetic subjects, hepati c glucose ou tput was signifi cantly increased (above 3 mg.kg 1.mi n 1) aft er an overnigh t fas t despite simult aneous hi gher basal plasma insulin levels; , moreover, a compl ete inhibition of the hepati c glucose output was on ly observed for much higher plasma insulin leve ls th an those necessary in lean and even obese non -d iabeti c subjec ts (Fig 2). These results confirm th at the obese subjec ts already have significant insu lin resistance al the muscle and hepati c sit es but that these abnormalities become much more marked in the di abetic patient . la sically, a shift of the dose- response curve to the ri ght indica tes a reduction in insulin sensitivity (increased ED50) which corres pond to a defect at the receptor level (predominan t in the obese subjec ts); in contrast, a lower maximal metabolic response (Vmax) signs a lower responsiveness and corresponds to a defect at the
post-receptor level (predomin ant in the diabetic patient s) ( 14 ). Bes ide fat -mediated metabolic changes and genetic cellul ar defects, it has been suggested that insulin re istance could be potentiatcd by obesity-induced changes in the biophysical properti es of skeletal mu sc le (musc le ce ll s are hypen rophied and capi ll aries in mu cle are more widely spaced in the obese subjects) (2). In order to verify that the peripheral in ulin res istance is an early defect in the natu ral hi story of IDDM , we measured the glucose MCR during a eug lycaemi c hyperinsulin aemic glucose clamp ( 100 mU .kg ·1.h·1 for 120 min) in 3 groups of subjects: 15 lea n control s, 16 non-diabetic obe e subjects and 37 pati ent wi th mild NIDDM whose fasting blood glucose levels with diet alone ranged from 5.2 to 13.8 mmol.1 1 (Fig 3). The glucose MCR was signifi cantl y lower in the obese than in the lean non-di abetic subjec ts: 7.5 ± 0.5 ml.kg·' min·' y.s_ I0.2 ± I. I; f.l < 0.05. The gluco e MCR was much more red uced in the type 2 di abeti c Acta
/inica Belgica 47, suppl. 14 ( 1992)
FROM OBESITY TO 1YPE 2 DIABETES
34
J
12 ~
I c:
.E
f 1 CONTROLS
0
10
~
I O'I
.:.'.
E
.
8 6
TYPE 2 DIABETIC PATIENTS
•
IOI OBESE • SUBJECTS e
0:::
u
~
w
4
•
VJ
0
u
::> _J
r
2
= 0,71
n =
p ( 0.001
(,,'.)
0 2
3
4
5
6
7
8
37
••
9 10 11 12 13 14
FASTING BLOOD GLUCOSE mmol . I -1
Fig. 3 : Relationship between the metabolic clearance rate (MCR) of glucose measured during a euglycaemic I hyperinsulinaemic glucose clamp (insulin delivery rate: 100 mU.kg·1.1r 1) and the fasting blood glucose levels in three groups of subjects: lean controls (mean ±SEM; n = 15), non-diabetic obese subjects (mean ±SEM; n = 16) and type 2 diabetic patients (n = 37).
patients: 4.0 ± 0.3 ml.kg·1.min-1; p < 0.001. Moreover, in thi population, there was a remarkable inverse relationship between glucose MCR measured during the clamp and fas ting blood gluco e level : r =- 0. 7 1; p < 0.00 I. This indicate that the higher the blood gluco e level, the lower the effi cacy of insulin to stimulate musc ul ar glucose di posal ( I). The defect in gluco e utili zation, more particu larly the storage to glycogen, appears to be an early defect in the natural hi story of type 2 diabetes mellitus ( I, 2, 11 , 15).
Finall y, we recently reported that in the type 2 diabetic patients, the pre ence of obesity slightly but ignificantly reduces the insulin-mediated glucose di sposal and thu further aggravates in ulin resistance ( 16). All these results demonstrate that both obesity and NIDDM are characterized by significant insulin resistance located both al the peri pheral (muscles) and hepatic sites. Numerous data Acta Clinica Belg_ica 47, suppl. 14 ( 1992)
indicate that thi in ulin resistance is potenti ated by the presence of obesity and hyperglycaemi a in patients with type 2 diabetes mellitus. I
INTERPLAY B ETWEEN INSULIN SECRETION AND ACTIO N I
These observations underscore the important interplay between in ulin resistance and insu lin secreti on ( 1, 2, 10, 17). Both abnonnalities mu st be looked at in concert. Insulin res istance alone is, in most instances, insuffi cient to cause oven glu cose intolera nce. Quantitati ve ly, insu lin resistance is eq ually severe in non-diabetic obese subjects and in some diabetic individuals, but only the latter group is overtly glucose intolerant. Glucose tolerance remains normal in most obese subjects because the 8 -cell is able to augment its insulin secretory capac ity to offset the impairment in insulin action. To observe the development of frank diabetes mellitu , a defect in
f
1
:S FROM OBESIIT TO ITPE 2 DIABETES
insulin secretion must be superimposed on insulin resistance. When NIDDM patients first present to a Physician, most have had diabetes for many Years, and defects in both insulin action and insulin secretion are present ( 11 , 15). At thi s stage, it is imposs ibl e to define which defect came first in the evolution of their di sease. However, it seems likely that in any given diabeti c patient, whatever defect initiates the disturbance in glucose metabolism, it will eventu ally be followed by the emergence of its counterpart . A lot of ev idences demonstrate that receptor/post receptor insulin defect and B-cell ex hausti on can agg ravat e in sulin deficiency and insulin resistance, respectively , through the common step of prolon ged hyperglycaemi a, whether induced by one orthe other priming defect (review in 17). Thi s new concept is known as glucotoxicity (18). Once it develops, either from insulin defic iency or from insulin resis tance, hyperglycaemia wil l exacerbate both defects, thereby closi ng a pathologic feedback loop (1, 17 , 18).
I
I CONCLUSIONS Obesity has to be considered a a major ri sk fac tor for non-in s ulin -depe nd ent diabetes rnellitus. The natural hi story of the di sease is now better understood and de se rve s ste p-w ise therapeuti c strategy comb inin g dietary and pharmacological approaches ( 19, 20). It is known that diabetes generall y appears many years after the beginning of obesi ty ( 11 , l 5). The first stage, impaired glucose tol erance, seems to be primarily due to a reduction in in ulin action ; then the pancreatic B-cell is still able to secrete more insu lin, thus contributing to peripheral hyper1 insulini sm in most obese subjects. The moderately elevated pl asma glucose levels and the markedly , increased pl asma insulin concentration s may initiate a cycle leading to B-ce ll unresponsiveness and to greater cellul ar insulin resistance, thus
35
resulting in diabetes mellitus. Thi s hypothesis suggests that the deve lopmen t of !DOM in obese subj ec ts may be a two-s tep process involving in sulin resistance followed by B-ce ll fai lure (2 1).
ACKNOWLEDGMENTS I am grateful to Pr. P.J. Lefebvre for critical discussion of the manuscript. I am indebted to Ors M. Casti llo (Granada, Spain), G. Paolisso (Naples, Italy) and B. Jandrain (Liege, Belgium) for their help during the various experimental protocols. I also thank Ms M. Jehasse for secretarial support.
REFERENCES I.
DeFronzo RA . The triumvirate: B-cell , muscle, li ver. A co llu sion respo nsible for NIDDM. Diabetes . l 988; 37 : 667-87.
2. Lillioja S, Bogardus C. Obesity and in ulin resistance: lessons learned from the Pima indians. Diabetes Metab Rev. 1988; 4: 517-40.
3. Vague J. The degree of masculine differenti ation of obes ities. A factor determining predisposition to diabetes, athero clerosi , gout and uriccalculous disease. Am J C /in Nu tr. 1956; 4: 20-8. 4. Kissebah AH , Peiris AN . Biology of regional body fat distribut ion: relationship to non insulindependent diabetes mellitus. Diabetes Metab Rev. 1989; 5: 83 - 109.
5. National Diabetes Data Group. Classification and diagnos is of diabetes mellitus and other categories of glucose intolerance. Diabetes. 1979; 28: I03957.
6. Scheen AJ, Castillo M, Paolisso G, Jandrain B, Lefebvre PJ. Normal feedback inhibition of insulin secre ti on by in sulin but reduced metaboli c clearance rate of the hormone in obese subjects. In : G. Ailhaud, B. Guy-Grand, M. Lafontan and D. Ricq uier, eds. Obesity in Europe 9 1, John Libbey & Company Ltd, 1992: 20 1-5. 7. Saad MF, Knowler WC, Peltitt DJ, Nel son RG, Mott DM, Bennelt PH. Sequen tial changes in serum insulin concentration during development of non-insulin-depc ndent diabetes. Lancet. 1989; I: 1356-59.
8. Bergman RN, Finegood DT, Ader M. Assessment Acta C linica Belt:ica 47, s uppl. 14 ( 1992)
36
FROM OBESITY TO TYPE2 DIABETES (
( of insulin sensitivity in vivo. Endocr Rev. 1985; 6: 45-86. 9. Porte D Jr, Kahn SE. Hyperproinsulinemia and amyloid in NIDDM. Clues to etiology of islet 8 cell dysfunction ? Diabetes. 1989; 38: 1333-36. 10. Turner RC, Matthews DR, Clark A, O' Rahilly S, Rudenski AS, Levy J. Pathogenesis ofNIDDM - a disease of deficient insulin secretion. Bailliere' s Clin Endocrinol Metab . 1988; 2: 327-42. 11 . Felber JP, Golay A, Felley Ch. De l'obCsite au diabe te: aspect metaboliques. In : Joumees Annuelles de Diabetologie de l'H6tel-Dieu, Flammarion Medecine-Science , Paris. 1987: 199-208. 12. Scheen AJ, Castillo M, Letebvre PJ. Insulin sensitivity in anorexia nervo a - A mirror image of obesity ? Diabetes Metab Rev. 1988; 4: 68 1-90. 13. Scheen AJ, Paolisso G, Salvatore T, Lefebvre PJ . Improvement of insulin-i nduced gluco e disposal in obese patients wi th NIDDM after I-wk treatment wi thd-fennuramine. Diabetes Care. 199 1; 14: 32532. 14. Koltennan OG, Gray RS, Griffin J, Bur tei n P, lnsel J, Scarlett JA , Olefsky JM . Receptor and postreceptor defects contribute to the in ulin res i tance in non in ulin -de pend en t diabetes mellitus. J Clin In vest. 198 1; 68: 957-69. 15. Jallut D, Golay A, MungerR, Frascarolo P, Schutz
Acta Clinica Belgica 47, suppl. 14 ( 1992)
Y, JequierE, Felber JP. Impaired glucose tolerance ( and diabetes in obesity: a 6-year follow-up study of glucose metabolism. Metabolism. 1990; 39: ( 1068-75. 16. Scheen AJ , Paolisso G, Casti llo M, Jandrain B, { Lefebvre PJ. Modest but significant innuence of obesity in the reduction of insulin-induced glucose disposal in type 2 diabe tes mellitus. Int J Obesity. 199 1; 15 : Suppl. 1,42. 17. Scheen AJ, Paq uot N, Lefebvre PJ. La cellule B dans le diabe tede type II: coupableou victime ? In : Joumees Annuelles de Diabetologie de l'HotelDieu, Flammarion MedecineSciences, Paris, 199 1: 153-69. 18. Rossetti L, Giaccari A, DeFronzo RA. Gluco e ( toxicity. Diabetes Care . 1990; 13: 610-30. 19. Scheen A, Lefebv re PJ. Etiopathogtfo ie, phy siopathologie et prin cipes generaux du trai tement du diabete de type-2. Rev Med liege. 1988; 43: 205- 11. 20. Lefebvre PJ, Scheen AJ . Management of noninsul in-dependent diabetes mellitus. Drugs. 1992; in press. 21. Saad MF, Knowler WC. Pettitt DJ, Nelson RG, Charles MA , Bennett PH . A two-step model for development of non-insulin -dependent diabetes. Am J Med. 199 1; 90: 229-35.
ISSN: 1784-3286 (Print) 2295-3337 (Online) Journal homepage: http://www.tandfonline.com/loi/yacb20
From Obesity to Type 2 Diabetes A.J. Scheen* To cite this article: A.J. Scheen* (1992) From Obesity to Type 2 Diabetes, Acta Clinica Belgica, 47:sup14, 30-36, DOI: 10.1080/17843286.1992.11718274 To link to this article: https://doi.org/10.1080/17843286.1992.11718274
Published online: 16 May 2016.
Submit your article to this journal
Article views: 1
View related articles
Citing articles: 2 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=yacb20
30
FROM OBESITY TO TYPE 2 DIABETES A.J. SCHEEN *
SUMMA RY Obes ity is a we ll -known ri sk fac tor for the deve lopmen t of non-in ulin -depend ent di abetes mellitus (N IDDM). Both insulin resistance and concomitant B-cell dys fun ction are necessary for the development of NIDDM. In ulin resistance, probably geneti ca lly determined but worsened by obesity, appears to be the primary defect that lead to impaired glucose tolerance. However, B-cell dy function pl ays a critical role during progre ive deterioration from mild impaired glucose t lerance to severe NIDDM.
INTR DUCTION Type 2 or non-in ulin-dependent di abetes mell itus (N IDDM) i apopulartopic in biomedica l cience becau e of it high preva lence (2-4 % of our popul ation), its important morbidity (both mi cro- and macroangiopathy), and its till undefin ed pathophy iology ( I). Besides a we ll -known geneti c bac kground , obe it y probably play an important role in the deve lopmen t of NIDDM as most type 2 di abeti c patient have indeed a ignifi cant we ight excess. Thus, NIDDM is considered by many as an inherit ed di sease which is expres ed late in life but whose progress ion can be accelerated by overeating and obe ity.
*Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medici ne, CHU Li ~ge , Sart Tilman, 4000 Liege I. Ac/a Clinica Be/Rica 47. suppl. 14 ( 1992)
The reason why obe ity and type 2 di abetes mellitus are often associated are not fully known, but it is hypothesized th at insulin resistance, wh ich is a common findin g in NIDDM and obe ity, is involved (2). Jean Vague reported 35 years ago (3) that subjec ts wi th NIDDM have a more centra li ze d di stributi on of body fa t compared to non-di abetic subjects and recent papers howed that ubjects with trunca l or upperbody di stributi on of body fat («android ») are more in ulin-resistant than equally obese subjects w ith predomin antl y lower -body obes ity ( «gynoid») (rev iew in 4)(see paper of Yan Gaal in thi s is ue of Acta Clinica Belgica)). The reaso n(s) for the assoc iation of central obesity with reduced in ulin ac tion is (are) still unknown. In partic ul ar, it is not establi shed whether they arc causa lly related to each other or are only both econdary to a pathogeni c third factor (4). As both obesity and NIDDM are characteri zed by variou s abnorm alit ies in insulin secretion and acti on, it is interesting to consider both aspects of the «g lucose- insulin » feedback loop in order to appreciate the interrelati onships between the e two metabolic di orders.
INSULIN SECRETION We have measured the plasma insulin response during ora l glucose (I 00 g) tolerance test (OGTT) 1 in evera l groups of obese subjects. The mean body mass index was similar in all groups (about , 33 kg/m2) . The subjects were separated according to either their glucose tolerance (norma l or
FROM OBESITY TO TYP E 2 DIABETES
impaired) or the severit y of fa stin g hyperglycaemi a in those fulfillin g th e revi sed Nati onal Diabetes Data Group crit eria for the di agnosis of diabetes mellitus (5).
3t
Because thi s inverted-U shaped curve relating the insulin response to the fasting bl ood glucose co nce ntration so stron g ly resse mbl es th e Starling's curve of the heart, DeFronzo (I) called it the «Starling'scurveofthe pancreas». However, it is noteworth y that, when viewed in absolute term s, onl y the most hyperglycae mic obese subj ects (g roup 8) arc in ulinopeni c wh en compared to the lean cont rols (group I) (Fig la).
The relati onship between the pl asma insulin response and the severity of di abetes is complex, the two parameters being linked in a charac teri stic in vert ed-.U-s haped curve (Fi g la). The pl asma insulin response increased from the lea n cont ro ls (group I) to the obese subjects with norm al glucose tolerance (group 2), and even more in the obese subjects with impaired glucose tol erance (group ( 3). We have rece ntl y re po rt ed th at th e hyperinsulini sm assoc iated with obes ity not onl y results from an increased insulin secreti on by the pancreas (despite a nonn al feedback inhibition of in sul in ccretion by insulin itself), but also coul d be parti ally attributed to a decreased metabolic clearance rate (M R) of the hormone, presu mabl y at the hepati c itc (6). When the obese subjects started to become diabeti c (gro up 4), the pl asma insulin response further increased to reach a max imum when fasting bl ood glu cose levels averaged 5.8 mmol/l . Beyond th is lim it, further increments in fasting blood glucose levels were associated with a progressive dec line in the insulin respon e (from group 5 to group 8).
Due to the stri ct int errelationship between glucose and insulin , the insulin response has to be interpreted regarding the simultaneous glucose response during the OGTT (8). The latter of course increased progre sive ly from the obese subjects with normal glucose tolerance (group 2) to the obese ubj ects with the highest fas ting blood glucose leve ls (group 8). When the pl asma insul in response was corrected fortheconcomitant glucose stimulu s (Fig lb), the inverted-U-shaped curve still persi. ted but the defec t in insulin sec retion is more apparent. All the di abetic obc e patient s (from group 4 to group 8) had lower in sulin/glucose rati o than the non-diabeti c obese subjects (group 2) and all obese diabeti c subjects with a fasting bl ood glucose level above 6 mmol/ I (from group 5 to group 8) had a lower insulin/ glucose rati o th an the lea n control s (group 1).
Our results, as tho eof others ( I), were obtai ned in cross-sectional studies using different groups of subjects bu t they were confirm ed recentl y in a long itudina l study perfonned in Pima indians (7). These results can be interpreted as fo llows {I): as the obese subject starts to become glucose{ intolera nt and later on diabeti c, the B-cc ll «recog ni zes» th at th e glu cose homeos tati c mechani sm has been disru pted, and it augments r its in sulin sec retory capac ity in an attempt to overcome the disturbance in gluco c metaboli sm. However, once the fasting glucose levels exceed about 6 mmol/l , the B-cell can no longer maintain 1 its accelerated rate of insulin secretion, and further , increments in the blood glucose concentration s 1 areas ociatedwith a progress ive decline ininsulin secretion.
The data pre cntcd in fi gure I document that the plasma insulin levels, when viewed in absolute terms, are normal or increased in most obese diabeti c patients with mild-to-moderate fa sting hyperglycaemi a. Therefore. insulin resistance app ea rs to pl ay an import ant rol e in the . uevelopment of the glucose intolerance ( 1,2). However, the insul in secretion can be overestimated in obese type 2 di abetic patients due to either a reduced MCR of insulin by the liver (6) or an interference in the radioimmunoassay by intact proinsulin or split proinsulin products (9). Moreover, when the insulin response is corrected for the simultaneous hyperglycaemic stimulus, the defect in insulin secretion is obvious in all diabeti c patients when all groups are adequately matched for body mass index (I 0). Acta Clinica Belgica 47, suppl. 14 ( 1992)
FROM OBESITY TO TYPE 2 DIABETF,S
32
INSULIN /GLUCOSE RATIO
PLASMA INSULIN A . U . C .
U . 1- 1
m U . mmoi-1
X 180 min
22 14
20
14 oet:Sl
10
.J 2I
2~
SUBJECTS
4
16
12
OllCSl
12
18
I
8
.\ ~
S
SUllJCCTS
16
6
10
8 COHTllOl.S
2
4
PATl(NT1i
.
~
4
6
_,
OIAllCTIC
C~
0+--t--+---t-~~+--+--t--+--+--i~~
2 2
J
4
5
6
7
8
9
10 11 12 1J 14
FASTING BLOOD GLUCOSE mmol . I - l
2
J
4
5
6
7
8
9
10 11 12 1J 14
FASTING BLOOD GLUCOSE mmol . I - 1
Fig. I : hanges in plasma insulin response expressed ei1h er in abso/u1e Jerms (figure la : lefl panel) or re/a1i vely 10 !h e concomi1a111 hyperglycaemic slimulus (figure lb: righl pane/) during an oral glucose 1olera11ce 1es1 in eight groups of subjec1s: I ) lean controls: 2) obese subjec1s wi1h normal glucose IOI era nee; 3) obese subjec1s wiih impaired gluco e 10/erance; and 4 10 8) ohese subjects wi1h NIDDM of various severity according 10 the fas1ing blood glucose concen1ra1io11s. Th e response is determined by 1he area under 1he curve (A .U.C.) of plasma insulin levels measured at 0, 60, 120 and 180 min after an oral load of JOOg glucose. Each point corresponds to th e mean ± SEM of 12 to 30 subjects.
INSULIN ACTIO The increa ed fat ma in obe e individual is a soc iated wi th an enhanced rate of lipoly i , which lead to a ri e in the pla ma free fa tty acid circu lating level s. By a ma s-action, this promotes lipid oxid ati on in the mu sc le (and consequently inhibits in ulin -medi ated glu co e di posa l)(l, 11 ) and timulate. gluconeogenes i in the liver (and thu s increases hepati c glu cose producti on des pite normal or increa ed plasma in ulin leve ls) ( I). The mo t conclusive documentati on of insulin re istance in obesi ty and NIDDM has come from tudi es th at have employed the euglycaemi c hyperinsulinaemic glu cose clamp tec hnique (review in I and 8). Thi s technique all ows to prec i ely mea ure the insulin - ti mu lated gluco e di posa l in conditions where more than 90 o/t of gluco e uptake occurs in ex trahepatic ti ss ues (mainly the skel etal muscle ). Moreover, when it is used together wi th a priming-constant infu sion of tritiated gluco e, it allow to tudy the insulinAc1a
linica Belgica 47. suppl. 14 ( 1992)
mediated inhibition in endogeno us (mai nl y hepatic) gluco e production .
I
W e measured the glucose di sposa l and the endogeno u s g lu cose produ c ti o n durin g euglycaemic gl ucoseclamps performed at various pl asma insulin levels in order to study the charac teri stics of the dose-re pon se curves in non- , diabeti c obese ubjects and in type 2 di abeti c pati ents (Fi g 2) ( 12, 13). The insulin -mediated gluco e dispo al curve wa sli ghtly but significantl y shifted to the ri ght in the non-di abetic obese subject ; however, in the di abeti c patients, the ri ght shift wa more obvious and the max i rn al res pon se was markedl y redu ced even when supraphys iologica l plasma in sulin levels (above 700 mU/l) were tested.
Basa l hepatic glucose output wa simil ar in Jean and obe e non-diabeti c subject (around 2 mg. kg·1.min- 1). However, a complete inhibition , by in ulin required signifi cantly hi gher plasma in ulin concentration s in obese th an in lean
33
FROM OBESITY TO TYPE 2 DIABETES
ENDOGENO US GLUCOSE PRODUCTION
GLUCO SE MCA
ml . kg - 1 .
mg . kg - 1 .
min - 1
8
3
6
2
min- 1
4
2
0
5 10 20
50100
500 1000
5 10 20
50100
PLASMA INSULIN LEVELS
500 1000
mu .
I- 1
Fig. 2: Dose-response cun•es ofeither the metabolic clearance rate (MCR ) of11 /urose (le/I panel) or the endo11eno11s glucose production {right panel) versus the plasma i11su/i11 levels measured i11 1he basal Slate and during e11g/ycaemic hyperi11.m/i11aemic glucose clamps in th ree groups ofs11bjec1s: lean con1rols (n = 8), no11-diabe1icobese s11bjec1s (n = 10) and obese patie111s with NIDDM (n = 10) .
subjects, suggesting the presence of reduced insu lin sensitivity at the hepati c site in pre ence of obesity. In the type 2 di abetic subjects, hepati c glucose ou tput was signifi cantly increased (above 3 mg.kg 1.mi n 1) aft er an overnigh t fas t despite simult aneous hi gher basal plasma insulin levels; , moreover, a compl ete inhibition of the hepati c glucose output was on ly observed for much higher plasma insulin leve ls th an those necessary in lean and even obese non -d iabeti c subjec ts (Fig 2). These results confirm th at the obese subjec ts already have significant insu lin resistance al the muscle and hepati c sit es but that these abnormalities become much more marked in the di abetic patient . la sically, a shift of the dose- response curve to the ri ght indica tes a reduction in insulin sensitivity (increased ED50) which corres pond to a defect at the receptor level (predominan t in the obese subjec ts); in contrast, a lower maximal metabolic response (Vmax) signs a lower responsiveness and corresponds to a defect at the
post-receptor level (predomin ant in the diabetic patient s) ( 14 ). Bes ide fat -mediated metabolic changes and genetic cellul ar defects, it has been suggested that insulin re istance could be potentiatcd by obesity-induced changes in the biophysical properti es of skeletal mu sc le (musc le ce ll s are hypen rophied and capi ll aries in mu cle are more widely spaced in the obese subjects) (2). In order to verify that the peripheral in ulin res istance is an early defect in the natu ral hi story of IDDM , we measured the glucose MCR during a eug lycaemi c hyperinsulin aemic glucose clamp ( 100 mU .kg ·1.h·1 for 120 min) in 3 groups of subjects: 15 lea n control s, 16 non-diabetic obe e subjects and 37 pati ent wi th mild NIDDM whose fasting blood glucose levels with diet alone ranged from 5.2 to 13.8 mmol.1 1 (Fig 3). The glucose MCR was signifi cantl y lower in the obese than in the lean non-di abetic subjec ts: 7.5 ± 0.5 ml.kg·' min·' y.s_ I0.2 ± I. I; f.l < 0.05. The gluco e MCR was much more red uced in the type 2 di abeti c Acta
/inica Belgica 47, suppl. 14 ( 1992)
FROM OBESITY TO 1YPE 2 DIABETES
34
J
12 ~
I c:
.E
f 1 CONTROLS
0
10
~
I O'I
.:.'.
E
.
8 6
TYPE 2 DIABETIC PATIENTS
•
IOI OBESE • SUBJECTS e
0:::
u
~
w
4
•
VJ
0
u
::> _J
r
2
= 0,71
n =
p ( 0.001
(,,'.)
0 2
3
4
5
6
7
8
37
••
9 10 11 12 13 14
FASTING BLOOD GLUCOSE mmol . I -1
Fig. 3 : Relationship between the metabolic clearance rate (MCR) of glucose measured during a euglycaemic I hyperinsulinaemic glucose clamp (insulin delivery rate: 100 mU.kg·1.1r 1) and the fasting blood glucose levels in three groups of subjects: lean controls (mean ±SEM; n = 15), non-diabetic obese subjects (mean ±SEM; n = 16) and type 2 diabetic patients (n = 37).
patients: 4.0 ± 0.3 ml.kg·1.min-1; p < 0.001. Moreover, in thi population, there was a remarkable inverse relationship between glucose MCR measured during the clamp and fas ting blood gluco e level : r =- 0. 7 1; p < 0.00 I. This indicate that the higher the blood gluco e level, the lower the effi cacy of insulin to stimulate musc ul ar glucose di posal ( I). The defect in gluco e utili zation, more particu larly the storage to glycogen, appears to be an early defect in the natural hi story of type 2 diabetes mellitus ( I, 2, 11 , 15).
Finall y, we recently reported that in the type 2 diabetic patients, the pre ence of obesity slightly but ignificantly reduces the insulin-mediated glucose di sposal and thu further aggravates in ulin resistance ( 16). All these results demonstrate that both obesity and NIDDM are characterized by significant insulin resistance located both al the peri pheral (muscles) and hepatic sites. Numerous data Acta Clinica Belg_ica 47, suppl. 14 ( 1992)
indicate that thi in ulin resistance is potenti ated by the presence of obesity and hyperglycaemi a in patients with type 2 diabetes mellitus. I
INTERPLAY B ETWEEN INSULIN SECRETION AND ACTIO N I
These observations underscore the important interplay between in ulin resistance and insu lin secreti on ( 1, 2, 10, 17). Both abnonnalities mu st be looked at in concert. Insulin res istance alone is, in most instances, insuffi cient to cause oven glu cose intolera nce. Quantitati ve ly, insu lin resistance is eq ually severe in non-diabetic obese subjects and in some diabetic individuals, but only the latter group is overtly glucose intolerant. Glucose tolerance remains normal in most obese subjects because the 8 -cell is able to augment its insulin secretory capac ity to offset the impairment in insulin action. To observe the development of frank diabetes mellitu , a defect in
f
1
:S FROM OBESIIT TO ITPE 2 DIABETES
insulin secretion must be superimposed on insulin resistance. When NIDDM patients first present to a Physician, most have had diabetes for many Years, and defects in both insulin action and insulin secretion are present ( 11 , 15). At thi s stage, it is imposs ibl e to define which defect came first in the evolution of their di sease. However, it seems likely that in any given diabeti c patient, whatever defect initiates the disturbance in glucose metabolism, it will eventu ally be followed by the emergence of its counterpart . A lot of ev idences demonstrate that receptor/post receptor insulin defect and B-cell ex hausti on can agg ravat e in sulin deficiency and insulin resistance, respectively , through the common step of prolon ged hyperglycaemi a, whether induced by one orthe other priming defect (review in 17). Thi s new concept is known as glucotoxicity (18). Once it develops, either from insulin defic iency or from insulin resis tance, hyperglycaemia wil l exacerbate both defects, thereby closi ng a pathologic feedback loop (1, 17 , 18).
I
I CONCLUSIONS Obesity has to be considered a a major ri sk fac tor for non-in s ulin -depe nd ent diabetes rnellitus. The natural hi story of the di sease is now better understood and de se rve s ste p-w ise therapeuti c strategy comb inin g dietary and pharmacological approaches ( 19, 20). It is known that diabetes generall y appears many years after the beginning of obesi ty ( 11 , l 5). The first stage, impaired glucose tol erance, seems to be primarily due to a reduction in in ulin action ; then the pancreatic B-cell is still able to secrete more insu lin, thus contributing to peripheral hyper1 insulini sm in most obese subjects. The moderately elevated pl asma glucose levels and the markedly , increased pl asma insulin concentration s may initiate a cycle leading to B-ce ll unresponsiveness and to greater cellul ar insulin resistance, thus
35
resulting in diabetes mellitus. Thi s hypothesis suggests that the deve lopmen t of !DOM in obese subj ec ts may be a two-s tep process involving in sulin resistance followed by B-ce ll fai lure (2 1).
ACKNOWLEDGMENTS I am grateful to Pr. P.J. Lefebvre for critical discussion of the manuscript. I am indebted to Ors M. Casti llo (Granada, Spain), G. Paolisso (Naples, Italy) and B. Jandrain (Liege, Belgium) for their help during the various experimental protocols. I also thank Ms M. Jehasse for secretarial support.
REFERENCES I.
DeFronzo RA . The triumvirate: B-cell , muscle, li ver. A co llu sion respo nsible for NIDDM. Diabetes . l 988; 37 : 667-87.
2. Lillioja S, Bogardus C. Obesity and in ulin resistance: lessons learned from the Pima indians. Diabetes Metab Rev. 1988; 4: 517-40.
3. Vague J. The degree of masculine differenti ation of obes ities. A factor determining predisposition to diabetes, athero clerosi , gout and uriccalculous disease. Am J C /in Nu tr. 1956; 4: 20-8. 4. Kissebah AH , Peiris AN . Biology of regional body fat distribut ion: relationship to non insulindependent diabetes mellitus. Diabetes Metab Rev. 1989; 5: 83 - 109.
5. National Diabetes Data Group. Classification and diagnos is of diabetes mellitus and other categories of glucose intolerance. Diabetes. 1979; 28: I03957.
6. Scheen AJ, Castillo M, Paolisso G, Jandrain B, Lefebvre PJ. Normal feedback inhibition of insulin secre ti on by in sulin but reduced metaboli c clearance rate of the hormone in obese subjects. In : G. Ailhaud, B. Guy-Grand, M. Lafontan and D. Ricq uier, eds. Obesity in Europe 9 1, John Libbey & Company Ltd, 1992: 20 1-5. 7. Saad MF, Knowler WC, Peltitt DJ, Nel son RG, Mott DM, Bennelt PH. Sequen tial changes in serum insulin concentration during development of non-insulin-depc ndent diabetes. Lancet. 1989; I: 1356-59.
8. Bergman RN, Finegood DT, Ader M. Assessment Acta C linica Belt:ica 47, s uppl. 14 ( 1992)
36
FROM OBESITY TO TYPE2 DIABETES (
( of insulin sensitivity in vivo. Endocr Rev. 1985; 6: 45-86. 9. Porte D Jr, Kahn SE. Hyperproinsulinemia and amyloid in NIDDM. Clues to etiology of islet 8 cell dysfunction ? Diabetes. 1989; 38: 1333-36. 10. Turner RC, Matthews DR, Clark A, O' Rahilly S, Rudenski AS, Levy J. Pathogenesis ofNIDDM - a disease of deficient insulin secretion. Bailliere' s Clin Endocrinol Metab . 1988; 2: 327-42. 11 . Felber JP, Golay A, Felley Ch. De l'obCsite au diabe te: aspect metaboliques. In : Joumees Annuelles de Diabetologie de l'H6tel-Dieu, Flammarion Medecine-Science , Paris. 1987: 199-208. 12. Scheen AJ, Castillo M, Letebvre PJ. Insulin sensitivity in anorexia nervo a - A mirror image of obesity ? Diabetes Metab Rev. 1988; 4: 68 1-90. 13. Scheen AJ, Paolisso G, Salvatore T, Lefebvre PJ . Improvement of insulin-i nduced gluco e disposal in obese patients wi th NIDDM after I-wk treatment wi thd-fennuramine. Diabetes Care. 199 1; 14: 32532. 14. Koltennan OG, Gray RS, Griffin J, Bur tei n P, lnsel J, Scarlett JA , Olefsky JM . Receptor and postreceptor defects contribute to the in ulin res i tance in non in ulin -de pend en t diabetes mellitus. J Clin In vest. 198 1; 68: 957-69. 15. Jallut D, Golay A, MungerR, Frascarolo P, Schutz
Acta Clinica Belgica 47, suppl. 14 ( 1992)
Y, JequierE, Felber JP. Impaired glucose tolerance ( and diabetes in obesity: a 6-year follow-up study of glucose metabolism. Metabolism. 1990; 39: ( 1068-75. 16. Scheen AJ , Paolisso G, Casti llo M, Jandrain B, { Lefebvre PJ. Modest but significant innuence of obesity in the reduction of insulin-induced glucose disposal in type 2 diabe tes mellitus. Int J Obesity. 199 1; 15 : Suppl. 1,42. 17. Scheen AJ, Paq uot N, Lefebvre PJ. La cellule B dans le diabe tede type II: coupableou victime ? In : Joumees Annuelles de Diabetologie de l'HotelDieu, Flammarion MedecineSciences, Paris, 199 1: 153-69. 18. Rossetti L, Giaccari A, DeFronzo RA. Gluco e ( toxicity. Diabetes Care . 1990; 13: 610-30. 19. Scheen A, Lefebv re PJ. Etiopathogtfo ie, phy siopathologie et prin cipes generaux du trai tement du diabete de type-2. Rev Med liege. 1988; 43: 205- 11. 20. Lefebvre PJ, Scheen AJ . Management of noninsul in-dependent diabetes mellitus. Drugs. 1992; in press. 21. Saad MF, Knowler WC. Pettitt DJ, Nelson RG, Charles MA , Bennett PH . A two-step model for development of non-insulin -dependent diabetes. Am J Med. 199 1; 90: 229-35.
