Hyperinsulinaemia in obesity is not accompanied by an increase in serum proinsulin/insulin ratio in groups of human subjects with and without glucose intolerance

Diabetologia, Oct 1991

Summary Serum proinsulin is disproportionately elevated compared to insulin in Type 2 (non-insulin-dependent) diabetes mellitus. We studied the effect of obesity on serum proinsulin with varying degrees of glucose intolerance. Serum proinsulin and insulin were measured during a 75 g oral glucose tolerance test in 73 obese and 74 non-obese subjects with normal, borderline or diabetic-type glucose tolerance. Proinsulin was assayed by a direct radioimmunoassay using proinsulin-specific antiserum. Fasting serum proinsulin and insulin and the summed values of proinsulin and insulin during oral glucose tolerance test were significantly, or tended to be, higher in obese subjects than in those without obesity in each category of glucose tolerance. However, the molar ratio of proinsulin to insulin was nearly the same between obese and non-obese groups with a similar degree of glucose tolerance. On the other hand, the proinsulin/insulin ratio increased progressively with the deterioration of glucose tolerance. We conclude that proinsulin secretion is disproportionately increased in the presence of glucose intolerance but not by obesity itself. Each Beta cell seems to function normally in obese subjects while glucose tolerance remains normal.

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Hyperinsulinaemia in obesity is not accompanied by an increase in serum proinsulin/insulin ratio in groups of human subjects with and without glucose intolerance

Diabetologia H y p e r i n s u l i n a e m i a in obesity is not a c c o m p a n i e d by an increase in serum proinsulin/insulin ratio in groups o f human subjects with and without glucose intolerance* I. Shiraishi 0 Y. Iwamoto 0 T. Kuzuya 0 A. Matsuda 0 S. Kumakura 0 0 Division of Endocrinology and Metabolism, Jichi Medical School , Minamikawachi-Machi, Tochigi-ken , Japan Summary. Serum proinsulin is disproportionately elevated compared to insulin in T y p e 2 (non-insulin-dependent) diabetes mellitus. We studied the effect of obesity on serum proinsulin with varying degrees of glucose intolerance. Serum proinsulin and insulin were measured during a 75 g oral glucose tolerance test in 73 obese and 74 non-obese subjects with normal, borderline or diabetic-type glucose tolerance. Proinsulin was assayed by a direct radioimmunoassay using proinsulin-specific antiserum. Fasting serum proinsulin and insulin and the summed values of proinsulin and insulin during oral glucose tolerance test were significantly, or tended to be, higher in obese subjects than in those without obesity in each category of glucose tolerance. However, the molar ratio of proinsulin to insulin was nearly the same between obese and non-obese groups with a similar degree of glucose tolerance. On the other hand, the proinsulin/insulin ratio increased progressively with the deterioration of glucose tolerance. We conclude that proinsulin secretion is disproportionately increased in the presence of glucose intolerance but not by obesity itself. Each Beta cell seems to function normally in obese subjects while glucose tolerance remains normal. Obesity; Type 2 (non-insulin-dependent) diabetes mellitus; hyperinsulinaemia; serum proinsulin; proinsulin/insulin ratio; insulin secretion 9 Springer-Verlag1991 In pancreatic B e t a cells, proinsulin is produced by the removal of the signal peptide from preproinsulin when it moves from the ribosome into the cisternae of endoplasmic reticulum [ 1 ]. It is then transferred to the Golgi apparatus, and then to coated immature beta granules, where the cleavage reaction into insulin and C-peptide seems to occur [ 2 ]. Mature beta granules contain a small percentage of proinsulin and conversion intermediates. T h e y are secreted in a small amount together with insulin [ 3 ]. It is known that the serum proinsutin/insulin ratio (PI/I ratio) is elevated in patients with Type 2 (non-insulin-dependent) diabetes mellitus c o m p a r e d to healthy subjects [ 4-8 ]. It is usually supposed that proinsulin is secreted in a disproportionately greater amount c o m p a r e d with insulin in Type 2 diabetic patients, although the altered metabolism of proinsulin relative to insulin cannot be ruled out. We p r e s u m e d that the elevation of PI/I ratio resulted from a functional change in the B e t a cells, the m o r e immature secretory granules being mobilized by overworked B e t a cells due to a greater n e e d for insulin [ 8 ]. * This work was presented at the 6th International Congress on Obesity in October 1990,Kobe, Japan Obesity is one of the most important factors in causing insulin resistance and thereby inducing Type 2 diabetes. Obesity is usually accompanied by hyperinsulinaemia both at fasting and after glucose challenge [ 9, 10 ]. It is considered to result from increased insulin secretion produced as a compensatory response to the Beta cells. T h e r e have only b e e n a few studies on proinsulin secretion in obesity [ 11, 12 ]. Therefore, we have c o m p a r e d the proinsulin response during oral glucose tolerance test ( O G T T ) in obese and non-obese subjects with varying degrees of glucose intolerance, and found that obesity itself does not affect the serum PI/I ratio unless it is accompanied by glucose intolerance. Subjects and methods Type 2 diabetic patients were selected from those attending Jichi Medical School Hospital. None of them had ever been treated with oral hypoglycaemic drugs or insulin. The healthy control subjects were either volunteers from among hospital employees, or selected from subjects attending hospital for a health check. The subjects were informed about the purpose and procedure of the study, and gave their written consent to the test. After an overnight fast, 75 g glucosewas given orally as Trelan G (Shimizu Seiyaku Co., Shimizu, OGTs Japan). Blood was withdrawn from the antecubital vein at fasting, 30, 60, 90, 120 and 180 min after ingestion of Trelan G. Plasma glucose was determined by the glucose-oxidase method using Glucoroder S (Noda, Japan). Serum insulin was assayed by Phadeseph R I A Kit (Pharmacia, Uppsata, Sweden), and proinsulin by the double-antibody radioimmunoassay method using proinsulin-specific antiserum as reported previously [ 8 ]. As described earlier [ 8 ], this antiserum did not cross-react with human insulin or C-peptide, but cross-reacted with various conversion intermediates of human proinsulin. By competitive inhibition of ~2SI-proinsulinbinding to the antiserum, the cross-reaction was estimated to be 50-57% with des(64,65)- and 65-66 split proinsulin, and 0.%2% with des(31,32)and 32-33 split proinsulin. Serum insulin values were corrected by subtraction from the assay values of cross-reaction with intact proinsulin. The types of glucose tolerance were classified according to the criteria of the Committee of the Japan Diabetes Society [ 13 ]. Normal glucose tolerance was defined when fasting, 1-h and 2-h plasma glucose values were lower than 6.1 retool/l, 8.9mmol/1 and 6.7 mmol/1, respectively. Diabetes was defined when fasting plasma glucose exceeded 7.8 mmol/l and/or 2-h plasma, glucose exceeded 11.1 mmol/1. Those values which were intermediate between the normal and diabetic types were treated as borderline. Diabetes, as described here is that defined by World Health Organisation (WHO) criteria [ 14 ], but the normal type was defined more strictly than the WHO recommendation. Therefore, the borderline type included not only impaired glucose tolerance by WHO standard, but also a selection of subjects who would have been regarded as 'norreal' by WHO criteria9 Obesity was defined by the body mass index (weight/height 2in kg/mz) exceeding 25.0. Statistical analysis Statistical significance was calculated by the Student's t-test. Differences were judged as significant when p was less than 0.05. For evaluation of the effects of gender and age, the analysis of variance was used in part. Results T a b l e 1 shows t h e clinical characteristics o f the subjects studied. O f t h e 147 subjects, 73 w e r e o b e s e a n d 74 n o n obese. W i t h r e g a r d to glucose t o l e r a n c e , 33 h a d n o r m a l , 78 b o r d e r l i n e a n d 36 h a d diabetic t y p e glucose t o l e r a n c e . T h e diabetic g r o u p c o n t a i n e d m o r e m a l e subjects, a n d t h e m e a n age was significantly h i g h e r in n o n - o b e s e subjects (p < 0.01). T h e possible effects o f these biases w e r e evalua t e d by the 2 - w a y analysis o f v a r i a n c e , b u t t h e differences in insulin a n d p r o i n s u l i n p a r a m e t e r s b e t w e e n d i a b e t e s a n d t h e o t h e r g r o u p s w e r e n o t a f f e c t e d b y t h e sex ratio o r "5 20 500 -5 400 g age. T h e r e was no difference in sex ratio and m e a n age between the non-obese and obese groups in any category of glucose t o l e r a n c e . T h e d e g r e e o f b o d y m a s s index f o r the n o n - o b e s e a n d o b e s e g r o u p s did n o t differ b e t w e e n n o r mal, b o r d e r l i n e a n d diabetic categories. F i g u r e 1 shows c h a n g e s in p l a s m a glucose d u r i n g O G T T . P l a s m a glucose v a l u e s w e r e similar b e t w e e n t h e o b e s e a n d n o n - o b e s e g r o u p s in e a c h t y p e o f glucose t o l e r a n c e , e x c e p t f o r t h e 120-rain values in n o r m a l type. A s s h o w n in F i g u r e 2, insulin r e s p o n s e s d u r i n g O G T T w e r e d e l a y e d in t h e g r o u p s w i t h glucose i n t o l e r a n c e . Insulin values w e r e g e n e r a l l y h i g h e r in the o b e s e groups 9 T h e d i f f e r e n c e s w e r e significant at fasting irrespective o f glucose t o l e r a n c e . I n addition, t h e o b e s e g r o u p s h o w e d significantly h i g h e r insulin values at 60 m i n in t h e b o r d e r line type, a n d at 60, 90, 120 a n d 180 rain in t h e diabetic type. A s s h o w n in T a b l e 2, t h e s u m m e d insulin values in t h e o b e s e g r o u p s w e r e h i g h e r t h a n in the n o n - o b e s e groups, b u t t h e d i f f e r e n c e w a s n o t significant f o r the b o r derline type. W i t h i n e a c h o f t h e l e a n a n d o b e s e groups, fasting insulin levels i n c r e a s e d p r o g r e s s i v e l y with t h e d e t e r i o r a t i o n o f g l u c o s e t o l e r a n c e , w h e r e a s t h e s u m m e d insulin values i n c r e a s e d in t h e b o r d e r l i n e c o m p a r e d t o ,, ,]., * 610 l~g.2. Changes in serum immunoreactive insulin during 75 g oral glucose tolerance test in obese (---) and non-obese (--) subjects with varying degrees of glucose tolerance. Mean and SEM are shorn1. Insulin values are corrected for cross-reaction with proinsulin. Significance of difference is shown by *** p < 0.001, ** p <0.01, * p < 0 . 0 5 a n d t P<0.1 the n o r m a l groups b u t d e c r e a s e d in diabetes (Table 2 and Table 3). Figure 3 shows s e r u m proinsulin r e s p o n s e s during O G T T . A s c o m p a r e d with insulin, proinsulin increased at a m u c h slower rate in the n o r m a l type, the p e a k level being at 120 min b o t h in the n o n - o b e s e and o b e s e groups. P r o insulin r e s p o n s e was higher in the b o r d e r l i n e and diabetic 100 -~ 80 ._c 60 ._. 40 E 03 20 0 60 Normal Borderline Diabetes Fig.3. Changes in serum proinsulin during 75 g oral glucose tolerance test in obese (---) and non-obese (--) subjects with varying degrees of glucose tolerance. Mean and SEM are shown. Significance of difference is shown by *** p < 0.001, ** p < 0.01, * p < 0.05 and t P < 0.1 types t h a n in the n o r m a l type in the absence and p r e s e n c e of obesity. In e a c h c a t e g o r y of glucose tolerance, the o b e s e g r o u p h a d higher s e r u m proinsulin values in general. T h e fasting values w e r e significantly different in all categories. F u r t h e r m o r e , s e r u m proinsulin was higher in the o b e s e g r o u p at 30 and 60 rain in the n o r m a l a n d b o r d e r l i n e types. T h e s u m m e d proinsulin values of the o b e s e g r o u p s w e r e g r e a t e r t h a n in c o r r e s p o n d i n g n o n - o b e s e groups, but there was only a significant difference in the b o r d e r l i n e type (Table 2). B o t h the fasting and s u m m e d P I values increased significantly with the d e t e r i o r a t i o n of glucose t o l e r a n c e in e a c h of the lean and o b e s e g r o u p s (Tables 2 a n d 3). T h e m o l a r ratios of fasting P I to insulin and the s u m m e d P I to insulin values are s h o w n in Table 2. B o t h the fasting and s u m m e d P I / I ratios significantly i n c r e a s e d with the d e t e r i o r a t i o n of glucose t o l e r a n c e (Table 3). H o w e v e r , there was n o difference in fasting or in the s u m m e d P I / I ratio b e t w e e n the o b e s e a n d n o n - o b e s e g r o u p s in e a c h c a t e g o r y of n o r m a l , b o r d e r l i n e and diabetic types. T h e fasting PI/I ratio t e n d e d to be higher t h a n the s u m m e d P I / I ratio in each group. T h e r e were 10, 22 and 6 subjects with B M I exceeding 27.0 in normal, b o r d e r l i n e and diabetic type groups, respectively. T h e m e a n fasting PI/I ratios in these subjects w e r e 20.7%, 30.6% a n d 31.4%, and the s u m m e d P I / I ratios w e r e 10.3%, 15.7% and 25.7%, respectively. T h e y did n o t differ significantly f r o m the c o r r e s p o n d i n g values o f the n o n - o b e s e subjects in Table 2. D i s c u s s i o n In this study, we f o u n d t h a t obesity was associated with the elevation of s e r u m proinsulin c o n c e n t r a t i o n as well as s e r u m insulin. B u t the P I / I ratios at fasting or after glucose challenge did n o t differ in the p r e s e n c e or absence of obesity. O n the o t h e r hand, the s e r u m P I / I ratio did increase in the p r e s e n c e of glucose intolerance. E l e v a t i o n of the s e r u m P I / I ratio in diabetic patients has b e e n r e p o r t e d in several studies [ 4-8 ]. T h e relative increase in s e r u m proinsulin c o n c e n t r a t i o n is n o t restricted to Type 2 diabetes. L u d v i g s s o n et al. r e p o r t e d t h a t s e r u m PI/C-peptide ratio was elevated in newly diagnosed Type 1 diabetic patients [ 15 ]. O u r present data are in agreement with these previous studies in Type 2 diabetic patients with and without obesity. T h e mechanism of the increase in PI/I ratio in Type 2 diabetes is still unknown. T h e PI/I ratio could be elevated either by an increase in the proportion of the amount of proinsulin in Beta-cell secretion, or by modulation of the metabolic clearance of proinsulin c o m p a r e d with that of insulin in the diabetic state. Proinsulin is metabolized at a slower rate than insulin. Therefore, the fasting serum PI/I ratio is higher than the ratio of amounts of PI/I immediately after secretion from Beta cells. W h e n insulin secretion is stimulated, the serum PI/I ratio is decreased due to dilution with newly secreted insulin. The proinsulin clearance rate in Type 2 diabetic patients has never b e e n studied, but it is unlikely that it is much affected by the diabetic state because the half-life of exogenously administered proinsulin was r e p o r t e d to be similar in both healthy subjects and Type 1 diabetic patients [ 16 ]. Assuming that diabetic B e t a cells secrete proinsulin at a larger amount relative to insulin, there would be still several different possibilities. First, the diabetic state may impair conversion of proinsulin to insulin as a consequence of metabolic alterations. Second, there may be a more inherent defect in diabetic patients in the processing of proinsulin, as suggested by Porte et al. [ 17 ]. Third, it is also possible that the relative increase in proinsulin may occur as a functional response of B e t a cells to a non-physiological over-stimulation. T h a t is, if B e t a cells are over-stimulated, mobilization of proinsulin-rich immature secretory granules may occur. We found that the increase in PI/I ratio in Type 2 diabetes is a reversible abnormality. The elevated PI/I ratio in obese Type 2 diabetic patients was nearly normalized by successful dietary therapy [ 18 ]. Therefore, the increase in PI/I ratio is likely to be due to a functional abnormality in Beta cells rather than being an intrinsic defect in Type 2 diabetes. Obesity is known to be associated with hyperinsulinaemia [ 9,10 ] and thought insulin secretion is to increase to compensate for insulin resistance in obesity. The Beta-cell mass is known to increase with obesity both in experimental animal models [19] and in man [ 20 ]. We found that serum PI/I ratio was nearly identical between lean and obese groups with similar degrees of glucose tolerance. Insulin secretion could be augmented either by increasing the n u m b e r of Beta cells with each producing the normal amount of insulin, or by increasing the insulin production of each B e t a cell, or by combination of the two. We presume that the PI/I ratio would be unchanged by each B e t a cell functioning normally. If hyperinsulinaemia in human obesity results primarily from an increase in Beta-cell mass, it is natural that the function of each Beta cell does not deviate from the normal state while glucose tolerance remains normal. With regard to the effect of obesity on PI/I ratio, Saad et al. [ 12 ] r e p o r t e d that fasting serum PI/I decreased with the increase in body mass index in Pima Indians. One possible difference between their data and ours may derive from the difference in degree of obesity. The Pima Indian group included more obese subjects (BMI > 35) than we had in our study in which the B M I rarely exceeded 30. In our data, PI/I ratios in subjects with BMI exceeding 27.0 did not differ significantly from the corresponding non-obese groups. In obese subjects, the PI/I ratio rose only when glucose tolerance became impaired. T h e degree of elevation of PI/I ratio was similar between the lean and obese groups when the degree of glucose intolerance was matched. Namely, the degree of abnormality of Beta-cell function is related to the degree of glucose tolerance but not to obesity. As Leahy suggested [ 21 ], the decrease in Beta-cell mass might predispose to diabetes as well as to an increase in PI/I ratio. These results remind us of the study by Bagdade and Porte [ 9 ] on the effect of Type 2 diabetes and obesity on insulin-secretory response during OGTT. T h e basal insulin level increased in obese subjects whether or not they had diabetes. The early insulin response was decreased and the peak delayed in diabetic c o m p a r e d to non-diabetic subjects, but the time course and the relative increases from the basal insulin level were similar between lean and obese groups whether or not they had diabetes. Our data on the PI/I ratio suggest that obesity results in a quantitative increase in Beta-cell secretion but has little effect on the function of each Beta-cell. Qualitative alteration of Beta-cell function seems to occur only when glucose tolerance is impaired. However, this point needs further study, because there are reports suggesting an increase in PI/C-peptide ratio not only in Type 1 diabetic patients but also in their non-diabetic twins or close relatives [ 22, 23 ]. Our data also suggest that the relative degradation rates of proinsulin and insulin are not altered by obesity. An increase in fasting insulin concentration despite the decreased insulin response to a glucose challenge in diabetes was noted by us, as was r e p o r t e d by other authors [ 24 ]. Our insulin values were corrected for cross-reaction with intact human proinsulin but not for PI conversion intermediates. Recently, Sobey et al. [ 25 ] developed a specific two-site immunoradiometric assay for human proinsulin conversion intermediates using monoclonal antibodies, and found that the serum concentration of 32-33 split PI was as high as that of intact PI, but the concentration of 65-66 split PI was very low. Temple et al. reported that the 32-33 split PI was elevated in Type 2 diabetes similarly to intact PI, and raised the question of whether Type 2 diabetes is indeed associated with true fasting hyperinsulinaemia [ 26 ]. As our present PI assay cross-reacts little with 32-33 split PI, the insulin values in Table 2 are not corrected for cross-reaction with this conversion intermediate. Therefore, the present data leave the above question unanswered. In conclusion, we showed that PI/I ratio is elevated by glucose intolerance but not by obesity. The PI/I ratio seems to be used as a m a r k e r to assess the qualitative functional abnormality of Beta cells in clinical situations. Acknowledgements. We thank Ms. R. Suzuki for her technical assistance and Ms. EAoki for preparation of this manuscript. Human proinsulin was kindly donated by Dr. B. H. Frank, Eli Lilly,Indianapolis. This work was supported in part by a Grant-in-Aid for Scientific Research (No.02671107) from the Ministry of Education, Science and Culture, and a Grant for Diabetes Research from the Ministry of Health and Welfare, Japan. 1. Steiner D F ( 1977 ) Insulin today . Diabetes 26 : 322 - 340 2. Orci L , Ravazzola M , Amherdt M , Madsen O , Vassalli J-D , Perrelet A ( 1985 ) Direct identification of prohormone conversion site in insulin-secreting cells . Cell 42 : 671 - 681 3. Melani F , Rubenstein AH , Steiner DF ( 1970 ) Human serum proinsulin . J Clin Invest 49 : 497 - 507 4. Gorden R Hendricks CM , Roth J ( 1974 ) Circulating proinsuhnlike component in man: increased proportion in hypoinsulinemic states . Diabetologia 10 : 45 % 474 5. 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I. Shiraishi, Y. Iwamoto, T. Kuzuya, A. Matsuda, S. Kumakura. Hyperinsulinaemia in obesity is not accompanied by an increase in serum proinsulin/insulin ratio in groups of human subjects with and without glucose intolerance, Diabetologia, 1991, 737-741, DOI: 10.1007/BF00401520