This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chin, D. Articles by Levine, L. S. Search for Related Content PubMed PubMed Citation Articles by Chin, D. Articles by Levine, L. S.

Proinsulin in Girls: Relationship to Obesity, Hyperinsulinemia, and Puberty

Department of Pediatrics (D.C., S.E.O., M.E.S., A.M.M., L.S.L.), Division of Pediatric Endocrinology, and Department of Medicine (D.A.), Columbia University, College of Physicians and Surgeons, New York, New York 10032; and Nathan Kline Institute (D.J.M.), Orangeburg, New York 10962

Address all correspondence and requests for reprints to: Daisy Chin, M.D., Columbia University, College of Physicians and Surgeons, Division of Pediatric Endocrinology, 630 West 168th Street, PH 5 East-522, New York, New York 10032. E-mail: dc61{at}columbia.edu.

Abstract

In adults with impaired glucose tolerance (IGT) and obesity (OB), an elevated proinsulin (PI) is predictive of type 2 diabetes mellitus (DM) and precedes the diagnosis by 5–20 yr. In type 2 DM, the PI is disproportionately elevated, i.e. increased PI/insulin ratio (PI/I). Few studies have evaluated PI in children at risk for type 2 DM. In the face of the current epidemic, we evaluated the relationship of PI and PI/I to IGT, insulin resistance (IR) defined by homeostasis model of assessment (HOMA), degree of OB, and stage of puberty in 70 girls (mean age 10.8 yr; body mass index z-score 3.5; ethnicity 64% Hispanic, 19% white, 16% African-American, and 1% other). Family history of DM was reported in 83%, and acanthosis nigricans was present in 80%. Subjects underwent a 2-h oral glucose tolerance test with glucose, insulin, and PI determinations every 30 min. All had normal hemoglobin A1c and fasting glucose. Five had IGT. With higher HOMA-IR, PI increased (P < 0.05), yet the ratio of fasting PI/I was lower (P < 0.05). Girls with body mass index z-score greater than 4 (n = 29) had higher PI than nonobese girls (n = 19, P < 0.05), but PI/I ratios were not different. PI-0 was increased in late puberty (n = 29), compared with prepuberty (n = 26, P < 0.05), but PI/I ratios showed no statistical difference. We found PI increased with increasing IR and OB in girls. Overall, PI/I was not different, suggesting the elevated PI reflects increased ß-cell output proportional to the elevated insulin in these groups and not a defect in PI processing or secretion. In fact, the lower fasting PI/I of the highest HOMA-IR quartile vs. the lowest HOMA quartile indicates more efficient conversion of PI to I in the presence of increasing IR in these girls.

THE INCREASING INCIDENCE of type 2 diabetes mellitus (DM), which by some reports now accounts for up to 45% of newly diagnosed diabetes in children, is related to the epidemic of childhood obesity in the United States (1, 2). Children with type 2 DM are often overweight, have a strong family history of DM, are of certain high-risk ethnic groups, and have signs of insulin resistance (IR) (3, 4, 5). The metabolic derangements that lead to type 2 DM in childhood have not been fully defined but are presumed to be similar to that of adults, i.e. a reduction in peripheral I sensitivity with relatively inadequate although still elevated pancreatic I secretion (6, 7, 8). In adults with type 2 DM and impaired glucose tolerance (IGT), this relative inadequate I secretion has been accompanied by an elevation of its precursor, proinsulin (PI), and an abnormal increased ratio of PI to I (PI/I) suggesting inefficient ß-cell conversion (9, 10).

An elevated fasting PI has been reported to be predictive of development of type 2 DM in certain at-risk groups and may precede the diagnosis by 5–20 yr (11, 12, 13, 14, 15). Studies of nondiabetic subjects suggest PI is more strongly associated with cardiovascular disease than is I (16, 17, 18). There are few investigations of the relationship of PI to I in children at risk or diagnosed with type 2 DM or IGT (19, 20, 21). In this cross-sectional study, we sought to evaluate PI and its ratio to I in a pediatric female cohort with varying degrees of risk of DM as defined by glucose (G) intolerance, IR by homeostasis model assessment (HOMA), and obesity. If dysregulation of conversion were observed, further studies to determine the utility of analysis of PI or PI/I in young at-risk groups would be warranted. We also examined the relationship of PI to puberty, a period of life that is associated with a relative though transient increase in IR.

Subjects and Methods

The subjects were healthy girls recruited for and reported in two previously published investigations in girls with IR and premature adrenarche (22, 23). None of the subjects had medical conditions that required chronic medical treatment. A parent or legal guardian provided informed consent and all girls over 7 yr of age gave written assent. A complete history including family history was obtained from each participant. All subjects had a complete physical examination with Tanner staging by the same physician. Weight was measured to the nearest 0.1 kg on a medical balance scale. Height was measured to the nearest 0.1 cm using a Harpenden stadiometer. Body mass index (BMI) was calculated as weight in kilograms divided by the square of the height in meters. BMI z-score (BMI-z) was determined using the 85th percentile as one SD, i.e. z = 1 (24). Obesity was defined as a BMI-z of greater than 2. Obese girls were further classified as moderately obese (Mod OB) with a BMI-z between 2 and 4 or as severely obese (Severe OB) with a BMI-z of greater than 4. Tanner staging of breast development defined the pubertal groups: Prepubertal girls (PrePub) were Tanner stage I, early pubertal were Tanner II and III, and late pubertal were Tanner IV and V.

Baseline blood levels were drawn the morning after a 10- to 12-h fast. A standard oral G tolerance test (OGTT) was administered with 1.75 g/kg or maximum of 75 g anhydrous G given after the baseline levels were obtained. Samples were drawn at 0, 30, 60, 90, and 120 min for plasma G, serum I, and serum PI determinations.

Plasma G (milligrams per deciliter) was measured by glucose hexokinase method. All sera for PI and I determinations were stored in a -30C freezer until assayed (Esoterix, Calabasas Hills, CA). Serum I (picomoles per liter) was measured by a two-site immunochemiluminometric assay with a sensitivity of 7.17 pM/liter. The assay did not cross-react with PI or C-peptide. The reported intraassay percent coefficient of variation (%CV) was approximately 5.2–6.8%. The interassay %CV was 7.1–9.8%. Reference laboratory normal ranges for fasting I are reported as: prepubertal children less than 14.4 to 93.3 pM/liter and pubertal children and adults 14.4 to less than 122.0 pM/liter. PI (picomoles per liter) was measured by a two-site immunochemiluminometric assay. The assay sensitivity was 1 pM. This two-site methodology measured intact human PI, the 32–33 and 65–66 split forms of PI and did not cross-react with I, C-peptide, IGF-I, or IGF-II. The reported intraassay %CV was 6.0–12% and the interassay %CV was 8.0–14%. Normal ranges for the reference lab for fasting PI are 1.8–10 pM/liter for children and 1.7–12 pM/liter for adults.

Data analysis and statistical methods

PI and its ratio with I were compared in all subjects according to classification by G tolerance using 1997 American Diabetes Association criteria (25); IR defined by HOMA (26); degree of obesity defined by BMI-z; and pubertal status defined by Tanner staging of breast development. Data are presented as mean ± SD, and G, I, and PI determinations are specified by time in minutes, i.e. G-0 indicates fasting glucose and I-120 indicates I measured at 120 min. The area under the curve (AUC) was calculated by trapezoidal method using 0-, 30-, 60-, 90-, and 120-min time points. PI/I were calculated as molar ratios. PI, I, and PI/I ratios were natural log transformed for all statistical analyses secondary to large variance of data. Estimation of reliability of between-group differences was made using analysis of covariance, with age, BMI-z, and/or fasting I entered as continuous covariates where indicated. The Tukey Kramer method was used to adjust for multiple comparisons in the post hoc analysis. All statistical analyses were performed using SAS (version 8; SAS Institute, Inc., Cary, NC, 1999).

Results

Seventy girls (mean age 10.8 ± 3.6 yr, range 5–18 yr) participated in our study and underwent OGTT. Five of the 70 girls (7%) who completed the 2-h OGTT had IGT defined as G-120 of 140 mg/dl or more. None of the subjects were found to have type 2 diabetes or impaired fasting glucose. The ethnic background reported was 45 Hispanic (64%), 13 white (19%), 11 African American (16%), and 1 Other (1%). A family history of DM was reported by 83%. The mean BMI-z was 3.5 ± 2.2 (range -1.31 to +9.04). Eighty percent had acanthosis nigricans on examination and 67 of 70 had a normal hemoglobin A1c, mean 5.1% ± 0.28% (not obtained in three subjects). Twenty-six girls (37%) were prepubertal and 44 (63%) were premenarchal. Average age of menarche was 11.6 ± 1.2 yr in the 26 postmenarchal girls.

Overall, the variability in total proinsulin levels in our subjects was substantial despite small differences in blood glucose and relative lack of cross-reactivity of the PI assay used. Again, all PI and I data were natural log transformed before analyses given the large variance. The entire cohort of 70 was then analyzed by the following four conditions.

IGT (Table 1)

Of the five girls with IGT, three were Hispanic, one white, and one other. Two were Tanner stage I and three were Tanner stage V. The girls with IGT had higher BMI-z (P < 0.05), and thus BMI-z was entered as a covariate for analysis. Fasting G, I, and PI were not statistically different between the IGT and normal glucose-tolerant girls. At 120 min, both PI and I were higher in the IGT group (P < 0.05). The ratios of PI to I were not significantly different.

IR defined by HOMA (Table 2)

All 70 subjects were divided into four groups by HOMA quartiles for comparison by analysis of covariance, with age and BMI-z entered as covariates. Family history of DM was present in 13 of the 17 in quartile I, 17 of the 18 in quartile II, 13 of the 17 in quartile III, and 15 of the 18 girls in quartile IV. The number of Hispanic children in each quartile was 13 in quartile I, 6 in quartile II, 8 in quartile III, and 9 in quartile IV. As IR increased, mean PI at 0 and 120 min increased dramatically (P < 0.005 and P < 0.05, respectively). PI-0 was 5 times higher in the most IR (quartile IV), compared with the least IR group (quartile I), 46.3 ± 27.5 vs. 9.0 ± 7.3 pM/liter. With increasing IR, the ratio PI/I-0 was lower, quartile IV vs. quartile I (P < 0.05).

Obesity (Table 3 and Fig. 1)

To evaluate for differences with increasing obesity, the subjects were divided into three groups by BMI-z: nonobese (Non-OB), BMI-z less than 2; Mod OB, BMI-z 2 to 4; and Severe OB, BMI-z greater than 4. One girl did not have a height recorded and was excluded from this analysis related to BMI. There was no difference in mean age of these three groups. The mean BMI-z of these three groups were: Non-OB, 0.8 ± 0.8, n = 19; Mod OB, 3.07 ± 0.57, n = 21; and Severe OB, 5.4 ± 1.2, n = 29.

View larger version (22K): [in this window] [in a new window]   Figure 1. Two-hour OGTT. Comparison by severity of obesity.

The fasting PI and PI-120 were 2-fold higher in the Severe OB, compared with Non-OB (P < 0.005). Both obese groups had significantly higher PI-AUC than the Non-OB group (P < 0.05 Mod OB vs. Non-OB and P < 0.0001 Severe OB vs. Non-OB) and were also different from each other (P < 0.05 Mod OB vs. Severe OB). However, PI/I ratios were not different for any of the BMI groups.

Puberty (Table 4)

The 70 subjects consisted of 26 PrePub girls with Tanner stage I breast development, 15 girls in early puberty (Tanner stage II and III), and 29 in late puberty (Tanner stage IV and V). Mean BMI-z was not different among the three groups, 3.6 ± 2.9 vs. 3.8 ± 1.6 vs. 3.3 ± 1.8, respectively. Fasting G, G-120, and G-AUC were not different. Statistically significant differences in I and PI were found between PrePub and late puberty girls, but no statistical differences were found between PrePub vs. early puberty or early puberty vs. late puberty girls. Fasting I and PI levels were statistically higher in the late puberty girls, compared with the PrePub girls (P < 0.05). However, PI/I was not significantly different.

Our study sought to evaluate PI and PI/I in 70 girls with different degrees of G tolerance, IR, and obesity and at different stages of puberty. The subjects were originally recruited to evaluate validity of measures of I sensitivity, and the majority reported a family history of diabetes and had acanthosis nigricans, a dermatological marker of IR, on examination. This may reflect the large number of Hispanic subjects in our sample, and we may have recruited subjects with greater risk of DM based on the original recruitment objective. Indeed the occurrence of diabetes and obesity in Hispanic children in the United States has increased faster than that of any other racial and ethnic group (5).

Only five subjects (7%) were found to have IGT resulting in insufficient power for analysis to render any conclusions regarding the differences between IGT and normal glucose-tolerant girls from our study. Previous studies in children with IGT also reported elevated PI (19, 20). A recently published study, with a 20+% prevalence of IGT in markedly overweight children and adolescents, reported significantly elevated fasting PI levels in those with IGT without significant differences in PI/I, compared with normal glucose tolerant (21). In studies of adults with IGT, results have been conflicting, and some investigators suggest a defect in PI processing combined with decreased total I secretion (27). Others believe the defect in conversion of PI is overcome when the activity of the islet cell is strongly stimulated (28). Interestingly, others have reported that fasting PI, not PI/I, was predictive of development of type 2 DM within 12–36 months of diagnosis of IGT (11).

IR in our subjects was defined by HOMA, which has been validated against standard clamp techniques in adults (26). Increasing IR was associated with increasing fasting PI levels (P < 0.005) and lower fasting PI/I (P < 0.05). The same trend was found in a study of adults with IR (29). This suggests enhanced conversion of PI to I by the ß-cell when under the increased secretory demand of IR. However, once morbidity is present, PI is reported to be disproportionately increased as in nondiabetic adults with the insulin resistance syndrome from the San Antonio Heart Study. In fact, the fasting PI/I increased significantly with the number of metabolic disturbances associated with the syndrome (30). Elevated PI/I may indicate impaired stimulus-secretion coupling in ß-cells leading to metabolic disturbances such as in IR syndrome and type 2 DM (31, 32).

The prevalence of childhood obesity has doubled from 1980 to 1994 (3). This epidemic has contributed to the rising incidence of type 2 DM as well as other I-resistant states in childhood. Interestingly, in our study, there were no statistical differences in mean G, I, or PI levels during the OGTT between the obese girls with BMI-z between 2 and 4 (Mod OB) and the obese girls with a BMI-z of greater than 4 (Severe OB). The mean PI-AUC, however, was significantly higher in Severe OB, compared with Mod OB (P < 0.05). Long-term follow-up to evaluate the predictive value of the higher PI levels in Severe OB may demonstrate a distinct risk separate from obesity and I levels as has been shown in adults (12, 16, 17, 18). As in adults, PI elevations in the obese girls were not accompanied by changes in the ratio to I and suggest a proportional rise with increased I secreted (33, 34).

Puberty is recognized as a transient state of IR unique to childhood. Girls in our study were grouped into three pubertal groups, PrePub, early puberty, and late puberty. Fasting I was significantly higher in pubertal girls. The levels were highest in late puberty, compared with early puberty, although this difference did not reach statistical significance. In our cohort analyzed with BMI-z and fasting I as covariates, mean fasting PI levels were higher in pubertal, compared with prepubertal girls (P < 0.05). Otherwise, there was no statistical difference in PI at 120 min or AUC or in PI/I. It appeared that the increased IR of puberty was met by increased production and efficient conversion of PI such that the ratio of PI/I was unchanged.

Prior studies have suggested PI to be an independent and perhaps stronger predictor of morbidities such as type 2 DM, metabolic disturbances associated with syndrome X, and cardiovascular disease. An elevated PI/I has been documented in many groups with actual disease. Our preliminary study of girls found fasting PI to be increased in conditions of relative IR, as defined by increased HOMA, obesity, and puberty. The elevation paralleled the higher fasting I levels such that the PI/I was not different (except in girls with the greatest degree of IR as defined by HOMA, wherein the ratio was lower). This suggests the hyperproinsulinemia reflects increased ß-cell output with elevated I in these groups and not a defect in PI processing or secretion until a certain degree of IR is present. The failure to increase PI with the increased I output may indicate impending dysfunction and may serve as a marker for risk of morbidity.

Acknowledgments

Footnotes

This work was supported in part by grants from the NIH (Grant RR-00645); Eli Lilly, Co.; Pharmacia, Upjohn, Inc.; and Genentech, Inc. Data were presented in part at the Lawson Wilkins Pediatric Endocrine Society (LWPES)/European Society of Paediatric Endocrinology 6th Joint Meeting, Montreal, Canada, 2001. D.C. is a recipient of an LWPES travel award.

Abbreviations: AUC, Area under the curve; BMI, body mass index; BMI-z, BMI z-score; DM, diabetes mellitus; G, glucose; HOMA, homeostasis model of assessment; I, insulin; IGT, impaired glucose tolerance; IR, insulin resistance; Mod OB, moderately obese; non-OB, nonobese; OGTT, oral glucose tolerance test; %CV, percent coefficient of variation; PI, proinsulin; PI/I, proinsulin/insulin ratio; PrePub, prepubertal; Severe OB, severely obese.

Received September 21, 2001.

Accepted July 2, 2002.

References

1. Libman I, Arslanian SA 1999 Type II diabetes mellitus: no longer just adults. Pediatr Ann 28:589–593[Medline]
2. Dietz WH 1998 Health consequences of obesity in youth: childhood predictors of adult disease. Pediatrics 101:518–525[Abstract/Free Full Text]
3. Troiano RP, Flegal KM 1998 Overweight children and adolescents: description, epidemiology, and demographics. Pediatrics 101:497–504[Abstract/Free Full Text]
4. Fagot-Campagna A 2000 Emergence of type 2 diabetes mellitus in children: epidemiological evidence. J Pediatr Endocrinol Metab 13(Suppl 6):1395–1402
5. Dabelea D, Pettitt DJ, Jones KL, Arslanian SA 1999 Type 2 diabetes mellitus in minority children and adolescents: an emerging problem. Endocrinol Metab Clin 28:709–730
6. Kahn BB 1998 Type 2 diabetes: when insulin secretion fails to compensate for insulin resistance. Cell 92:593–596[CrossRef][Medline]
7. Porte D, Kahn SE 2001 ß-Cell dysfunction and failure in type 2 diabetes: potential mechanisms. Diabetes 50(Suppl):S160–S163
8. Grill V, Björklund A 2001 Overstimulation and ß-cell function. Diabetes 50(Suppl 1):S122–S124
9. O’Rahilly S, Gray H, Humphreys PJ, Krook A, Polonsky KS, White A, Gibson S, Taylor K, Carr C 1995 Impaired processing of prohormones associated with abnormalities of glucose homeostasis and adrenal function. N Engl J Med 333:1386–1390[Free Full Text]
10. Hostens K, Ling Z, van Schravendijk C, Pipeleers D 1999 Prolonged exposure of human ß-cells to high glucose increases their release of proinsulin during acute stimulation with glucose or arginine. J Clin Endocrinol Metab 84:1386–1390[Abstract/Free Full Text]
11. Nijpels G, Popp-Snijders C, Kostense PJ, Bouter LM, Heine RJ 1996 Fasting proinsulin and 2-h post load glucose levels predict the conversion to NIDDM in subjects with impaired glucose tolerance: the Hoorn Study. Diabetologia 39:113–118[Medline]
12. Wareham NJ, Byrne CD, Williams R, Day NE, Hales CN 1999 Fasting proinsulin concentrations predict the development of type 2 diabetes. Diabetes Care 22:262–270[Abstract/Free Full Text]
13. Kahn SE, Leonetti DL, Prigeon RL, Boyko EJ, Bergstom RW, Fujimoto WY 1996 Proinsulin levels predict the development of non-insulin-dependent diabetes mellitus in Japanese-American men. Diabet Med 13(9 Suppl 6):S63–S66
14. Haffner SM, Gonzalez C, Mykkänen, Stern M 1997 Total immunoreactive proinsulin, immunoreactive insulin and specific insulin in relation to conversion to NIDDM: the Mexico City Diabetes Study. Diabetologia 40:830–837[CrossRef][Medline]
15. Mykkänen L, Haffner SM, Kuusisto J, Pyorala K, Hales CN, Laasko M 1995 Serum proinsulin levels are disproportionately increased in elderly prediabetic subjects. Diabetologia 38:1176–1182[Medline]
16. Lindahl B, Dinesen B, Eliasson M, Roder M, Hallmans G, Stegmayr B 2000 High proinsulin levels precede first-ever stroke in a nondiabetic population. Stroke 31:2936–2941[Abstract/Free Full Text]
17. Lindahl B, Dinesen B, Eliasson M, Roder M, Jansson JH, Huhtasaari F, Hallmans G 1999 High proinsulin concentration precedes myocardial infarction in a nondiabetic population. Metabolism 48:1197–1202[CrossRef][Medline]
18. Yudkin JS, Denver AE, Mohamed-Ali V, Ramaiya KL, Nagi DK, Goubet S, McLarty DG, Swai A 1997 The relationship of concentrations of insulin and proinsulin-like molecules with coronary heart disease prevalence and incidence. A study of two ethnic groups. Diabetes Care 20:1093–1100[Abstract]
19. Rosenbloom AL, Starr JI, Juhn D, Rubenstein AH 1975 Serum proinsulin in children and adolescents with chemical diabetes. Diabetes 24:753–757[Abstract]
20. Burghen GA, Etteldorf JN, Trouy RL, Kitabchi AE 1976 Insulin and proinsulin in normal and chemical diabetic children. J Pediatr 89:48–53[CrossRef][Medline]
21. Sinha R, Fisch G, Teague B, Tamborlane WV, Banyas B, Allen K, Savoye M, Rieger V, Taksali S, Barbetta G, Sherwin RS, Caprio S 2002 Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med 346:801–810
22. Silfen ME, Manibo AM, Ferin M, McMahon DJ, Levine LS, Oberfield SE 2002 Elevated free IGF-I levels in prepubertal Hispanic girls with premature adrenarche: relationship with hyperandrogenism and insulin sensitivity. J Clin Endocrinol Metab 87:398–403[Abstract/Free Full Text]
23. Silfen ME, Manibo AM, McMahon DJ, Levine LS, Murphy AR, Oberfield SE 2001 Comparison of simple measures of insulin sensitivity in young girls with premature adrenarche: the fasting glucose to insulin ratio may be a simple and useful measure. J Clin Endocrinol Metab 86:2863–2868[Abstract/Free Full Text]
24. Must A, Dallal GE, Dietz WH 1991 Reference data for obesity: 85th and 95th percentiles of body mass index (wt/ht²) and triceps skinfold thickness. Am J Clin Nutr 53:839–846[Abstract/Free Full Text]
25. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus1997 Report of the ADA Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183–1197
26. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC 1985 Homeostasis model assessment: insulin resistance and ß-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419[CrossRef][Medline]
27. Larrson H, Ahren B1999 Relative hyperproinsulinemia as a sign of islet dysfunction in women with impaired glucose intolerance. J Clin Endocrinol Metab 84:2068–2074
28. Stumvoll M, Fritsche A, Stefan N, Hardt E, Häring H 2001 Evidence against a rate-limiting role of proinsulin processing for a maximal insulin secretion in subjects with impaired glucose tolerance and ß-cell dysfunction. J Clin Endocrinol Metab 86:1235–1239[Abstract/Free Full Text]
29. Mykkänen L, Haffner SM, Hales CN, Rönnemaa T, Laakso M 1997 The relation of proinsulin, insulin, and proinsulin-to-insulin ratio to insulin sensitivity and acute insulin response in normoglycemic subjects. Diabetes 46:1990–1995[Abstract]
30. Haffner SM, Mykkänen L, Valdez RA, Stern MP, Holloway DL, Monterrosa A, Bowsher RR 1994 Disproportionately increased proinsulin levels are associated with the insulin resistance syndrome. J Clin Endocrinol Metab 79:1806–1810[Abstract]
31. Kahn SE, Halban PA 1997 Release of incompletely processed proinsulin is the cause of the disproportionate proinsulinemia of NIDDM. Diabetes 46:1725–1732[Abstract]
32. Roder ME, Porte D, Schwartz RS, Kahn SE 1998 Disproportionately elevated proinsulin levels reflect the degree of impaired ß-cell secretory capacity in patients with non-insulin dependent diabetes mellitus. J Clin Endocrinol Metab 83:604–608[Abstract/Free Full Text]
33. Saad MF, Kahn SE, Nelson RG, Pettitt DJ, Knowler WC, Schwartz MW, Kowalyk S, Bennett PH, Porte D 1990 Disproportionately elevated proinsulin in Pima Indians with non-insulin dependent diabetes mellitus. J Clin Endocrinol Metab 70:1247–1253[Abstract]
34. Koivisto VA, Yki-Järvinen H, Hartling SV, Pelkonen R The effect of exogenous hyperinsulinemia on proinsulin secretion in normal man, obese subjects, and patients with insulinoma. J Clin Endocrinol Metab 63:1117–1120

This article has been cited by other articles:

				B. M. Shields, B. Knight, H. Hopper, A. Hill, R. J. Powell, A. T. Hattersley, and P. M. Clark Measurement of Cord Insulin and Insulin-Related Peptides Suggests That Girls Are More Insulin Resistant Than Boys at Birth Diabetes Care, October 1, 2007; 30(10): 2661 - 2666. [Abstract] [Full Text] [PDF]

				V. Hirschler, C. Aranda, M. d. L. Calcagno, G. Maccalini, and M. Jadzinsky Can Waist Circumference Identify Children With the Metabolic Syndrome? Arch Pediatr Adolesc Med, August 1, 2005; 159(8): 740 - 744. [Abstract] [Full Text] [PDF]

				M. Maliqueo, I. Atwater, R. Lahsen, F. Perez-Bravo, B. Angel, and T. Sir-Petermann Proinsulin serum concentrations in women with polycystic ovary syndrome: a marker of {beta}-cell dysfunction? Hum. Reprod., December 1, 2003; 18(12): 2683 - 2688. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chin, D. Articles by Levine, L. S. Search for Related Content PubMed PubMed Citation Articles by Chin, D. Articles by Levine, L. S.