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Manger WM, Gifford RW: 1993. Pheochromocytoma: current diagnosis and management. Clevel Clin J Med 60:365–378. Mayo-Smith WW, Lee MJ, McNicholas MM, Hahn PF, Boland GW, Saini S: 1995. Characterization of adrenal masses (<5 cm) by use of chemical shift MR imaging: observer performance versus quantitative measures. Am J Radiol 165:91–95. Melby JC. 1985. Diagnosis and treatment of primary aldosteronism and isolated hypoaldosteronism. Clin Endocrinol Metab 14: 977–995. Mena A, Lawson M, Kabadi UM: 1997. Pheochromocytoma. Endocr Pract 3:98–105. Osella G, Terzolo M, Boretta G, et al.: 1994. Endocrine evaluation of incidentally discovered adrenal masses. J Clin Endocrinol Metab 79:1532–1539. Osella G, Terzolo M, Reimondo G, et al.: 1997.

Serum markers of bone and collagen turnover in patients with Cushing’s syndrome and in subjects with adrenal incidentalomas. J Clin Endocrinol Metab 82:3303–3307. Outwater EK, Siegelman ES, Radecki PD, Piccoli CW, Mitchell DG: 1995. Distinction between benign and malignant adrenal masses: value of T1-weighted chemical-shift MR imaging. Am J Radiol 165:579–583. Outwater EK, Siegelman ES, Huang AB, Birnbaum BA: 1996. Adrenal masses: correlation between CT attenuation value and chemical shift ratio at MR imaging with inphase and opposed phase sequences. Radiology 200:749–752. Ravichandran R, Lafferty F, McGinniss MJ, Taylor HC: 1996. Congenital adrenal hyperplasia presenting as massive adrenal incidentalomas in the sixth decade of life: report of two patients with 21-hydroxylase deficiency. J Clin Endocrinol Metab 81:1776–1779.

Reincke M, Nieke J, Krestin GP, Saeger W, Allolio B, Winkelmann W: 1992. Preclinical Cushing’s syndrome in adrenal “incidentalomas”: comparison with adrenal Cushing’s syndrome. J Clin Endocrinol Metab 75: 826–832. Ross NS, Aron DC: 1990. Hormonal evaluation of the patient with an incidentally discovered adrenal mass. N Engl J Med 323: 1401–1405. Shirkhoda A, Katz RI: 1985. Diagnostic approach to incidental adrenal nodules in the cancer patient. Cancer 55:1995–2000. Ukimura O, Inui E, Ochiai A, Kojima M, Watanabe H: 1995. Combined adrenal myelolipoma and pheochromocytoma. J Urol 254:1470. Valloton MB: 1996. Primary aldosteronism. Part 1: diagnosis of primary aldosteronism. Clin Endocrinol 45:47–52.

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Insulin Secretion, Insulin Sensitivity and Diabetes in Black Children Silva Arslanian and Kapriel Danadian

Historically, type 2 diabetes has been considered rare in the pediatric population. However, over the last decade, there has been a disturbing upswing in the rate of non-type 1 diabetes in the pediatric age group, particularly adolescents, with a greater proportion of Black children being affected. In this review, the following questions will be addressed: (1) what are the clinical characteristics of youth-onset atypical diabetes, (2) how common is it, (3) what are the risk factors, and (4) how should it be treated? African Americans are at an increased risk for type 2 diabetes, gestational diabetes, obesity and cardiovascular disease mortality (Harris 1990, Cowie et al. 1993, Tull and Roseman 1995). Moreover, they continue to experience a dramatic increase in their rate of diagnosed diabetes, which has tripled during the past 30 years (Tull and Roseman 1995). Historically, type 2 diabetes has been considered rare in the pediatric population. However, there is an

alarming trend of increasing non-type 1 diabetes, specifically in adolescents, with a greater proportion of Black children being affected. The aims of this review are: (1) to discuss the clinical characteristics of non-type 1 or youthonset atypical diabetes, (2) to review the risk factors for the increased rates of non-type 1 diabetes in Black youths, (3) to present recent observations of Black/White differences in insulin secretion and sensitivity in children, and (4) to discuss treatment options.

S. Arslanian and K. Danadian are at the Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, Children’s Hospital, University of Pittsburgh, Pittsburgh, PA 15213-2583, USA.

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Youth-onset Atypical Diabetes (YOAD)

Incidence rates of type 1 diabetes in White children range from 13.8 to 16.9 per 100 000 per year, whereas for Black children the rates are almost half, ranging from 3.3 to 11.8 per 100 000 per year (Laporte et al. 1986, Wagenknecht et al. 1989, Tull and Roseman 1995). However, diabetes in Black American youths occasionally presents in an unusual clinical form as neither typical type 1 diabetes nor classic type 2 diabetes but may have features of both. For lack of a better classification, the term youth-onset atypical diabetes (YOAD) will be applied. Frequently used literature references include youth non-insulin-dependent diabetes mellitus (NIDDM), atypical diabetes mellitus (ADM) and maturity-onset diabetes of youth (MODY) (Winter et al. 1987). The last of these terms was coined in 1987, and was one of the earlier descriptions of youth-onset atypical diabetes in Black children. However, after the clear identification of the various genetic mutations responsible for MODY, it became clear that youth-onset atypical diabetes is quite different from MODY. Clinical Characteristics of YOAD (Table 1) Youths with atypical diabetes present with symptoms spanning a spectrum

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BMI, body mass index; NIDDM, non-insulin dependent diabetes mellitus.

from severe manifestations of insulin deficiency to mild incidental hyperglycemia. At presentation, the patient may have ketonuria and/or ketoacidosis, and acute signs compatible with type 1 diabetes (polyuria, polydipsia, nocturia and weight loss), which require insulin therapy (Pinhas-Hamiel et al. 1997). With this clinical picture, often the distinction from type 1 diabetes is not possible until months to years later, when insulin requirements decline (beyond that of the honeymoon period) and a non-insulin dependent course develops without dependence on insulin for life. During this non-insulin-dependent period, glycosuria, hyperglycemia and elevated glycohemoglobin may or may not persist. Remitting recurrences of severe hyperglycemia and ketonuria are not unusual during intercurrent acute illness (Winter et al. 1987, Winter 1991, Pinhas-Hamiel et al. 1996, Glaser 1997, Scott et al. 1997, Neufeld et al. 1998). On the other hand, the patient may be totally asymptomatic. One-third of patients have been diagnosed by urinalysis during routine physical examination (Pinhas-Hamiel and Zeitler 1997). Characteristically, the mean age at diagnosis is around 13 years with the majority of patients in mid-puberty (Winter et al. 1987, Pinhas-Hamiel et al. 1996, Scott et al. 1997, Neufeld et al. 1998). Unlike type 1 diabetes, there is an excess of female to male patients ranging from 1.6:1 to 3:1 in different studies (Winter 1991, Pinhas-Hamiel et al. 1996, Scott et al. 1997). Among patients with YOAD, there is a preponderance of Black children ranging from 68% to 100% of reported cases (Winter 1991, Pinhas-Hamiel et al. TEM Vol. 9, No. 5, 1998

Epidemiology of YOAD An important limitation in discussing the epidemiology of YOAD is that almost all of the literature reports are retrospective chart reviews of diabetes clinic populations. Given this limitation, the prevalence of this disorder is likely to be higher than that reported thus far. However, there is unanimous agreement that estimates of atypical diabetes in youth are on the rise and that YOAD is emerging as a serious clinical entity among Black American and Latino youths (Winter 1991, Pinhas-Hamiel et al. 1996, Glaser 1997, Pinhas-Hamiel and Zeitler 1997, Scott et al. 1997). Until recently, type 2 diabetes has been considered uncommon in the pediatric age group, with estimates of ~2% of newly diagnosed cases with diabetes (Arslanian et al. 1994). However, recent reports show an alarming trend (Fig. 1). In the greater Cincinnati area, between 1982 and 1994, the incidence of type 2 diabetes in adolescents increased ten-fold from 0.7 per 100 000 to 7.2 per 100 000 per year (PinhasHamiel et al. 1996). Adolescents presenting with YOAD in 1982 accounted for ~5% of new-onset cases with diabetes, while in 1994 this figure increased to 40%. The majority of the increase occurred in females, more so in Blacks.

A 20 No. of patients

◆ Preponderance of black children ◆ Mean age at diagnosis ~13.5 yrs ◆ Increased female-to-male ratio ◆ Majority of patients in mid-puberty ◆ Increased BMI ◆ Acanthosis nigricans ◆ Family history of NIDDM

1996, Scott et al. 1997). Also, it is more common in Mexican American youths (Neufeld et al. 1998). Obesity is present in the majority of patients, with body mass index (BMI) exceeding the 85th percentile for age and sex in almost 95% of patients with YOAD (PinhasHamiel et al. 1996, Scott et al. 1997, Neufeld et al. 1998). Acanthosis nigricans is present in 60–86% of patients (Pinhas-Hamiel et al. 1996, Scott et al. 1997). A strong family history of type 2 diabetes is characteristic of patients with YOAD. 72% to 85% of patients have a family history of NIDDM, often with multiple affected family members in more than one generation (Glaser 1997, Neufeld et al. 1998). However, in general there is no autosomal dominant inheritance pattern, thus distinguishing YOAD from MODY.

15 10 5 0

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Table 1. Clinical characteristics of youth-onset atypical diabetes

15 10 5 0

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Figure 1. Number of cases of youth-onset atypical diabetes by year and race (open bars, Whites; closed bars, Blacks). (A) Data from Arkansas Children’s Hospital and (B) data from Children’s Hospital Medical Center of Cincinnati. Adapted by permission from Pihoker et al. (1998) and Pinhas-Hamiel et al. (1996).

Similarly, between 1988 and 1995, the number of children diagnosed with YOAD increased by ~8.5-fold in the Arkansas Children’s Hospital (Scott et al. 1997). In Allegheny County, between 1990 and 1994, the incidence of childhood diabetes in Black adolescents (15–19 years) was three times higher than in White adolescents (Libman et al. in press). Biochemical Characteristics of YOAD Data remain quite scanty regarding the biochemical characteristics of youths who present with atypical diabetes. The major limiting factor is that the diagnosis is frequently made in retrospect, with lack of uniformity in data collection and follow-up. However, the available information suggests that in comparison with type 1 diabetes, children with YOAD present with lesser degrees of hyperglycemia, have significantly higher levels of insulin and Cpeptide, are less frequently ketonuric, and have milder degrees of acidosis (Glaser 1997, Scott et al. 1997). Autoimmunity and YOAD It has been proposed that a large proportion of Blacks with YOAD might have 195

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Risk Factors

Insulin Sensitivity/Insulin Secretion in Black Children There are convincing epidemiologic data that Black children are hyperinsulinemic compared with their White counterparts. The Bogalusa Heart study

196

A 100 Insulin (mU ml–1)

evaluated plasma glucose and insulin levels during an oral glucose tolerance test (OGTT) in 5–17-year-old children and adolescents from a bi-racial Black and White community. Black children, especially girls, had higher insulin responses and higher insulin:glucose ratios than their White counterparts (Svec et al. 1992). In 7–11-year-old children, after controlling for fatness, Black children had significantly higher insulin levels than White children (Gutin et al. 1994). Such observations suggest that Black children are more insulin resistant than White children. Moreover, this insulin resistance might not be limited to glucose metabolism only, but might also affect fat metabolism, because insulin to free fatty acid ratios were also higher in Black than White children (Radhakrishnamurthy et al. 1985). On the other hand, hyperinsulinemia could be mediated partly through decreased insulin clearance, as was suggested recently by the lower C-peptide to insulin ratios in Black children (Jiang et al. 1996). To investigate whether Black/White differences in insulinemia result from differences in insulin sensitivity and secretion, we investigated healthy Black American vs White American children aged eight years and above. Insulin secretion was assessed during a 2-h hyperglycemic clamp at 225 mg dl-1. Our data indicate that Black children have higher insulin secretion both before and during puberty (Fig. 2) (Arslanian and Suprasongsin 1996b, Arslanian et al. 1997). However, differences in insulin sensitivity were only detectable during puberty. Insulin sensitivity was 35% lower in Black adolescents compared with White adolescents (Arslanian and Suprasongsin 1996b). Such data suggest that Black/White differences in insulinemia detected in the first decade of life are most likely a compensatory mechanism to adapt to subtle decrements in insulin sensitivity in Black children. During periods of physiological and/or pathophysiological reductions in insulin action, the Black/White difference in insulin sensitivity becomes evident. We and others have shown that during pubertal development, adolescents are insulin

ns p = 0.016

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a non-autoimmune form of diabetes (Winter et al. 1987). Such a proposal is based on the following observations. More Blacks with YOAD lack the high risk human leukocyte antigen (HLA) DR3 and DR4 alleles as compared with White patients with type 1 diabetes (30% vs 5.6%) (Winter et al. 1987). Second, YOAD does not seem to segregate with any HLA haplotype, in contrast to classic type 1 diabetes. Third, the frequency of islet cell autoantibody (ICA) positivity in Blacks with YOAD is much less than in Whites with type 1 diabetes (34% vs 63%) (Winter et al. 1987). In the study from greater Cincinnati, ICAs were absent in 100% of children with the clinical diagnosis of NIDDM (Pinhas-Hamiel et al. 1996). In Allegheny County, ~42% of Black adolescents with diabetes have no evidence of autoantibodies compared with only 10% of White adolescents (Libman et al. 1997). The varying frequencies of autoantibodies in Black children with atypical diabetes could be a reflection of ascertainment bias resulting from a lack of uniformity in the definitions and/or classification of YOAD. Recently, we had the anecdotal experience of taking care of a Black adolescent who presented with atypical diabetes, obesity and acanthosis nigricans, but who also had evidence of islet cell autoimmunity detected by autoantibodies to glutamic acid decarboxylase GAD65. This patient has gone for up to two years not requiring insulin after her initial presentation while maintaining normoglycemia (Witchel and Arslanian, unpublished). Therefore, the presentation of atypical diabetes could be precipitated by an acute b-cell autoimmune process that might or might not result in persistent autoimmune destruction of the pancreas, a model consistent with the latent b-cell defect model of NIDDM etiology (Rewers and Hamman 1995).

p = 0.012 p = 0.0003

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Figure 2. Means of basal, first-phase and second-phase insulin concentrations during a hyperglycemic clamp (~225 mg dl-1) in African American (closed bars) vs White American (open bars) children. (A) Prepubertal children and (B) pubertal adolescents. NS, not significant. Adapted with permission from Arslanian (1998).

resistant compared with prepubertal children or adults (Amiel et al. 1986, Caprio et al. 1989, Arslanian and Kalhan 1994). In vivo insulin activity is ~30% lower in adolescents (Arslanian and Kalhan 1994) but recovers after completion of puberty. Such observations of deteriorating insulin activity during puberty, which is more pronounced in Blacks, could explain the increased rates of YOAD in Black children at around 13 years of age. Moreover, the increased female to male ratio in patients with YOAD could be because of a lower insulin sensitivity in Black girls vs Black boys (Arslanian et al. 1997). However, additional studies are needed, with careful attention to body compositional differences between genders. Finally, it remains to be determined whether the observed racial differences in insulin secretion or action are genetically determined or environmentally modulated. Obesity in Black Children One of the clinical characteristics of patients with YOAD is elevated BMI or obesity. Obesity is a major risk factor TEM Vol. 9, No. 5, 1998

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for insulin resistance and NIDDM. Is it possible that the increasing rates of YOAD are a reflection of increasing rates of obesity in the US children? Between 1960 and 1980, there has been a 54% increase in obesity prevalence among children 6–11 years of age, and a 39% increase among 12–17-year-old children. In addition, the prevalence of superobesity (triceps skinfolds greater than or equal to the 95th percentile) increased by 98% and 64% in the same age groups (Gortmaker et al. 1987). When analyzed by race and gender, this increase is most pronounced in Black boys and Black girls (Gortmaker et al. 1987, Campaigne et al. 1994, Troiano et al. 1995). The question that arises again is whether: (1) Black children have a genetic predisposition to obesity, (2) the observed differences are purely environmentally modulated, or (3) both genetic and environmental factors are operative. BMI is consistently higher in all age groups between 25 and 74 years for Blacks compared with Whites (Harris 1990). Differences in body weight between Blacks and Whites emerge after adolescence, and prevalence of obesity increases in Blacks relative to their White counterparts during pubertal maturation (Gartside et al. 1984, Campaigne 1994, Melnyk and Weinstein 1994, Morrison et al. 1994). These epidemiological observations could be reconciled with our observations of lower rates of resting energy expenditure in Black children and lower rates of fat oxidation in Black adolescents (Arslanian and Suprasongsin 1996b, Arslanian et al. 1997). In prepubertal children, resting energy expenditure was 10% lower in Black compared with White children. Similar findings were reported by two other groups (Kaplan et al. 1996, Morrison et al. 1996). Lower energy expenditure in Black children (heredity vs lifestyle) would predispose them to obesity in the presence of excess energy intake. However, before any definitive conclusions are made regarding Black/White differences in energy metabolism, free-living energy balance studies are needed. A number of recent investigations in humans have shown that a high

y = –0.23x + 15.9

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Figure 3. Relationship of body mass index (BMI) and percent body fat to fasting insulin concentrations [A (r = 0.64, p = 0.0005) and B (r = 0.71, p = 0.0005)] and insulin-mediated glucose disposal [C (r = –0.72, p = 0.0005) and D (r = –0.65, p = 0.0005)] during a hyperinsulinemiceuglycemic clamp in African American children (prepubertal, open circles; pubertal, closed circles).

respiratory quotient (RQ) and a low ratio of fat to carbohydrate oxidation were associated with actual and/or subsequent weight gain (Zurlo et al. 1990, Seidel et al. 1992, Schutz 1995). We found around 30% lower rates of fat oxidation in Black adolescents compared with their White counterparts (Arslanian and Suprasongsin 1996b). Could this explain the Black/ White divergence in weight gain after puberty? This attractive hypothesis needs to be pursued. Racial differences in diet and lifestyle could also be important factors predisposing to obesity. Black children have been reported to have higher total fat and cholesterol intake and to prefer greater sweetness in liquids (Kimm et al. 1990, Bacon et al. 1994). Black girls were found to have higher total energy intake and to spend more time watching television (Falkner 1993). Socioculturally, heavy Black adolescents

do not perceive themselves as heavy, and more Black girls express a desire to be on the fat side (Desmond et al. 1989). Black adolescents are less active than their White counterparts (Aaron et al. 1993). Each or all of these differences could be important metabolic and/or environmental factors predisposing to obesity. Obesity and Insulin Sensitivity in Black Children It is well established that body composition is a major determinant of insulin sensitivity. Our studies in White American children demonstrated that adiposity accounts for 55% of the variability in insulin sensitivity (Arslanian and Suprasongsin 1996a). Fig. 3 depicts the relationship between BMI and body composition measured by dual energy X-ray absorptiometry (DEXA), with fasting serum insulin and insulin sensitivity in healthy Black children. 197

As BMI and percent adiposity increase, insulin sensitivity decreases and insulinemia increases. In the background of increasing rates of obesity in Black youths, and the negative impact of obesity on insulin sensitivity, it is not surprising that rates of type 2 diabetes or YOAD are on the rise. It remains to be determined, however, whether Black children are more insulin resistant than their White counterparts of comparable body composition. Race and Acanthosis Nigricans In adolescents with YOAD, acanthosis nigricans (AN) occurs in up to 86% of cases (Scott et al. 1997). Acanthosis nigricans is characterized by velvety, hyperpigmented patches in intertriginous areas (Stuart et al. 1998). The medical importance of AN is its association with insulin resistance/ hyperinsulinemia and an increased risk for type 2 diabetes. In a survey of public school sixth and eighth graders, acanthosis nigricans was present in 7.1% of the 1412 children examined. The prevalence was highest in Blacks (13.3%), followed by Latinos (5.5%) and Whites (0.5%) (Stuart et al. 1989). In every ethnic group, AN shows a strong association with obesity. However, in African Americans the prevalence of AN is 25-fold higher, despite comparable prevalence of obesity to other minorities (Stuart et al. 1998). It remains questionable whether this is a reflection of a higher prevalence of insulin resistance/hyperinsulinemia, as the latter correlates with the presence and severity of AN (Stuart et al. 1994). Moreover, prevalence of diabetes in African American subjects with AN is six times higher than among African Americans of the general population (Stuart et al. 1998). Thus, AN is an important physical/phenotypic correlate of insulin resistance/hyperinsulinemia. Because of its association with higher rates of type 2 diabetes in Black adults, and because of its increased prevalence in patients with YOAD, it could be useful as a screening tool for the identification of high-risk subjects for youth NIDDM.

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Therapy

Youth-onset atypical diabetes has become a major clinical problem for the pediatric endocrinologist. It remains a poorly understood entity and incompletely investigated on a population basis. Similarly, not much is known about the therapeutic management of this disorder in childhood (Glaser and Jones 1996, Glaser 1997, PinhasHamiel and Zeitler 1997). Therefore, any discussion about therapy will be anecdotal and based on personal experience and bias. However, there are a few well-recognized facts that should serve as guides for future therapeutic intervention strategies. (1) The majority of youths with atypical diabetes are obese. Therefore, it is reasonable to determine whether lifestyle changes that incorporate dietary and activity intervention are feasible and efficacious. Because of a strong family history of diabetes in these patients, such interventions must focus on the whole family unit. Unfortunately, extrapolating from the adult experience one cannot be too optimistic about the success of such interventions, especially in the long-term. (2) A high percentage of patients with YOAD have evidence of insulin resistance. Isn’t it then rational to test the efficacy and safety of insulin-sensitizing agents in this age group? Such patients are being treated with a variety of oral hypoglycemic agents, with no safety or efficacy data. Multicenter studies of pharmacological interventions have to be performed before any discussions or recommendations can be made regarding therapy. (3) When the patient presents with ketoacidosis, it is only intuitive to correct the ketoacidosis with insulin therapy. Last but not least, it has to be remembered that YOAD could remain unrecognized for years and thereby lead to diabetic complications. Therefore, a high index of suspicion should lead to increased screening of individuals at risk. In closing, the alarming increase in the rate of YOAD over the last decade is disconcerting. It is incumbent on health care professionals to gear their research efforts towards a better understanding of this entity. This should

include the examination of its metabolic and immunological basis, with the intent to provide insights into genetic and/or environmental causes. Until such efforts are organized, YOAD will remain incompletely understood and most likely inadequately cared for. •

Acknowledgements

The authors would like to thank Drs I. Libman and D. Becker for the sharing of data. The authors also thank Pat Antonio for excellent secretarial assistance. The research studies would not have been possible without the commitment of the volunteer children and their parents, and the recruitment efforts of Lynnette Orlansky. This work was supported by NIH grant HD27503 and USPHS Grant MO1-RR00084 (GCRC). References Aaron DJ, Kriska AM, Dearwater SR, et al.: 1993. The epidemiology of leisure physical activity in an adolescent population. Med Sci Sports Exerc 25:847–853. Amiel SA, Sherwin RS, Simonson DC, Lauritano AA, Tamborlane WV: 1986. Impaired insulin action in puberty: a contributing factor to poor glycemic control in adolescents with diabetes. New Engl J Med 315:215–219. Arslanian S: 1998. Insulin secretion and sensitivity in healthy African-American vs American White children. Clin Pediatr 37:81–88. Arslanian SA, Kalhan SC: 1994. Correlations between fatty acid and glucose metabolism: potential explanation of insulin resistance of puberty. Diabetes 43:908–914. Arslanian S, Suprasongsin C: 1996a. Insulin sensitivity, lipids and body composition in children: is ‘syndrome X’ present? J Clin Endocrinol Metab 81:1058–1062. Arslanian S, Suprasongsin C: 1996b. Differences in the in vivo insulin secretion and sensitivity in healthy black vs white adolescents. J Pediatr 129:440–444. Arslanian S, Becker D, Drash A: 1994. Diabetes mellitus in the child and adolescent. In Kappy MS, Blizzard RM, Migeon CJ, eds. The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence. Springfield, IL: Charles C. Thomas, pp 961–1026. Arslanian S, Suprasongsin C, Janosky J: 1997. Insulin secretion and sensitivity in Black versus White prepubertal healthy children. J Clin Endocrinol Metab 82:1923–1927.

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