The National Institute of Diabetes & Digestive & Kidney Diseases

To help answer the question as to whether this recent increase was for type 1 or type 2 diabetes, autoantibody data were collected from patients from one of the largest local hospitals, Children's Hospital of Pittsburgh. ICA, GAD65, and IA-2 autoantibodies were determined for approximately 441 children with clinically diagnosed IDDM. The prevalence of these antibodies was significantly lower in African Americans than in whites. About 90% of whites (both younger and older) had autoantibodies (and thus presumably had type 1 diabetes), whereas African Americans, especially the older African American children, had a substantially lower prevalence of autoantibodies. The percentage of those patients aged 0-19 with no evidence of any autoantibodies was 25% for African Americans compared with 5.5% for whites. Dividing now by age group, Dr. Libman showed that 3.1% of whites less than 11 years and 8.7% 11 years old and older had no autoantibodies, whereas 40% of African Americans 11-19 had none (and presumably thus had type 2 diabetes).

Among a group of 40 African American diabetic children (67.5% autoantibody-positive and 32.5% autoantibody-negative), the mean age of the autoantibody-positive group was 8.7, whereas the mean age of the autoantibody-negative group was the significantly greater 12.9; 30% of the autoantibody-positive group was obese, whereas 62% of the autoantibody-negative group was obese (greater than 85 percentile). A group worth investigating further is the 38% of the autoantibody-negative group that were not obese (i.e., that were below the 85 percentile). These children are putatively non-type 1 (because they are autoantibody negative) and also putatively non-type 2 (because they are not obese).

In summary, African Americans that were autoantibody-negative were older at diagnosis, had a higher prevalence of obesity, and had a greater tendency to have a parent with diabetes. These studies continue at present.

Lawrence M. Dolan, M.D., of the Children's Hospital Medical Center of Cincinnati and the chair of this session, spoke next. Dr. Dolan discussed his data on 128 pediatric type 2 diabetes patients diagnosed between 1992 and 1998, who are predominantly African American and female. He stressed the importance of autoantibody data in pediatric diabetes classification and noted that 96 of these patients had been tested for the presence of autoantibodies and that had all been autoantibody-negative. By Dr. Dolan's criteria, the presence of autoantibodies is sufficient to classify the disease as type 1, even if the patients present with other type 2 indications (e.g., obesity, in which case their records are flagged with an asterisk for special followup attention).

Dr. Dolan stated that his study is not looking at any genetic markers but rather for possible autosomal-dominant inheritance (e.g., MODY), by screening family history for diabetic relatives. In addition, although he notes in his patients the presence of acanthosis nigricans and levels of insulin and C-peptide, these are neither inclusion nor exclusion criteria for type 1 or type 2 classification.

Dr. Dolan calculated prevalence and incidence rates using the 124 records of patients within the eight-county Greater Cincinnati service area, which demographically is 87% non-Hispanic white, 12% African American, and 1% other (including Hispanics). As of December 1998, the overall prevalence of type 2 diabetes was 0.14 per 1,000 (0.014%) for 0-19-year olds. The children with type 2 diabetes tend to be female, African American, and in older adolescence (aged 15-19). Incidence rate determinations for type 1 pediatric diabetes were not possible before 1990, given that there were then only 1 or 2 patients per year in Greater Cincinnati. The overall incidence rate of type 2 diabetes increased greatly during the years 1992-1994; since then the incidence rate has been relatively stable.

Overall, the average age for children with type 2 diabetes is 15.1 years, which does not vary much by gender or race. The average BMI is 36.3 (again no real difference by gender or race). Acanthosis nigricans is present in 71% of the population (African Americans 82%, whites 54%).

Dr. Dolan next described the complications that he has seen in this type 2 diabetes population. High blood pressure, above the 90 percentile (corrected for age and height), was seen in a fair number of the 66 patients for whom data were available. High blood pressure was determined within 3 months of initial diagnosis but only once the patient was metabolically stable. There was a statistically significant relationship between systolic pressure and BMI.

Prevalence of hyperlipidemia was determined by fasting lipid profiles also obtained no later than 3 months after diagnosis (mean = 29 days). Using 95 percentile limit for total cholesterol, triglycerides and LDL cholesterol, and an analogous 5 percentile limit for HDL cholesterol, Dr. Dolan noted that among 27 patients tested, 23 (85%) had at least one lipid abnormality: 14 among 17 of the African Americans (82%) and 9 among 10 (90%) of the non-Hispanic whites.

Ophthalmologic abnormalities, such as retinopathy, were not seen. Dr. Dolan remarked that one group of Japanese investigators used fluorescein angiography to identify retinopathy and found up to a 38% risk for this disorder within 2 years of the onset of type 2 diabetes. Using the less sensitive method of direct ophthalmoscopy, Dr. Dolan could not detect any abnormalities; however, he believes that this is an important issue that needs to be addressed.

Albumin excretion rate was checked to screen for diabetic nephropathy. Among the 11 children with type 2 diabetes who underwent testing, 3 (27%) had elevated excretion rates (greater than 20 m g/min as measured by timed overnight urine collection), signaling possible incipient nephropathy.

Finally, Dr. Dolan addressed the complication of ketoacidosis, defined as serum bicarbonate level less than or equal to 15 milliequivalents/L. Among the 128 patients with type 2 diabetes, 17 presented in ketoacidosis (13%): divided equally by gender but heavily weighted toward the African Americans (19% of whom presented with ketoacidosis).

Dr. Dolan continued by discussing the issue of ascertainment bias; whether his group of pediatric diabetes patients is a referral population. He said that it was particularly important to determine whether the sharp increase in the incidence rate of diabetes seen in Cincinnati during 1992-1994 was an artifact of ascertainment bias. Dr. Dolan and colleagues have not attempted the capture-recapture method, which is considered to be the gold standard for determination of ascertainment bias. The Cincinnati Children's Hospital, however, is, and has been since the 1970s, the only hospital in the eight-county region where pediatric diabetes cases are referred, thus ensuring a high level of completeness. Evidence for this is the hospital's calculated incidence rates for pediatric type 1 diabetes - 15-18 per 100,000 - which are similar to rates seen elsewhere (e.g., Allegheny County, Pennsylvania). An exhaustive 1995 survey of pediatric diabetes caseloads of Cincinnati diabetes educators leads Dr. Dolan to estimate that he is seeing 75-80% of children with type 2 diabetes.

Dr. Dolan then discussed whether there had been a recent change in the referral pattern to the diabetes center at the Cincinnati Children's Hospital. He said there had been no change over time in the diagnostic criteria for type 2 diabetes; the market share of the hospital; the ethnic pattern of referrals; the referral patterns by the practicing physicians; and the geographic distribution by ZIP code of either physicians or referrals. Nonetheless, Dr. Dolan asserted that his patient database is probably a significant underestimate of the whole type 2 pediatric diabetes disease process. Evidence for this includes Dr. Dolan's review of the chief complaint of patients on hospitalization: only 59% had the classic symptoms of polyuria and polydipsia; 40% had nonclassic symptoms, and 13% presented only with a positive urinalysis for glucose, obtained during a routine physical examination.

Dr. Dolan asked Dr. Lipton to discuss her contention that the pediatric type 2 epidemic among minorities did not start suddenly in the mid-1990s, but has been steadily growing for a much longer period. Dr. Lipton reiterated her point that a substantial proportion of diabetic children in Chicago had type 2 diabetes (or at least not type 1) in 1985-1987. She also stated that she still suspects that there may be some ascertainment bias in the sudden big jumps in type 2 incidence that Dr. Libman and Dr. Dolan saw in the early 1990s. An example of ascertainment bias that Dr. Lipton saw in her own Chicago studies was her identification of 23 African Americans who had died over a period of 8 years at onset of symptoms; some of these patients were only diagnosed at autopsy. Dr. Lipton thus suggested to the other attendees that they check the death records from county medical examiners for unexplained deaths that were later related to type 2 diabetes after the fact at autopsy. Dr. Lipton predicted that by taking account of these early, hitherto missed cases of type 2 diabetes, one might sufficiently increase the incidence in the early years to smooth out the "sudden" increases in incidence seen by some in the mid-1990s.

Dr. William Knowler made the point that what is being called complete ascertainment of cases of type 2 diabetes is really complete ascertainment of cases that have been diagnosed and what should be focused on instead is how much total diabetes there is, both diagnosed and undiagnosed. Dr. Knowler offered, and the other attendees concurred, that true, complete ascertainment can never be achieved by using registries or hospital case series and that population samples should be tested and screened. Dr. Lipton then reviewed the Japanese experience, where school-based universal screening of children by urinalysis was used to determine that the proportion of all pediatric diabetes classified as type 2 is 66-75% (i.e., the type 2 rates are two to three times as high as the type 1 rates). Dr. Knowler predicted that U.S. proportions would be similar.

An attendee made a further point that in the registries described earlier, cases of girls with type 2 diabetes who were also pregnant were not being categorized as type 2 but were often categorized instead as having gestational diabetes.

As to autoantibody tests, an attendee stated that there are no U.S. data comparing the performance of the four common autoantibody reagents, nor have antibody protocols been sufficiently standardized to allow comparisons of data taken at two different times in two different locales.

Another attendee commented that elevated serum insulin and elevated C-peptide levels are strong indicators of insulin resistance and are thus powerful tools in confirming the diagnosis of type 2 diabetes. These tools must be used cautiously, however. Serum glucose must first be brought under control; otherwise, the insulin and C-peptide determinations are unreliable because their values may be suppressed.

Dr. Burghen commented that the presence in children of syndrome X symptoms, such as hyperinsulinemia, is indicative of insulin resistance and that these are children at high risk of developing type 2 diabetes. Even if children never progress to full-blown diabetes, syndrome X symptoms may be dangerous to their health, and these children should be monitored. There was a consensus that longitudinal studies are needed to learn the natural history of type 2 diabetes in children.

Carol Feld, Associate Director of NIDDK for Scientific Programs and Policy Analysis, discussed the implementation process for the NIDDK Strategic Plan. The recommendation that NIDDK, along with all the other Institutes within NIH, promulgate a Strategic Plan came from a congressionally directed Institute of Medicine (IOM) study on improving NIH's setting of priorities and public input. Among the IOM recommendations that have been put in motion are that all NIH Institutes establish an Office of Public Liaison, that a Council of Public Representatives to the NIH Office of the Director is established, and that Strategic Plans are formulated (they are due to be submitted in draft form by December 31, 1999).

The NIDDK Strategic Plan will have the following features:

• Organization by cross-cutting scientific themes, rather than by diseases within the NIDDK research mission
• A catalog of scientific opportunities and needs
• Implementation strategies (what tools, reagents, techniques, and personnel are needed)
• Five-year time horizon
• Public involvement
• A final document written in lay language
• A widely distributed plan, both electronically and in hard copy

The cross-cutting working groups are:

• Genes and Disease - Regulation, Expression, Screening
• Cells - Integration of Biological Mechanisms in Health
• Causes and Mechanisms of Disease and Injury
• Prevention and Treatment of Disease - Epidemiologic and Clinical Investigation
• Infrastructure - Human Resources, Technology, and Research Facilities

Kelly Moore, M.D., the Acting Chief Medical Officer/Area Diabetes Consultant at the Billings Area Indian Health Services, was the chair for this session, as well as the first speaker. Dr. Moore noted that the Native American/Alaska Native population is a growing one, with a 1994 population of 2.2 million and a projected population of 4.3 million by 2050. More than 550 tribal groups are federally recognized and reside within 34 States; about one-half live in urban areas. About one-third of the Native American/Alaska Native population live in poverty, as compared with about 13% for the total U.S. population.

Dr. Moore referred to Canadian aboriginal data from Dr. Heather Dean's studies, in which the average age at diagnosis of type 2 diabetes is 10-14 years, similar to data from other populations. Also, BMI for males in this Canadian aborginal group is nearly always above the 95 percentile. In addition, Type 2 diabetes tends to be more common in females in this population, whereas type 1 diabetes tends to occur equally in males and females. Finally, 76% of the children with type 2 diabetes have mothers with diagnosed diabetes.

Next, Dr. Moore compared the Canadian data on diabetes with data collected from the Pima Indians in Arizona. She noted that most of the cases are being first diagnosed in children between 10-19 years and again the gender ratio for type 2 diabetes tends to favor females, although recent data show relative increases in male incidence. Also, the Pima diabetes population shows a high percentage of exposure to diabetes in utero, which is proposed to be a major risk factor in this population for the development of type 2 diabetes.

In a discussion of fasting insulin levels, Dr. Moore presented data from the Canadian study showing that about 62 of 103 (60%) study participants have increased insulin levels. Hyperinsulinemia has been shown to be a good predictor for the development of type 2 diabetes in Pima children; the 10-year diabetes incidence rate is much higher in those children with elevated fasting insulin. Frequency distribution data of fasting insulin and fasting glucose levels show that Pima children have markedly higher levels than do white children, with a marked rightward shift of the distribution curves.

Dr. Moore next reviewed data on diabetes in nationwide American Indian/Alaska Native populations from 1991-1997 collected by the Indian Health Service (IHS) and analyzed by the CDC. The data were collected from 151 IHS service units. Persons with diabetes were identified according to the ICD-9 code 250. The denominators in these prevalence rate determinations were taken from U.S. Census data covering each of these IHS service units; 46 IHS service units (representing 16% of the HIS population) were excluded because of incomplete or missing data.

It has long been known that adults in the American Indian/Alaska Native population have high prevalence rates of diabetes. Dr. Moore showed that the data revealed an increase during 1991-1997 in diabetes in all of the age groups studied, particularly in adolescents aged 15-19 (up 32%), young adults aged 20-24 (up 36%), and in adults aged 25-34 (up 28%). The increase seen in young men was about twice that seen among young women. Dividing up the American Indian/Alaska Native data by region, it was apparent that the Alaskan region is the region with the lowest prevalence of diabetes in children, adolescents, and young adults. All of the regions showed a steady increase in diabetes over the period 1991-1997.

Dr. Moore listed three limitations of the data: (1) the case definition does not distinguish between type 1 and type 2 diabetes, (2) there may be inaccuracies in the estimations of the populations, and (3) only data on American Indians treated within the IHS are collected (e.g., many urban Indians do not use the IHS and thus these cases are not captured).

Heather J. Dean, M.D., Professor of Pediatric Endocrinology and Metabolism at the University of Manitoba, was the next speaker. Dr. Dean discussed several regional studies on diabetes prevalence in aboriginal populations in Canada (also known as First Nation). The largest language grouping is the Algonquin, which is Cree-Ojibwa; they also have the highest rate of diabetes. Diabetes prevalence is lowest in the Haida community in the west and in the Inuit communities in the north. In contrast to the U.S. Native American community, 70% of the First Nation inhabitants live on reserves, not in urban areas. In Manitoba, there are 60,000 First Nation inhabitants, 70% of whom live in small isolated villages in the north.

Dr. Dean reviewed 1990s prevalence data from three regional diabetes registries, which all show type 2 diabetes prevalence between 1.7 per 1000 and 2.5 per 1000. For one of the registries - a Manitoba region registry - Dr. Dean showed by capture-recapture techniques that there is a 95% ascertainment rate of pediatric diabetes.

Next, Dr. Dean presented data from diabetes screening programs. Among three youth populations screened in the mid-1990s, prevalence rates averaged around 16 per 1000, that is, about 10 times higher than the prevalence rates from the registry data.

Dr. Dean then outlined the following research priorities:

• Development of standard diagnostic criteria
• Use of standard age groups (e.g., 0-4, 5-9, 10-14, 15-19)
• Universal differentiation between type 1 and type 2 diabetes in registry databases
• Acceptance of standardized, uniform methods for large-scale population-based screening

Dr. Dean stressed that in screening initiatives in large populations, the protocols may have to be more practical (e.g., capillary blood glucose vs. drawn blood, random blood glucose instead of fasting blood glucose, etc.).

Pima Indians

William C. Knowler, M.D., Dr.P.H., Chief of the Diabetes and Arthritis Epidemiology Section, NIDDK, was the next speaker. Dr. Knowler remarked that diabetes prevalence in Pima Indian adolescents, which is historically high, has dramatically increased in 1976-1996. The type 2 diabetes prevalence rate is now 8-10 times higher than rates in comparable white populations from Rochester, Minnesota.

Dr. Knowler then discussed the risk factors for type 2 diabetes in the Pima population. Family history of diabetes is a strong risk factor; interestingly, if only one parent has diabetes, then the risk for the child is greater if the mother, rather than the father, has diabetes. The strongest family risk factor, in fact, is in utero exposure to a diabetic mother, rather than simply inheritance of diabetes susceptibility genes. Dr. Knowler showed that much of the recent increase in type 2 diabetes prevalence is attributable to the increase in the proportion of Pima women who are diabetic while pregnant.

Another risk factor for type 2 diabetes is birth weight. Either very low or very high birth weight markedly increases the risk for diabetes. An independent risk factor for type 2 diabetes is bottle feeding.

Metabolic Phenotyping

Arlan L. Rosenbloom, M.D., Distinguished Service Professor Emeritus of the University of Florida, was the chair for this session.

The first speaker was Silva A. Arslanian, M.D., Professor of Pediatrics at Children's Hospital of Pittsburgh. She described a hyperglycemic clamp experiment, in which healthy African American adolescent volunteers were matched with healthy white adolescents for BMI, pubertal development, and hormonal development. The hyperglycemic clamp experiment measures the amount of insulin secretion over120 minutes while blood glucose is clamped at a constant, hyperglycemic level of 225 mg/dL. Dr. Arslanian demonstrated that, for the same glucose level, African Americans on average secrete significantly more insulin than do whites. From these experiments, Dr. Arslanian derived an insulin sensitivity index for each of the volunteers; insulin sensitivity was approximately 35-40% lower in the African American adolescents than in their matched white peers.

Dr. Arslanian noted that the mean age of onset of pediatric type 2 diabetes ranges from 13 to 15 years (midpuberty). Puberty is normally associated with insulin resistance ¾ i.e., a plot of age vs. fasting insulin level rises before adolescence, peaks at around age 15, and then declines again to prepubertal levels. She measured in vivo insulin sensitivity by the hyperinsulinemic euglycemic clamp technique and found that adolescents have approximately 30% lower insulin sensitivity than either preadolescents or adults. Her recent data implicate a spurt of growth hormone at the time of puberty as the cause of this phenomenon. Insulin sensitivity (controlling for BMI) is less in girls than in boys and is inversely proportional both to BMI and to total percent body fat. Fasting insulin levels, a marker of insulin resistance, also as expected, increase with increasing BMI, even when measured in normal nondiabetic children. Gender differences in insulin sensitivity need further evaluation with careful attention to body composition differences.

Dr. Arslanian then presented data on the relative contributions of visceral vs. subcutaneous fat, which she measured by CAT scan. As seen for total percent body fat, insulin sensitivity declines (and fasting insulin levels increase) with increasing percentages of either visceral or subcutaneous fat; however, the slopes are much more steep for visceral fat. The impact of excessive visceral fat is thus more deleterious than the impact of subcutaneous fat. Dr. Arslanian hypothesized that if, as some have said, the waist circumference is a better predictor of type 2 diabetes risk than BMI, this is because waist circumference is a proxy measurement for the percentage of visceral fat.

Dr. Arslanian mentioned that hyperandrogenism and related syndromes, such as polycystic ovarian syndrome and hirsutism, are associated with increased risk for type 2 diabetes. She conducted a study comparing obese (BMI = 33) hyperandrogenic adolescents with nonhyperandrogenic adolescents matched for BMI, percent body fat, lean body mass, and abdominal adiposity. The fasting insulin levels were twofold higher with similar hepatic glucose product and the insulin sensitivity 30-40% lower in the hyperandrogenic adolescents. Thus, here data indicate both hepatic and skeletal muscle insulin resistance. This correlates well with the increased risk for developing type 2 diabetes seen in hyperandrogenic adolescents. Dr. Arslanian also detected evidence of a decrease in pancreatic beta-cell function in these hyperandrogenic adolescents who have impaired glucose tolerance. Young children (10 years old) with a family history of type 2 diabetes had lower insulin sensitivity than peers without family history.

The next speaker was Steven M. Willi, M.D., Associate Professor of Pediatrics at the Medical University of South Carolina. Dr. Willi described a study of 97 South Carolina African American children and young adults (53 females and 44 males) with diabetes who required insulin therapy before the age of 20. Comprehensive islet cell autoantibody testing was undertaken, including ICA, anti-GAD antibodies, and antityrosine phosphatase antibodies. In addition, Dr. Willi measured C-peptide after withholding intermediate-acting insulin for at least 24 hours and short-acting insulin for at least 12 hours. Of these 97 patients, only 50 were classified as having type 1 diabetes, with antibodies directed at one or more islet cell antigens, and a fasting C-peptide level less than 0.6 ng/mL (the Diabetes Control and Complications Trial [DCCT] standard). The remaining 47 patients were diagnosed as having pediatric type 2 diabetes: they were autoantibody-negative and had significantly elevated C-peptide levels (mean = 2.8 ng/mL).

Similar to what others presented at this meeting, the peak age at onset for the type 2 diabetes children was 13-14 years. This age coincides with the peak age of insulin resistance in adolescents and was much later than the peak age at onset for the type 1 diabetes children. The type 2 children were also much heavier; half of them had a BMI above 30. A family history of diabetes was much more common in the children with type 2 diabetes.

Acanthosis nigricans was also much more prevalent in the type 2 children (more than 50%) than in the type 1 children (14%). A substantial proportion (two-thirds) of these type 2 children had a history of significant ketoacidosis.

HLA-DR/DQ typing was also performed and compared with an unrelated African American control population from the region. Not surprisingly, the clearest associations were observed in the children with type 1 diabetes, with the anticipated increased incidence of DR3 and DR4 as well as increases in the DQ types 0201 and 0302. There was also a significantly increased incidence of DR5 seen in the children with type 2 diabetes.

As seen elsewhere, the trend in South Carolina over the last several years has been for pediatric type 2 diabetes to increase in prevalence. Currently, type 2 diabetes is the predominant form among African American children in South Carolina.

Dr. Willi next described the 4-day inpatient metabolic studies that were undertaken on some type 2 patients in the medical school's General Clinical Research Center, along with young adult African American controls and a group of type 1 patients matched for age and race. The protocol included a total body dual-energy x-ray absorptiometry (DEXA) scan, determination of glycohemoglobin (hemoglobin A1c assay), and urinary C-peptide secretion. The patients with type 2 diabetes, who were evaluated only after a period of improved metabolic control at the time the study (as evidenced by their mean hemoglobin A1c = 8.4%), were quite obese (mean BMI = 33). Insulin secretion and sensitivity were measured by conducting a 0.5 g/Kg intravenous (IV) glucose challenge followed by IV insulin injection at 20 minutes. The insulin secretory response of IV glucagon was also evaluated, and a euglycemic hyperinsulinemic glucose clamp experiment was performed in conjunction with indirect calorimetry.

Dr. Willi presented data showing that the fasting insulin level of the pediatric type 2 diabetes group was elevated at 50.2 m units/mL compared with 14.6 m units/mL in the control population. Despite this elevation in fasting insulin level among the type 2 patients, their urine C-peptide levels were significantly lower.

Insulin response to IV glucose in the patients with type 2 diabetes was paradoxical: the first phase of insulin secretion, which typically occurs within five minutes of glucose exposure, is completely absent. In contrast to IV glucose, the response of insulin to IV glucagon in the type 2 patients was quite pronounced and was greater than in the controls. This insulin response to glucagon was rapid, and the kinetics suggest that a relatively large pool of stored insulin granules exist within the beta cells, yet cannot be released in response to glucose.

Dr. Willi evaluated the second phase of insulin secretion by monitoring C-peptide levels over a 3-hour time course after IV glucose challenge. In the predominantly African American pediatric patients with type 2 diabetes this second phase is quite blunted as compared to the control group. As expected, the C-peptide response to glucose in the matched patients with type 1 diabetes was absent.

Dr. Willi next reviewed the results of the euglycemic hyperinsulinemic glucose clamp experiment. The patients with pediatric type 2 diabetes exhibited insulin resistance, as reflected in a mean glucose disposal rate of 6 mg · kg lean body mass ^-1 · min ^-1.

In summary, Dr. Willi stated that his studies suggest that a significant subset of young African Americans with diabetes have a form of type 2 disease that may be ketosis prone. These patients present during adolescence, are frequently obese, and have acanthosis nigricans. After metabolic stabilization, fasting insulin levels appear to be elevated. Despite a high fasting insulin level, first-phase glucose-stimulated insulin release is nearly absent; however, insulin response to glucagon is preserved. The euglycemic hyperinsulinemic glucose clamp experiments demonstrate severe insulin resistance in these patients, even after correcting for their obesity.

Furthermore, Dr. Willi said that obese African American adolescents with ketosis-prone type 2 diabetes manifest a combination of abnormal beta-cell function and insulin action. This selective defect in glucose-insulin coupling in these patients suggests an abnormality in either uptake or metabolism of glucose by the beta cell, as well as in the periphery.

The next speaker was Joan DiMartino-Nardi, M.D., Associate Professor of Pediatric Endocrinology at the Montefiore Medical Center, Bronx, NY. Dr. DiMartino-Nardi discussed her research using patient records for 73 patients with type 2 diabetes diagnosed between 1990 and 1999. Test results for type 1 diabetes-specific autoantibodies were available for 70% of them; any patient who had positive titres of antibodies was excluded from the study. Dr. DiMartino-Nardi was able to identify 68 patients with type 2 diabetes; 35 were African American, 29 were Caribbean Hispanic, and 4 were Asian Indians. There was a preponderance of females to males.

Looking back over the past several years, Dr. DiMartino-Nardi has also detected an increasing trend in the percentage of pediatric patients with diabetes who are type 2. She noted a tenfold increase in the number of pediatric patients with type 2 diabetes since the early 1990s.

Of the pediatric patients with type 2 diabetes, more than 80% had acanthosis nigricans, 50% had polyuria/polydipsia, 20-25% had weakness, and 25-30% had weight loss. Of particular concern to Dr. DiMartino-Nardi was that 30% of the patients were completely asymptomatic at the time of diagnosis. Although most of the patients were morbidly obese, a substantial number had normal or near-normal BMI (some due to recent diabetes-related weight loss). The mean age for the African American patients with type 2 diabetes was 13.7, and for the Caribbean Hispanics it was 14.8 years. Most of the patients were in mid-late puberty (Tanner IV/Tanner V), 15-25% were in early puberty, and none were prepubertal. At the time of diagnosis, all of the diabetic children had fasting blood glucose above 126 mg/dl, 5 children presented with severe ketoacidosis, 10% had normal hemoglobin A1c levels, and the vast majority had elevated insulin levels.

Dr. DiMartino-Nardi next discussed the role of the fasting glucose-to-insulin ratio in the assessment of insulin sensitivity in girls with premature adrenarche, which recent reports indicate may be a risk factor for the development of polycystic ovarian syndrome.

Many of Dr. DiMartino-Nardi's patients with premature adrenarche have several of the features of syndrome X: obesity, acanthosis nigricans, and strong family history of diabetes. Many patients also have marked hyperandrogenism (e.g., ACTH-stimulated 17-hydroxypregnenolone levels greater than 2 standard deviations above the mean for early pubertal children). Furthermore, more than 50% of her patients have decreased insulin sensitivity, as measured by the frequently sampled IV glucose tolerance test (FSIVGTT). Interestingly, the more insulin-resistant children were also the children to have the more severe hyperandrogenism.

Dr. DiMartino-Nardi next discussed the recent reports of using the fasting glucose-to-insulin ratio as an indicator of insulin sensitivity, as an alternative to the more involved standard tests: FSIVGTT and the euglycemic hyperinsulinemic glucose clamp procedure. She reviewed recent published reports by R.S. Legro and A. Dunaif that a low fasting glucose-to-insulin ratio (less than 4.5) in obese women with polycystic ovarian syndrome was a very sensitive and specific tool for identifying women with insulin resistance when compared with the FSIVGTT.

The FSIVGTT has several advantages: it is a well-validated method for measuring insulin sensitivity, and it correlates very closely with insulin sensitivity as determined by the euglycemic insulin clamp. However, FSIVGTT is time consuming, is labor and cost intensive, and is not amenable to large-scale studies or to routine assessment or followup of patients with insulin resistence.

Dr. DiMartino-Nardi described a study she conducted that looked at whether the fasting glucose-to-insulin ratio, compared with the FSIVGTT, was useful as a screening tool for assessing insulin sensitivity in children with premature adrenarche. She studied 33 prepurbertal girls with premature adrenarche (22 Caribbean Hispanic, 11 African American; mean age 6.8 years). Among them, 15 were identified as insulin resistant using the FSIVGTT; 13 of these girls had a fasting glucose-to-insulin ratio less than 7, giving a true positive rate or sensitivity of 87% and a specificity of 89%. The degree of insulin resistance in the girls with premature adrenarche was, as expected, a function of their BMI. This dependent relationship was seen whether the fasting glucose-to-insulin ratio or the FSIVGTT was used; the data were superimposible, again validating the utility of the fasting glucose-to-insulin ratio test.

The girls who had premature adrenarche and were insulin resistant also had several other abnormal biochemical markers: lower insulin-like growth factor binding protein 1 (IGF BP-1); significantly higher levels of ACTH-stimulated 17-hydroxypregnenolone; higher free testosterone; lower sex hormone-binding globulin levels; and lower HDL levels. Again, these relationships held whether insulin resistance was assayed using the fasting glucose-to-insulin ratio assay or the FSIVGTT.

In conclusion, Dr. DiMartino-Nardi stated that she hopes the fasting glucose-to-insulin ratio assay will identify which girls with premature adrenarche also have syndrome X-type metabolic abnormalities and are thus at risk for developing attendant possible complications, such as polycystic ovarian syndrome and pediatric type 2 diabetes.

The next speaker was Philip Scott Zeitler, M.D., Ph.D., Assistant Professor of Pediatrics at the Children's Hospital of Denver. Dr. Zeitler presented data that were gathered while he was in Cincinnati to analyze the characteristics of adolescents with type 2 diabetes and their families. A goal of the study was to refine a profile of at-risk individuals and families, to allow the development of early-intervention strategies for children at risk for type 2 diabetes.

Dr. Zeitler studied 11 families that had both parents present and an adolescent with type 2 diabetes. All family members, including siblings, were studied, for a total of 42 participants. Among them, type 2 diabetes had already been diagnosed in 45% of the mothers and 40% of the fathers before the study, and Dr. Zeitler diagnosed type 2 diabetes in 27% more of the fathers during the medical examination. In 27% of the families, both parents had type 2 diabetes. The diabetic parents tended to have poor metabolic control; for example, the mothers with type 2 diabetes had elevated mean hemoglobin A1c levels of 13%.

All of the family members were obese (e.g., skinfold measurements were all greater than 95 percentile) and the diets were very high in fats and low in fiber, even if the mother had known she had type 2 diabetes and had been educated on good dietary practices. Many of the family members showed signs of binge-eating behavior. None of the patients participated in structured exercise programs, and 85% engaged in no physical activity; 45% of the siblings also reported no physical activity. Family members, however, reported watching television and/or playing video games and/or using computers 3-5 hours per day.

Although none of the siblings had frank diabetes, all had elevated fasting insulin and C-peptide levels, suggesting insulin resistance, syndrome X, or both.

In conclusion, Dr. Zeitler stated that the siblings and parents of adolescents with type 2 diabetes exhibit many of the risk factors for the disease and should be screened. Furthermore, given the frequency of lifestyle risk factors in these families, the entire family needs to be considered as the target for both screening and intervention.

The next speaker was Kenneth Lee Jones, M.D., Professor of Pediatrics at the University of California at San Diego. Dr. Jones described the ethnic characteristics of the San Diego population as it relates to diabetes incidence. As is true in most localities, the incidence of type I diabetes in San Diego is largely the same in all ethnic groups except for Asian Americans, who have a low incidence. An interesting observation about the ethnic data on type 2 diabetes is that in the San Diego Asian community many more males than females have the disease. A similar male predominance has been seen in Asian communities in Hong Kong.

Dr. Jones then focused on those rare type 2 diabetes patients who are not obese. In the San Diego population that Dr. Jones studied, all African Americans with type 2 diabetes were obese, whereas some Mexican Americans and Asian Americans with type 2 diabetes were not obese. Total mean BMI for type 2 patients also varied by ethnicity, with mean BMI ranked as follows from highest to lowest: African Americans, Mexican Americans, whites, Asian Americans.

Dr. Jones did not observe acanthosis nigricans in any of the Asian American or white females but it was seen in both males and females among the African Americans and Mexican Americans.

Dr. Jones next discussed a study of the predictive value of C-peptide levels at time of diagnosis in 41 patients who had type 1 diabetes and in 38 patients who had type 2 diabetes. The predictive value of fasting C-peptide analysis as a criterion for type 2 diabetes was 91%.

Dr. Jones then discussed a study by Peter Reaven and colleagues that followed both Mexican American and white school populations and showed that by age 11 the mean of the BMI for the Mexican Americans was already higher. Study results also showed a significantly higher fasting insulin level among Mexican Americans. Both findings suggest that syndrome X develops disproportionately in the Mexican American school population. The researchers developed a rank score for syndrome X, involving a large number of test results values, and showed that, in general, Mexican American children in San Diego have significantly higher syndrome X scores than do matched white controls.

Dr. Jones pointed out that these data show that, as early as age 11, it is possible to identify in large populations of nonaffected individuals those children who are at risk for type 2 diabetes because they display syndrome X factors. These children would then be candidates for potential early intervention strategies.

The final speaker for this session was William E. Winter, M.D., Professor of Pathology and Pediatrics at the University of Florida. Dr. Winter discussed maturity-onset diabetes of youth (MODY), which is a familial, youth-onset form of diabetes in individuals who are not obese that results primarily from insulinopenia. MODY was first described by Dr. S.S. Fajans in the 1960s, who defined what Dr. Winter calls classic MODY as follows:

• Diabetes onset before age 25
• Correction of fasting hyperglycemia without insulin for at least 2 years after diagnosis
• Nonketotic disease
• Autosomal-dominant mode of inheritance

In 1987, Dr. Winter described what he called an atypical form of diabetes in African Americans younger than age 40. He used this term because the patients' symptoms were similar to symptoms of type 1 diabetes (i.e., ketoacidosis, severe weight loss, polyuria/polydipsia), but after a number of months to years, the disease developed a non-insulin-dependent course. This atypical diabetes is transmitted in families with an autosomal-dominant mode of inheritance. Dr. Winter's atypical diabetes differs from classic MODY in several respects¾ MODY has not been described in African Americans; classic MODY is not a disease of acute onset; and, in general, patients with classic MODY never have ketoacidosis.

Dr. Winter's atypical diabetes of African Americans represents at least 10% of diabetes in African Americans under 40; classic MODY represents less than 5% of diabetes in whites.

Five different genetic loci have been associated with MODY. Four of the genetic abnormalities involve transcription factors that regulate insulin production; one gene (MODY 2) codes for glucokinase, which is involved in the beta-cell sensing of glucose elevations. Dr. Fajan's classic MODY is MODY 1, a genetic defect in hepatic nuclear factor-4 (HNF-4 ). MODY 1 causes progressive insulinopenia and is an uncommon cause of type 2 diabetes in adults. MODY 2 is the most common form of MODY, but is also an uncommon cause of type 2 diabetes in adults. MODY 3 also causes a progressive insulinopenia due to gradual loss of beta-cell function and is the most common cause of MODY in the British population. MODY 4 regulates beta-cell development in utero. The latest MODY to be described, MODY 5, is very rare.

Dr. Winter has described two mutations in atypical diabetes of African Americans: (1) a mutation in glucokinase, and (2) a mutation in NADH dehydrogenase subunit 1.

In terms of severity of illness at onset, atypical diabetes of African Americans is the most severe; then MODY 1 and MODY 3, with progressive insulinopenia. The least severe is the nonprogressive MODY 2 glucokinase mutation.

Atypical diabetes of African Americans over time is characterized by relatively unchanging fasting C-peptide levels, which is evidence that this is not a progressive disease.

Dr. Hale asked Dr. Winter to comment on the physical phenotype of MODY and atypical diabetes of African American patients. Dr. Winter responded that the white MODY patients, as described by Dr. Fajans, were lean and lacked acanthosis nigricans. In contrast, approximately 40% of the atypical diabetes of African American patients are obese (likely reflecting the prevalence of obesity in the African American population generally). There was no dyslipidemia among the patients with atypical diabetes.

Dr. Knowler questioned Dr. DiMartino-Nardi on her advocacy of the fasting glucose-to-insulin ratio for classifying patients with insulin resistance, and recommended that she also look at the glucose-to-insulin product, which he thought might have a greater correlation with insulin resistance.

Dr. Rosenbloom commented that early kidney failure in young Japanese patients with type 2 diabetes for many years reinforced the point that children who develop type 2 diabetes in adolescence will have many complications, such as nephropathy, that will manifest when these individuals are in their 30s or 40s.

Dr. Barbara Linder of NIDDK said that a lot of interesting information had been presented during the day and that it was now the task of the attendees to assimilate it and to return the next day to formulate the critical key pieces of information that are missing as related to epidemiology and diagnostic criteria. Dr. Linder suggested that the attendees set priorities for the research community.

Epidemiology Summary

Dr. Fagot-Campagna conducted a summary presentation of the epidemiology of pediatric type 2 diabetes. She noted that the disease was first described 20 years ago by Dr. P.J. Savage and co-workers reporting on the Pima Indians.

Dr. Fagot-Campagna reviewed 9 case series, with a total of 578 cases of pediatric type 2 diabetes: 94% of the patients with type 2 diabetes were members of minority groups, and 56-92% of the patients had acanthosis nigricans. Elevated hemoglobin A1c levels, which are indicative of insufficient metabolic control of diabetes, were quite high: 10-13%.

Next, Dr. Fagot-Campagna reviewed data on pediatric type 2 diabetes in the Pima Indians. At an average of 9 years after initial diagnosis, followup data showed little improvement and increased incidence of complications, such as elevated hemoglobin A1c, hypercholesterolemia, microalbuminuria, and macroalbuminuria.

A review of the screening data for pediatric type 2 diabetes from population-based studies of American Indian youth revealed that there are many communities in which the prevalence is 1.4-5.1% of all those screened. Alarmingly, reported prevalence data for American Indians from registries, clinics, and hospitals tend to be tenfold lower, around 0.12-0.45%.

Dr. Fagot-Campagna summarized data, including some presented at the meeting, demonstrating that the proportion of newly diagnosed pediatric diabetes cases that are type 2 ranges up to 46% in some minority communities.

There was then a discussion about the need to capture data on Asian American children (e.g., Korean Americans in Chicago, Chinese Americans in San Francisco) given the anecdotal evidence of increased type 2 diabetes and obesity in these populations.

Metabolic Phenotyping Summary

Dr. Rosenbloom summarized the presentations on metabolic phenotyping of pediatric type 2 diabetes. He noted that as long ago as 1970 obesity in children was recognized as being associated with hyperinsulinism, glucose intolerance, and a form of diabetes different than typical type 1. He noted that the Bogalusa Heart Study has documented relative hyperinsulinemia in African-American compared to white youngsters.

The key points in the various presentations on metabolic phenotyping were reviewed by Dr. Rosenbloom as follows: