The National Institute of Diabetes & Digestive & Kidney Diseases

Silva A. Arslanian, M.D.
Children's Hospital of Pittsburgh

George Burghen, M.D.
University of Tennessee

Heather J. Dean, M.D.
University of Manitoba

Joan DiMartino-Nardi, M.D.
Montefiore Medical Center

Lawrence M. Dolan, M.D.
Children's Hospital Medical Center of Cincinnati

Anne Fagot-Campagna, M.D., Ph.D.
Centers for Disease Control and Prevention

Carol Feld National Institute of Diabetes and Digestive and Kidney Diseases

Katherine Flegal, Ph.D.
Centers for Disease Control and Prevention

Daniel E. Hale, M.D.
University of Texas Health Science Center at San Antonio

Kenneth Lee Jones, M.D.
University of California, San Diego

William C. Knowler, M.D., Dr.P.H.
National Institute of Diabetes and Digestive and Kidney Diseases

Ingrid M. Libman, M.D., Ph.D.
Children's Hospital of Pittsburgh

Rebecca Lipton, Ph.D.
University of Illinois at Chicago

Kelly Moore, M.D.
Billings Area Indian Health Services

Arlan L. Rosenbloom, M.D.
University of Florida Children's Medical Services Center

Steven M. Willi, M.D.
Medical University of South Carolina

William E. Winter, M.D.
University of Florida

Philip Scott Zeitler, M.D., Ph.D.
The Children's Hospital of Denver

WELCOME

Richard Eastman, M.D., Director of the Division of Diabetes, Endocrinology, and Metabolic Diseases at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and Chairman of the Diabetes Mellitus Interagency Coordinating Committee (DMICC), welcomed attendees to the meeting and introduced Charles A. Wells. Ph.D., Executive Secretary of the DMICC, as the meeting’s emcee. Barbara Linder, M.D., Ph.D., Program Director at NIDDK, and the organizer of the meeting, then previewed the day’s upcoming sessions and defined the meeting’s goals as pinpointing the critical deficiencies in scientific knowledge about pediatric type 2 diabetes mellitus and prioritizing the research agenda.

Descriptive Epidemiology

Anne Fagot-Campagna, M.D., Ph.D., who is Medical Epidemiologist in the Division of Diabetes Translation at the Centers for Disease Control and Prevention (CDC), served as chair of this session.

Katherine Flegal, Ph.D., of the National Center for Health Statistics (NCHS) of the CDC, discussed the National Health Examination Surveys and the National Health and Nutrition Examination Surveys and the definition and measurement of obesity in children using body mass index (BMI). She also presented trends in obesity incidence in boys and girls and among various demographic groups. Finally, Dr. Flegal speculated on the causes of the increase in obesity, including agent, host, and environment.

Daniel E. Hale, M.D., Associate Professor of Pediatrics at the University of Texas Health Science Center at San Antonio, spoke next on type 2 diabetes in Mexican American youth, using San Antonio as a model.

Dr. Hale first reviewed the demographics of the site and then described the pediatric diabetic population in San Antonio: 77% type 1, 18% type 2, and 5% other types. Next, Dr. Hale described the rising incidence of pediatric type 2 diabetes in various demographic groups in San Antonio and then focused on the Mexican American population. He presented data on a small survey on 1,500 children in San Antonio that included examination of family history; measurement of BMI; and detection of fasting hyperinsulinism, acanthosis nigricans, impaired fasting glucose, and undiagnosed diabetes. Finally, in response to a question, Dr. Hale related a list of five questions he asks when presented with a new case of pediatric diabetes to distinguish between type 1 and type 2 diabetes.

Lawrence M. Dolan, M.D., Professor of Pediatrics and Director of the Diabetes Program at Children's Hospital Medical Center of Cincinnati, was the chair for this session. Dr. Dolan stated that the following major issues would be addressed during the session:

• Diagnostic criteria for type 2 diabetes and the data on pediatric diabetes prevalence in the survey regions.
• Estimates of what the incidence and prevalence of pediatric type 2 diabetes are in the African American population.
• Clinical characteristics within the African American population.
• Strengths and weaknesses of the available data.
• Ascertainment bias.

Rebecca Lipton, Ph.D., Associate Professor of Epidemiology at the University of Illinois at Chicago, was the next speaker. Dr. Lipton spoke about a type 1 diabetes registry she has worked on that has since expanded its scope to include early-onset type 2 diabetes and atypical diabetes. She stressed that she sees as one of the major research goals of the registry the quantification of prevalence of each of these types of diabetes.

Dr. Lipton described a continuum of glucose tolerance in children in an attempt to explain how pediatric atypical diabetes cases develop. Dr. Lipton also described the minority populations in Chicago and then how diabetes cases were captured in the registry. She also described a phenomenon of an increasing proportion over time of pediatric type 2 and atypical diabetes in certain subpopulations: African American and Hispanic males and females. Among the 0-4, 5-9, 10-14, and 15-19 age groups over time, Dr. Lipton identified type 2 diabetes in 0-4-year-old African American females, and in 5-9-year-old Hispanic males. She reported that the male-to-female ratio at onset for type 1 diabetes in African American children was about 1:1, whereas for putative type 2 diabetes there were substantially more females. In contrast, Dr. Lipton reported that in the Hispanic type 2 diabetes group, there were more males than females. Finally, Dr. Lipton described various strengths and weaknesses of her data.

George Burghen, M.D., Professor of Pediatrics and Chief of the Division of Endocrinology and Metabolism at the University of Tennessee at Memphis, was the next speaker. Dr. Burghen presented data showing the frequency distribution for serum insulin in his patients. He also used his survey data to demonstrate how autoantibody data could be used to type the diabetes patients, especially islet cell autoantibodies (ICA) and glutamic acid decarboxylase (GAD) autoantibodies.

Dr. Burghen then discussed an Arkansas study (Carla Scott, et al. Pediatrics 1997) ending in 1995 that compared children who had type 2 diabetes with children who had type 1 diabetes, of the same age range and gender and from the same geographic area. Dr. Burghen described biochemical differences between the two Arkansas groups. Next, he presented some of his data generated from the LeBonhear Children's Medical Center in Memphis, comparing incidence and prevalence rates of pediatric type 2 diabetes in African American and Caucasian children as well as presenting increasing trends in both population groups.

Dr. Burghen next described some data from the Diamond project in Shelby County, Tenn., including BMI, diastolic blood pressure, and blood lipids.

The next speaker was Ingrid M. Libman, M.D., Ph.D., of the Department of Pediatrics at the Children's Hospital of Pittsburgh, who presented data from the Allegheny County Diabetes Registry in Pennsylvania. First she outlined inclusion criteria and the primary (hospitals) and secondary (pediatricians and endocrinologists) sources of case information.

Dr. Libman reviewed the data from the first 25 years of the registry, from 1965-1989, and then the more recent data from 1990-1994. For the whole 0-19 age group, the incidence rate of diabetes has been steadily increasing since the 1970s, both for whites and especially for African Americans. She reported a large increase in the incidence rate for African Americans in the 15-19-year-old age group in the 1990-1994 period as compared with the 1965-1989 period¾ an incidence rate that significantly exceeds that in whites.

To help determine 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. Autoantibody data were examined with obesity data, and, 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.

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. The overall incidence rate of type 2 diabetes increased greatly during the years 1992-1994; since then the incidence rate has been relatively stable.

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 next described the complications that he has seen in this type 2 diabetes population, including high blood pressure, hyperlipidemia, possible incipient nephropathy, and ketoacidosis. Ophthalmologic abnormalities were not seen. Dr. Dolan concluded by discussing the issue of possible ascertainment bias and strengths and weaknesses of the data.

After the panel discussion of pediatric diabetes in African Americans led by Dr. Dolan, Ms. Carol Feld, Associate Director for Scientific Program and Policy Analysis at NIDDK, made a presentation on the NIDDK Strategic Planning Process. She described the features of the strategic plan, listed the cross-cutting thematic working groups, and reported on her office’s various efforts to solicit public input.

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 and then compared that 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 that 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.

Next, Dr. Moore presented data from the Canadian study on fasting insulin levels, as this measure has been shown to be a good predictor for the development of type 2 diabetes in Pima children. 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 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. 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. Finally, Dr. Moore listed three limitations of the data.

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. Next, Dr. Dean presented data from mid-1990s diabetes screening programs, which showed prevalence rates averaging about 16 per 1000, that is, about 10 times higher than the prevalence rates from the registry data. Dr. Dean then outlined several research priorities and, finally, stressed the need for practicality in screening initiatives in large populations.

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, including family history of diabetes (especially in the mother, and especially with in utero exposure), birth weight, and 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, from which she derived an insulin sensitivity index. She found that insulin sensitivity was approximately 35-40% lower in the African American adolescents than in their matched white peers. Dr. Arslanian also found that adolescents in general 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.

Dr. Arslanian then presented data on the relative contributions of visceral vs. subcutaneous percentage of 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 with visceral fat. She then addressed the issue of waist circumference measurement (versus BMI) as the better predictor of type 2 diabetes risk.

Dr. Arslanian also mentioned that hyperandrogenism and related syndromes, such as polycystic ovarian syndrome and hirsutism, are associated with increased risk for type 2 diabetes. She then described a study she conducted to investigate the associations.

The next speaker was Steven M. Willi, M.D., Associate Professor of Pediatrics at the Medical University of South Carolina. Dr. Willi presented data derived through autoantibody testing; C-peptide measurement; HLA-DR/DQ typing; and inpatient metabolic studies including hemoglobin A1c assays, measurement of urinary C-peptide secretion, an intravenous (IV) glucose challenge followed by IV insulin injection, measurement of the insulin secretory response to IV glucagon, and the conduct of a euglycemic hyperinsulinemic glucose clamp experiment in conjunction with indirect calorimetry.

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 and noted a tenfold increase in the number of pediatric patients with type 2 diabetes since the early 1990s. Next, she profiled the pediatric type 2 diabetic patients in her research with respect to acanthosis nigricans, polyuria/polydipsia, weakness, weight loss, BMI, pubertal status, and the presence of the following at the time of diagnosis: fasting blood glucose above 126 mg/dl, severe ketoacidosis, abnormal hemoglobin A1c levels, and elevated insulin levels.

She also discussed measurement of insulin sensitivity with the frequently sampled IV glucose tolerance test (FSIVGTT) and the euglycemic hyperinsulinemic glucose clamp procedure and compared them to the less involved fasting glucose-to-insulin ratio as an indicator of insulin sensitivity. Dr. DiMartino-Nardi presented data that validated the utility of the fasting glucose-to-insulin ratio test.

In addition to insulin sensitivity, several other biochemical markers were also abnormal in girls who had premature adrenarche and were insulin resistant, including 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. 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 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. Dr. Zeitler stated in conclusion that the parents and siblings of adolescents with type 2 diabetes exhibit many of the risk factors for the disease (type 2 diabetes as well as poor metabolic control of such, obesity, high-fat/low-fiber diet and binge-eating behaviors, and physical inactivity) 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 and then focused on those rare type 2 diabetes patients who are not obese, providing a comparison of various population groups.

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 that examined BMI, fasting insulin levels, and the development of syndrome X. Dr. Jones showed how his data indicate 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 and are therefore 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. Classic MODY is described as follows: diabetes onset before age 25, correction of fasting hyperglycemia without insulin for at least 2 years after diagnosis, nonketotic disease, and 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. This atypical form 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 abnormailities involve transcription factors that regulate insulin production; one gene codes for glucokinase, which is involved in the beta-cell sensing of glucose elevations. 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.

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

After a panel discussion of metabolic phenotyping, Dr. Barbara Linder of NIDDK said that a lot of interesting information had been presented during the day and that it now was the task of the attendees to assimilate it and 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.

Summary and Discussion

After Dr. Fagot-Campagna presented a summary of the epidemiology of pediatric type 2 diabetes and Dr. Rosenbloom presented a summary of the metabolic phenotyping of pediatric type 2 diabetes, Dr. Hale led a discussion period¾ the goal of which was to reach consensus on important gaps in knowledge.

Dr. Hale then presented a series of candidate consensus statements and asked the attendees to comment on them.

Dr. Hale then directed the discussion toward identifying which blood tests make the most sense to use in large-scale screening. Dr. Hale next directed the attendees to discuss fasting vs. random glucose testing. They agreed that for many routine blood tests (glucose, hemoglobin, blood lipids) random testing is as good or better than fasting testing and is certainly less problematic.

Dr. Hale asked for the attendees' opinion on the oral glucose tolerance test for use in population-based screening. The consensus was that the test is very useful for detecting diabetes cases that are missed by other methods but that there are problems with cost and patient acceptance.

Dr. Hale concluded by saying that population screening will help identify a pre-diabetic group of children who can then be observed longitudinally.

Dr. Hale thanked Dr. Linder and Dr. Wells and their staff for organizing such a successful meeting.

The meeting adjourned at 12 p.m. on July 21, 1999.

Approved by:___________________________________ Date:__________________
Richard Eastman, M.D., Chairman
Diabetes Mellitus Interagency Coordinating
Committee, NIDDK

Approved by:___________________________________ Date:__________________
Charles A. Wells, Ph.D., Executive Secretary
Diabetes Mellitus Interagency Coordinating
Committee, NIDDK