Search

Hyperglycemic hyperosmolar syndrome (HHS) is a clinical entity not identical to diabetic ketoacidosis (DKA), and with a markedly higher mortality. Children with HHS can also present with concomitant DKA. Patients with HHS (with or without DKA) are profoundly dehydrated but often receive inadequate fluid resuscitation as well as intravenous insulin therapy based on traditional DKA protocols, and this can lead to devastating consequences. In this article, we briefly review HHS along with a report of an adolescent who presented with HHS and DKA and was initially managed as DKA. She went into hypotensive shock and developed severe, multiorgan failure. A thorough understanding of the pathophysiology of HHS and its differences from DKA in terms of initial management is crucial to guide management and improve outcomes. Additionally, fluid therapy in amounts concordant with the degree of dehydration remains the mainstay therapy.

To compare indices of insulin secretion, insulin sensitivity (IS), and oral disposition index (oDI) during the liquid mixed-meal test in obese youth with clinically diagnosed type 2 diabetes mellitus (T2DM) and negative autoantibodies (Ab(-)) versus those with T2DM and positive autoantibodies (Ab(+)) to examine whether differences in β-cell function can be detected between the 2 groups.Twenty-seven youth with Ab(-) and 15 youth with Ab(+) clinically diagnosed T2DM underwent a mixed-meal test (Boost; 55% carbohydrate, 25% protein, and 20% fat). Fasting and mixed-meal-derived insulin and C-peptide indices of IS, secretion (30-minute insulinogenic [ΔI(30)/ΔG(30)] and C-peptide [ΔC(30)/ΔG(30)]), and oDI were calculated.Indices of insulin secretion were ~40%-50% lower in patients with Ab(+) T2DM compared with those with Ab(-) T2DM. After controlling for body mass index, ΔI(30)/ΔG(30), ΔC(30)/ΔG(30), C-peptide area under the curve (AUC)/glucose AUC, and insulin AUC/glucose AUC were significantly (P.05) lower in the Ab(+) group compared with the Ab(-) group. Sensitivity indices were significantly higher in the Ab(+) group. The oDI, 1/fasting insulin × ΔI(30)/ΔG(30) (0.04 ± 0.02 vs 0.12 ± 0.02 mg/dL(-1); P = .005), and 1/fasting C-peptide × ΔC(30)/ΔG(30) (0.02 ± 0.009 vs 0.05 ± 0.006 mg/dL(-1); P = .018) were lower in the Ab(+) group. Receiver operating characteristic curve analyses revealed that fasting C-peptide3.2 ng/mL had 87% sensitivity and 74% specificity and ΔC(30)/ΔG(30)0.075 ng/mL per mg/dL had 93% sensitivity and 80% specificity for identifying youth with Ab(+) T2DM.During a liquid mixed-meal test, indices of β-cell function were lower and IS was higher in patients with Ab(+) T2DM versus those with Ab(-) T2DM, with high sensitivity and specificity for fasting and stimulated C-peptide as markers of Ab(+) status. Indices of insulin secretion during this standardized mixed-meal test could be used to assess β-cell function in therapeutic trials of β-cell restoration in youth with T2DM.

The pathophysiology of type 2 diabetes (T2DM) in youth involves impairments in insulin sensitivity and β-cell function, translating to around 86% lower insulin secretion relative to insulin sensitivity, compared with non-diabetic controls of similar body composition and abdominal adiposity (1, 2). Progressive deterioration of β-cell function is a well-recognized feature of the disease in adults (3, 4) and is a major challenge in maintaining glycemic control (3). Given the novelty of the disease and the paucity of patients in the pediatric age group, there are limited longitudinal data regarding the natural history of T2DM in youth (5–7). These reports indicate rapid deterioration of β-cell function (6) during the course of treatment (7) compared to what is reported in adult large epidemiologic (3, 4) and cohort studies (8). In youth with recent onset T2DM, residual β-cell function is a significant determinant of glycemic control in small- (1) and large-scale studies such as the treatment options for type 2 diabetes in youth (TODAY) study (9). Glycemic control is an important factor to avert the comorbidities and complications of diabetes (10), which are identified in youth even at the time of diagnosis (11–13). However, data are sparse with respect to the rate of deterioration of β-cell function in youth with T2DM. Thus, we aimed to investigate prospectively the changes in insulin secretion and sensitivity in obese adolescents with T2DM. On the basis of our previous case reports (5, 6), we hypothesized that youth with T2DM will demonstrate accelerated deterioration in β-cell function compared with published data in adults.

Bacha F, Gungor N, Lee S, Arslanian SA. Type 2 diabetes in youth: are there racial differences in β-cell responsiveness relative to insulin sensitivity? Objective: Non-diabetic African American (AA) youth have an upregulated insulin secretion relative to insulin sensitivity (IS) compared with their American White (AW) peers. We investigated if similar racial differences exist in youth with T2DM. Research Design and Methods: Fourteen AAs and 14 AWs T2DM adolescents underwent evaluation of IS and clearance (hyperinsulinemic–euglycemic clamp), first- and second-phase insulin and C-peptide secretion (hyperglycemic clamp); body composition (DEXA); and abdominal adiposity (CT). Results: AA and AW T2DM had similar HbA1c, diabetes duration, BMI, and % body fat, with lower visceral fat in AAs (p = 0.013). While insulin-stimulated glucose disposal was similar in AA and AW (7.5 ± 1.0 vs. 7.3 ± 0.9 mg/kg FFM/min), IS tended to be lower (2.5 ± 0.4 vs. 3.8 ± 0.6 mg/kg FFM/min per µU/mL, p = 0.081). First-phase insulin (175.7 ± 52.9 vs. 66.6 ± 10.8 µU/mL, p = 0.01) and second-phase insulin (236.2 ± 40.7 vs. 105.1 ± 17.9 µU/mL, p = 0.008), and first-phase C-peptide (8.2 ± 1.2 vs. 5.0 ± 0.3 ng/mL, p = 0.02) and second-phase C-peptide (10.8 ± 0.9 vs. 7.6 ± 0.6 ng/mL, p = 0.012) were higher in AA. β-Cell function relative to IS was higher in AA vs. AW (259.5 ± 35.3 vs. 168.8 ± 25.1 mg/kg FFM/min, p = 0.043). Conclusions: Racial differences in insulin secretion can be demonstrated with the clamp technique in obese adolescents with T2DM. Similar to non-diabetic youth, AA adolescents with T2DM compared with their AW counterparts have an upregulated β-cell function relative to IS, the reasons for which remain to be investigated.

OBJECTIVE Overweight in youth is associated with the risk of developing type 2 diabetes. We hypothesized that β-cell function relative to insulin sensitivity decreases with increasing 2-h glucose levels based on an oral glucose tolerance test (OGTT) in overweight youth. RESEARCH DESIGN AND METHODS A total of 147 overweight (BMI ≥85th percentile for age and sex) youth, aged 8 to RESULTS Insulin sensitivity, first-phase insulin, and DI declined significantly as 2-h glucose concentrations increased. The highest DI was found in youth with 2-h plasma glucose concentrations CONCLUSIONS These data in overweight youth demonstrate that impairment in insulin secretion relative to insulin sensitivity is apparent even with normal glucose tolerance. Below the current cutoff of 140 mg/dL for impaired glucose tolerance, there is a >30% decline in β-cell function relative to insulin sensitivity. Against this back drop of metabolically heightened risk for type 2 diabetes, preventive measures should target the β-cell alongside insulin sensitization.

Cardiomyopathy is a rare but life-threatening condition in children. Myocarditis is the leading cause of dilated cardiomyopathy (DCM) and prognosis is generally poor without heart transplantation. We report a rare case of hypocalcemic DCM due to primary hypoparathyroidism in a male infant. In our patient, aggressive management of hypoparathyroidism significantly improved the manifestations of DCM. He is currently 10 years old and has no symptoms of exercise intolerance. Latest echocardiogram revealed near-normal cardiac function. Our case emphasizes that early diagnosis of this treatable cause of cardiomyopathy prevents serious sequelae.

OBJECTIVE Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are considered pre-diabetes states. There are limited data in pediatrics in regard to their pathophysiology. We investigated differences in insulin sensitivity and secretion among youth with IFG, IGT, and coexistent IFG/IGT compared with those with normal glucose tolerance (NGT) and type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 24 obese adolescents with NGT, 13 with IFG, 29 with IGT, 11 with combined IFG/IGT, and 30 with type 2 diabetes underwent evaluation of hepatic glucose production ([6,6-2H2]glucose), insulin-stimulated glucose disposal (Rd, euglycemic clamp), first- and second-phase insulin secretion (hyperglycemic clamp), body composition (dual-energy X-ray absorptiometry), abdominal adiposity (computed tomography), and substrate oxidation (indirect calorimetry). RESULTS Adolescents with NGT, pre-diabetes, and type 2 diabetes had similar body composition and abdominal fat distribution. Rd was lower (P = 0.009) in adolescents with type 2 diabetes than in those with NGT. Compared with adolescents with NGT, first-phase insulin was lower in those with IFG, IGT, and IFG/IGT with further deterioration in those with type 2 diabetes (P < 0.001), and β-cell function relative to insulin sensitivity (glucose disposition index [GDI]) was also lower in those with IFG, IGT, and IFG/IGT (40, 47, and 47%, respectively), with a further decrease (80%) in those with type 2 diabetes (P < 0.001). GDI was the major determinant of fasting and 2-h glucose levels. CONCLUSIONS Obese adolescents who show signs of glucose dysregulation, including abnormal fasting glucose, glucose intolerance or both, are more likely to have impaired insulin secretion rather than reduced insulin sensitivity. Given the impairment in insulin secretion, they are at high risk for progression to type 2 diabetes. Further deterioration in insulin sensitivity or secretion may enhance the risk for this progression.

OBJECTIVE Using the clamp technique, youths with a clinical diagnosis of type 2 diabetes (CDx-type 2 diabetes) and positive pancreatic autoantibodies (Ab+) were shown to have severe impairment in insulin secretion and less insulin resistance than their peers with negative antibodies (Ab−). In this study, we investigated whether oral glucose tolerance test (OGTT)-derived indexes of insulin secretion and sensitivity could distinguish between these two groups. RESEARCH DESIGN AND METHODS A total of 25 Ab−, 11 Ab+ CDx-type 2 diabetic, and 21 obese control youths had an OGTT. Fasting and OGTT-derived indexes of insulin sensitivity (including the Matsuda index, homeostasis model assessment [HOMA] of insulin resistance, quantitative insulin sensitivity check index, and glucose-to-insulin ratio) and insulin secretion (HOMA of insulin secretion and 30-min insulogenic and C-peptide indexes) were used. Glucagon and glucagon-like peptide (GLP)-1 responses were assessed. RESULTS Fasting C-peptide and C-peptide–to–glucose ratio, and C-peptide area under the curve (AUC) were significantly lower in the Ab+ CDx-type 2 diabetic patients. Other OGTT-derived surrogate indexes of insulin sensitivity and secretion were not different between the Ab+ versus Ab− patients. GLP-1 during the OGTT was highest in the Ab+ youths compared with the other two groups, but this difference disappeared after adjusting for BMI. Ab+ and Ab− CDx-type 2 diabetes had relative hyperglucagonemia compared with control subjects. CONCLUSIONS The clinical measures of fasting and OGTT-derived surrogate indexes of insulin sensitivity and secretion, except for fasting C-peptide and C-peptide AUC, are less sensitive tools to distinguish metabolic/pathopysiological differences, detected by the clamp, between Ab+ and Ab− CDx-type 2 diabetic youths. This underscores the importance of using more sensitive methods and the importance of determining antibody status in obese youths with CDx-type 2 diabetes.

OBJECTIVE— Some obese youth with a clinical diagnosis of type 2 diabetes have evidence of islet cell autoimmunity with positive autoantibodies. In this study, we investigated the differences in insulin sensitivity and secretion between autoantibody-negative (Ab−) and -positive (Ab+) youth with clinically diagnosed type 2 diabetes in comparison with control subjects. RESEARCH DESIGN AND METHODS— Sixteen Ab− and 26 Ab+ clinically diagnosed type 2 diabetic patients and 39 obese control youth underwent evaluation of insulin sensitivity (3-h hyperinsulinemic-euglycemic clamp), substrate oxidation (indirect calorimetry), first- and second-phase insulin secretion (2-h hyperglycemic clamp), body composition and abdominal adiposity (dual energy X-ray absorptiometry and computed tomography scan, respectively), and glucose disposition index (first-phase insulin secretion × insulin sensitivity). RESULTS— Insulin-stimulated total, oxidative, and nonoxidative glucose disposal, and suppression of fat oxidation during hyperinsulinemia were significantly lower in Ab− compared with Ab+ clinically diagnosed type 2 diabetic and control subjects with no difference between the latter two. First- and second-phase insulin secretion and C-peptide were lower in Ab+ compared with Ab− type 2 diabetes. Glucose disposition index was not different between the Ab− and Ab+ clinically diagnosed type 2 diabetic patients, but both were significantly lower than that in control subjects. Systolic blood pressure and alanine aminotransferase were higher in Ab− versus Ab+ clinically diagnosed type 2 diabetic patients, whereas the frequency of ketonuria at diagnosis was higher in Ab+ versus Ab− patients. CONCLUSIONS— Islet-cell Ab− clinically diagnosed type 2 diabetic youth are characterized by severe insulin resistance and relative insulin deficiency, whereas Ab+ youth have severe insulin deficiency and β-cell failure. The former group has additional features of insulin resistance. These important metabolic differences could influence the natural history of hyperglycemia, insulin dependence, and clinical outcomes in these youth.

OBJECTIVE—Impaired glucose tolerance (IGT) represents a pre-diabetic state. Controversy continues in regards to its pathophysiology. The aim of this study was to investigate the differences in insulin sensitivity (IS) and secretion in obese adolescents with IGT compared with those with normal glucose tolerance (NGT) and type 2 diabetes. RESEARCH DESIGN AND METHODS—A total of 12 obese adolescents with NGT, 19 with IGT, and 17 with type 2 diabetes underwent evaluation of insulin sensitivity (3-h hyperinsulinemic [80mu/m2/min]–euglycemic clamp), first-phase insulin and second-phase insulin secretion (2-h hyperglycemic clamp), body composition, and abdominal adiposity. Glucose disposition index (GDI) was calculated as the product of first-phase insulin × insulin sensitivity. RESULTS—Insulin-stimulated glucose disposal was significantly lower in subjects with type 2 diabetes compared with subjects with NGT and IGT, with no difference between the latter two. However, compared with youth with NGT, youth with IGT have significantly lower first-phase insulin and C-peptide levels and GDI (P = 0.012), whereas youth with type 2 diabetes have an additional defect in second-phase insulin. Fasting and 2-h glucose correlated with GDI (r = −0.68, P < 0.001 and r = −0.73, P < 0.001, respectively) and first-phase insulin but not with insulin sensitivity. CONCLUSIONS—Compared with youth with NGT, obese adolescents with IGT have evidence of a β-cell defect manifested in impaired first-phase insulin secretion, with a more profound defect in type 2 diabetes involving both first- and second-phase insulin. GDI shows a significantly declining pattern: it is highest in NGT, intermediate in IGT, and lowest in type 2 diabetes. Such data suggest that measures to prevent progression or conversion from pre-diabetes to type 2 diabetes should target improvement in β-cell function.

OBJECTIVE—We examined the relationship of in vivo insulin sensitivity to the components of the metabolic syndrome and biomarkers of endothelial dysfunction in youth. RESEARCH DESIGN AND METHODS—Subjects included 216 youths (8–19 years of age) who participated in a 3-h hyperinsulinemic-euglycemic clamp. RESULTS—Independent of race, the frequencies of central obesity, high triglycerides, low HDL, high blood pressure, impaired fasting glucose, and impaired glucose tolerance were significantly higher (P < 0.05) in the lowest versus highest quartile of insulin sensitivity. BMI, abdominal adiposity, systolic blood pressure, and triglycerides increased and adiponectin and HDL decreased significantly (P for trend for all 0.05) once visceral adipose tissue was controlled for. CONCLUSIONS—The prevalence of the individual components of metabolic syndrome increases with decreasing insulin sensitivity in black and white youth. In whites but not blacks, insulin resistance is associated with increased circulating endothelial biomarkers. It remains to be determined if lower abdominal adiposity and triglycerides in blacks underlies the racial differences in risk translation.

OBJECTIVE—The purpose of this study was to investigate 1) whether adiponectin is associated with insulin sensitivity independent of visceral adipose tissue in African-American and Caucasian youth and 2) whether adiponectin is associated with racial differences in insulin sensitivity. RESEARCH DESIGN AND METHODS—Total body fat was measured by dual-energy X-ray absorptiometry and abdominal adipose tissue with computed tomography. Insulin sensitivity was measured by a 3-h hyperinsulinemic-euglycemic clamp. RESULTS—Adiponectin was inversely associated (P < 0.01) with visceral adipose tissue, fasting insulin, and proinsulin and was positively related (P < 0.01) to insulin sensitivity after controlling for Tanner stage and sex independent of race. Stepwise multiple regression revealed that adiponectin was a strong independent predictor of insulin sensitivity, explaining 27% of the variance in insulin sensitivity. When subjects were categorized into tertiles of visceral adipose tissue and further low (≤50th) and high (>50th) adiponectin groups, insulin sensitivity was significantly different across the visceral adipose tissue groups (main effect, P < 0.01) in both races. However, within each visceral adipose tissue group, subjects with high adiponectin had higher insulin sensitivity (main effect, P < 0.05) than subjects with low adiponectin, independent of race. Racial differences in insulin sensitivity remained significant (P < 0.01) after controlling for leptin and visceral adipose tissue but not (P > 0.05) after additional adjustment for adiponectin. CONCLUSIONS—Adiponectin is associated with insulin sensitivity independent of visceral adipose tissue in both African-American and Caucasian youth. Low adiponectin in African-American youth may be a biological marker that predisposes them to a greater risk of insulin resistance.

The pathophysiology of type 2 diabetes (T2DM) involves insulin resistance and relative insulin deficiency in at-risk youth. We-report longitudinal changes in insulin sensitivity and secretion in a high-risk African-American youth with obesity and polycystic ovary syndrome who progressed from normal glucose tolerance to impaired glucose tolerance to T2DM within 5 yr. This report demonstrates that in our patient: (i) insulin resistance was the pre-existing abnormality, but it was the marked decline in insulin secretion which led to T2DM and (ii) surrogate estimates of insulin sensitivity using fasting glucose and insulin concentrations were not reliable indices in reflecting the changes in in vivo insulin sensitivity in this case.

OBJECTIVE—This study evaluates insulin sensitivity, pancreatic β-cell function (BCF), and the balance between the two in youth with type 2 diabetes and assesses the relationship of diabetes duration and HbA1c to insulin sensitivity and BCF. RESEARCH DESIGN AND METHODS—The subjects were 14 adolescents with type 2 diabetes and 20 obese control subjects of comparable age, BMI, body composition, and puberty. Insulin sensitivity was evaluated with a 3-h hyperinsulinemic (80 mU · m–2 · min–1) euglycemic clamp. First-phase insulin secretion (FPIS) and second-phase insulin secretion (SPIS) were evaluated with a 2-h hyperglycemic (12.5 mmol/l) clamp. Fasting glucose rate of appearance was determined with the use of [6,6-2H2]glucose. RESULTS—Fasting glucose rate of appearance was higher in type 2 diabetic patients than in obese control subjects (16.5 ± 1.1 vs. 12.3 ± 0.5 μmol · kg–1 · min–1; P = 0.002). Insulin sensitivity was lower in type 2 diabetic patients than in obese control subjects (1.0 ± 0.1 vs. 2.0 ± 0.2 μmol · kg–1 · min–1 per pmol/l; P = 0.001). Fasting insulin was higher in type 2 diabetic patients than in obese control subjects (289.8 ± 24.6 vs. 220.2 ± 18.0 pmol/l; P = 0.007), and FPIS and SPIS were lower (FPIS: 357.6 ± 42.0 vs. 1,365.0 ± 111.0 pmol/l; SPIS: 652.2 ± 88.8 vs. 1,376.4 ± 88.8 pmol/l; P < 0.001 for both). The glucose disposition index (GDI = insulin sensitivity × FPIS) was ∼86% lower in type 2 diabetic patients than in obese control subjects. HbA1c correlated with FPIS (r = −0.61, P = 0.025) with no relationship to insulin sensitivity. CONCLUSIONS—Despite the impairment in both insulin sensitivity and BCF in youth with type 2 diabetes, the magnitude of the derangement is greater in BCF than insulin sensitivity when compared with that in obese control subjects. The inverse relationship between BCF and HbA1c may either reflect the impact of deteriorating BCF on glycemic control or be a manifestation of a glucotoxic phenomenon on BCF. Future studies in youth type 2 diabetes should target the natural course of β-cell failure and means of retarding and/or preventing it.

OBJECTIVE—Adiponectin is an adipose tissue protein that enhances insulin sensitivity and has antiatherogenic properties. The present study investigated the relationship of adiponectin levels in adolescents to 1) obesity and body fat distribution and 2) insulin sensitivity and the components of syndrome X. RESEARCH DESIGN AND METHODS—Twenty-three normal-weight and 26 obese adolescents had fasting adiponectin, lipid profile, and proinsulin measurements performed. Hepatic and peripheral insulin sensitivity were assessed with constant-rate [6,6-2H2]glucose infusion and a 3-h hyperinsulinemic-euglycemic clamp, respectively. Body composition was evaluated by dual-energy X-ray absorptiometry, and visceral adipose tissue (VAT) and subcutaneous adipose tissue were measured by computed tomography scan at the L4-L5 level. RESULTS—Obese adolescents had ∼50% lower adiponectin than normal-weight adolescents. Moreover, obese adolescents with high (111.8 ± 9.3 cm2) versus low (55.4 ± 2.1 cm2) VAT had lower adiponectin levels (6.2 ± 0.9 vs. 9.0 ± 1.0 μg/ml, P = 0.05). Plasma adiponectin correlated positively with peripheral and hepatic insulin sensitivity (r = 0.67, P < 0.001 and r = 0.54, P < 0.001, respectively) and HDL (r = 0.52, P < 0.001) and negatively with fasting proinsulin and the proinsulin-to-insulin ratio (r = −0.64, P < 0.001 and r = −0.43, P = 0.003, respectively). In a multiple regression analysis, adiponectin, independently and together with BMI, explained 73% (R2 = 0.73, P < 0.001) of the variance in insulin sensitivity. Adiponectin, but not adiposity, was the significant independent determinant of the proinsulin-to-insulin ratio (R2 = 0.18, P = 0.008) and of HDL (R2 = 0.45, P < 0.001). CONCLUSIONS—In summary, hypoadiponectinemia in youth is a strong and independent correlate of insulin resistance, β-cell dysfunction, visceral adiposity, and syndrome X. The antidiabetogenic and antiatherogenic properties of adiponectin are evident early in life and compromised in youth-onset obesity.

The incidence of type 2 diabetes mellitus in children is increasing with the increasing prevalence of obesity, particularly in African-American children. We hypothesized that African-American obese adolescents are more insulin resistant than their white peers, but have lower insulin secretion, thus increasing their risk of type 2 diabetes mellitus. The present study investigated insulin sensitivity and secretion, visceral adiposity (VAT), and cardiovascular disease (CVD) risk profile in black obese adolescents (BOA) vs. white obese adolescents (WOA). Twenty-four BOA and 26 WOA underwent a hyperinsulinemic-euglycemic clamp to assess insulin sensitivity, a hyperglycemic clamp to determine insulin secretion, dual energy x-ray absorptiometry for body composition and computed tomography scan at L4-L5 to measure VAT and sc abdominal adipose tissue. Fasting lipid and automated blood pressure measurements were obtained. The WOA and BOA groups were divided into low VAT and high VAT groups. BOA compared with WOA of similar body mass index and percent body fat had less visceral adiposity, lower hepatic glucose production, and lower lipid levels. Visceral adiposity was associated with lower insulin sensitivity in both groups [low vs. high VAT; BOA, 2.9 +/- 0.4 vs. 1.7 +/- 0.2 micromol/kg x min per pmol/liter (P = 0.016); WOA, 2.6 +/- 0.5 vs. 1.5 +/- 0.1 (P = 0.032)]. However, this was compensated by higher insulin secretion in whites (low VAT, 934.8 +/- 121.8; high VAT, 1590.6 +/- 232.8 pmol/liter; P = 0.037), but not in blacks (low VAT, 1398.9 +/- 214.0; high VAT, 1423.7 +/- 108.7 pmol/liter). Glucose disposition index (insulin sensitivity x first phase insulin) was lower in high VAT vs. low VAT BOA, but not in WOA. In each racial group, high VAT groups had elevation of systolic and diastolic blood pressure, but dyslipidemia was worse in WOA with high VAT. In conclusion, a given level of body mass index confers different metabolic risks for WOA vs. BOA. Although differences in fat patterning may help explain the more atherogenic risk profile in whites, the cause of the more diabetogenic insulin sensitivity/secretion profile in blacks remains unknown and needs to be investigated further.

Type 2 diabetes mellitus was considered an exclusive disease of adulthood until the late 1970s, when reports of an increased prevalence in the pediatric age group emerged in the literature. The concerning upswing in the rate of diagnosis of type 2 diabetes mellitus in children and adolescents has continued, parallel to the increasing rates of obesity. The disease is not specific to the U.S.; it has proven to be a global problem. The current information on type 2 diabetes mellitus in children and adolescents is mostly extrapolated from studies in adults with type 2 diabetes mellitus, due to the paucity of studies conducted in youth. Obesity, family history of type 2 diabetes mellitus, minority ethnicity and race, polycystic ovary syndrome, maternal diabetes mellitus or impaired glucose tolerance during gestation, and acanthosis nigricans are the major risk factors and markers of youth-onset type 2 diabetes mellitus. The pathophysiology, which involves both an insulin secretion defect and resistance to insulin, needs further clarification in pediatric studies. Current management approaches involve lifestyle modification (nutritional and exercise) along with pharmacologic agents, such as insulin and oral antihyperglycemic medications, as indicated. A recent study on the use of metformin in childhood-onset type 2 diabetes mellitus demonstrated the drug to be effective and to have a good safety profile in this population. However, the outcomes of ongoing studies and future studies focusing on type 2 diabetes mellitus in the pediatric age group will be crucial in terms of fine-tuning management plans and setting up appropriate prevention strategies.

Obesity among children, adolescents and adults has emerged as one of the most serious public health concerns in the 21st century. The worldwide prevalence of childhood obesity has increased remarkably over the past 3 decades. The growing prevalence of childhood obesity has also led to appearance of obesity-related comorbid disease entities at an early age. Childhood obesity can adversely affect nearly every organ system and often causes serious consequences, including hypertension, dyslipidemia, insulin resistance, dysglycemia, fatty liver disease and psychosocial complications. It is also a major contributor to increasing healthcare expenditures. For all these reasons, it is important to prevent childhood obesity as well as to identify overweight and obese children at an early stage so they can begin treatment and attain and maintain a healthy weight. At present, pharmacotherapy options for treatment of pediatric obesity are very limited. Therefore, establishing a comprehensive management program that emphasizes appropriate nutrition, exercise and behavioral modification is crucial. The physician's role should expand beyond the clinical setting to the community to serve as a role model and to advocate for prevention and early treatment of obesity.

A total of 38 patients with Ullrich-Turner syndrome underwent standard otological and audiometric evaluation as well as high frequency audiological tests. Some 26 (68.4%) patients had a history of middle ear infections, and ten (26.3%) had required otolaryngological surgery. Conventional audiometry (125-8000 Hz) demonstrated normal hearing in only 25 of the ears (33%); between 500-4000 Hz, 16 ears (21.0%) had a mixed type and eight ears (10.5%) had conductive hearing loss. High frequency audiometry (8-18 kHz) revealed sensorineural hearing loss in 98.7% of the ears. Our results for conventional audiometry are in accordance with the literature.The detection of a high prevalence of hearing loss in the high frequency range brings a significant new perspective to the pursuit of the aetiology of ear and hearing problems in Ullrich-Turner syndrome. This pathology seems to be a premature variant of presbycusis and it may underlie future hearing impairment which will come to clinical attention only after it progresses to conventional testing frequencies. While further studies are underway to evaluate this aspect, routine otological and audiological follow-up of patients with Ullrich-Turner syndrome is warranted from the time of diagnosis.

The liver plays a major role in the formation of H2S, a novel signaling molecule. Diabetes is associated with lower blood levels of H2S. This study investigated the activities of cystathionine-γ-lyase (CSE, the enzyme that catalyzes H2S formation) in livers of type 1 diabetic (T1D) animals and in peripheral blood mononuclear cells (PBMC) isolated from T1D patients. T1D is associated with both hyperketonemia (acetoacetate and β-hydroxybutyrate) and hyperglycemia. This study also examined the role of hyperglycemia and hyperketonemia per se in decreased CSE activity using U937 monocytes and PBMC isolated from healthy subjects. Livers from streptozotocin-treated T1D rats demonstrated a significantly higher reactive oxygen species production, lower CSE protein expression and activity, and lower H2S formation compared with those of controls. Studies with T1D patients showed a decrease in CSE protein expression and activity in PBMC compared with those of age-matched normal subjects. Cell culture studies demonstrated that high glucose (25 mm) and/or acetoacetate (4 mm) increased reactive oxygen species, decreased CSE mRNA expression, protein expression, and enzymatic activity, and reduced H2S levels; however, β-hydroxybutyrate treatment had no effect. A similar effect, which was also observed in PBMC treated with high glucose alone or along with acetoacetate, was prevented by vitamin D supplementation. Studies with CSE siRNA provide evidence for a relationship between impaired CSE expression and reduced H2S levels. This study demonstrates for the first time that both hyperglycemia and hyperketonemia mediate a reduction in CSE expression and activity, which can contribute to the impaired H2S signaling associated with diabetes.

We had previously reported that stromal cell-derived factor 1 (SDF-1) mediates chemorepulsion of diabetogenic T cell adhesion to islet microvascular endothelium through unknown mechanisms in NOD mice. Here we report that SDF-1-mediated chemorepulsion occurs through slit homologue (SLIT)2-roundabout, axon guidance receptor, homologue 1 (Drosophila) (ROBO1) interactions.C-X-C receptor (CXCR)4 and ROBO1 protein expression was measured in mouse and human T cells. Parallel plate flow chamber adhesion and detachment studies were performed to examine the molecular importance of ROBO1 and SLIT2 for SDF-1-mediated T cell chemorepulsion. Diabetogenic splenocyte transfer was performed in NOD/LtSz Rag1(-/-) mice to examine the effect of the SDF-1 mimetic CTCE-0214 on adoptive transfer of diabetes.CXCR4 and ROBO1 protein expression was elevated in diabetic NOD/ShiLtJ T cells over time and coincided with the onset of hyperglycaemia. CXCR4 and ROBO1 expression was also increased in human type 1 diabetic T cells, with ROBO1 expression maximal at less than 1 year post diagnosis. Cell detachment studies revealed that immunoneutralisation of ROBO1 prevented SDF-1-mediated chemorepulsion of NOD T cell firm adhesion to TNFα-stimulated islet endothelial cells. SDF-1 increased NOD T cell adhesion to recombinant adhesion molecules, a phenomenon that was reversed by recombinant SLIT2. Finally, we found that an SDF-1 peptide mimetic prevented NOD T cell adhesion in vitro and significantly delayed adoptive transfer of autoimmune diabetes in vivo.These data reveal a novel molecular pathway, which regulates diabetogenic T cell recruitment and may be useful in modulating autoimmune diabetes.

Cardiomyopathy is a rare but life-threatening condition in children. Myocarditis is the leading cause of dilated cardiomyopathy (DCM) and prognosis is generally poor without heart transplantation. We report a rare case of hypocalcemic DCM due to primary hypoparathyroidism in a male infant. In our patient, aggressive management of hypoparathyroidism significantly improved the manifestations of DCM. He is currently 10 years old and has no symptoms of exercise intolerance. Latest echocardiogram revealed near-normal cardiac function. Our case emphasizes that early diagnosis of this treatable cause of cardiomyopathy prevents serious sequelae.

OBJECTIVE To report a 7-year-old young girl who was found unresponsive and found to be in severe diabetic ketoacidosis (DKA). Presence of obesity, acanthosis nigricans, and strong family history of type 2 diabetes mellitus (T2DM) along with negative pancreatic autoimmune antibody evaluation suggested T2DM as the culprit. METHODS We present clinical findings, laboratory test results, and imaging reports as well as follow-up on this unique presentation of T2DM. RESULTS A 7-year-old girl was found unresponsive at home. Initial evaluation demonstrated severe DKA and diminished neurologic status. CT-scan of the head did not demonstrate cerebral edema. Her neurologic status deteriorated dramatically on four separate occasions requiring reintubation twice. She was transitioned to intensive insulin management, requiring up to 2 units/kg/day insulin. Her insulin sensitivity improved dramatically prior to discharge. Now 18 months from diagnosis, she remains on basal insulin and metformin. CONCLUSIONS New-onset T2DM is an increasing event in youth. Reports suggest that these youth may acutely deteriorate as opposed to the typical longer duration of onset in youth with new-onset type 1 diabetes mellitus. Attention to effective screening of those at risk and increasing public awareness of T2DM in youth is important and may reduce the risk of such dreadful presentations as described in the current report. The balance between insulin deficiency and insulin resistance is variable at different phases of the condition. This highlights the need for study of the natural history of T2DM in youth.

OBJECTIVE— Some obese youth with a clinical diagnosis of type 2 diabetes have evidence of islet cell autoimmunity with positive autoantibodies. In this study, we investigated the differences in insulin sensitivity and secretion between autoantibody-negative (Ab−) and -positive (Ab+) youth with clinically diagnosed type 2 diabetes in comparison with control subjects. RESEARCH DESIGN AND METHODS— Sixteen Ab− and 26 Ab+ clinically diagnosed type 2 diabetic patients and 39 obese control youth underwent evaluation of insulin sensitivity (3-h hyperinsulinemic-euglycemic clamp), substrate oxidation (indirect calorimetry), first- and second-phase insulin secretion (2-h hyperglycemic clamp), body composition and abdominal adiposity (dual energy X-ray absorptiometry and computed tomography scan, respectively), and glucose disposition index (first-phase insulin secretion × insulin sensitivity). RESULTS— Insulin-stimulated total, oxidative, and nonoxidative glucose disposal, and suppression of fat oxidation during hyperinsulinemia were significantly lower in Ab− compared with Ab+ clinically diagnosed type 2 diabetic and control subjects with no difference between the latter two. First- and second-phase insulin secretion and C-peptide were lower in Ab+ compared with Ab− type 2 diabetes. Glucose disposition index was not different between the Ab− and Ab+ clinically diagnosed type 2 diabetic patients, but both were significantly lower than that in control subjects. Systolic blood pressure and alanine aminotransferase were higher in Ab− versus Ab+ clinically diagnosed type 2 diabetic patients, whereas the frequency of ketonuria at diagnosis was higher in Ab+ versus Ab− patients. CONCLUSIONS— Islet-cell Ab− clinically diagnosed type 2 diabetic youth are characterized by severe insulin resistance and relative insulin deficiency, whereas Ab+ youth have severe insulin deficiency and β-cell failure. The former group has additional features of insulin resistance. These important metabolic differences could influence the natural history of hyperglycemia, insulin dependence, and clinical outcomes in these youth.

To evaluate clinically useful measures of beta-cell function derived from the oral glucose tolerance test (OGTT) or mixed-meal (ie, Boost) tolerance test to assess insulin secretion in comparison with the gold standard, the hyperglycemic clamp (Hyper-C) test.We hypothesized that OGTT/Boost-derived measures are useful estimates of beta-cell function and correlate well with insulin secretion measured by the Hyper-C test. This study was designed to assess the correlation between the ratio of the early incremental insulin/glucose responses at 15 and 30 minutes (DeltaI(15)/DeltaG(15) and DeltaI(30)/DeltaG(30)) of the OGTT and the Boost test with insulin secretion measured during the Hyper-C test (225 mg/dL). The same indices were evaluated using C-peptide. A total of 26 children (14 males, 12 females; mean age, 9.9 +/- 0.2 years; mean body mass index = 22.1 +/- 1.2 kg/m(2)) underwent a 2-hour Hyper-C test (225 mg/dL) and 3-hour OGTT and Boost tests with measurements of glucose, insulin, and C-peptide.Correlations between Hyper-C- and OGTT-derived measures of insulin secretion were stronger for the 15-minute index than for the 30-minute index of insulin secretion and stronger for C-peptide levels than for insulin levels (r = .7, P.001 for first-phase C-peptide vs both OGTT and Boost, DeltaC(15)/DeltaG(15)).In children with normal glucose tolerance, C-peptide rather than insulin level measured after 15 minutes of the OGTT or Boost test provides a reliable estimate of beta-cell function that correlates well with Hyper-C-derived insulin secretion.

We examined the relationship of in vivo insulin sensitivity to the components of the metabolic syndrome and biomarkers of endothelial dysfunction in youth.Subjects included 216 youths (8-19 years of age) who participated in a 3-h hyperinsulinemic-euglycemic clamp.Independent of race, the frequencies of central obesity, high triglycerides, low HDL, high blood pressure, impaired fasting glucose, and impaired glucose tolerance were significantly higher (P0.05) in the lowest versus highest quartile of insulin sensitivity. BMI, abdominal adiposity, systolic blood pressure, and triglycerides increased and adiponectin and HDL decreased significantly (P for trend for all0.05), with decreasing insulin sensitivity in both races. After controlling for BMI, insulin resistance remained associated (P0.05) with visceral adipose tissue in both races (P for trend = 0.01 in blacks and 0.08 in whites). In whites but not blacks, lower insulin sensitivity was associated (P0.05) with higher intercellular adhesion molecule-1 (ICAM-1) and E-selectin levels; however, these relationships did not remain significant (P0.05) once visceral adipose tissue was controlled for.The prevalence of the individual components of metabolic syndrome increases with decreasing insulin sensitivity in black and white youth. In whites but not blacks, insulin resistance is associated with increased circulating endothelial biomarkers. It remains to be determined if lower abdominal adiposity and triglycerides in blacks underlies the racial differences in risk translation.

EXCERPT The extent of the epidemic of childhood obesity has led to earlier onset of type 2 diabetes, affecting increasing numbers of pediatric patients. The purpose of this review is to 1) highlight scientific findings relevant to the epidemiology and pathophysiology of type 2 diabetes in youth, 2) summarize recommendations for identifying and screening youth at risk for type 2 diabetes, and 3) outline guidelines for the diagnosis and treatment of youth with type 2 diabetes. ABOUT THE AUTHORS Tamara S. Hannon, MD, is Assistant Professor of Pediatrics, Department of Pediatrics, Division of Weight Management and Wellness, and Division of Pediatric Endocrinology, Metabolism, and Diabetes Mellitus, Children’s Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA. Neslihan Gungor, MD, is Director, Division of Pediatrics, Anadolu Foundation Health Care System, Pediatrics/Endocrinology, Kocaeli Turkey. Silva A. Arslanian, MD, is Richard L. Day Professor of Pediatrics, Department of Pediatrics; Chief, Division of Weight Management and Wellness; and Director, General Clinical Research Center; Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, Children’s Hospital University of Pittsburgh Medical Center, Pittsburgh, PA. Address correspondence to: Tamara S. Hannon, MD, Children’s Hospital of Pittsburgh, 3705 5th Avenue at DeSoto Street, 4A, Room 424, Pittsburgh, PA 15213; tamara.hannon@chp.edu. The authors disclosed no relevant financial relationships. This work is supported by United States Public Health grants K24 HD01357 and K23 RR17250.

We examined whether the relationship between cardiorespiratory fitness (CRF) and insulin sensitivity (IS)/secretion is independent of adiposity in healthy African-American (n = 65) and white (n = 57) youth.IS and beta-cell function were evaluated by a 3-hour hyperinsulinemic-euglycemic and a 2-hour hyperglycemic (12.5 mM) clamp, respectively. Total fat was measured by DXA and abdominal fat with computed tomography. CRF (peak volume of oxygen) was measured using a graded maximal treadmill test.Independent of race, CRF was inversely (p0.05) related to total and abdominal fat, fasting insulin and first phase insulin secretion, and positively (p0.05) related to IS. When subjects were categorized into low (or = 50th) and high (50th) CRF groups, IS was significantly (p0.05) higher in the high compared with the low CRF group independently of race. Furthermore, first and second phase insulin secretion were lower (p0.05) in the high CRF group in comparison with the low CRF group in both races. However, in multiple regression analyses CRF was not (p0.05) an independent predictor of IS and acute insulin secretion after accounting for total adiposity.Our findings demonstrate that low CRF is associated with decreased IS compensated by higher insulin secretion in both African-American and white youth. However, this relationship disappears after adjusting for differences in adiposity, suggesting that the association between fitness and IS is mediated, at least in part, through fatness.

OBJECTIVE—Obesity is often associated with insulin resistance and the components of the metabolic syndrome. However, wide variations in insulin sensitivity are noted in obese youth. It is not clear if greater insulin resistance confers a higher risk of cardiovascular comorbidities and risk for type 2 diabetes. RESEARCH DESIGN AND METHODS—We investigated physical and metabolic features of 54 obese adolescents. Subsequently, we pair matched 17 moderately insulin-resistant (MIR group) to 17 severely insulin-resistant (SIR group) youth based on cut points for insulin sensitivity (MIR group insulin sensitivity within 2 SDs and SIR group RESULTS—SIR youth had higher visceral adiposity (78.3 ± 6.9 vs. 60.3 ± 6.9 cm2, P = 0.017) and waist-to-hip ratio (0.91 ± 0.01 vs. 0.86 ± 0.02, P = 0.026) and lower HDL (1.0 ± 0.03 vs. 1.16 ± 0.06 mmol/l, P = 0.015) than pair-matched MIR subjects. There was a tendency for adiponectin (6.1 ± 0.5 vs. 8.6 ± 1.1 μg/ml, P = 0.079) and CRF (49.9 ± 3.2 vs. 55.2 ± 3.5 ml · min−1 · kg−1 fat-free mass, P = 0.09) to be lower in SIR subjects. SIR youth also had an impaired balance between insulin sensitivity and β-cell compensation with a lower glucose disposition index. CONCLUSIONS—Despite similar BMI, the degree of insulin resistance impacts the risk for obesity-related metabolic comorbidities. The SIR youth are at greater risk for type 2 diabetes and cardiovascular disease.

The purpose of this study was to investigate 1) whether adiponectin is associated with insulin sensitivity independent of visceral adipose tissue in African-American and Caucasian youth and 2) whether adiponectin is associated with racial differences in insulin sensitivity.Total body fat was measured by dual-energy X-ray absorptiometry and abdominal adipose tissue with computed tomography. Insulin sensitivity was measured by a 3-h hyperinsulinemic-euglycemic clamp.Adiponectin was inversely associated (P0.01) with visceral adipose tissue, fasting insulin, and proinsulin and was positively related (P0.01) to insulin sensitivity after controlling for Tanner stage and sex independent of race. Stepwise multiple regression revealed that adiponectin was a strong independent predictor of insulin sensitivity, explaining 27% of the variance in insulin sensitivity. When subjects were categorized into tertiles of visceral adipose tissue and further low (or = 50th) and high (50th) adiponectin groups, insulin sensitivity was significantly different across the visceral adipose tissue groups (main effect, P0.01) in both races. However, within each visceral adipose tissue group, subjects with high adiponectin had higher insulin sensitivity (main effect, P0.05) than subjects with low adiponectin, independent of race. Racial differences in insulin sensitivity remained significant (P0.01) after controlling for leptin and visceral adipose tissue but not (P0.05) after additional adjustment for adiponectin.Adiponectin is associated with insulin sensitivity independent of visceral adipose tissue in both African-American and Caucasian youth. Low adiponectin in African-American youth may be a biological marker that predisposes them to a greater risk of insulin resistance.

Type 2 diabetes mellitus is a heterogeneous condition in which the clinical manifestation of hyperglycemia is a reflection of the impaired balance between insulin sensitivity and insulin secretion. Clinical experience and research in youth type 2 diabetes mellitus are in an early stage because of the relative novelty of the condition in pediatrics. This article discusses the amassed information in type 2 diabetes mellitus of youth to date with respect to the epidemiology, pathophysiology, risk factors, clinical presentation, screening, and management strategies.

Objectives We examined how well waist circumference (WC) reflects total and abdominal fat and whether WC predicts insulin resistance independent of body mass index (BMI) percentile in youths. Study design Body composition was measured by dual-energy x-ray absorptiometry and abdominal adiposity by computed tomography. Insulin sensitivity was measured by the hyperinsulinemic-euglycemic clamp. Results Both BMI percentile and WC were significantly associated (P < .01) with total and abdominal fat and insulin sensitivity. WC remained a significant (P < .01) correlate of total and abdominal fat and insulin sensitivity after controlling for BMI percentile. By contrast, BMI percentile did not remain a significant correlate of visceral fat and markers of insulin resistance after controlling for WC. Without exception, WC explained a greater variance in abdominal fat and metabolic profiles than did BMI percentile. Conclusions Our findings suggest that the prediction of health risks associated with obesity in youths is improved by the additional inclusion of WC measure to the BMI percentile. Such observations would reinforce the importance of including WC in the assessment of childhood obesity to identify those at increased metabolic risk due to excess abdominal fat.

Atherosclerotic cardiovascular disease (CVD) is the major cause of mortality and morbidity in adults with type 2 diabetes (1). The origin of atherosclerosis is early in childhood with progression toward clinically significant lesions in young adulthood (2,3). Carotid artery intima media thickness (IMT) and aortic pulse wave velocity (aPWV), a measure of arterial stiffness, are noninvasive measures of subclinical atherosclerosis that have been used as surrogate measures of cardiovascular events in various adult studies (4–9). Data regarding IMT and arterial stiffness in children are limited despite the increasing tide of obesity and type 2 diabetes. Therefore, in this pilot study, we aimed 1 ) to evaluate IMT and aPWV in obese adolescents with type 2 diabetes and 2 ) to investigate the relationship between these vascular markers and the clinical/metabolic risk factors of CVD. We studied 20 adolescents with type 2 diabetes (undetectable islet-cell and GAD65 autoantibodies, duration 1.7 ± 0.4 years) and 22 normal-weight and 20 obese healthy control subjects. The groups were comparable for age, sex, ethnicity, and puberty assessed by Tanner criteria (10) (Table 1). Type 2 diabetic subjects were receiving either metformin or rosiglitazone (7), metformin with insulin (5), insulin alone (1), and metformin and acarbose (1) in addition to lifestyle modification. None of the subjects had a family history of hereditary hyperlipidemia. Four subjects were smokers (three normal weight and one obese) with no significant difference among the three groups for …

This study evaluates insulin sensitivity, pancreatic beta-cell function (BCF), and the balance between the two in youth with type 2 diabetes and assesses the relationship of diabetes duration and HbA(1c) to insulin sensitivity and BCF.The subjects were 14 adolescents with type 2 diabetes and 20 obese control subjects of comparable age, BMI, body composition, and puberty. Insulin sensitivity was evaluated with a 3-h hyperinsulinemic (80 mU . m(-2) . min(-1)) euglycemic clamp. First-phase insulin secretion (FPIS) and second-phase insulin secretion (SPIS) were evaluated with a 2-h hyperglycemic (12.5 mmol/l) clamp. Fasting glucose rate of appearance was determined with the use of [6,6-(2)H(2)]glucose.Fasting glucose rate of appearance was higher in type 2 diabetic patients than in obese control subjects (16.5 +/- 1.1 vs. 12.3 +/- 0.5 micromol . kg(-1) . min(-1); P = 0.002). Insulin sensitivity was lower in type 2 diabetic patients than in obese control subjects (1.0 +/- 0.1 vs. 2.0 +/- 0.2 micromol . kg(-1) . min(-1) per pmol/l; P = 0.001). Fasting insulin was higher in type 2 diabetic patients than in obese control subjects (289.8 +/- 24.6 vs. 220.2 +/- 18.0 pmol/l; P = 0.007), and FPIS and SPIS were lower (FPIS: 357.6 +/- 42.0 vs. 1,365.0 +/- 111.0 pmol/l; SPIS: 652.2 +/- 88.8 vs. 1,376.4 +/- 88.8 pmol/l; P0.001 for both). The glucose disposition index (GDI = insulin sensitivity x FPIS) was approximately 86% lower in type 2 diabetic patients than in obese control subjects. HbA(1c) correlated with FPIS (r = -0.61, P = 0.025) with no relationship to insulin sensitivity.Despite the impairment in both insulin sensitivity and BCF in youth with type 2 diabetes, the magnitude of the derangement is greater in BCF than insulin sensitivity when compared with that in obese control subjects. The inverse relationship between BCF and HbA(1c) may either reflect the impact of deteriorating BCF on glycemic control or be a manifestation of a glucotoxic phenomenon on BCF. Future studies in youth type 2 diabetes should target the natural course of beta-cell failure and means of retarding and/or preventing it.

OBJECTIVE—Family history of type 2 diabetes is a major risk factor for type 2 diabetes in youth, which is increasing. This investigation aimed to evaluate the impact of family history of type 2 diabetes on insulin secretion relative to insulin sensitivity in healthy children. β-Cell compensation for insulin sensitivity was calculated as the product of insulin sensitivity × first-phase insulin secretion, termed glucose disposition index (GDI). RESEARCH DESIGN AND METHODS—A total of 28 healthy white children (12 boys and 16 girls; 12.1 ± 0.5 years of age) with a positive family history of type 2 diabetes and 26 healthy white children (13 boys and 13 girls; 11.5 ± 0.4 years of age) with a negative family history of type 2 diabetes underwent a 3-h 40 mU · m−2 · min−1 hyperinsulinemic-euglycemic clamp to assess insulin sensitivity and clearance and a 2-h hyperglycemic clamp to assess insulin secretion. Body composition and visceral adiposity were evaluated with dual-energy X-ray absorptiometry and computed tomography at the L4-L5 intervertebral space. RESULTS—Insulin sensitivity was lower in children with a family history of type 2 diabetes versus children without a family history (8.8 ± 0.9 vs. 12.2 ± 1.1 μmol · kg−1 · min−1 per pmol/l, P = 0.02). Similarly, insulin clearance was lower. First- and second-phase insulin levels were not different between groups with and without a positive family history. The GDI was lower in youth with versus youth without a positive family history (4.1 ± 0.3 vs. 5.2 ± 0.5 mmol · kg−1 · min−1, P = 0.039). IGF binding protein-1 (IGFBP-1) was 60% lower in youth with versus youth without the positive family history. CONCLUSIONS—These results demonstrate that family history of type 2 diabetes in white children is associated with decreased insulin sensitivity and clearance, decreased IGFBP-1, and an impaired relationship between insulin action and β-cell compensation. Detection of these alterations in hormonal and metabolic parameters in children with a positive family history suggests that at least some of the determinants of GDI are genetic/heritable.

The pathophysiology of type 2 diabetes mellitus (T2DM) involves insulin resistance and insulin deficiency. We report the progression in insulin sensitivity and secretion over a 6-year period in an adolescent with T2DM. This report further demonstrates that the earliest abnormality in youth T2DM is insulin resistance followed by progressive beta-cell failure.

Adiponectin is an adipose tissue protein that enhances insulin sensitivity and has antiatherogenic properties. The present study investigated the relationship of adiponectin levels in adolescents to 1) obesity and body fat distribution and 2) insulin sensitivity and the components of syndrome X.Twenty-three normal-weight and 26 obese adolescents had fasting adiponectin, lipid profile, and proinsulin measurements performed. Hepatic and peripheral insulin sensitivity were assessed with constant-rate [6,6-(2)H(2)]glucose infusion and a 3-h hyperinsulinemic-euglycemic clamp, respectively. Body composition was evaluated by dual-energy X-ray absorptiometry, and visceral adipose tissue (VAT) and subcutaneous adipose tissue were measured by computed tomography scan at the L(4)-L(5) level.Obese adolescents had approximately 50% lower adiponectin than normal-weight adolescents. Moreover, obese adolescents with high (111.8 +/- 9.3 cm(2)) versus low (55.4 +/- 2.1 cm(2)) VAT had lower adiponectin levels (6.2 +/- 0.9 vs. 9.0 +/- 1.0 microg/ml, P = 0.05). Plasma adiponectin correlated positively with peripheral and hepatic insulin sensitivity (r = 0.67, P0.001 and r = 0.54, P0.001, respectively) and HDL (r = 0.52, P0.001) and negatively with fasting proinsulin and the proinsulin-to-insulin ratio (r = -0.64, P0.001 and r = -0.43, P = 0.003, respectively). In a multiple regression analysis, adiponectin, independently and together with BMI, explained 73% (R(2) = 0.73, P0.001) of the variance in insulin sensitivity. Adiponectin, but not adiposity, was the significant independent determinant of the proinsulin-to-insulin ratio (R(2) = 0.18, P = 0.008) and of HDL (R(2) = 0.45, P0.001).In summary, hypoadiponectinemia in youth is a strong and independent correlate of insulin resistance, beta-cell dysfunction, visceral adiposity, and syndrome X. The antidiabetogenic and antiatherogenic properties of adiponectin are evident early in life and compromised in youth-onset obesity.

Objectives To compare insulin sensitivity and pancreatic β-cell function measured by the euglycemic and the hyperglycemic clamp, with simple estimates of insulin sensitivity and pancreatic β-cell function in youth. Study design We measured insulin sensitivity with a euglycemic clamp and first- and second-phase insulin secretion with a hyperglycemic clamp in 156 AA and white youths. Estimates of insulin sensitivity (fasting insulin level [IF], the ratio of fasting glucose [GF] to IF [GF/IF], homeostasis model assessment estimate of insulin sensitivity [HOMA IS], and quantitative insulin sensitivity check index [QUICKI]) and estimates of pancreatic β-cell function (IF, the ratio of IF to GF [IF/GF], and homeostasis model assessment estimate of pancreatic β-cell function [HOMA %B]) were derived from fasting measurements. Results In the total group, ISEu correlated strongly with IF (r = −0.92), GF/IF (r = 0.92), HOMA IS (r = 0.91), and QUICKI (r = 0.91) (P