Type 2 diabetes in youth: are there racial differences in β‐cell responsiveness relative to insulin sensitivity?

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.     

Differences in β‐cell function and insulin secretion in Black vs. White obese adolescents: do incretin hormones play a role?

Black youth are at higher risk for type 2 diabetes (T2D) than their White peers. Previously we demonstrated that for the same degree of insulin sensitivity, Black youth have an upregulated β‐cell function and insulin hypersecretion, in response to intravenous (iv) glucose, compared with Whites. To investigate if the same holds true during an oral glucose challenge and because of the important role of glucagon‐like peptide 1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) in augmenting insulin secretion, we examined β‐cell function and incretin hormones in 85 Black and 78 White obese adolescents, with normal glucose tolerance (NGT), during a 2‐h oral glucose tolerance test (OGTT) with mathematical modeling of plasma glucose and C‐peptide concentrations to assess β‐cell glucose sensitivity (βCGS), rate sensitivity, potentiation factor, and insulin sensitivity. Incretin, pancreatic polypeptide, and glucagon concentrations were measured during the OGTT. Black obese youth had a heightened early insulin secretion together with significantly greater βCGS, rate sensitivity, and potentiation factor compared with Whites, with no differences in incretin and glucagon concentrations. Basal and stimulated insulin clearance was lower (p = 0.001) in Black vs. White youth. In conclusion, during an OGTT Black obese youth with NGT demonstrate a pronounced early insulin secretion jointly with heightened β‐cell glucose sensitivity, rate sensitivity, and potentiation factor. These racial disparities in β‐cell function and the pathophysiological components of T2D are unlikely to be attributed to incretin hormones and remain to be investigated further to explain the metabolic basis for the enhanced risk of T2D in back youth.     

Type 2 diabetes in a 5‐year‐old and single center experience of type 2 diabetes in youth under 10

The worrisome rise in pediatric type 2 diabetes (T2DM) is most prevalent among minority ethnic/racial populations. Typically, T2DM occurs during puberty in high risk obese adolescents with evidence of insulin resistance. Screening for T2DM in obese youth can be a daunting task for pediatricians and differentiating between pediatric T1DM and T2DM in obese youth can be challenging for pediatric endocrinologists. There is very limited data regarding the prevalence of T2DM among youth < 10 years of age. Here we present the case of a 5‐year‐old Hispanic male diagnosed with T2DM after referral by his pediatrician for abnormal weight gain, acanthosis nigricans and an elevated HbgA1c. He subsequently became symptomatic for diabetes with confirmed hyperglycemia and HbgA1c of 9.7% (83 mmol/mol) at the time of formal diagnosis. Type 1 diabetes autoantibodies (GAD65, Islet, and ZincT8) and monogenic diabetes genetic tests were negative. Due to elevated liver enzymes and baseline HbgA1c, he received basal insulin as his initial therapy. In this paper, we will discuss this case and present an IRB approved retrospective review of the characteristics of the 20 T2DM patients <10 years of age identified to date in our pediatric diabetes center. This review highlights that while uncommon, the diagnosis of T2DM merits consideration even in prepubertal children. This is especially true when working with a high risk population, such as our Hispanic South Texas youth.     

Residual C‐peptide in type 1 diabetes: what do we really know?

Connecting peptide, or C‐peptide, is a protein that joins insulin's α and B chains in the proinsulin molecule. During insulin synthesis, C‐peptide is cleaved from proinsulin and secreted in an equimolar concentration to insulin from the β cells. Because C‐peptide experiences little first‐pass clearance by the liver, and because levels are not affected by exogenous insulin administration, it may be used as a marker of endogenous insulin production and a reflection of β‐cell function. Residual β‐cell function, as measured by C‐peptide in those with type 1 diabetes (T1D), has repeatedly been demonstrated to be clinically important. The Eisenbarth model of type 1 diabetes postulated immune‐mediated linear loss of β cells, with clinical diagnosis occurring when there was insufficient insulin secretion to meet glycemic demand. Moreover, the model also implied that all individuals with T1D rapidly and inevitably progressed to absolute insulin deficiency. Correspondingly, it was assumed that most people with longstanding T1D would show little to no residual C‐peptide secretion. While more than a quarter century of data confirms that this model remains largely true and appropriately serves as the basis for prevention studies, accumulating evidence suggests that the natural history of β‐cell function before, during and after diagnosis is more complex. In this review, we discuss the clinical benefits of residual insulin secretion and present recent data about the natural history of insulin secretion in those with, or at risk for T1D.     

The carriage of the type 1 diabetes‐associated R262W variant of human LNK correlates with increased proliferation of peripheral blood monocytes in diabetic patients

Lavrikova EY, Nikitin AG, Kuraeva TL, Peterkova VA, Tsitlidze NM, Chistiakov DA, Nosikov VV. The carriage of the type 1 diabetes‐associated R262W variant of human LNK correlates with increased proliferation of peripheral blood monocytes in diabetic patients. Objective: Lymphocyte adaptor protein (LNK) plays a pivotal role as a suppressor of T‐cell receptor‐mediated immune signaling and negative regulator of lymphopoiesis and early hematopoiesis. Recently, association between the R262W (c.784T>C) variant of the SH2B3 gene (rs3184504) encoding human LNK and type 1 diabetes (T1D) was found in several populations. In this study, we aimed to check whether this marker is associated with T1D in a Russian population. Methods: Using a Taqman allele discrimination assay, we genotyped 1062 unrelated Russian individuals with diabetes at childhood and adolescence onset and 1020 healthy controls. T‐cell proliferation assay based on the measurement of incorporation of bromo‐2′‐deoxyuridine incorporation into newly synthesized DNA was used to evaluate whether carriage of SH2B3 784T>C correlates with T‐cell proliferation in patients' peripheral mononuclear blood cells (PMBCs) stimulated with anti‐CD28 and anti‐CD3 antibodies. Results: The allele 784C of SH2B3 was related to a higher risk of T1D (odds ratio of 1.52, p = 1.2 × 10^?12). A correlation between the carriage of the predisposing C/C variant of LNK and increased proliferation of T lymphocytes was shown in PMBCs of both diabetic [C/C vs. C/T vs.T/T = optical density at 450 nm (OD₄₅₀) 6.3 ± 0.8 vs. 4.4 ± 0.7 vs. 2.7 ± 0.5, p = 0.0007] and non‐diabetic (C/C vs. C/T vs.T/T = OD₄₅₀2.9 ± 0.6 vs. 2.2 ± 0.4 vs. 1.7 ± 0.4, p = 0.022) patients. Conclusions: The SH2B3 784T>C variant could contribute to the pathogenesis of T1D through impaired immune response that promotes activation and expansion of self‐reactive lymphocytes in susceptible individuals.     

Glucose tolerance status in 510 children and adolescents attending an obesity clinic in Central Italy

Brufani C, Ciampalini P, Grossi A, Fiori R, Fintini D, Tozzi A, Cappa M, Barbetti F. Glucose tolerance status in 510 children and adolescents attending an obesity clinic in Central Italy. Childhood obesity is epidemic in developed countries and is accompanied by an increase in the prevalence of type 2 diabetes (T2DM). Aims: Establish prevalence of glucose metabolism alterations in a large sample of overweight/obese children and adolescents from Central Italy. Methods: The study group included 510 overweight/obese subjects (3–18 yr). Oral glucose tolerance test (OGTT) was performed with glucose and insulin determination. Homeostatic model assessment of insulin resistance (HOMA‐IR) and insulin sensitivity index (ISI) were derived from fasting and OGTT measurements. Beta‐cell function was estimated by insulinogenic index. Fat mass was measured by dual‐energy x‐ray absorptiometry. Results: Glucose metabolism alterations were detected in 12.4% of patients. Impaired glucose tolerance (IGT) was the most frequent alteration (11.2%), with a higher prevalence in adolescents than in children (14.8 vs. 4.1%, p < 0.001); silent T2DM was identified in two adolescents (0.4%). HOMA‐IR and glucose‐stimulated insulin levels were higher in patients with IGT than individuals with normal glucose tolerance (HOMA‐IR = 4.4 ± 2.5 vs. 3.4 ± 2.3, p = 0.001). Fat mass percentage and insulinogenic index were not different between the two groups. In multivariate analysis, age, fasting glucose, and insulin resistance influenced independently plasma glucose at 120 min of OGTT. Individuals with combined impaired fasting glucose/IGT (IFG/IGT) and T2DM were older and had reduced plasma insulin values at OGTT when compared to patients with simple IGT. Conclusions: Glucose metabolism alterations are frequently found among children and adolescents with overweight/obesity from Central Italy. Age, fasting glucose, and insulin resistance are main predictors of IGT. We suggest the use of OGTT as a screening tool in obese European adolescents.     

Controlling the blood glucose of type 1 diabetes mice by co‐culturing MIN‐6 β cells on 3D scaffold

T1D is an autoimmune disease, which may be caused by lack of insulin‐secreting β cells due to damage of autoimmune system. Living with T1D is a challenge for the child and the family; cell transplantation is a treatment option for diabetes in children. To establish a microenvironment suitable for cell growth and proliferation as well as for sustained cellular function, we used MIN‐6 β cells as seed cells and SF‐IV collagen as a 3D composite scaffold to construct artificial pancreas in this experiment. The cell viabilities were determined by MTT assay, and the response of cells to different glucose concentrations was observed by glucose stimulation test. Artificial pancreas was transplanted into the abdominal cavity of T1D mice, and the changes of blood glucose were monitored. After 10 days, insulin expression was detected by immunohistochemical method, and the claybank stained area showed effectiveness of insulin secretion. A series of experiments showed that implantation of 3D cell scaffold into the abdominal cavity can effectively control the blood glucose level of T1D mice. It also had longer‐lasting hypoglycemic effects than simple cell transplantation, which was expected to become a new method for the treatment of T1D.     

Hematopoietic stem cell transplantation recovers insulin deficiency in type 1 diabetes mellitus associated with IPEX syndrome

Immune dysregulation, polyendocrinopathy, enteropathy, and X‐linked (IPEX) syndrome is an autoimmune disorder caused by the dysfunction of FOXP3, which leads to regulatory T‐(Treg) cell dysfunction and subsequently autoimmunity including type 1 diabetes mellitus (T1D). Presently, allogeneic hematopoietic stem cell transplantation (HSCT) is a potential curative therapy for IPEX syndrome, but not for T1D. Generally, after complete loss of pancreatic β‐cells, HSCT cannot improve the prognosis of T1D. Here, we report the case of a 16‐year‐old adolescent with late‐onset of FOXP3 R347H mutation associated IPEX syndrome with T1D, where insulin dependency was ameliorated following HSCT. This patient with insulin‐dependent diabetes mellitus required insulin dosage of 1.28 U/kg/day for 1 month before HSCT. Although the results of glucose homeostasis before HSCT revealed impaired insulin secretion and low ΔC‐peptide immunoreactivity (CPR, 1.0 ng/mL), the patient withdrew insulin infusion and remained euglycemic at 15 months after HSCT, and had normal β‐cell function with improved ΔCPR (3.4 ng/mL) at 20 months after HSCT. The present case suggests that HSCT for T1D‐associated IPEX syndrome improves Treg deficiency and prevents elimination of β‐cells. We speculate that the period from the onset of T1D to HSCT could affect the therapeutic efficacy for T1D with IPEX, and early intervention with HSCT before or immediately after the onset of DM can rescue β‐cells and remit T1D completely. Our study elaborates not only the therapeutic strategy for T1D with IPEX, but also the pathogenic mechanism in general T1D.     

One‐hour plasma glucose concentration during the OGTT: what does it tell about β‐cell function relative to insulin sensitivity in overweight/obese children?

Tfayli H, Jung Lee S, Bacha F, Arslanian S. One‐hour plasma glucose concentration during the OGTT: what does it tell about β‐cell function relative to insulin sensitivity in overweight/obese children? Background: In adults 1‐h plasma glucose concentration cut‐point of 155 mg/dL (8.6 mmol/L) during the oral glucose tolerance test (OGTT) is a strong predictor of future diabetes risk. Objective: We tested the hypothesis that a 1‐h glucose concentration ≥155 mg/dL is associated with lower β‐cell function in overweight/obese youth. Research design and methods: One hundred and thirteen diabetes free overweight/obese youth aged 10–20 yr, underwent evaluation of β‐cell function during a 2 h hyperglycemic clamp ～225 mg/dL (12.5 mmol/L), and insulin sensitivity during a 3 h hyperinsulinemic–euglycemic clamp, and a standard 2 h OGTT. Body composition and abdominal adiposity were determined by DEXA and CT scan. The disposition index (DI) was calculated as the product of first‐phase insulin secretion and insulin sensitivity. Subjects were divided into two categories of 1‐h plasma glucose concentration: <155 mg/dL (n = 69) and ≥155 mg/dL (n = 44). Results: Youth with 1‐h glucose ≥155 mg/dL had lower DI than those with 1‐h glucose <155 mg/dL (295.1 ± 27.4 vs. 498.6 ± 37.7 mg/kg/min, p < 0.001), independent of the glucose tolerance status. In multiple regression models, DI was the strongest contributor to 1‐h glucose concentration explaining ～21% of its variance. Conclusions: Overweight/obese youth with 1‐h glucose ≥155 mg/dL during the oral glucose tolerance test have a significantly lower β‐cell function relative to insulin sensitivity even within the normal glucose tolerance range. Such youth may be at higher risk of future diabetes.     

Poorly controlled type 1 diabetes is associated with altered glutathione homeostasis in adolescents: apparent resistance to N‐acetylcysteine supplementation

Blood glutathione concentrations represent a measure of protection against oxidative damage. In earlier studies, we observed that, in adolescents with poorly controlled type 1 diabetes mellitus (T1DM), blood glutathione is significantly depleted because of increased rates of glutathione utilization. To determine whether increased availability of cysteine – one of the three constitutive amino acids of glutathione – would attenuate the alterations in glutathione metabolism, ten 16 ± 1 yr‐old adolescents with poorly controlled T1DM [hemoglobin A1c (HbA1c): 9.9 ± 1.3%] received 5‐h infusions of l ‐[3,3‐²H₂] cysteine and d ‐[6,6‐²H₂]glucose on two occasions, 3 wk apart, after a 10‐d oral supplementation with (i) N‐acetylcysteine (NAC, 30–45 mg/kg/d) or (ii) l ‐alanine, in randomized order, and with a 3‐wk ‘washout’ interim period. Blood glucose was maintained in the same hyperglycemic range on both infusion study days, using intravenous insulin. Glutathione fractional synthesis rate (FSR) was determined from ²H₂‐cysteine incorporation into blood glutathione. NAC supplementation failed to raise erythrocyte cysteine concentrations (23 ± 6 vs. 17 ± 1 μmol/L, p = 0.853) and did not alter erythrocyte glutathione concentrations (838 ± 106 vs. 793 ± 111 μmol/L, p = 0.220) or glutathione FSR (96 ± 20 vs. 89 ± 19%/d, p = 0.974). We conclude that in adolescents with poorly controlled T1DM, dietary cysteine supplementation alone cannot correct glutathione status. In the presence of relative insulinopenia, either higher amino acid doses or aggressive insulin therapy may be needed to achieve this goal. This would require further study.     

C-peptide in the classification of diabetes in children and adolescents

Ludvigsson J, Carlsson A, Forsander G, Ivarsson S, Kockum I, Lernmark Å, Lindblad B, Marcus C, Samuelsson U. C‐peptide in the classification of diabetes in children and adolescents. Aim: To report C‐peptide results in newly diagnosed patients and the relation to clinical diagnosis of diabetes. Methods: A nation‐wide cohort, the Better Diabetes Diagnosis study was used to determine serum C‐peptide at diagnosis in 2734 children and adolescents. Clinical data were collected at diagnosis and follow‐up. C‐peptide was determined in a validated and controlled time‐resolved fluoroimmunoassay. Results: The clinical classification of diabetes, before any information on human leukocyte antigen, islet autoantibodies, or C‐peptide was received, was type 1 diabetes (T1D) in 93%, type 2 diabetes (T2D) in 1.9%, maturity onset diabetes of the young (MODY) in 0.8%, secondary diabetes (0.6%), while 3.3% could not be classified. In a random, non‐fasting serum sample at diagnosis, 56% of the patients had a C‐peptide value >0.2 nmol/L. Children classified as T2D had the highest mean C‐peptide (1.83 + 1.23 nmol/L) followed by MODY (1.04 ± 0.71 nmol/L) and T1D (0.28 ± 0.25 nmol/L). Only 1/1037 children who had C‐peptide <0.2 nmol/L at diagnosis was classified with a type of diabetes other than T1D. Predictive value of C‐peptide >1.0 nmol/L for the classification of either T2D or MODY was 0.46 [confidence interval 0.37–0.58]. Conclusions: More than half of children with newly diagnosed diabetes have clinically important residual beta‐cell function. As the clinical diagnosis is not always straightforward, a random C‐peptide taken at diagnosis may help to classify diabetes. There is an obvious use for C‐peptide determinations to evaluate beta‐cell function in children with diabetes.     

The effectiveness of Internet-based blood glucose monitoring system on improving diabetes control in adolescents with type 1 diabetes

Landau Z, Mazor‐Aronovitch K, Boaz M, Blaychfeld‐Magnazi M, Graph‐Barel C, Levek‐Motola N, Pinhas‐Hamiel O. The effectiveness of Internet‐based blood glucose monitoring system on improving diabetes control in adolescents with type 1 diabetes. Objective: To determine whether the use of an Internet‐based blood glucose monitoring system could improve glycemic control in adolescents with type 1 diabetes mellitus (T1DM). Methods: In a randomized, controlled clinical trial, a total of 70 adolescent subjects with T1DM were recruited. Subjects randomized to the intervention group (n = 36) were instructed to submit their blood glucose levels weekly by Internet to the Diabetes Care Team during a period of 6 months. Subjects randomized to the control group (n = 34) did not submit results but were under routine follow‐up. Results: At baseline, patients were 15.1 ± 2.6 years of age with mean HbA1c of 8.3 ± 1.3%. At the 6‐month follow‐up period, no by‐group differences in change from baseline to end of treatment HbA1c levels were detected. In the intervention group, 12/36 did not submit blood glucose levels and were classified as non‐compliant. In a secondary exploratory analysis in which non‐compliant patients were omitted, HbA1c values in the compliant intervention group declined from 8.5 ± 1.7% at baseline to 8.2 ± 1.2% at 6 months, while in the control group HbA1c values increased from 8.2 ± 1.1 to 8.4 ± 1.1%, this difference did not reach statistical significance. Conclusions: An Internet‐based blood glucose monitoring system was not associated with improved glycemic control in adolescents with T1DM. Identification of a sub‐group of compliant subjects who may improve metabolic control by using this tool is needed.     

The prevalence of impaired fasting glucose and type 2 diabetes in a population‐based sample of overweight/obese children in the Middle East

Moadab MH, Kelishadi R, Hashemipour M, Amini M, Poursafa P. The prevalence of impaired fasting glucose and type 2 diabetes in a population‐based sample of overweight/obese children in the Middle East. Background: Type 2 diabetes mellitus (T2DM) and impaired fasting glucose (IFG) are increasing in young population who are facing an escalating trend of overweight. The aim of this study was to determine the prevalence of IFG and T2DM for the first time in a population‐based sample of Iranian obese children. Methods: This cross‐sectional, population‐based study was conducted in Isfahan, the second large city of Iran. Overall, 672 overweight and obese school students, selected from 7554 students, aged 6–19 yr, were screened for IFG and T2DM. Fasting plasma glucose (FPG) and lipid profile were measured in all participants. Oral glucose tolerance test and insulin level were measured in those children with IFG. Insulin resistance was defined as homeostasis model assessment for insulin resistance (HOMA‐IR) > 3.10. Results: Among the7554 students (48.7% boys and 51.3% girls) studied, 9.34% (n = 706) were overweight and 5.3% (n = 403) were obese. A number of 672 overweight and obese students including 302 (44.9%) boys and 370 (55.1%) girls, with a mean age of 12.8 ± 3.10 yr underwent biochemical work up. Overall, the prevalence of IFG was 4.61% (n = 31), the corresponding figure was 2% (n = 4) in the 6–10 yr age group, and 5% (n = 27) in those aged 10.1–19 yr. The prevalence of T2DM was 0.1% (n = 1; age, 18.00 yr). Impaired glucose tolerance and insulin resistance were detected in three and six participants with IFG, who consisted 0.4 and 0.8% of total obese and overweight students, respectively. Conclusions: Although the prevalence of T2DM is low in Iranian obese children, IFG is not uncommon. Preventive measures and screening of FPG should be considered for these children.     

Immunogenicity of different brands of human insulin and rapid‐acting insulin analogs in insulin‐naïve children with type 1 diabetes

Mianowska B, Szadkowska A, Pietrzak I, Zmys?owska A, Wegner O, Tomczonek J, Bodalski J, M?ynarski W. Immunogenicity of different brands of human insulin and rapid‐acting insulin analogs in insulin‐naïve children with type 1 diabetes. Aims: To determine (i) whether insulin preparations produced by three companies induce the same immune responses in insulin‐naïve children with type 1 diabetes (T1DM); (ii) if switching from human insulin to rapid‐acting insulin analogs influences this immune response; and (iii) if different insulin brands produce different clinical results during the first 2 yr after T1DM diagnosis. Methods: Insulin antibodies (IA) were measured for 140 patients aged 1.4–17.6 yr. Regular human insulin, neutral protamine Hagedorn (NPH) human insulin, and rapid‐acting insulin analogs (lispro or aspart) taken by the patients were produced by one of three companies: Bioton, Poland (A), Eli Lilly, USA (B) and NovoNordisk, Denmark (C). Results: Positive IA levels were found in 112 patients (80.0%) at baseline and in 137 (97.9%) at 6 and at 24 months after T1DM diagnosis. There was no difference in IA levels among patients taking insulin preparations produced by different companies at 6 months (mean ± SD, A 27.8 ± 15.7%; B 25.3 ± 15.4%; C 24.5 ± 14.2; p = 0.54) or at 24 months (A 25.6 ± 17.8%; B29.6 ± 17.0%; C 26.2 ± 17.0%; p = 0.52); HbA_1c and daily insulin dose did not differ significantly either. After 24 months, IA levels were similar for those who had used human insulin (mean ± SD, 25.7 ± 17.2%) and for those that had added rapid‐acting analogs (28.1 ± 17.3%, p = 0.41). Conclusions: Three brands of insulin preparations did not differ with respect to immunogenicity. Rapid‐acting analogs did not increase IA levels in patients previously treated with human insulin only. Patients using insulin preparations of different brands did not differ with respect to daily insulin dose or HbA_1c.     

Effect of recombinant human fibroblast growth factor‐2 on bone formation in rabbit mandibular distraction models using β‐tricalcium phosphate

This study was designed to evaluate the effect of recombinant human fibroblast growth factor‐2 (rhFGF‐2) on the amount and period of new bone formation in rabbit mandibular distraction models using β‐tricalcium phosphate (β‐TCP) as a bone graft substitute. Sixteen male Japanese White rabbits were divided into the following four experimental groups: 1, distraction alone; 2, distraction with β‐TCP granules; 3, distraction with rhFGF‐2 (25 µg/50 µL) injected into β‐TCP granules; and 4, distraction with rhFGF‐2 (100 µg/50 µL) injected into β‐TCP granules. The bones were harvested at 4 weeks after the operation and examined using soft radiography, micro‐computed tomography (micro‐CT), and peripheral quantitative computed tomography (pQCT). The dissected mandibles were stained using the Villanueva bone staining method, and the amount of new bone formed, bioresorption of β‐TCP, and new blood vessel formation were morphometrically calculated using bone histomorphometry. Radiopaque areas were observed more frequently in the distracted area of groups 3 and 4. Micro‐CT analysis revealed partial new bone formation in the central region of the distracted area in groups 3 and 4. pQCT analysis revealed increased bone mineral density in groups 3 and 4. Histomorphometric analysis revealed increased newly formed bone and blood vessel areas in groups 3 and 4. In group 4, the number of osteoclasts around the β‐TCP granules had significantly increased. The present findings suggested that the combined use of rhFGF‐2 and β‐TCP reduced the treatment period for distraction osteogenesis and accelerated the formation of a new high‐quality bone.     

Variables associated with severe hypoglycemia in children and adolescents with type 1 diabetes: a population‐based study

Blasetti A, Di Giulio C, Tocco AM, Verrotti A, Tumini S, Chiarelli F, Altobelli E. Variables associated with severe hypoglycemia in children and adolescents with type 1 diabetes: a population‐based study. Objective: Hypoglycemia remains a central problem in the management of type 1 diabetes mellitus (T1DM) and limits the achievement of good or normal glycemic control. The Diabetes Control and Complication Trial showed that intensive treatment of T1DM increased the risk of severe hypoglycemia (SH) when compared to conventional therapy. The aim of our study was to determine the incidence of SH and associated variables in a population of children and adolescents with T1DM. Research design and methods: We performed a 7.5‐yr prospective study enrolling 195 patients aged 13.9 ± 6.6 yr. The study was carried out by referring to the T1DM population‐based register in the Abruzzo region of Italy. The incidence of SH, defined as blood glucose levels <50 mg/dL (<2.77 mmol/L) associated with altered states of consciousness (including confusional state, seizures, and coma) was recorded. Glycated hemoglobin (HbA1c) percentage, insulin dose, insulin regimen, time since diagnosis, and age at onset were also recorded. Results: One hundred and thirty‐three severe hypoglycemic events occurred during the study period; the overall incidence was 9.4 episodes per 100 patient‐years. Significant predictors of hypoglycemia were diabetes duration >10 yr (p = 0.01), basal/bolus insulin ratio (ratio of daily basal insulin units to daily bolus insulin units) >0.8 (p = 0.01). No relationship was found between hypoglycemic episodes and HbA1c levels, daily insulin requirements, or insulin regimen. Conclusions: In these patients, a relatively low incidence of SH was recorded, without pronounced association with lower HbA1c or multiple daily injection insulin therapy. SH seems to be mainly related to management of diabetes. We believe that the main path to SH prevention is through patient and family education in the management of T1DM.     

Insulin resistance at diagnosis in Japanese children with type 2 diabetes mellitus

Background: Insulin resistance at diagnosis was investigated in Japanese children with type 2 diabetes mellitus (T2DM). Methods: A total of 160 children with T2DM were divided into groups on the basis of percent overweight at time of diagnosis: group A (n= 28), <20%; group B (n= 55), 20–39%; group C (n= 37), 40–59%; group D (n= 40), ≥60%. Indicators of insulin resistance at diagnosis were compared among the four patient groups, and also between the children with T2DM and the 201 age‐matched normal Japanese children. Results: There were no significant differences in plasma glucose (PG) levels among the four patient groups. The mean concentration of fasting plasma immunoreactive insulin (IRI) was significantly higher in group D than in groups A and B (39.2 µU/mL vs 16.2 µU/mL and 24.1 µU/mL, P < 0.05, respectively). The mean homeostasis model assessment (HOMA‐R) was significantly higher in group D than in all the other three groups (17.6 vs 7.8, 10.8 and 12.7, P < 0.05, respectively). The indicators HOMA‐R and fasting IRI were significantly higher in each diabetes group, even in non‐obese group A, than in normal children (P < 0.01, respectively). Conclusions: Japanese children with T2DM had insulin resistance at diagnosis regardless of percent overweight, and the degree of insulin resistance gradually increased with rise in percent overweight.     

Prevalence of low bone mass among adolescents with nontransfusion‐dependent hemoglobin E/β‐thalassemia and its relationship with anemia severity

1 Background

Low bone mass is common among adolescents with transfusion‐dependent β‐thalassemia despite adequate transfusion and iron chelation. However, there are few reports regarding bone mineral density (BMD) among adolescents with nontransfusion‐dependent thalassemia (NTDT). Indeed, only BMD data in patients with nontransfusion‐dependent (NTD) β‐thalassemia intermedia have been reported. No previous study has investigated BMD among adolescents with NTD hemoglobin (Hb) E/β‐thalassemia.

2 Objective

To determine the prevalence of low bone mass among adolescents with NTD Hb E/β‐thalassemia and factors relating to low bone mass.

3 Methods

We investigated BMD of lumbar spine (L2–L4; BMDLS) and total body (BMDTB), as measured by dual‐energy X‐ray absorptiometry, in 22 adolescents (aged 13.2–20 years) with NTD Hb E/β‐thalassemia.

4 Results

Low bone mass was found to be 18.2% and 22.7% at the lumbar spine (BMDLS Z‐score adjusted for bone age and height age) and 13.6% and 9.1% at the total body (BMDTB Z‐score adjusted for bone age and height age). Patients with mean Hb level <8 g/dl were more likely to have low bone mass (BMDLS and BMDTB Z‐scores adjusted for bone age) compared to those with Hb level ≥ 8 g/dl. Mean Hb level correlated with BMDLS and BMDTB Z‐scores adjusted for bone age.

5 Conclusion

We demonstrated that a low Hb level was associated with low bone mass among adolescents with NTD Hb E/β‐thalassemia. A significant proportion of low bone mass among these patients highlights the importance of appropriate management, including red cell transfusion, vitamin D and calcium supplementation for improved long‐term bone health.     

Preferences for type 2 diabetes health states among adolescents with or at risk of type 2 diabetes mellitus

Rhodes ET, Prosser LA, Lieu TA, Songer TJ, Ludwig DS, Laffel LM. Preferences for type 2 diabetes health states among adolescents with or at risk of type 2 diabetes mellitus. Objective: We evaluated how adolescents with or at risk of type 2 diabetes (T2DM) and their parent/guardians (parents) value health states associated with T2DM. Methods: We interviewed overweight/obese [Body Mass Index (BMI) ≥ 85th percentile], 12–18‐yr old adolescents with T2DM, prediabetes, or insulin resistance (IR) and a parent. The standard gamble (SG) method elicited preferences (utilities) for seven hypothetical T2DM health states reported on a scale from 0 (dead) to 1 (perfect health). Adolescent's current health was evaluated with the SG and Health Utilities Index (HUI). Results: There were 70 adolescents and 69 parents. Adolescents were 67.1% female and 15.5 ± 2.2 yr old; 30% had T2DM, 30% prediabetes, and 40% IR. Almost half (48.6%) had a BMI > 99th percentile. Parents (83% mothers) were 45.1 ± 7.3 yr old and 75% had at least some college/technical school education. Adolescents and parents rated T2DM with no complications treated with diet as most desirable [median (IQR); adolescent 0.72 (0.54, 0.98); parent 1.0 (0.88, 1.0)] and end‐stage renal disease as least desirable [adolescent 0.51 (0.31, 0.70); parent 0.80 (0.65, 0.94)]. However, adolescents' utilities were significantly lower (p ≤ 0.001) than parents for all health states assessed. Adolescents' assessments of their current health with the SG and HUI were not correlated. Conclusions: Adolescents with or at risk of T2DM rated treatments and sequelae of diabetes as significantly worse than their parents. These adolescent utilities should be considered in the evaluation of treatment strategies for youth with T2DM. Family‐based programs for T2DM must also be prepared to address conflicting preferences in order to promote shared decision‐making.