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Bayesian borrowing analyses have an important role in the design and analysis of pediatric trials. This paper describes use of a prespecified Pharmacometrics Enhanced Bayesian Borrowing (PEBB) analysis that was conducted to overcome an expectation for reduced statistical power in the pediatric DINAMO trial due to a greater than expected variability in the primary endpoint. The DINAMO trial assessed the efficacy and safety of an empagliflozin dosing regimen versus placebo and linagliptin versus placebo on glycemic control (change in HbA1c over 26 weeks) in young people with type 2 diabetes (T2D). Previously fitted pharmacokinetic and exposure-response models for empagliflozin and linagliptin based on available historical data in adult and pediatric patients with T2D were used to simulate participant data and derive the informative component of a Bayesian robust mixture prior distribution. External experts and representatives from the U.S. Food and Drug Administration provided recommendations to determine the effective sample size of the prior and the weight of the informative prior component. Separate exposure response-based Bayesian borrowing analyses for empagliflozin and linagliptin showed posterior mean and 95% credible intervals that were consistent with the trial results. Sensitivity analyses with a full range of alternative weights were also performed. The use of PEBB in this analysis combined advantages of mechanistic modeling of pharmacometric differences between adults and young people with T2D, with advantages of partial extrapolation through Bayesian dynamic borrowing. Our findings suggest that the described PEBB approach is a promising option to optimize the power for future pediatric trials., (© 2024. The Author(s).)

Background: The incidence of type 2 diabetes in young people is increasing, but treatments remain limited. We aimed to assess the efficacy and safety of an empagliflozin dosing regimen versus placebo and linagliptin versus placebo on glycaemic control in young people with type 2 diabetes., Methods: In this double-blind, placebo-controlled trial done in 108 centres in 15 countries, participants with type 2 diabetes (aged 10-17 years; HbA 1c 6·5-10·5% [48-91 mmol/mol]) who had been previously treated with metformin or insulin were randomly assigned (1:1:1) to oral empagliflozin 10 mg, oral linagliptin 5 mg, or placebo. Participants in the empagliflozin group who did not have HbA 1c below 7·0% (<53 mmol/mol) by week 12 underwent a second double-blinded randomisation (1:1) at week 14, either remaining on 10 mg or increasing to 25 mg. Participants in the placebo group were randomly reassigned (1:1:1) in a double-blinded manner at week 26 to linagliptin 5 mg or one of the empagliflozin doses (10 mg or 25 mg). Investigators were masked throughout the trial and received assignments of blinded medication kits through interactive response technology for all participants at the initial randomisation and for the re-randomisations at weeks 14 and 26. The primary outcome was change from baseline in HbA 1c at 26 weeks. For empagliflozin, results were based on a pooled analysis for all participants on empagliflozin. Safety was assessed until week 52. This trial is registered with ClinicalTrials.gov, NCT03429543., Findings: Between April 26, 2018, and May 26, 2022, of 262 screened participants, 158 (60%) were randomly assigned to treatment (53 [34%] to placebo, 52 [33%] to empagliflozin 10 mg, and 53 [34%] to linagliptin). For the primary outcome, the adjusted mean HbA 1c change from baseline at week 26 was -0·84% [-9·2 mmol/mol] in the empagliflozin pooled group versus placebo (95% CI -1·50 to -0·19 [-16·4 to -2·1]; p=0·012); the corresponding change from baseline for linagliptin versus placebo was -0·34% [-3·8 mmol/mol; 95% CI -0·99 to 0·30 [-10·8 to 3·3]; p=0·29). Adverse events occurred in 34 (64%) participants in the placebo group, 40 (77%) in the empagliflozin pooled group, and 37 (71%) in the linagliptin group, up to week 26. Of these, severe adverse events were reported in two (4%) participants in the placebo group, one (2%) in the empagliflozin pooled group, and one (2%) in the linagliptin group. Hypoglycaemia was the most frequently reported adverse event with higher rates for those on active drug treatment compared with placebo. No severe hypoglycaemia cases were reported., Interpretation: Empagliflozin provided clinically relevant placebo-corrected reductions in HbA 1c , whereas linagliptin did not, and might offer a new treatment option for young people with type 2 diabetes., Funding: The Boehringer Ingelheim and Eli Lilly and Company Alliance., Competing Interests: Declaration of interests LML has received consulting fees from Provention, Dompe, Medtronic, Roche, Janssen, Eli Lilly, Dexcom, Novo Nordisk, and Vertex. TD has received speaker, advisory panel, or research support from AstraZeneca, Bayer, Boehringer Ingelheim, Dexcom, Eli Lilly, Insulet, Lifescan, Medtronic, Novo Nordisk, Roche, and Sanofi; and is a shareholder of DreaMed Diabetes. WVT has received consulting fees from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, and Medtronic Diabetes. SW has served on a data safety monitoring board for the National Institute of Diabetes and Digestive and Kidney Diseases/US National Institutes of Health; and served on an advisory panel or board for Roche Diagnostics and Medtronic MiniMed. PZ has consulted for Boehringer Ingelheim, Merck, Eli Lilly, Janssen, I-ACT, and Novo Nordisk. DN and JM are employees of Boehringer Ingelheim. GJK declares no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

In clinical trials, sodium-glucose co-transporter (SGLT) inhibitor use as adjunct to insulin therapy in type 1 diabetes (T1D) provides glucometabolic benefits while diabetic ketoacidosis risk is increased. The SGLT2 inhibitor empagliflozin was evaluated in two phase III trials: EASE-2 and EASE-3. A low, 2.5-mg dose was included in EASE-3 only. As the efficacy of higher empagliflozin doses (i.e., 10 and 25 mg) in T1D has been established in EASE-2 and EASE-3, a modeling and simulation approach was used to generate additional supportive evidence on efficacy for the 2.5-mg dose. We present the methodology behind the development and validation of two modeling and simulation frameworks: M-EASE-1, a semi-mechanistic model integrating information on insulin, glucose, and glycated hemoglobin; and M-EASE-2, a descriptive model informed by prior information. Both models were developed independently of data from EASE-3. Simulations based on these models assessed efficacy in untested clinical trial scenarios. In this manner, the models provide supportive evidence for efficacy of low-dose empagliflozin 2.5 mg in patients with T1D, illustrating how pharmacometric analyses can support efficacy assessments in the context of limited data.

Extrapolation from adults to youth with type 2 diabetes (T2D) is challenged by differences in disease progression and manifestation. This manuscript presents the results of a mock-team workshop focused on examining the typical team-based decision process used to propose a pediatric development plan for T2D addressing the viability of extrapolation. The workshop was held at the American Society for Clinical Pharmacology and Therapeutics (ASCPT) in Orlando, Florida on March 21, 2018., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Aim: To confirm the observed reduction in HbA1c for the 2.5 mg dose in EASE-3 by modelling and simulation analyses., Materials and Methods: Independent of data from EASE-3 that tested 2.5 mg, we simulated the effect of a 2.5 mg dose through patient-level, exposure-response modelling in the EASE-2 clinical study. A primary semi-mechanistic model evaluated efficacy considering clinical insulin dose adjustments made after treatment initiation that potentially limited HbA1c reductions. The model was informed by pharmacokinetic, insulin dose, mean daily glucose and HbA1c data, and was verified by comparing the simulations with the observed HbA1c change in EASE-3. One of two empagliflozin phase 3 trials in type 1 diabetes (EASE-3 but not EASE-2) included a lower 2.5 mg dose. A placebo-corrected HbA1c reduction of 0.28% was demonstrated without the increased risk of diabetic ketoacidosis observed at higher doses (10 mg and 25 mg). Since only one trial included the lower dose, we aimed to confirm the observed reduction in HbA1c for the 2.5 mg dose by modelling and simulation analyses., Results: The simulated 26-week mean HbA1c change was -0.41% without insulin dose adjustment and -0.29% at 26 weeks with insulin dose adjustment. A simplified (descriptive) model excluding insulin dose and mean daily glucose confirmed the -0.29% HbA1c change that would have been observed had the EASE-2 population received a 2.5 mg dose for 26/52 weeks., Conclusions: The HbA1c benefit of low-dose empagliflozin directly observed in the EASE-3 trial was confirmed by two modelling and simulation approaches., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objective: While sodium-glucose cotransporter inhibitor (SGLTi) therapy has been evaluated in type 1 diabetes (T1D) trials, patient reactions to benefits and risks are unknown. Using established methodology, we evaluated patient preferences for different adjunct-to-insulin therapy options in T1D., Research Design and Methods: An online survey, completed by 701 respondents with T1D (231 U.S., 242 Canada, and 228 Germany), used conjoint analysis to present six hypothetical, masked, pairwise drug profile choices composed of different benefit-risk attributes and effect ranges. Data used in analyses were derived from actual phase 3 trials of a low-dose SGLTi (comparable to oral empagliflozin 2.5 mg q.d.), a high-dose SGLTi (comparable to oral sotagliflozin 400 mg q.d.), and an available adjunct-to-insulin therapy (comparable to subcutaneous pramlintide 60 μg t.i.d.)., Results: Conjoint analysis identified diabetic ketoacidosis risk as most important to patients (23% relative score; z test, P < 0.05); ranked second were HbA 1c reduction (14%), risk of severe hypoglycemia (13%), oral versus injectable treatment (12%), and risk of genital infection (12%). Next was risk of nausea (11%), followed by weight reduction (8%) and the risk of diarrhea (7%). A low-dose SGLTi drug profile was identified by conjoint analysis as the top patient preference (83% of participants; z test, P < 0.05) versus high-dose SGLTi (8%) or pramlintide (9%). Separate from conjoint analysis, when respondents were asked to choose their preferred adjunct-to-insulin therapy (masked to drug name/dose), 69%, 17%, 6%, and 9% of respondents chose low-dose SGLTi, high-dose SGLTi, pramlintide, and insulin therapy alone, respectively., Conclusions: Low-dose SGLTi profile was the favored adjunct-to-insulin therapy by persons with T1D., (© 2019 by the American Diabetes Association.)

Objective: To evaluate the safety and efficacy of empagliflozin 10- and 25-mg doses plus a unique lower dose (2.5 mg) as adjunct to intensified insulin in patients with type 1 diabetes (T1D)., Research Design and Methods: The EASE (Empagliflozin as Adjunctive to inSulin thErapy) program ( N = 1,707) included two double-blind, placebo-controlled phase 3 trials: EASE-2 with empagliflozin 10 mg ( n = 243), 25 mg ( n = 244), and placebo ( n = 243), 52-week treatment; and EASE-3 with empagliflozin 2.5 mg ( n = 241), 10 mg ( n = 248), 25 mg ( n = 245), and placebo ( n = 241), 26-week treatment. Together they evaluated empagliflozin 10 mg and 25 mg, doses currently approved in treatment of type 2 diabetes, and additionally 2.5 mg on 26-week change in glycated hemoglobin (primary end point) and weight, glucose time-in-range (>70 to ≤180 mg/dL), insulin dose, blood pressure, and hypoglycemia., Results: The observed largest mean placebo-subtracted glycated hemoglobin reductions were -0.28% (95% CI -0.42, -0.15) for 2.5 mg, -0.54% (-0.65, -0.42) for 10 mg, and -0.53% (-0.65, -0.42) for 25 mg (all P < 0.0001). Empagliflozin 2.5/10/25 mg doses, respectively, reduced mean weight by -1.8/-3.0/-3.4 kg (all P < 0.0001); increased glucose time-in-range by +1.0/+2.9/+3.1 h/day ( P < 0.0001 for 10 and 25 mg); lowered total daily insulin dose by -6.4/-13.3/-12.7% (all P < 0.0001); and decreased systolic blood pressure by -2.1/-3.9/-3.7 mmHg (all P < 0.05). Genital infections occurred more frequently on empagliflozin. Adjudicated diabetic ketoacidosis occurred more with empagliflozin 10 mg (4.3%) and 25 mg (3.3%) but was comparable between empagliflozin 2.5 mg (0.8%) and placebo (1.2%). Severe hypoglycemia was rare and frequency was similar between empagliflozin and placebo., Conclusions: Empagliflozin improved glycemic control and weight in T1D without increasing hypoglycemia. Ketoacidosis rate was comparable between empagliflozin 2.5 mg and placebo but increased with 10 mg and 25 mg. Ketone monitoring for early ketoacidosis detection and intervention and lower empagliflozin doses may help to reduce this risk., (© 2018 by the American Diabetes Association.)

Aims: This phase 2, double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov NCT02702011) with 4 sites in Japan investigated the pharmacodynamics (PD), pharmacokinetics (PK) and safety profile of empagliflozin in Japanese participants with type 1 diabetes mellitus (T1DM) as adjunctive therapy to insulin., Materials and Methods: Participants using multiple daily injections of insulin for ≥12 months, with HbA1c of 7.5%-10.0%, entered a 2-week, open-label, placebo run-in period, followed by a 4-week, double-blind period during which participants were randomized 1:1:1:1 to receive empagliflozin 2.5 mg (n = 13), empagliflozin 10 mg (n = 12), empagliflozin 25 mg (n = 12) or placebo (n = 11). The primary objective was to assess the effect of empagliflozin vs placebo on urinary glucose excretion (UGE) after 7 days of treatment., Results: PD: Empagliflozin resulted in a dose-dependent significant increase in 24-hour UGE compared with placebo (UGE placebo-corrected mean [95% confidence interval] change from baseline: 2.5 mg, 65.10 [43.29, 86.90] g/24 h; 10 mg, 81.19 [58.80, 103.58] g/24 h; 25 mg, 98.11 [75.91, 120.31] g/24 h). After 4 weeks of treatment, UGE increase was associated with improved glycaemic control, reduced body weight and decreased insulin needs. Empagliflozin treatment also resulted in dose-dependent increases in serum ketone bodies and free fatty acids. PK: Plasma empagliflozin levels increased in a dose-dependent manner and peaked at 1.5 hours. In this short study, empagliflozin was well tolerated, with no increase in rate of hypoglycaemia and no diabetic ketoacidosis events reported., Conclusions: Based on this short-duration phase 2 study, the PK/PD profile of empagliflozin in Japanese participants with T1DM is comparable to that of non-Japanese participants., (© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objective: To identify the dose of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin in pediatric patients with type 2 diabetes (T2D)., Methods: Double-blind, randomized, controlled parallel group study comparing linagliptin 1 and 5 mg once daily, with placebo in 39 patients with T2D aged 10 to below 18 years. The primary efficacy endpoint was the change from baseline in glycated hemoglobin (HbA1c) after 12 weeks of treatment. The key pharmacodynamic endpoint was DPP-4 inhibition during steady-state., Results: Compared to placebo, there was a dose-dependent reduction in mean HbA1c of 0.48% and 0.63% with linagliptin 1 and 5 mg, respectively, associated with corresponding declines in mean fasting plasma glucose (FPG) of 5.6 and 34.2 mg/dL. Median DPP-4 inhibition was 38% with linagliptin 1 mg and 79% with linagliptin 5 mg. Geometric mean trough levels of linagliptin were 3.80 and 7.42 nmol/L in the 1 and 5 mg groups, respectively; levels that were slightly higher than in adult patients with T2D that were most likely caused by higher plasma DPP-4 concentrations in the study population. There were no drug-related adverse events during treatment with either dose of linagliptin., Conclusions: Linagliptin was well tolerated and induced dose-dependent DPP-4 inhibition that was accompanied by corresponding reductions in HbA1c and FPG levels in young people with T2D. The results are consistent with the clinical efficacy and safety profile that have been reported for linagliptin in adult patients with T2D, favoring linagliptin 5 mg over 1 mg., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Sodium glucose cotransporter 2 inhibitors increase urinary glucose excretion (UGE) by lowering the renal threshold for glucose (RT G ). We aimed to quantify the effect of the sodium glucose cotransporter inhibitor empagliflozin on renal glucose reabsorption in patients with type 1 diabetes mellitus (T1DM) using a mechanistic population pharmacokinetic-pharmacodynamic (PK-PD) model and to compare results with analyses in patients with type 2 diabetes mellitus (T2DM). The PK-PD model was developed using data from a randomized phase 2 study in which patients with T1DM received oral once-daily empagliflozin 2.5 mg, empagliflozin 10 mg, empagliflozin 25 mg, or placebo as an adjunct to insulin. The model assumed that UGE was dependent on plasma glucose and renal function and that empagliflozin lowered RT G . The final model was evaluated using visual predictive checks and found to be consistent with observed data. Calculated RT G with placebo was 181 mg/dL, and with empagliflozin (steady state) 1 mg and 2.5 mg was 53.4 mg/dL and 12.5 mg/dL, respectively. Empagliflozin 10 mg and 25 mg yielded negative RT G values, implying RT G was reduced to a negligible value. Although estimated PK-PD parameters were generally comparable between patients with T1DM and patients with T2DM, slight differences were evident, leading to lower RT G and higher UGE in patients with T1DM compared with patients with T2DM. In conclusion, the model provided a reasonable description of UGE in response to administration of empagliflozin and placebo in patients with T1DM., (© 2017, The American College of Clinical Pharmacology.)

Background: Up to now, only limited data on long-term medical treatment in congenital hyperinsulinism (CHI) is available. Moreover, most of the drugs used in CHI are therefore not approved. We aimed to assemble more objective information on medical treatment in CHI with regard to type and duration, dosage as well as side effects., Methods: We searched MEDLINE (from 1947) and EMBASE (from 1988) using the OVID interface for relevant data to evaluate medical treatment in a large cohort of patients with CHI from different clinical centers. Randomized, controlled trials were not available. We evaluated case reports and case series. No language restrictions were made., Results: A total number of 619 patients were medically treated and information regarding conservative treatment was available. Drugs used were diazoxide (in 84% of patients), somatostatin analogues (16%), calcium channel antagonists (4%) and glucagon (1%). Mean dose of diazoxide was 12.5 (±4.3) mg/kg ⋅ d (range 2-60 mg/kg ⋅ d), mean duration of diazoxide treatment until remission was 57 months. Side effects of diazoxide were usually not severe. The causal relation between diazoxide and severe side effects, e.g. heart failure (3.7%) remains doubtful. Mean dose of octreotide was 14.9 (±7.5) μg/kg ⋅ d (range 2.3-50 μg/kg ⋅ d), of lanreotide 67.3 (±39.8) mg ⋅ month (range 10-120 mg ⋅ month). Mean duration of treatment with somatostatin analogues until remission was 49 months. Frequent side effects included tachyphylaxis and mild gastrointestinal symptoms. The risk of persistent growth deceleration was low (<5%)., Conclusions: Severe side effects are rare and a causal relation remains disputable. We conclude that long-term conservative treatment of CHI is feasible.

In the nervous system, NMDA receptors (NMDARs) participate in neurotransmission and modulate the viability of neurons. In contrast, little is known about the role of NMDARs in pancreatic islets and the insulin-secreting beta cells whose functional impairment contributes to diabetes mellitus. Here we found that inhibition of NMDARs in mouse and human islets enhanced their glucose-stimulated insulin secretion (GSIS) and survival of islet cells. Further, NMDAR inhibition prolonged the amount of time that glucose-stimulated beta cells spent in a depolarized state with high cytosolic Ca(2+) concentrations. We also noticed that, in vivo, the NMDAR antagonist dextromethorphan (DXM) enhanced glucose tolerance in mice, and that in vitro dextrorphan, the main metabolite of DXM, amplified the stimulatory effect of exendin-4 on GSIS. In a mouse model of type 2 diabetes mellitus (T2DM), long-term treatment with DXM improved islet insulin content, islet cell mass and blood glucose control. Further, in a small clinical trial we found that individuals with T2DM treated with DXM showed enhanced serum insulin concentrations and glucose tolerance. Our data highlight the possibility that antagonists of NMDARs may provide a useful adjunct treatment for diabetes.

Background: Medical treatment is a substantial therapeutic measure to achieve glycemic control and prevent hypoglycemic brain damage without surgery in patients with congenital hyperinsulinism (CHI). However, only few drugs are available and even fewer are approved as a medical therapy to maintain normal blood glucose levels. The established therapies are demanding for caregivers and complicated by different side effects such as gastrointestinal symptoms, hypertrichosis, and obesity. Therefore, it is important to develop new strategies to improve blood glucose control., Methods: We report the use of the very-long-acting somatostatin analogue lanreotide autogel in 6 patients with CHI over a mean duration of 40.8 months. Blood glucose levels before and after the start and dosage titration of lanreotide in these patients are compared., Results: In 3 of 6 patients, switching to lanreotide raised mean blood glucose levels and reduced individually as well as overall the risk for hypoglycemic episodes (odds ratio 0.38) significantly., Conclusion: Lanreotide autogel can be used as an alternative pharmacological treatment and may be beneficial in conservatively treated patients with CHI., (Copyright © 2012 S. Karger AG, Basel.)

Context: Worldwide, only nine cases of revealing slipped capital femoral epiphysis (SCFE) associated with primary hyperparathyroidism (PHP) have been reported., Case Illustration: This study included adolescent subjects with the described association, the clinical course, and exhibiting the leading pathogeneses., Methods: Here, we reviewed all known cases and developed an effective approach to the management of SCFE and PHP., Results: In cases of emergency, SCFE fixation is primarily done regardless of any preexistent hypercalcemia due to PHP and followed by parathyroidectomy as soon as possible. In cases of mild and moderate hypercalcemia, whether SCFE fixation is followed by parathyroidectomy and vice versa or resolved during a single operating session depends on manifest side effects due to hyercalcemia. Patients with severe hypercalcema should undergo urgent parathyroidectomy, followed by immediate orthopedic surgery, even as a simultaneous procedure. This is to avoid onset of hypercalcemic side effects or worsening of preexisting side manifestations resulting from hypercalcemia., Conclusion: Our report demonstrates that SCFE presenting with hypercalcemia, with signs of low bone density, or in atypical age deserves further workup for secondary causes. In addition, the newly developed systematic approach toward achieving an effective, efficient management should help to improve the patients' long-term outcome.

Context: Worldwide, only nine cases of slipped capital femoral epiphysis (SCFE) associated with primary hyperparathyroidism (PHP) have been reported., Case Illustration: This is a report on adolescent subjects with SCFE associated with PHP exhibiting the leading pathogenesis and clinical course., Methods: Here, we reviewed all known cases and developed an effective approach to the management of SCFE and PHP., Results: In cases of emergency, SCFE fixation is primarily done regardless of any preexistent hypercalcemia due to PHP and is followed by parathyroidectomy as soon as possible. In cases of mild and moderate hypercalcemia, whether SCFE fixation is followed by parathyroidectomy and vice versa or resolved during a single operating session depends on the side effects of hypercalcemia. Severely hypercalcemic patients should undergo urgent parathyroidectomy followed by immediate orthopedic surgery or even as a simultaneous procedure. This is to avoid onset of hypercalcemic side effects or worsening of preexisting side manifestations resulting from hypercalcemia., Conclusion: Our report demonstrates that SCFE patients presenting with hypercalcemia, signs of low bone density, or with non-typical age of onset deserve further workup for secondary causes. In addition, the newly developed systematic approach toward achieving an effective, efficient management should help in improving the patients' long-term outcome.

Rare forms of congenital hyperinsulinism (CHI) are caused by mutations in GLUD1 (encoding glutamate dehydrogenase), GCK (encoding glucokinase), HADH (encoding for L-3-hydroxyacyl-CoA dehydrogenase), SLC16A1 (encoding the monocarboxylat transporter 1), HNF4A (encoding hepatocyte nuclear factor 4α) or UCP2 (encoding mitochondrial uncoupling protein 2). The clinical presentation is very heterogeneous in regards to age of onset, severity, and manner of symptoms, as well as the response to medical treatment. Special individual characteristics have to be accounted in diagnosis and treatment. Diazoxide is the first-line drug for the rare forms of CHI for long-term treatment but is not entirely effective in some of these rarer defects (GCK, MCT1). The use of diazoxide is often limited by side effects and the use of octreotide as second-line drug has to be considered. A near-total pancreatectomy is only reserved for patients with diffuse disease and resistance to medical treatment as a last resort. Patients with CHI should be managed by centers with a highly experienced team in diagnostic work-up and treatment of this disease., (2011 Elsevier Inc. All rights reserved.)

Advances in imaging and surgical techniques allow a complete cure for children with focal-type congenital hyperinsulinism (CHI). In contrast, management of diffuse-type CHI remains a matter of controversy. To prevent hypoglycemic brain damage, extensive surgery has been recommended in the past, resulting in diabetes. On the basis of 2 data sets of patients with congenital hyperinsulinism, the German registry for CHI with 235 patients (ages 1 day to 19 years) and the diabetes treatment register (Diabetes Patienten-Verlaufsdokumentationssystem initiative), a follow-up study was initiated for diabetes mellitus and the intellectual and physical development as well as motor function. In our ongoing study, we investigated 20 patients with CHI (12 male, mean ages 9.9 years). Six of 20 patients had undergone subtotal pancreatectomy. In early infantile development (0-3 years) we observed a trend to motor and speech delay. In early childhood (2.5-7 years) there appeared a trend to an advantage of results of nonverbal tasks compared with verbal tasks. Before 1990 most patients (∼75%) were treated by subtotal pancreatectomy; since 2000, a more conservative approach is obvious (4/68). All patients with diabetes (n = 25) developed the condition after undergoing subtotal pancreatectomy. No spontaneous manifestation of diabetes was noted before adulthood. There was a wide range of age (0-17.7 years) at manifestation indicating a long period during which glucose tolerance is compensated. Compared with >40.000 children with type 1 diabetes mellitus from the Diabetes Patienten-Verlaufsdokumentationssystem registry, we found significant differences with a tendency for being overweight as well as small stature. Mean daily insulin dose and HbA1c was comparable in both groups., (2011 Elsevier Inc. All rights reserved.)

A severe rare complication in patients with branched-chain organic acidurias (BCOA) is pancreatitis with a limited number of patients published so far. Here, we report on a patient with methylmalonic aciduria (MMA) who developed chronic pancreatitis after several episodes of acute pancreatitis. In addition, an overview is given about some previous published cases with BCOA who developed pancreatitis in the course of the disease. In half of the published MMA patients with pancreatitis, an acute pancreatitis was reported while the rest suffered from a chronic form of this disease. Acute pancreatitis in BCOA patients can clinically present in the context of recurrent vomiting and an impaired general physical condition even without typical signs of pancreatitis. Any form of pancreatitis should be ruled out in the assessment of acutely ill patients with BCOA.

Background: Low-glycemic index (GI) diet vs. high-GI diet improves glycemic control, but it is not clear whether a low-GI diet is superior to an optimized mixed diet (OMD)., Methods: This was a 12-week parallel-group pilot-trial including 17 children with type 1 diabetes. A separate dietary education into the allocated diet (OMD vs. low-GI) was performed. Nutrition was recorded by means of a three-day dietary record., Objectives: The primary objective was to determine the macro- and micronutrient composition of the different diets, the secondary objective was to determine the short-term effect on HbA(1c) levels., Results: In the low-GI group carbohydrate intake decreased, fat intake increased by trend. In the OMD group fat and energy intake decreased. No changes of HbA(1c) levels between the groups were observed., Conclusion: OMD could have positive effects in overweight and obese diabetic children, since a reduction in fat and energy intake can be achieved. The findings of this pilot-trial suggest that OMD could be superior to a low-GI diet.