Phenotypic Characterization of Congenital Hyperinsulinism Due to Novel Activating Glucokinase Mutations.

The importance of glucokinase (GK) in the regulation of insulin secretion has been highlighted by the phenotypes of individuals with activating and inactivating mutations in the glucokinase gene (GCK). Here we report 10 individuals with congenital hyperinsulinism (HI) caused by eight unique activating mutations of GCK. Six are novel and located near previously identified activating mutations sites. The first recognized episode of hypoglycemia in these patients occurred between birth and 24 years, and the severity of the phenotype was also variable. Mutant enzymes were expressed and purified for enzyme kinetics in vitro. Mutant enzymes had low glucose half-saturation concentration values and an increased enzyme activity index compared with wild-type GK. We performed functional evaluation of islets from the pancreata of three children with GCK-HI who required pancreatectomy. Basal insulin secretion in perifused GCK-HI islets was normal, and the response to glyburide was preserved. However, the threshold for glucose-stimulated insulin secretion in perifused glucokinase hyperinsulinism (GCK-HI) islets was decreased, and glucagon secretion was greatly suppressed. Our evaluation of novel GCK disease-associated mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response. ARTICLE HIGHLIGHTS: Our evaluation of six novel and two previously published activating GCK mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response. These studies provide insights into the pathophysiology of GCK-hyperinsulinism and the dual role of glucokinase in ß-cells and α-cells to regulate glucose homeostasis.

Effects of GLP-1 and GIP on Islet Function in Glucose-Intolerant, Pancreatic-Insufficient Cystic Fibrosis.

Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in cystic fibrosis (CF) is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (n = 16) or GIP (n = 16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions, with either incretin or placebo infused, in a randomized, double-blind, cross-over fashion. Another four adults with PI-CF and normal glucose tolerance (NGT) and four matched control participants without CF underwent similar assessment with GIP. In PI-CF with AGT, GLP-1 substantially augmented second-phase insulin secretion but without effect on the acute insulin response to GPA or the proinsulin secretory ratio (PISR), while GIP infusion did not enhance second-phase or GPA-induced insulin secretion but increased the PISR. GIP also did not enhance second-phase insulin in PI-CF with NGT but did so markedly in control participants without CF controls. These data indicate that GLP-1, but not GIP, augments glucose-dependent insulin secretion in PI-CF, supporting the likelihood that GLP-1 agonists could have therapeutic benefit in this population. Understanding loss of GIP's insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis.

Exendin-(9-39) Effects on Glucose and Insulin in Children With Congenital Hyperinsulinism During Fasting and During a Meal and a Protein Challenge.

OBJECTIVE: The aim of this study was to assess whether exendin-(9-39) will increase fasting and postprandial plasma glucose and decrease the incidence of hypoglycemia in children with hyperinsulinism (HI). RESEARCH DESIGN AND METHODS: This was an open-label, four-period crossover study. In periods 1 and 2, the effect of three different dosing regimens of exendin-(9-39) (group 1, 0.28 mg/kg; group 2, 0.44 mg/kg; group 3, 0.6 mg/kg) versus vehicle on fasting glucose was assessed in 16 children with HI. In periods 3 and 4, a subset of eight subjects received either vehicle or exendin-(9-39) (0.6 mg/kg) during a mixed-meal tolerance test (MMTT) and an oral protein tolerance test (OPTT). RESULTS: Treatment group 2 showed 20% (P = 0.037) increase in the area under the curve (AUC) of fasting glucose. A significant increase in AUC of glucose was also observed during the MMTT and OPTT; treatment with exendin-(9-39) resulted in 28% (P ≤ 0.001) and 30% (P = 0.01) increase in AUC of glucose, respectively. Fasting AUC of insulin decreased by 57% (P = 0.009) in group 3. In contrast, AUC of insulin was unchanged during the MMTT and almost twofold higher (P = 0.004) during the OPTT with exendin-(9-39) treatment. In comparison with vehicle, infusion of exendin-(9-39) resulted in significant reduction in likelihood of hypoglycemia in group 2, by 76% (P = 0.009), and in group 3, by 84% (P = 0.014). Administration of exendin-(9-39) during the OPTT resulted in 82% (P = 0.007) reduction in the likelihood of hypoglycemia. CONCLUSIONS: These results support a therapeutic potential of exendin-(9-39) to prevent fasting and protein-induced hypoglycemia in children with HI.

The Bihormonal Bionic Pancreas Improves Glycemic Control in Individuals With Hyperinsulinism and Postpancreatectomy Diabetes: A Pilot Study.

OBJECTIVE: To determine whether the bihormonal bionic pancreas (BHBP) improves glycemic control and reduces hypoglycemia in individuals with congenital hyperinsulinism (HI) and postpancreatectomy diabetes (PPD) compared with usual care (UC). RESEARCH DESIGN AND METHODS: Ten subjects with HI and PPD completed this open-label, crossover pilot study. Coprimary outcomes were mean glucose concentration and time with continuous glucose monitoring (CGM) glucose concentration <3.3 mmol/L. RESULTS: Mean (SD) CGM glucose concentration was 8.3 (0.7) mmol/L in the BHBP period versus 9 (1.8) mmol/L in the UC period (P = 0.13). Mean (SD) time with CGM glucose concentration <3.3 mmol/L was 0% (0.002) in the BHBP period vs. 1.3% (0.018) in the UC period (P = 0.11). CONCLUSIONS: Relative to UC, the BHBP resulted in comparable glycemic control in our population.

Reduced ß-Cell Secretory Capacity in Pancreatic-Insufficient, but Not Pancreatic-Sufficient, Cystic Fibrosis Despite Normal Glucose Tolerance.

Patients with pancreatic-insufficient cystic fibrosis (PI-CF) are at increased risk for developing diabetes. We determined ß-cell secretory capacity and insulin secretory rates from glucose-potentiated arginine and mixed-meal tolerance tests (MMTTs), respectively, in pancreatic-sufficient cystic fibrosis (PS-CF), PI-CF, and normal control subjects, all with normal glucose tolerance, in order to identify early pathophysiologic defects. Acute islet cell secretory responses were determined under fasting, 230 mg/dL, and 340 mg/dL hyperglycemia clamp conditions. PI-CF subjects had lower acute insulin, C-peptide, and glucagon responses compared with PS-CF and normal control subjects, indicating reduced ß-cell secretory capacity and α-cell function. Fasting proinsulin-to-C-peptide and proinsulin secretory ratios during glucose potentiation were higher in PI-CF, suggesting impaired proinsulin processing. In the first 30 min of the MMTT, insulin secretion was lower in PI-CF compared with PS-CF and normal control subjects, and glucagon-like peptide 1 and gastric inhibitory polypeptide were lower compared with PS-CF, and after 180 min, glucose was higher in PI-CF compared with normal control subjects. These findings indicate that despite "normal" glucose tolerance, adolescents and adults with PI-CF have impairments in functional islet mass and associated early-phase insulin secretion, which with decreased incretin responses likely leads to the early development of postprandial hyperglycemia in CF.

Use of Propranolol for Treating Hemangiomas in Infants with Previously Diagnosed Hypoglycemic Conditions.

Infantile hemangiomas (IHs) are the most common pediatric vascular tumors. They require therapy when they cause severe complications such as ulceration, amblyopia, or airway constriction. Propranolol is the only treatment that the U.S. Food and Drug Administration has approved for complicated IHs and has become first-line therapy for IHs that need to be treated. Older therapies such as systemic corticosteroids and surgery are now rarely used. Propranolol can have potentially serious adverse side effects, including bradycardia, hypotension, and hypoglycemia. There is sparse literature on the use of propranolol for IHs in patients with preexisting hypoglycemic conditions. We report three cases of infants with preexisting hypoglycemic conditions requiring diazoxide whose complicated hemangiomas were successfully and safely treated with oral propranolol.

Postoperative surveillance and detection of postprandial hypoglycemia after fundoplasty in children.

OBJECTIVE: To evaluate the prevalence of postprandial hypoglycemia (PPH) after fundoplasty after the initiation of a universal postoperative glucose surveillance plan in the neonatal intensive care unit (NICU). STUDY DESIGN: This was a retrospective chart review of children (newborn to 18 years) who underwent fundoplasty at The Children's Hospital of Philadelphia during the 2-year-period after the launch of a surveillance protocol in the NICU and other units. The rate of screening, frequency of PPH (postprandial blood glucose <60 mg/dL [3.3 mmol/L] on 2 occasions), frequency of postprandial hyperglycemia preceding PPH, timing of PPH presentation, and related symptoms were evaluated. RESULTS: A total of 285 children were included (n = 64 in the NICU; n = 221 in other units). Of the children screened in all units, 24.0% showed evidence of PPH, compared with 1.3% of unscreened children. Hyperglycemia preceded PPH in 67.7% (21/31) of all screened children. Within the NICU, most children had PPH within 1 week, but only 53.3% exhibited symptoms of dumping syndrome. CONCLUSIONS: This study supports the use of universal postoperative blood glucose surveillance in identifying PPH in children after fundoplasty. Earlier identification of PPH would lead to earlier treatment and minimize the effects of unidentified hypoglycemic events.