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Cardiac Hypertrophy, Heart Failure and Cardiomyopathy
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
Cardiac hypertrophy is reported in infants of diabetic mothers, in approximately 40% of infants with congenital hyperinsulinism, in 61% of infants with leprechaunism and in up to 60% of patients with congenital generalized lipodystrophy. The correct diagnosis is of importance since there is a large variation in prognoses and therapies to treat hyperinsulinemic diseases.
Pancreatectomy for hyperinsulinism
Published in Mark Davenport, James D. Geiger, Nigel J. Hall, Steven S. Rothenberg, Operative Pediatric Surgery, 2020
The first successful pancreatectomy in a child with HI was performed in 1934 by Evarts Ambrose Graham, an American surgeon working in St Louis, Missouri, USA. Searching for what was thought to be an adenoma, a subtotal pancreatectomy was done and the patient's hypoglycemia resolved. The operation was done 20 years before the first description of the disease by Irvine McQuarrie in 1954, and was initially termed “syndrome of idiopathic hypoglycemia of infants.” In the 1970s the disease was named “nesidioblastosis,” a term abandoned in the 1990s after advances in molecular diagnosis showed that it results from a variety of genetic derangements that alter the regulatory mechanisms of insulin secretion and glucose homeostasis. The term “congenital hyperinsulinism” is the current term for the family of diseases characterized as a heterogeneous genetic disorder of insulin metabolism that results in severe persistent neonatal hypoglycemia, often associated with neurological complications.
Endocrinology
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Mehul Dattani, Catherine Peters
If hypoglycaemia is proven, investigations should be performed to exclude other pathology (e.g. congenital hyperinsulinism, β-oxidation defect). If a reduced growth velocity is documented, investigations should be carried out to exclude coincident pathology (e.g. GHI). A karyotype may be indicated if a genetic syndrome is suspected.
From pathogenesis to novel therapies in primary hyperoxaluria
Published in Expert Opinion on Orphan Drugs, 2019
Gill Rumsby, Sally-Anne Hulton
RNAi of GO and LDHA are both under active investigation in human trials. The anticipated difficulties with these treatments include mode of administration, off-target effects, long term effects and the wider consequences of inactivating a normal enzyme. GO inhibition, only really applicable to PH1, would not appear to have any additional sequelae as patients have been described with natural deficiency of this enzyme, in two cases in conjunction with another, unrelated, pathological disorder [82,83] and in one case as an incidental finding in an apparently normal individual [84]. These individuals have markedly elevated urine glycolate, more than twice that typically seen in PH1, but that in itself is not thought to be of consequence as it is relatively soluble. In one case, however, urine oxalate was also found to be elevated [83]. It is not yet clear whether this was a side effect of treatment for the congenital hyperinsulinism also present in this patient. Phase 1 clinical trials are underway with Lumasiran (ALN-GO1) (NCT02706886) [85]. Preliminary results show reduction of urine oxalate with corresponding increase of urinary glycolate [86].
A unique allosteric insulin receptor monoclonal antibody that prevents hypoglycemia in the SUR-1−/− mouse model of KATP hyperinsulinism
Published in mAbs, 2018
Puja Patel, Lawrenshey Charles, John Corbin, Ira D. Goldfine, Kirk Johnson, Paul Rubin, Diva D. De León
Congenital hyperinsulinism (HI) is a genetic disorder of pancreatic β-cell function characterized by failure to suppress insulin secretion in the setting of hypoglycemia, resulting in severe hypoglycemia that can cause brain damage or death if inadequately treated. Loss-of-function mutations of the ATP-sensitive potassium channels (composed of two subunits: Kir6.2 and SUR-1) are responsible for the most common and severe form of hyperinsulinism (KATPHI). Children with KATPHI present shortly after birth with severe hypoglycemia and require glucose infusion rates up to four times higher than physiologic requirement to maintain normal plasma glucose concentrations.1 Diazoxide, the mainstay of medical therapy for hyperinsulinism, suppresses insulin by promoting the opening of the β-cell KATP channel and is ineffective in patients with KATPHI. Thus, most of these children require pancreatectomy to control the hypoglycemia. Children with a focal form of the disease can be cured by limited pancreatic resection, but for children with the diffuse form, a near-total pancreatectomy only partially controls the hypoglycemia2 and results in insulin-requiring diabetes later in life.3,4 There are no comprehensive published studies describing the natural history of the disease; however, there is evidence that the severity of the disease ameliorates with age.5 Age-related changes on insulin sensitivity may contribute to the amelioration of the hypoglycemia overtime.6 Thus, we hypothesize that modulating insulin responsiveness at the level of the insulin receptor (INSR) may be a novel mechanism for treating congenital hyperinsulinism.
Evaluating dasiglucagon as a treatment option for hypoglycemia in diabetes
Published in Expert Opinion on Pharmacotherapy, 2020
Shujuan Li, Ying Hu, Xueying Tan, Dongwei Wang, Jingbo Hu, Ping Zou, Li Wang
The liquid-stable dasiglucagon simultaneously opens the door for a wide clinical application. Dasiglucagon has been currently studied as a potential treatment for congenital hyperinsulinism (CHI). It is a rare disease in neonates and children with persistent hypoglycemia throughout childhood due to excessive insulin secretion caused by a genetic deficiency in pancreatic beta cells, with no effective treatment and potentially undergoing pancreatectomy. A continuous IV infusion of glucagon and a continuous subcutaneous infusion (CSI) glucagon via an insulin pump have been developed as the off-label manners for CHI treatment [33]. The former has been used to treat CHI in an emergency situation, while the latter has been usually employed when CHI is unresponsive to oral diazoxide or nifedipine, as well as s.c. octreotide, etc. CSI of glucagon also contributed to the reduction of glucose used to keep euglycemia in patients with CHI [34]. However, traditional glucagon has been associated with infusion line and CSI pump occlusions due to its instability with fibrils formation, increasing the risk of hypoglycemia occurrence and complexity in using CSI pump. Dasiglucagon represents a promising alternative to glucagon for CHI treatment without pump blockage and drug infusion interruption based on its established aqueous solubility and stability. It has also been granted as orphan drug designation for CHI treatment by the U.S. FDA and the European Commission in 2017 [35]. Two phase 3 trials are underway to evaluate the efficacy and safety of long-term dasiglucagon infusions delivered via a pump to prevent hypoglycemia in children with CHI [36,37]. Dasiglucagon potentially provides an effective non-surgical approach for CHI treatment.