The study of human islets isolated from the pancreas of infants with congenital hyperinsulinism (HI) during the previous funding cycle has afforded us the unique opportunity to examine the islet phenotype in KATPHI integrating function, metabolomics, and genomics. Our findings revealed a complex pathophysiology in which the primary KATP channel defect leads to secondary consequences affecting gene expression, fuel metabolism, and both the triggering and amplifying pathways of insulin secretion. However, many critical questions for addressing unmet needs for the treatment of HI and for the understanding of normal physiological mechanisms of insulin secretion remain unanswered. We are particularly interested in examining the role of two ion channels that are differentially expressed in HI islets in the normal regulation of insulin secretion and their potential role in the pathophysiology of HI: TMEM16A, a Ca2+-activated Cl? channel encoded by ANO1 which is markedly upregulated in KATPHI islets, and Kv7.1, encoded by KCNQ1, whose expression is markedly decreased in islets isolated from the pancreases of children with Beckwith Wiedemann syndrome and HI. In preliminary studies we found that pharmacological modulation of these channels alters insulin secretion. Our overall hypothesis is that both Kv7.1 and TMEM16A play critical roles in the termination of insulin secretion by keeping ?-cell Vm hyperpolarized at rest and facilitating ?-cell Vm repolarization after stimulation. To test this hypothesis, we propose two aims to examine the role of Kv7.1 and TMEM16A in the regulation of insulin secretion in normal and HI islets. To accomplish these aims we will use genetic and pharmacological approaches to modulate the activity of these channels in normal and HI human and mouse islets. We will examine: 1) the contribution of TMEM16A and Kv7.1 to ?-cell Vm at resting and stimulated states; 2) the effect of TMEM16A and Kv7.1 activation and inhibition on cytosolic calcium and insulin secretion in normal human and mouse islets; 3) the effect of genetic inactivation of TMEM16A and Kv7.1 on glucose homeostasis in vivo and fuel-stimulated insulin secretion in vivo and in isolated islets using genetically modified mouse models. This study will expand our understanding of the pathophysiology of HI and will facilitate the identification of new genetic causes and potential new therapeutic targets for this devastating disease. The study may also have implications for the understanding of the mechanisms implicated in the progressive ?-cell failure that leads to type 2 diabetes.

Public Health Relevance

Relevance Congenital hyperinsulinism is a severe genetic disorder associated with high rates of neurodevelopmental impairment. This study will expand our understanding of the pathophysiology of hyperinsulinism and will facilitate the identification of new molecular mechanisms of disease and potential new therapeutic targets for this devastating disease. This study will improve our understanding of the mechanisms regulating insulin secretion in health and disease, which in turn, will be helpful for understanding the mechanisms implicated in the progressive -cell failure that leads to type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK098517-06A1
Application #
9885218
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Eggerman, Thomas L
Project Start
2013-09-15
Project End
2023-12-31
Budget Start
2020-03-01
Budget End
2020-12-31
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19146
Vajravelu, Mary Ellen; De León, Diva D (2018) Genetic characteristics of patients with congenital hyperinsulinism. Curr Opin Pediatr 30:568-575
Adzick, N Scott; De Leon, Diva D; States, Lisa J et al. (2018) Surgical treatment of congenital hyperinsulinism: Results from 500 pancreatectomies in neonates and children. J Pediatr Surg :
Vajravelu, Mary Ellen; Chai, Jinghua; Krock, Bryan et al. (2018) Congenital Hyperinsulinism and Hypopituitarism Attributable to a Mutation in FOXA2. J Clin Endocrinol Metab 103:1042-1047
Herrera, Adriana; Vajravelu, Mary Ellen; Givler, Stephanie et al. (2018) Prevalence of Adverse Events in Children With Congenital Hyperinsulinism Treated With Diazoxide. J Clin Endocrinol Metab 103:4365-4372
Tung, Joanna Yuet-Ling; Boodhansingh, Kara; Stanley, Charles A et al. (2018) Clinical heterogeneity of hyperinsulinism due to HNF1A and HNF4A mutations. Pediatr Diabetes 19:910-916
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Lu, Ming; Li, Changhong (2018) Nutrient sensing in pancreatic islets: lessons from congenital hyperinsulinism and monogenic diabetes. Ann N Y Acad Sci 1411:65-82
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Li, Changhong; Ackermann, Amanda M; Boodhansingh, Kara E et al. (2017) Functional and Metabolomic Consequences of KATP Channel Inactivation in Human Islets. Diabetes 66:1901-1913

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