Table 1.
Genetic defects leading to dysregulated beta cell insulin secretion.
| Mechanism affected | Genes | Impact of genetic defect | Type of disease | References |
|---|---|---|---|---|
| Glucose import and metabolism | GCK | Reduced or increased glucokinase activity results in abnormal glycolytic flux, ATP generation, and insulin secretion | ND, MODY, T2D, CHI | (18, 19, 49) |
| G6PC2 | Loss of function mutations are associated with reduced fasting glycemia | T2D | (50) | |
| SLC2A2 (GLUT2) | Loss of function mutations result in impaired glucose uptake | ND, T2D | (11, 51) | |
| HK1 | Abnormal silencing of HK1 in beta-cells results in increased glycolytic flux, ATP generation and insulin secretion | CHI | (52) | |
| SLC16A1 (MCT1) | Promoter mutations impair SLC16A1 silencing in beta-cells, resulting in abnormal pyruvate uptake, increased ATP generation, and insulin secretion | CHI | (53) | |
| GLUD1 | Gain of function mutations result in increased entrance of glutamate in TCA cycle, increased ATP generation, and insulin secretion | CHI | (54) | |
| HADH | Loss of function mutations result in abnormal activation of GLUD1, increased glutamate into TCA, ATP generation, and insulin secretion | CHI | (55, 56) | |
| UCP2 | Gain or loss of function mutations alter the mitochondrial uncoupling activity of UCP2, resulting in abnormal ATP generation and insulin secretion | T2D, CHI | (57, 58) | |
| mtDNA | Mitochondrial DNA mutations impair oxidative phosphorylation, ATP generation, and insulin secretion | – | (59) | |
| Membrane depolarization | KCNJ11 | Gain or loss of function mutations result in abnormal closure or opening of the channel, altered membrane depolarization, and insulin secretion | ND, MODY, T2D, CHI | (55, 60–62) |
| ABCC8 | Gain or loss of function mutations result in abnormal closure or opening of the channel, altered membrane depolarization, and insulin secretion | ND, MODY, T2D, CHI | (14, 15, 55, 63, 64) | |
| KCNQ1 | Genetic variants in this locus are associated with T2D risk. | T2D | (11, 65) | |
| Membrane receptors | GLP1R | Genetic variants in this locus are associated with lower fasting glucose levels. Altered GLP-1 signaling affects amplification of insulin secretion. | T2D | (66) |
| GIPR | Genetic variants associated with reduced GIP signaling, impair incretin-mediated amplification of insulin secretion. | T2D | (67) | |
| MTNR1B | A genetic variant increasing melatonin signaling lowers cAMP levels, inhibiting insulin secretion. | T2D | (68) | |
| Insulin synthesis and secretion | INS | Loss of function mutations disrupt INS protein synthesis, folding, transport or bioactivity. | ND, MODY, T2D | (11, 69) |
| SLC30A8 (ZNT8) | Different coding genetic variants increase risk or protect against T2D. | T2D | (70–72) | |
| ADCY5 | Non-coding genetic variant reduces ADCY5 expression, which couples glucose to cAMP generation, increasing T2D risk. | T2D | (73, 74) | |
| ER homeostasis | WFS1 | Loss of function mutations lead to elevated ER stress and beta cell dysfunction. | ND, T2D | (75) |
| CDKAL1 | Loss of function mutations induce beta cell ER stress and hypersensitivity to glucotoxicity and lipotoxicity. | T2D | (76) | |
| THADA | Coding genetic variants associated with increased T2D risk. | T2D | (77) | |
| MANF | Loss of function mutations cause childhood diabetes and a neurodevelopmental disorder. | ND, T2D | (78, 79) | |
| YIPF5 | Loss of function mutations impaired ER-to-Golgi trafficking leading to increased beta cell ER-stress. | ND | (80) | |
| Transcriptional regulation | PDX1 | Loss of function mutations impair transcriptional regulation of pancreatic development and adult islet cell function. | ND, MODY, T2D | (81–84) |
| RFX6 | Loss of function mutations impair transcriptional regulation of pancreatic development and adult islet cell function. | ND, MODY | (85–87) | |
| NEUROD1 | Loss of function mutations impair transcriptional regulation of pancreatic development and adult islet cell function. | ND, MODY | (88–90) | |
| GLIS3 | Coding and non-coding genetic variants impair transcriptional pancreatic development and adult islet cell function | ND, MODY, T2D | (91–93) | |
| HNF1A | Coding and non-coding genetic variants impair transcriptional pancreatic development and adult islet cell function. | MODY, T2D, CHI | (16, 17, 94) | |
| HNF1B | Coding and non-coding genetic variants impair transcriptional pancreatic development and adult islet cell function. | ND, MODY, T2D | (95, 96) | |
| HNF4A | Coding and non-coding genetic variants impair transcriptional pancreatic development and adult islet cell function. | MODY, T2D, CHI | (54, 97) | |
| TCF7L2 | Coding and non-coding genetic variants impair transcriptional pancreatic development and adult islet cell function. | T2D | (98, 99) |
ND, Neonatal Diabetes; MODY, Maturity Onset Diabetes of the Young; T2D, Type 2 Diabetes; CHI, Congenital Hyperinsulinism.
Summary of genetic variants that impact on molecular mechanisms involved in insulin secretion by the beta cell, classified by the mechanism affected and detailing the impact of the genetic defect.