1Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
2Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
Copyright © 2023 Korean Diabetes Association
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Variable | Function | Mouse | Human | Reference | |
---|---|---|---|---|---|
Endocrine | |||||
Islets | |||||
α | Glucagon | + | + | [29,40-42] | |
β | Insulin | + | + | [29,40-44] | |
δ | Somatostatin | + | Unknown | [29,40,41] | |
PP | Pancreatic polypeptide | + | Unknown | [40] | |
ε | Ghrelin | Unknown | Unknown | - | |
Enterochromaffin cell | Serotonin, motilin, substance P, histamine, and kinins | Unknown | Unknown | - | |
G-cell | Gastrin | Unknown | Unknown | - | |
Exocrine | |||||
Acinar cell | Digestive enzymes such as trypsin, chymotrypsin, amylase, and carboxypeptidase | – | – | [16,29,43] | |
Centroacinar cell | Mucin, bicarbonates | + | + | [16,27,29,43] | |
Ductal epithelial cell | Mucin, bicarbonates | + | + | [16,28,29,43] |
Gene | Mutation type | Phenotype |
Reference | |
---|---|---|---|---|
Exocrine pancreas | Endocrine pancreas | |||
Alms1 | Constitutive, homozygous (–/–) | Unaffected | Islet hyperplasia, hypertrophy, and cystic change | [74,81] |
Partially degranulated β-cells | ||||
Hyperinsulinemia and insulin resistance | ||||
Impaired glucose tolerance, diabetes (>80% in foz/foz mouse) | ||||
Bbs4 | Constitutive, homozygous (–/–) | Not examined | Normal islet morphology | [80] |
Impaired glucose tolerance | ||||
Chibby1 | Constitutive, homozygous (–/–) | Ductal dilation | Normal islet structure | [43] |
Mucus accumulation and lipomatosis | ||||
Disorganized acinar cells with zymogen granule accumulation | ||||
Progressive loss of acinar cells with chronic pancreatitis | ||||
Hnf6 | Constitutive, homozygous (–/–) | Pancreatic cysts with dysmorphic epithelial lining | Not examined | [77] |
Ift88 (Tg737) | Constitutive, hypomorphic mutation (Tg737orpk) | Reduced pancreas mass | Normal islet architecture | [16] |
Collagen deposition | Clustering of islets | |||
Progressive acinar cell loss | Impaired glucose tolerance | |||
Ductal hyperplasia with cyst formation | ||||
Conditional (Pdx1-CreER), homozygous (–/–) | Not examined | ↓ β-Cell mass | [79] | |
↑ β-Cell apoptosis | ||||
↓ Glucose-stimulated insulin secretion | ||||
Impaired glucose tolerance | ||||
Conditional (Ins1-Cre), homozygous (–/–) | Not examined | ↓ β-Cell mass | [42] | |
↑ δ-Cell mass | ||||
↓ Insulin content and secretion | ||||
↑ Glucagon, somatostatin secretion | ||||
impaired glucose tolerance | ||||
Inv | Constitutive, homozygous (–/–) | Pancreatic cysts | Islet cell hyperplasia and disorganization | [76] |
Vacuolization of the acinar cells | ||||
Ductal dilation | ||||
Kif3a | Conditional (Pdx1-Cre), homozygous (–/–) | Ductal dilation and cyst formation | Normal islet structure | [72] |
Acinar-to-ductal metaplasia | Normal glucose tolerance | |||
Progressive acinar cell loss | ||||
Extensive fibrosis and lipomatosis | ||||
Lkb1 | Conditional (Pdx1-CreER), homozygous (–/–) | Not examined | ↑ β-Cell size | [54] |
Altered β-cell polarity (clustering of β-cell nuclei) | ||||
Enhanced glucose tolerance | ||||
Pkd1 | Constitutive, homozygous (–/–) | Pancreatic cyst | ↓ Islet number | [75] |
Ductal dilation | ||||
↓ Acinar number | ||||
Pkhd1 | Constitutive, homozygous (del2/del2) | Pancreatic cysts | Not examined | [78] |
Ductal dilation and thickening | ||||
Constitutive, homozygous (del4/del4) | Pancreatic cysts (10%) | Not examined | [73] | |
Ductal dilation | ||||
Periductal fibrosis | ||||
Rfx3 | Constitutive, homozygous (–/–) | Unaffected | Small and disorganized islets | [40] |
↓ α-, β-, and ghrelin cell mass | ||||
↑ PP cell mass | ||||
↓ Insulin content/secretion, glucagon, and ghrelin | ||||
↑ PP | ||||
Impaired glucose tolerance |
Ciliopathy | Gene | Inheritance | Affected ciliary structure | Clinical phenotype | T2DM prevalence | Reference |
---|---|---|---|---|---|---|
ADPKD | PKD1, PKD2 | AD | Axoneme | Renal and extra-renal cyst formation, loss of renal function, cardiovascular abnormalities, impaired glucose tolerance/insulin secretion | NA | [107,110-112] |
Alström syndrome | ALMS1 | AR | Centrosome, basal body | Central obesity, T2DM, insulin resistance, hyperinsulinemia, hyperlipidemia, short stature, neurosensory deficits, hypogonadotropic hypogonadism, polycystic ovary syndrome, growth hormone deficiency, hypothyroidism, developmental delay, cardiomyopathy, progressive pulmonary, hepatic, and renal dysfunction | 50%–75% | [105,106,113] |
Bardet-Biedl syndrome | BBS1-21, CEP164, SCLT1, SCAPER | AR | BBsome, basal body, chaperonin complex, centriole | Central obesity, T2DM, retinal rod-cone dystrophy, polydactyly, cognitive impairment, polycystic ovary syndrome, hypogonadism, genitourinary, renal, gastrointestinal, and dental abnormalities, congenital heart disease, developmental delay, ataxia, anosmia/hyposmia | <25% | [105,114-116] |
MOPD II | PCNT | AR | Pericentrin | Growth retardation, severe insulin resistance, early-onset of T2DM, facial dysmorphism, bone and dental dysplasia, cerebrovascular abnormalities | 47% | [108,109] |
Renal-hepatic-pancreatic dysplasia | NPHP3, NEK8/NPHP9 | AR | Axoneme, centrosome | Renal, hepatic, and pancreatic cyst, fibrosis, or dysplasia, congenital heart defects, hypoplastic lung, situs abnormalities | NA | [117,118] |
OFD syndrome I | OFD1 | X-linked dominant | Basal body centriole, transition zone, axoneme | Abnormalities of the face, oral cavity, and digits, developmental and cognitive defects, pancreatic, renal, hepatic, and ovarian cysts | NA | [119] |
VHL disease | VHL | AD | Axoneme | Pancreatic cyst (>70%) and neuroendocrine tumors, retinal or CNS hemangioblastomas, renal cysts, renal cell carcinoma, pheochromocytoma | NA | [120,121] |
PP, pancreatic polypeptide.
ALMS, Alström syndrome 1; Bbs4, Bardet-Biedl syndrome 4; Hnf6, hepatocyte nuclear factor 6; Ift88, intraflagellar transport 88; orpk, oak ridge polycystic kidney; Pdx1, pancreatic and duodenal homebox 1; CreER, Cre-estrogen receptor; Ins1, insulin 1; Inv, inversin; Kif3a, kinesin family member 3A; Lkb1, liver kinase B1; Pkd1, polycystin 1; Pkhd1, polycystic kidney and hepatic disease 1; del, deletion; Rfx3, regulatory factor X3; PP, pancreatic polypeptide.
T2DM, type 2 diabetes mellitus; ADPKD, autosomal dominant polycystic kidney disease; PKD1, polycystin 1; PKD2, polycystin 2; AD, autosomal dominant; NA, not available; ALMS1, Alstöm syndrome 1; AR, autosomal recessive; BBS1-21, Bardet-Biedl syndrome 21; CEP164, centrosomal protein 164; SCLT1, sodium channel and clathrin linker 1; SCAPER, S-phase cyclin A associated protein in the endoplasmic reticulum; MOPD II, microcephalic osteodysplastic primordial dwarfism type II; PCNT, pericentrin; NPHP3, nephrocystin 3; NEK8/NPHP9, NIMA related kinase 8/nephrocystin 9; OFD, oral-facial-digital; VHL, von Hippel-Lindau; CNS, central nervous system.