Zebrafish as a preclinical model for diabetes mellitus and its complications: From monogenic to gestational diabetes and beyond

Table 1 Characteristics of maturity-onset diabetes of the young subtypes 1 to 14

Type of MODY	Mutant gene	Clinical characteristics	Therapeutic method	Ref.
MODY 1	HNF4α mutations	Macrosomia; transient neonatal hypoglycemia; insulin secretory defect in adolescence or early adulthood	Low dose sulfonylurea; diet; insulin	[81-83]
MODY2	GCK gene mutation	Small rise in 2-hour PG level on OGTT; higher glucose threshold; nonprogressive elevated fasting blood glucose	Diet and exercise modification (usually no treatment is needed)	[82,84]
MODY3	HNF1A mutation	Lowered renal threshold for glucosuria; insulin secretory defect in adolescence or early adulthood; rise in 2-hour PG level on OGTT	Sulfonylureas	[83,85,86]
MODY4	Mutation of PDX1	Postpuberty; mild form of diabetes	Insulin; OHAs	[87]
MODY5	HNF1B mutation	Renal disease; genitourinary abnormalities; atrophy of the pancreas; hyperuricemia; gout	Early insulin therapy; OHAs (sulfonylurea or repaglinide)	[13]
MODY6	NEUROD1 mutation	Variable age of onset; different degrees of hyperglycemia	Insulin; OHAs	[88]
MODY7	Mutation of KLF11 gene	Variable age of onset; decreased sensitivity to insulin; mild hyperglycemia	Insulin	[89]
MODY8	Mutation of CEL gene	> 25 years; Impaired pancreatic function	Insulin; OHAs	[90]
MODY9	PAX4 gene mutation	Post-puberty; progressive hyperglycemia; occurrences of ketoacidosis	Diet; insulin; OHAs	[91]
MODY10	INS gene mutation	> 10 years; hyperglycemia; diabetes	Insulin; diet	[92]
MODY11	Mutation of BLK gene	Variable age of onset; hyperglycemia; diabetes	Diet; insulin; OHAs	[93]
MODY12	Mutation of ABCC8 gene	Variable age of onset: Diabetes; rarely developmental delay	Sulfonylureas	[94]
MODY13	Gene mutation in member 11 of the inward rectifying potassium ion channel subfamily J (KCNJ11)	After second decade of life; diabetes; possible developmental delay and seizures	Low dose sulfonylures	[95-97]
MODY14	Heterozygous mutation in the APPL1 gene on chromosome 3p14	10-50 years; hyperglycemia; diabetes	Diet; insulin; OHAs	[98]

PG: Plasma glucose; OGTT: Oral glucose tolerance test; OHAs: Oral hypoglycemic agents; MODY: Maturity-onset diabetes of the young; GCK: Glucokinase; HNF1A: Hepatocyte nuclear factor 1A; PDX1: Mutation of pancreatic and duodenal homeobox; NEUROD1: Neurogenic differentiation factor 1; KLF11: Krüppel like factor 11; CEL: Carboxyl ester lipase; PAX4: Paired box gene 4; BLK: B lymphocyte kinase; ABCC8: ATP-binding cassette subfamily C member 8.

Table 2 Applications of zebrafish model in diabetes

Types of diabetes	Advantages	Disadvantages	Ref.
T1DM	High degree of similarity to the human pancreas and most genes have been deciphered by the human body; it compensates for the shortcomings of rodents, such as high reproductive rate	Zebrafish are variable temperature animals and it is difficult to measure their insulin content	[77,79,99]
T2DM
Monogenic diabetes		There have been few studies on monogenic diabetes based on the zebrafish model
GDM	For assessing the health status of infants born to mothers with a history of diabetes or gestational diabetes	There have been few studies on pregnancy diabetes with zebrafish as the model	[76]

T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; GDM: Gestational diabetes mellitus.

Table 3 Characteristics of animal models for diabetes except for zebrafish

Animal model	Experimental cycles	Costs	Stability	Human similarity	Ref.
Pig	Long experimental cycles	Compared with other animals, increased experimental costs; larger breeding space required	High for experimental research	About 98%	[100]
Monkey	Long experimental cycles	Compared with other animals, increased experimental costs	Spontaneously develop diabetes, which interferes with experimental results	About 90%	[101]
Mouse	Short experimental cycles	Compared with other animals, lower experimental costs	Instability as there are innate immune differences between the two, adding uncertainty and risk to experimental research	About 95%	[9,102]
Dog	Long experimental cycles	High experimental costs	As they share the same environment as humans, they are naturally exposed to many risk factors	About 95%	[103]