Diabetes mellitus

Summary

Diabetes mellitus (MONDO:0005015) is a disease (an umbrella term covering 8 Mondo subtypes) caused by variants in ABCC8, EIF2S3, PAX6, and 1 other genes, with 26 cohort genes (1,497 GWAS associations across 132 studies) and 6,047 clinical trials. The dominant Reactome pathway is Regulation of gene expression in beta cells (5 cohort genes). Top therapeutic interventions include insulin degludec, insulin detemir, and insulin aspart.

At a glance

• Causal genes: ABCC8 (GenCC Definitive), EIF2S3 (GenCC Strong), PAX6 (GenCC Strong), ZBTB20 (GenCC Strong)
• Umbrella term: 8 Mondo subtypes
• Cohort genes: 26
• GWAS associations: 1,497
• ClinVar variants: 45
• Clinical trials: 6,047

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	diabetes mellitus
Mondo ID	MONDO:0005015
EFO	EFO:0000400
MeSH	D003920
DOID	DOID:9351
ICD-10-CM	E08-E13
ICD-11	465177735
NCIT	C2985
SNOMED CT	73211009
UMLS	C0011849
MedGen	8350
Is cancer (heuristic)	no

Also known as: diabetes · diabetes mellitus · diabetes mellitus (disease) · DM

Data availability: 45 ClinVar variants · 1,497 GWAS associations (132 studies) · 4 GenCC gene-disease records · 1 HPO phenotype · 93 cell lines.

Disease family

An umbrella term covering 8 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › digestive system disorder › pancreas disorder › endocrine pancreas disorder › diabetes mellitus

Related subtypes (11): gastrin secretion abnormality, abnormality of glucagon secretion, hyperinsulinism, post-surgical hypoinsulinemia, pancreatic cholera, aggressive insulitis, benign insulitis, pancreatic neuroendocrine neoplasm, islet cell adenomatosis, insulin-resistance syndrome type A, insulin-resistance syndrome type B

Subtypes (8): type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes, maternally-inherited diabetes and deafness, diabetic ketoacidosis, monogenic diabetes, type 5 diabetes mellitus, cystic fibrosis-related diabetes

Genetics & variants

GWAS landscape

1,497 GWAS associations across 132 studies. Top hits map to 18 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
chr10:114749734	1e-323		G	0.26
rs34872471	1e-323	TCF7L2	T	0.26
rs7903146	1e-302	TCF7L2	C	0.25
rs1421085	8e-207	FTO	T	0.12
chr11:2858546	1e-193		?	0.27
chr3:185506892	7e-154		C	0.11
rs247617	1e-149	HERPUD1 - CETP	?
chr7:127253550	4e-127		?	0.36
rs7766070	3e-124	CDKAL1	C	0.1
chr6:20680678	1e-123		?	0.2
rs10811661	9e-117	CDKN2B-AS1	T	0.12
chr9:22133284	1e-114		?	0.19
chr3:185511687	5e-114		G	0.12
rs56094641	5e-113	FTO	A	0.12
rs964184	2e-108	ZPR1	?
chr10:94470515	4e-100		T	0.08
rs35198068	7e-98	TCF7L2	?
rs9859406	8e-98	IGF2BP2	G	0.12
rs2203452	3e-95	NYAP2 - MIR5702	A	0.08
rs780094	4e-91	GCKR	?
rs11558471	7e-85	SLC30A8	A	0.08
rs4234731	3e-81	WFS1	A	0.07
rs76895963	4e-77	CCND2-AS1, CCND2	T	0.34
rs10811662	2e-75	CDKN2B-AS1	G	0.13
rs1635852	3e-74	JAZF1	T	0.07
rs7756992	2e-69	CDKAL1	A	0.1
rs8082812	5e-67	THEMIS3P - AKR1B1P6	?
chr2:43633268	5e-66		T	0.1
chr8:41519248	5e-64		T	0.07
rs7630554	6e-63	IGF2BP2	A	0.12

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90038599	Donertas HM	2021	51,949	432,649	Common genetic associations between age-related diseases.
GCST90042689	Jiang L	2021	39,259	378,667	A generalized linear mixed model association tool for biobank-scale data.
GCST90042676	Jiang L	2021	37,943	357,277	A generalized linear mixed model association tool for biobank-scale data.
GCST90042703	Jiang L	2021	30,458	327,103	A generalized linear mixed model association tool for biobank-scale data.
GCST90038633	Donertas HM	2021	24,659	459,939	Common genetic associations between age-related diseases.
GCST90078949	Backman JD	2021	22,058	407,681	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90082935	Backman JD	2021	22,058	407,681	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90043627	Jiang L	2021	21,969	433,048	A generalized linear mixed model association tool for biobank-scale data.
GCST90435700	Zhou W	2018	20,203	388,756	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90077722	Backman JD	2021	17,927	313,827	Exome sequencing and analysis of 454,787 UK Biobank participants.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	3
Tier 3: regulatory	0
Tier 4: intronic/intergenic	46

MAF distribution

Bucket	Variants
common (>=0.05)	41
low_freq (0.01-0.05)	1
rare (<0.01)	0
unknown	8

Functional consequences

Consequence	Count
unknown	22
intron_variant	16
intergenic_variant	6
3_prime_UTR_variant	3
non_coding_transcript_exon_variant	2
missense_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
chr10:114749734				0.229			1e-323	Tier 4: intronic/intergenic
rs34872471	10	112994312	T>C	0.292	intron_variant	TCF7L2	1e-323	Tier 4: intronic/intergenic
rs7903146	10	112998590	C>G,T	0.29	intron_variant	TCF7L2	1e-302	Tier 4: intronic/intergenic
rs1421085	16	53767042	T>C	0.407	intron_variant	FTO	8e-207	Tier 4: intronic/intergenic
chr11:2858546							1e-193	Tier 4: intronic/intergenic
chr3:185506892				0.312			7e-154	Tier 4: intronic/intergenic
rs247617	16	56956804	C>A	0.05	intergenic_variant	HERPUD1 - CETP	1e-149	Tier 4: intronic/intergenic
chr7:127253550							4e-127	Tier 4: intronic/intergenic
rs7766070	6	20686342	C>A,G,T	0.267	intron_variant	CDKAL1	3e-124	Tier 4: intronic/intergenic
chr6:20680678							1e-123	Tier 4: intronic/intergenic
rs10811661	9	22134095	T>A,C	0.174	intergenic_variant	CDKN2B-AS1	9e-117	Tier 4: intronic/intergenic
chr9:22133284							1e-114	Tier 4: intronic/intergenic
chr3:185511687				0.315			5e-114	Tier 4: intronic/intergenic
rs56094641	16	53772541	A>G,T	0.407	intron_variant	FTO	5e-113	Tier 4: intronic/intergenic
rs964184	11	116778201	G>C	0.05	3_prime_UTR_variant	ZPR1	2e-108	Tier 2: splice/UTR
chr10:94470515				0.369			4e-100	Tier 4: intronic/intergenic
rs35198068	10	112995025	T>C	0.05	intron_variant	TCF7L2	7e-98	Tier 4: intronic/intergenic
rs9859406	3	185816694	G>A	0.313	intron_variant	IGF2BP2	8e-98	Tier 4: intronic/intergenic
rs2203452	2	226230042	A>C,G	0.363	intergenic_variant	NYAP2 - MIR5702	3e-95	Tier 4: intronic/intergenic
rs780094	2	27518370	T>A,C,G	0.05	intron_variant	GCKR	4e-91	Tier 4: intronic/intergenic
rs11558471	8	117173494	A>G	0.311	3_prime_UTR_variant	SLC30A8	7e-85	Tier 2: splice/UTR
rs4234731	4	6298187	A>C,G,T	0.396	intron_variant	WFS1	3e-81	Tier 4: intronic/intergenic
rs76895963	12	4275678	T>C,G	0.017	non_coding_transcript_exon_variant	CCND2-AS1, CCND2	4e-77	Tier 4: intronic/intergenic
rs10811662	9	22134254	G>A,C	0.172	intergenic_variant	CDKN2B-AS1	2e-75	Tier 4: intronic/intergenic
rs1635852	7	28149792	T>A,C	0.499	intron_variant	JAZF1	3e-74	Tier 4: intronic/intergenic
rs7756992	6	20679478	A>G,T	0.273	intron_variant	CDKAL1	2e-69	Tier 4: intronic/intergenic
rs8082812	18	8522684	C>A	0.05	intergenic_variant	THEMIS3P - AKR1B1P6	5e-67	Tier 4: intronic/intergenic
chr2:43633268				0.105			5e-66	Tier 4: intronic/intergenic
chr8:41519248				0.242			5e-64	Tier 4: intronic/intergenic
rs7630554	3	185808274	A>G	0.373	intron_variant	IGF2BP2	6e-63	Tier 4: intronic/intergenic

ClinVar germline variants

45 retrieved; paginated sample, class counts are floors:

15 pathogenic, 9 likely pathogenic, 6 uncertain significance, 4 pathogenic/likely pathogenic, 3 benign, 3 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 pathogenic/likely pathogenic/likely risk allele, 1 likely risk allele, 1 uncertain significance/uncertain risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
36263	NM_000162.5(GCK):c.871A>T (p.Lys291Ter)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
918070	NM_000162.5(GCK):c.772G>A (p.Gly258Ser)	GCK	Pathogenic	reviewed by expert panel
381588	NM_000545.8(HNF1A):c.599G>A (p.Arg200Gln)	HNF1A	Pathogenic	reviewed by expert panel
429750	NM_000545.8(HNF1A):c.475C>T (p.Arg159Trp)	HNF1A	Pathogenic	reviewed by expert panel
449403	NM_000545.8(HNF1A):c.812G>A (p.Arg271Gln)	HNF1A	Pathogenic	reviewed by expert panel
918065	NM_000545.8(HNF1A):c.824A>T (p.Glu275Val)	HNF1A	Pathogenic	no assertion criteria provided
431443	NM_000207.3(INS):c.-152C>G	INS	Pathogenic	criteria provided, multiple submitters, no conflicts
158682	NM_000525.4(KCNJ11):c.679G>A (p.Glu227Lys)	KCNJ11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158683	NM_000525.4(KCNJ11):c.685G>A (p.Glu229Lys)	KCNJ11	Pathogenic/Likely pathogenic/Likely risk allele	criteria provided, multiple submitters, no conflicts
21203	NM_000525.4(KCNJ11):c.964G>A (p.Glu322Lys)	KCNJ11	Pathogenic	criteria provided, multiple submitters, no conflicts
8668	NM_000525.4(KCNJ11):c.601C>T (p.Arg201Cys)	KCNJ11	Pathogenic	criteria provided, multiple submitters, no conflicts
374107	NM_001370259.2(MEN1):c.654+1del	MEN1	Pathogenic	criteria provided, single submitter
7706	NM_000303.3(PMM2):c.422G>A (p.Arg141His)	PMM2	Pathogenic	criteria provided, multiple submitters, no conflicts
497	NM_173560.4(RFX6):c.224-12A>G	RFX6	Pathogenic	no assertion criteria provided
132142	NM_001379610.1(SPINK1):c.194+2T>C	SPINK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
198835	NM_006005.3(WFS1):c.1672C>T (p.Arg558Cys)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
349320	NM_006005.3(WFS1):c.1839G>A (p.Trp613Ter)	WFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
916728	NM_006005.3(WFS1):c.1362_1377del (p.Pro453_Tyr454insTer)	WFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
918063	NM_006005.3(WFS1):c.1514G>A (p.Cys505Tyr)	WFS1	Pathogenic	no assertion criteria provided
918066	NM_006005.3(WFS1):c.817G>T (p.Glu273Ter)	WFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
916726	NM_000545.8(HNF1A):c.1139del (p.Val380fs)	HNF1A	Likely pathogenic	criteria provided, single submitter
916727	NM_000545.8(HNF1A):c.1310-1G>A	HNF1A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
918061	NM_000545.8(HNF1A):c.404A>C (p.Asp135Ala)	HNF1A	Likely pathogenic	criteria provided, single submitter
918062	NM_000545.8(HNF1A):c.639C>G (p.Ile213Met)	HNF1A	Likely pathogenic	no assertion criteria provided
916729	NM_000207.3(INS):c.174del (p.Glu59fs)	INS	Likely pathogenic	criteria provided, single submitter
158676	NM_000525.4(KCNJ11):c.498C>G (p.Cys166Trp)	KCNJ11	Likely pathogenic	criteria provided, single submitter
812999	NM_000303.3(PMM2):c.584A>G (p.His195Arg)	PMM2	Likely pathogenic	criteria provided, single submitter
918064	NM_006005.3(WFS1):c.961A>C (p.Thr321Pro)	WFS1	Likely pathogenic	criteria provided, single submitter
918069	NM_006005.3(WFS1):c.2015T>C (p.Leu672Pro)	WFS1	Likely pathogenic	criteria provided, single submitter
918067	NM_000207.3(INS):c.286T>C (p.Cys96Arg)	INS-IGF2	Likely risk allele	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 59 · Orphanet: 67 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ABCC8	Definitive	Semidominant	diabetes mellitus	32
EIF2S3	Strong	X-linked	diabetes mellitus	7
PAX6	Strong	Autosomal dominant	diabetes mellitus	14
ZBTB20	Strong	Autosomal dominant	diabetes mellitus	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ABCC8	Orphanet:276575	Autosomal dominant hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:276598	Diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:552	MODY
ABCC8	Orphanet:79134	DEND syndrome
ABCC8	Orphanet:79643	Autosomal recessive hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
ABCC8	Orphanet:99886	Transient neonatal diabetes mellitus
ZBTB20	Orphanet:3042	Intellectual disability-cataracts-calcified pinnae-myopathy syndrome
EIF2S3	Orphanet:85282	MEHMO syndrome
PAX6	Orphanet:1065	Aniridia-cerebellar ataxia-intellectual disability syndrome
PAX6	Orphanet:2253	Foveal hypoplasia-presenile cataract syndrome
PAX6	Orphanet:2334	Autosomal dominant keratitis
PAX6	Orphanet:250923	Isolated aniridia
PAX6	Orphanet:35737	Morning glory disc anomaly
PAX6	Orphanet:708	Peters anomaly
PAX6	Orphanet:893	WAGR syndrome
PAX6	Orphanet:98942	Coloboma of choroid and retina
PAX6	Orphanet:98943	Coloboma of eye lens
PAX6	Orphanet:98944	Coloboma of iris
PAX6	Orphanet:98945	Coloboma of macula
PAX6	Orphanet:98946	Coloboma of eyelid
PAX6	Orphanet:98947	Coloboma of optic disc
SALL1	Orphanet:857	Townes-Brocks syndrome
SPINK1	Orphanet:103918	Tropical pancreatitis
SPINK1	Orphanet:700124	Autosomal recessive hereditary chronic pancreatitis
HNF1A	Orphanet:319303	Chromophobe renal cell carcinoma
HNF1A	Orphanet:324575	Hyperinsulinism due to HNF1A deficiency
HNF1A	Orphanet:404511	Clear cell papillary renal cell carcinoma
HNF1A	Orphanet:552	MODY
HNF1B	Orphanet:1309	Medullary sponge kidney
HNF1B	Orphanet:1331	Familial prostate cancer
HNF1B	Orphanet:2578	Mayer-Rokitansky-Küster-Hauser syndrome type 2
HNF1B	Orphanet:261265	17q12 microdeletion syndrome
HNF1B	Orphanet:93111	HNF1B-related autosomal dominant tubulointerstitial kidney disease
HNF1B	Orphanet:93172	Renal dysplasia, unilateral
HNF1B	Orphanet:93173	Renal dysplasia, bilateral
HNF1B	Orphanet:97363	Unilateral multicystic dysplastic kidney
HNF1B	Orphanet:97364	Bilateral multicystic dysplastic kidney
KLF11	Orphanet:552	MODY
WFS1	Orphanet:3463	Wolfram syndrome
WFS1	Orphanet:411590	Wolfram-like syndrome
WFS1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
WFS1	Orphanet:98991	Early-onset nuclear cataract
ARMC9	Orphanet:475	Isolated Joubert syndrome
RFX6	Orphanet:293864	Hypoplastic pancreas-intestinal atresia-hypoplastic gallbladder syndrome
GLIS3	Orphanet:79118	Neonatal diabetes-congenital hypothyroidism-congenital glaucoma-hepatic fibrosis-polycystic kidneys syndrome
GCK	Orphanet:552	MODY
GCK	Orphanet:79299	Congenital glucokinase-related hyperinsulinism
GCK	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
INS	Orphanet:552	MODY

Cohort genes → proteins

26 cohort genes, 26 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	7
multi_evidence	19

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ABCC8	HGNC:59	ENSG00000006071	Q09428	ATP-binding cassette sub-family C member 8	gencc,clinvar
ZBTB20	HGNC:13503	ENSG00000181722	Q9HC78	Zinc finger and BTB domain-containing protein 20	gencc
EIF2S3	HGNC:3267	ENSG00000130741	P41091	Eukaryotic translation initiation factor 2 subunit 3	gencc
PAX6	HGNC:8620	ENSG00000007372	P26367	Paired box protein Pax-6	gencc
SALL1	HGNC:10524	ENSG00000103449	Q9NSC2	Sal-like protein 1	gwas
SPINK1	HGNC:11244	ENSG00000164266	P00995	Serine protease inhibitor Kazal-type 1	clinvar
HNF1A	HGNC:11621	ENSG00000135100	P20823	Hepatocyte nuclear factor 1-alpha	clinvar
HNF1B	HGNC:11630	ENSG00000275410	P35680	Hepatocyte nuclear factor 1-beta	clinvar
KLF11	HGNC:11811	ENSG00000172059	O14901	Krueppel-like factor 11	clinvar
TLR1	HGNC:11847	ENSG00000174125	Q15399	Toll-like receptor 1	gwas
TMEFF2	HGNC:11867	ENSG00000144339	Q9UIK5	Tomoregulin-2	gwas
WFS1	HGNC:12762	ENSG00000109501	O76024	Wolframin	clinvar
TLR10	HGNC:15634	ENSG00000174123	Q9BXR5	Toll-like receptor 10	gwas
TLR6	HGNC:16711	ENSG00000174130	Q9Y2C9	Toll-like receptor 6	gwas
KSR2	HGNC:18610	ENSG00000171435	Q6VAB6	Kinase suppressor of Ras 2	clinvar
THADA	HGNC:19217	ENSG00000115970	Q6YHU6	tRNA (32-2’-O)-methyltransferase regulator THADA	gwas
ARMC9	HGNC:20730	ENSG00000135931	Q7Z3E5	LisH domain-containing protein ARMC9	clinvar
RFX6	HGNC:21478	ENSG00000185002	Q8HWS3	DNA-binding protein RFX6	clinvar
GLIS3	HGNC:28510	ENSG00000107249	Q8NEA6	Zinc finger protein GLIS3	clinvar
PLEKHH2	HGNC:30506	ENSG00000152527	Q8IVE3	Pleckstrin homology domain-containing family H member 2	gwas
INS-IGF2	HGNC:33527	ENSG00000129965	F8WCM5	Insulin, isoform 2	clinvar
GCK	HGNC:4195	ENSG00000106633	P35557	Hexokinase-4	clinvar
INS	HGNC:6081	ENSG00000254647	P01308	Insulin	clinvar
KCNJ11	HGNC:6257	ENSG00000187486	Q14654	ATP-sensitive inward rectifier potassium channel 11	clinvar
MEN1	HGNC:7010	ENSG00000133895	O00255	Menin	clinvar
PMM2	HGNC:9115	ENSG00000140650	O15305	Phosphomannomutase 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ABCC8	ATP-binding cassette sub-family C member 8	Regulator subunit of pancreatic ATP-sensitive potassium channel (KATP), playing a major role in the regulation of insulin release.
ZBTB20	Zinc finger and BTB domain-containing protein 20	May be a transcription factor that may be involved in hematopoiesis, oncogenesis, and immune responses.
EIF2S3	Eukaryotic translation initiation factor 2 subunit 3	Member of the eIF2 complex that functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA.
PAX6	Paired box protein Pax-6	Transcription factor with important functions in the development of the eye, nose, central nervous system and pancreas.
SALL1	Sal-like protein 1	Transcriptional repressor involved in organogenesis.
SPINK1	Serine protease inhibitor Kazal-type 1	Serine protease inhibitor which exhibits anti-trypsin activity.
HNF1A	Hepatocyte nuclear factor 1-alpha	Transcriptional activator that regulates the tissue specific expression of multiple genes, especially in pancreatic islet cells and in liver.
HNF1B	Hepatocyte nuclear factor 1-beta	Transcription factor that binds to the inverted palindrome 5’-GTTAATNATTAAC-3'.
KLF11	Krueppel-like factor 11	Transcription factor.
TLR1	Toll-like receptor 1	Participates in the innate immune response to microbial agents.
TMEFF2	Tomoregulin-2	May be a survival factor for hippocampal and mesencephalic neurons.
WFS1	Wolframin	Participates in the regulation of cellular Ca(2+) homeostasis, at least partly, by modulating the filling state of the endoplasmic reticulum Ca(2+) store.
TLR10	Toll-like receptor 10	Participates in the innate immune response to microbial agents.
TLR6	Toll-like receptor 6	Participates in the innate immune response to Gram-positive bacteria and fungi.
KSR2	Kinase suppressor of Ras 2	Location-regulated scaffold connecting MEK to RAF.
THADA	tRNA (32-2’-O)-methyltransferase regulator THADA	Together with methyltransferase FTSJ1, methylates the 2’-O-ribose of nucleotides at position 32 of the anticodon loop of substrate tRNAs.
ARMC9	LisH domain-containing protein ARMC9	Involved in ciliogenesis.
RFX6	DNA-binding protein RFX6	Transcription factor required to direct islet cell differentiation during endocrine pancreas development.
GLIS3	Zinc finger protein GLIS3	Acts both as a repressor and an activator of transcription.
PLEKHH2	Pleckstrin homology domain-containing family H member 2	In the kidney glomerulus may play a role in linking podocyte foot processes to the glomerular basement membrane.
GCK	Hexokinase-4	Catalyzes the phosphorylation of hexose, such as D-glucose, D-fructose and D-mannose, to hexose 6-phosphate (D-glucose 6-phosphate, D-fructose 6-phosphate and D-mannose 6-phosphate, respectively).
INS	Insulin	Insulin decreases blood glucose concentration.
KCNJ11	ATP-sensitive inward rectifier potassium channel 11	Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells.
MEN1	Menin	Essential component of a MLL/SET1 histone methyltransferase (HMT) complex, a complex that specifically methylates ‘Lys-4’ of histone H3 (H3K4).
PMM2	Phosphomannomutase 2	Involved in the synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions.

Protein-family classification

Druggable: 6 · Difficult: 8 · Unknown: 12 · Druggable fraction: 0.23

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	7	2.2×	0.218
Ion channel	1	4.3×	0.500
Transporter	1	3.0×	0.500
Kinase	2	2.1×	0.500
Enzyme (other)	2	0.9×	0.883
Other/Unknown	12	0.8×	0.883
Scaffold/PPI	1	0.7×	0.883

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABCC8	Transporter	yes		ABCC8/9, ABCC8, ABC_transporter-like_ATP-bd
ZBTB20	Transcription factor	no		BTB/POZ_dom, SKP1/BTB/POZ_sf, Znf_C2H2_type
EIF2S3	Enzyme (other)	yes	3.6.5.3	T_Tr_GTP-bd_dom, EFTu-like_2, Transl_B-barrel_sf
PAX6	Transcription factor	no		HD, Paired_dom, Homeodomain-like_sf
SALL1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Sal_C2H2-zinc-finger
SPINK1	Other/Unknown	no		Prot_inh_Kazal-m, Kazal_dom, Kazal_dom_sf
HNF1A	Transcription factor	no		HD, HNF1b_C, HNF1a_C
HNF1B	Transcription factor	no		HD, HNF1b_C, HNF-1_N
KLF11	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
TLR1	Other/Unknown	no		TIR_dom, Cys-rich_flank_reg_C, Leu-rich_rpt
TMEFF2	Other/Unknown	no		EGF, Kazal_dom, Kazal_dom_sf
WFS1	Other/Unknown	no		TPR-like_helical_dom_sf, Wolframin, Wolframin_fam
TLR10	Other/Unknown	no		TIR_dom, Cys-rich_flank_reg_C, Leu-rich_rpt
TLR6	Other/Unknown	no		TIR_dom, Cys-rich_flank_reg_C, Leu-rich_rpt
KSR2	Kinase	yes	2.7.11.25	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
THADA	Other/Unknown	no		ARM-type_fold, THADA/TRM732_DUF2428, tRNA_methyltransferase_THADA
ARMC9	Other/Unknown	no		LisH, ARM-like, ARM-type_fold
RFX6	Other/Unknown	no		DNA-bd_RFX, WH-like_DNA-bd_sf, WH_DNA-bd_sf
GLIS3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
PLEKHH2	Scaffold/PPI	no		FERM_domain, MyTH4_dom, PH_domain
INS-IGF2	Other/Unknown	no		Insulin, Insulin-like, Insulin-like_sf
GCK	Kinase	yes	2.7.1.1	Hexokinase, Hexokinase_BS, Hexokinase_N
INS	Other/Unknown	no		Insulin, Insulin-like, Ins/IGF/rlx
KCNJ11	Ion channel	yes		K_chnl_inward-rec_Kir6.2, K_chnl_inward-rec_Kir_cyto, Ig_E-set
MEN1	Other/Unknown	no		Menin
PMM2	Enzyme (other)	yes	5.4.2.8	PMM, HAD-SF_hydro_IIB, HAD_sf

Expression context

Cohort genes with no expression data: 0.

24 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	1
broad (>20)	25
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	6
body of pancreas	4
calcaneal tendon	3
right hemisphere of cerebellum	2
type B pancreatic cell	2
ventricular zone	2
epithelial cell of pancreas	2
oocyte	2
primordial germ cell in gonad	2
secondary oocyte	2
leukocyte	2
monocyte	2
mononuclear cell	2
middle temporal gyrus	2
cerebellar hemisphere	1
caput epididymis	1
cauda epididymis	1
corpus epididymis	1
germinal epithelium of ovary	1
oviduct epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ABCC8	185	broad	marker	islet of Langerhans, right hemisphere of cerebellum, cerebellar hemisphere
ZBTB20	292	ubiquitous	marker	corpus epididymis, caput epididymis, cauda epididymis
EIF2S3	261	ubiquitous	marker	germinal epithelium of ovary, oviduct epithelium, parietal pleura
PAX6	201	broad	marker	palpebral conjunctiva, type B pancreatic cell, ventricular zone
SALL1	195	broad	marker	ventricular zone, inferior vagus X ganglion, renal medulla
SPINK1	192	broad	marker	body of pancreas, islet of Langerhans, epithelial cell of pancreas
HNF1A	81	tissue_specific	yes	right lobe of liver, mucosa of transverse colon, liver
HNF1B	74	broad	marker	metanephros cortex, adult mammalian kidney, kidney
KLF11	260	ubiquitous	marker	secondary oocyte, oocyte, primordial germ cell in gonad
TLR1	218	broad	marker	monocyte, mononuclear cell, leukocyte
TMEFF2	197	broad	marker	middle temporal gyrus, Brodmann (1909) area 46, dorsal root ganglion
WFS1	280	ubiquitous	marker	right ovary, left ovary, body of uterus
TLR10	166	tissue_specific	marker	lymph node, ileal mucosa, ileum
TLR6	157	broad	marker	monocyte, mononuclear cell, leukocyte
KSR2	114	broad	marker	Brodmann (1909) area 23, middle temporal gyrus, postcentral gyrus
THADA	276	ubiquitous	marker	calcaneal tendon, right uterine tube, right lobe of thyroid gland
ARMC9	244	ubiquitous	marker	stromal cell of endometrium, secondary oocyte, oocyte
RFX6	55	tissue_specific	marker	islet of Langerhans, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
GLIS3	213	ubiquitous	marker	buccal mucosa cell, epithelial cell of pancreas, pancreatic ductal cell
PLEKHH2	234	broad	marker	calcaneal tendon, tibia, right lung
INS-IGF2	20	broad	marker	islet of Langerhans, pancreas, body of pancreas
GCK	155	tissue_specific	marker	pituitary gland, adenohypophysis, islet of Langerhans
INS	137	tissue_specific	marker	type B pancreatic cell, islet of Langerhans, body of pancreas
KCNJ11	161	broad	yes	gastrocnemius, hindlimb stylopod muscle, muscle of leg
MEN1	271	ubiquitous	marker	granulocyte, lower esophagus mucosa, right hemisphere of cerebellum
PMM2	139	ubiquitous	marker	body of pancreas, calcaneal tendon, rectum

Protein interactions among cohort

Intra-cohort edges: 31.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
INS	11,670
MEN1	5,226
PAX6	4,971
EIF2S3	3,709
WFS1	3,409
TLR1	3,071
ABCC8	2,826
HNF1A	2,491
GCK	2,245
SALL1	2,189

Intra-cohort edges

A	B	Sources
ABCC8	GCK	string_interaction
ABCC8	GLIS3	string_interaction
ABCC8	HNF1A	string_interaction
ABCC8	INS	string_interaction
ABCC8	KCNJ11	biogrid_interaction, intact, string_interaction
ABCC8	KLF11	string_interaction
ABCC8	WFS1	string_interaction
GCK	HNF1A	string_interaction
GCK	HNF1B	string_interaction
GCK	INS	string_interaction
GCK	KCNJ11	string_interaction
GCK	KLF11	string_interaction
GCK	RFX6	string_interaction
GLIS3	KCNJ11	string_interaction
GLIS3	RFX6	string_interaction
HNF1A	HNF1B	biogrid_interaction, intact, string_interaction
HNF1A	INS	string_interaction
HNF1A	KCNJ11	string_interaction
HNF1A	KLF11	string_interaction
HNF1B	KLF11	string_interaction
INS	KCNJ11	string_interaction
INS	KLF11	string_interaction
INS	WFS1	string_interaction
KCNJ11	KLF11	string_interaction
KCNJ11	WFS1	string_interaction
KLF11	RFX6	string_interaction
PLEKHH2	THADA	string_interaction
TLR1	TLR10	intact, string_interaction
TLR1	TLR6	biogrid_interaction, intact, string_interaction
TLR10	TLR6	intact, string_interaction
TLR10	WFS1	intact

Structural data

PDB: 18 · AlphaFold-only: 8 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
INS	P01308	382
MEN1	O00255	69
GCK	P35557	35
EIF2S3	P41091	25
KSR2	Q6VAB6	9
KCNJ11	Q14654	9
ABCC8	Q09428	8
PMM2	O15305	7
HNF1A	P20823	6
TLR1	Q15399	6
SPINK1	P00995	5
INS-IGF2	F8WCM5	4
HNF1B	P35680	3
ZBTB20	Q9HC78	2
PAX6	P26367	2
THADA	Q6YHU6	2
TLR10	Q9BXR5	1
TLR6	Q9Y2C9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
WFS1	O76024	73.85
ARMC9	Q7Z3E5	71.71
TMEFF2	Q9UIK5	68.63
PLEKHH2	Q8IVE3	67.21
RFX6	Q8HWS3	59.23
GLIS3	Q8NEA6	49.95
KLF11	O14901	49.73
SALL1	Q9NSC2	49.54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 130. Enrichment computed across 26 evidence-associated genes (19 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 19 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of gene expression in beta cells	5	136.6×	2e-08	HNF1A, RFX6, GCK, INS, PAX6
Defective ABCC8 can cause hypo- and hyper-glycemias	2	601.0×	2e-04	ABCC8, KCNJ11
ATP sensitive Potassium channels	2	300.5×	7e-04	ABCC8, KCNJ11
Regulation of insulin secretion	3	34.7×	0.003	ABCC8, INS, KCNJ11
Integration of energy metabolism	3	27.7×	0.004	ABCC8, INS, KCNJ11
Inwardly rectifying K+ channels	2	75.1×	0.007	ABCC8, KCNJ11
MyD88 deficiency (TLR2/4)	2	63.3×	0.008	TLR1, TLR6
IRAK4 deficiency (TLR2/4)	2	60.1×	0.008	TLR1, TLR6
Regulation of TLR by endogenous ligand	2	52.3×	0.009	TLR1, TLR6
ABC transporter disorders	2	46.2×	0.011	ABCC8, KCNJ11
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	2	40.1×	0.013	GCK, INS
Defective PMM2 causes PMM2-CDG	1	601.0×	0.017	PMM2
Defective GCK causes maturity-onset diabetes of the young 2 (MODY2)	1	601.0×	0.017	GCK
Developmental Lineage of Pancreatic Acinar Cells	2	31.6×	0.017	SPINK1, HNF1B
Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome	1	300.5×	0.029	KCNJ11
IRAK4 deficiency (TLR5)	1	150.3×	0.052	TLR10
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	2	16.0×	0.052	TLR1, TLR6
IRS activation	1	120.2×	0.056	INS
Disorders of transmembrane transporters	2	14.7×	0.056	ABCC8, KCNJ11
Potassium Channels	2	14.1×	0.056	ABCC8, KCNJ11
ER-Phagosome pathway	2	13.7×	0.057	TLR1, TLR6
Synthesis of GDP-mannose	1	100.2×	0.059	PMM2
ABC-family protein mediated transport	2	12.8×	0.059	EIF2S3, KCNJ11
Regulation of gene expression in early pancreatic precursor cells	1	75.1×	0.072	HNF1B
Recycling of eIF2:GDP	1	66.8×	0.076	EIF2S3
Post-translational protein phosphorylation	2	10.5×	0.076	WFS1, MEN1
Cellular response to mitochondrial stress	1	60.1×	0.080	EIF2S3
Signal attenuation	1	54.6×	0.081	INS
Formation of the anterior neural plate	1	54.6×	0.081	PAX6
POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation	1	46.2×	0.082	SALL1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 25 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glucose homeostasis	6	31.4×	9e-06	HNF1A, WFS1, RFX6, GCK, INS, PAX6
regulation of insulin secretion	4	62.7×	7e-05	ABCC8, RFX6, GCK, KCNJ11
pancreas development	3	80.9×	7e-04	HNF1A, HNF1B, WFS1
toll-like receptor signaling pathway	3	72.2×	8e-04	TLR1, TLR10, TLR6
negative regulation of transcription by RNA polymerase II	8	5.7×	0.003	SALL1, HNF1B, KLF11, WFS1, ZBTB20, GLIS3, MEN1, PAX6
type B pancreatic cell differentiation	2	168.5×	0.003	RFX6, PAX6
glucose metabolic process	3	30.6×	0.006	GCK, INS, KCNJ11
nervous system process	2	96.3×	0.008	WFS1, KCNJ11
positive regulation of glycogen biosynthetic process	2	79.3×	0.010	GCK, INS
endocrine pancreas development	2	74.9×	0.010	HNF1B, RFX6
obsolete inorganic cation transmembrane transport	2	74.9×	0.010	ABCC8, KCNJ11
positive regulation of lipid biosynthetic process	2	71.0×	0.010	ZBTB20, INS
negative regulation of gluconeogenesis	2	64.2×	0.010	GCK, INS
positive regulation of interleukin-6 production	3	20.0×	0.010	TLR1, ZBTB20, TLR6
positive regulation of tumor necrosis factor production	3	18.4×	0.012	ABCC8, TLR1, ZBTB20
positive regulation of glycolytic process	2	53.9×	0.013	ZBTB20, INS
pituitary gland development	2	51.9×	0.013	SALL1, PAX6
microglial cell activation	2	49.9×	0.013	TLR1, TLR6
kidney development	3	16.9×	0.013	SALL1, HNF1B, WFS1
pancreatic A cell development	1	674.1×	0.013	PAX6
oligodendrocyte cell fate specification	1	674.1×	0.013	PAX6
forebrain-midbrain boundary formation	1	674.1×	0.013	PAX6
somatic motor neuron fate commitment	1	674.1×	0.013	PAX6
inductive cell-cell signaling	1	674.1×	0.013	SALL1
regulation of pronephros size	1	674.1×	0.013	HNF1B
pronephric nephron tubule development	1	674.1×	0.013	HNF1B
negative regulation of integrin biosynthetic process	1	674.1×	0.013	TMEFF2
ureteric bud elongation	1	674.1×	0.013	HNF1B
obsolete negative regulation of mesenchymal cell apoptotic process involved in mesonephric nephron morphogenesis	1	674.1×	0.013	HNF1B
negative regulation of neuroblast migration	1	674.1×	0.013	ABCC8

Therapeutics

Drugs indicated for this disease

65 approved, 48 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Acarbose	Approved (phase 4)
Acetohexamide	Approved (phase 4)
Albiglutide	Approved (phase 4)
Atenolol	Approved (phase 4)
Benfluorex	Approved (phase 4)
Bexagliflozin	Approved (phase 4)
Buformin	Approved (phase 4)
Candesartan Cilexetil	Approved (phase 4)
Chlorpropamide	Approved (phase 4)
Dapagliflozin	Approved (phase 4)
Dasiglucagon Hydrochloride	Approved (phase 4)
Dulaglutide	Approved (phase 4)
Empagliflozin	Approved (phase 4)
Evogliptin	Approved (phase 4)
Exenatide	Approved (phase 4)
Felodipine	Approved (phase 4)
Fenofibrate	Approved (phase 4)
Glibornuride	Approved (phase 4)
Gliclazide	Approved (phase 4)
Glimepiride	Approved (phase 4)
Glipizide	Approved (phase 4)
Glucagon	Approved (phase 4)
Glyburide	Approved (phase 4)
Insulin Aspart	Approved (phase 4)
Insulin Degludec	Approved (phase 4)
Insulin Detemir	Approved (phase 4)
Insulin Glargine	Approved (phase 4)
Insulin Glulisine	Approved (phase 4)
Insulin Human	Approved (phase 4)
Insulin Human Zinc	Approved (phase 4)
Insulin Human, Isophane	Approved (phase 4)
Insulin Icodec	Approved (phase 4)
Insulin Lispro	Approved (phase 4)
Insulin Purified Beef	Approved (phase 4)
Insulin Purified Pork	Approved (phase 4)
Insulin, Neutral	Approved (phase 4)
Ipragliflozin	Approved (phase 4)
Linagliptin	Approved (phase 4)
Liraglutide	Approved (phase 4)
Lixisenatide	Approved (phase 4)
Metformin	Approved (phase 4)
Miglitol	Approved (phase 4)
Nateglinide	Approved (phase 4)
OMEGA-3-ACID ETHYL ESTERS	Approved (phase 4)
Olmesartan Medoxomil	Approved (phase 4)
Phenformin	Approved (phase 4)
Pioglitazone	Approved (phase 4)
Pramlintide	Approved (phase 4)
Ramipril	Approved (phase 4)
Repaglinide	Approved (phase 4)
Rosiglitazone	Approved (phase 4)
Semaglutide	Approved (phase 4)
Sitagliptin	Approved (phase 4)
Sodium Chloride	Approved (phase 4)
Sotagliflozin	Approved (phase 4)
Telmisartan	Approved (phase 4)
Teneligliptin	Approved (phase 4)
Tirzepatide	Approved (phase 4)
Tolazamide	Approved (phase 4)
Tolbutamide	Approved (phase 4)
Tolrestat	Approved (phase 4)
Troglitazone	Approved (phase 4)
Valsartan	Approved (phase 4)
Vildagliptin	Approved (phase 4)
Voglibose	Approved (phase 4)
Alirocumab	Phase 3 (in late-stage trials)
Aliskiren	Phase 3 (in late-stage trials)
Alogliptin	Phase 3 (in late-stage trials)
Amlodipine	Phase 3 (in late-stage trials)
Ascorbic Acid	Phase 3 (in late-stage trials)
Aspirin	Phase 3 (in late-stage trials)
Atorvastatin	Phase 3 (in late-stage trials)
Benazepril	Phase 3 (in late-stage trials)
Biguanide	Phase 3 (in late-stage trials)
Cabergoline	Phase 3 (in late-stage trials)
Chlorthalidone	Phase 3 (in late-stage trials)
Cinnamon	Phase 3 (in late-stage trials)
Denosumab	Phase 3 (in late-stage trials)
Dorzagliatin	Phase 3 (in late-stage trials)
Doxazosin	Phase 3 (in late-stage trials)
Enavogliflozin	Phase 3 (in late-stage trials)
Ertugliflozin	Phase 3 (in late-stage trials)
Estrogens, Conjugated	Phase 3 (in late-stage trials)
Ezetimibe	Phase 3 (in late-stage trials)
Fasiglifam	Phase 3 (in late-stage trials)
Finerenone	Phase 3 (in late-stage trials)
Gemigliptin	Phase 3 (in late-stage trials)
Glucagon Hydrochloride	Phase 3 (in late-stage trials)
Imiglitazar	Phase 3 (in late-stage trials)
Insulin Pork	Phase 3 (in late-stage trials)
Insulin Susp Isophane Beef	Phase 3 (in late-stage trials)
Insulin Susp Isophane Recombinant Human	Phase 3 (in late-stage trials)
Insulin Zinc Susp Recombinant Human	Phase 3 (in late-stage trials)
Lisinopril Anhydrous	Phase 3 (in late-stage trials)
MK-0767	Phase 3 (in late-stage trials)
Mecasermin	Phase 3 (in late-stage trials)
Medroxyprogesterone Acetate	Phase 3 (in late-stage trials)
Mitiglinide	Phase 3 (in late-stage trials)
Muraglitazar	Phase 3 (in late-stage trials)
Omarigliptin	Phase 3 (in late-stage trials)
Oxygen	Phase 3 (in late-stage trials)
Ozone	Phase 3 (in late-stage trials)
POLYETHYLENE GLYCOL 3350	Phase 3 (in late-stage trials)
POLYETHYLENE GLYCOL 4000	Phase 3 (in late-stage trials)
Pantoprazole	Phase 3 (in late-stage trials)
Pravastatin	Phase 3 (in late-stage trials)
Progesterone	Phase 3 (in late-stage trials)
Retatrutide	Phase 3 (in late-stage trials)
Sildenafil	Phase 3 (in late-stage trials)
Simvastatin	Phase 3 (in late-stage trials)
Somatropin	Phase 3 (in late-stage trials)
Thiazolidinedione	Phase 3 (in late-stage trials)
Urea	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Allopurinol, Amitriptyline, Anakinra, Apabetalone, Azilsartan, Cholecalciferol, Cyclosporine, Daclizumab, Dextrose, Duloxetine, Eculizumab, Efpeglenatide, Ergocalciferol, Lobeglitazone, Metformin Glycinate, Phentermine, Pregabalin, Ranibizumab, Rosuvastatin, Ruboxistaurin, Succinobucol, Tacrolimus Anhydrous, Topiramate, Ursodiol, Xylitol.

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 4 · Phased (≥1): 5 · Undrugged: 21

Druggability breadth: 11 of 26 evidence-associated genes (42%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ABCC8	REPAGLINIDE
KCNJ11	PINACIDIL ANHYDROUS
MEN1	LOPERAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MEN1	475	4
KCNJ11	7	4
ABCC8	6	4
GCK	5	2
PMM2	1	3
ZBTB20	0	0
EIF2S3	0	0
PAX6	0	0
SALL1	0	0
SPINK1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
REPAGLINIDE	4	ABCC8
DIAZOXIDE	4	ABCC8, KCNJ11
GLYBURIDE	4	ABCC8, KCNJ11, MEN1
PINACIDIL ANHYDROUS	4	KCNJ11
PROPAFENONE	4	KCNJ11
LOPERAMIDE	4	MEN1
CANDESARTAN CILEXETIL	4	MEN1
EVANS BLUE FREE ACID	4	MEN1
DIENESTROL	4	MEN1
BEXAROTENE	4	MEN1
IFOSFAMIDE	4	MEN1
PROGESTERONE	4	MEN1
CLOTRIMAZOLE	4	MEN1
AMINOCAPROIC ACID	4	MEN1
LATANOPROST	4	MEN1
FLUORESCEIN	4	MEN1
OXCARBAZEPINE	4	MEN1
SALMETEROL XINAFOATE	4	MEN1
AMIODARONE HYDROCHLORIDE	4	MEN1
TRICLABENDAZOLE	4	MEN1
TRYPAN BLUE FREE ACID	4	MEN1
MIGALASTAT	4	MEN1
DROPERIDOL	4	MEN1
ARIPIPRAZOLE	4	MEN1
AMOXAPINE	4	MEN1
RALOXIFENE HYDROCHLORIDE	4	MEN1
IDARUBICIN	4	MEN1
ACETAMINOPHEN	4	MEN1
OXYBUTYNIN CHLORIDE	4	MEN1
DECAMETHONIUM BROMIDE	4	MEN1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GCK	228	Binding:226, ADMET:1, Functional:1
KCNJ11	102	Functional:59, Binding:43
MEN1	93	Binding:86, Functional:7
ABCC8	84	Functional:52, Binding:32
TLR1	59	Binding:59
TLR6	28	Binding:28
KSR2	28	Binding:28
INS	8	Binding:7, ADMET:1
PMM2	3	Binding:3
HNF1A	1	Binding:1
WFS1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EIF2S3	3.6.5.3	protein-synthesizing GTPase
KSR2	2.7.11.25	mitogen-activated protein kinase kinase kinase
GCK	2.7.1.1	hexokinase
PMM2	5.4.2.8	phosphomannomutase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
GCK	228
KCNJ11	102

Pharmacogenomics

Cohort genes with a PharmGKB record: 26; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

28 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
DIAZOXIDE	4	ABCC8, KCNJ11
PINACIDIL ANHYDROUS	4	KCNJ11
PROPAFENONE	4	KCNJ11
LOPERAMIDE	4	MEN1
CANDESARTAN CILEXETIL	4	MEN1
EVANS BLUE FREE ACID	4	MEN1
DIENESTROL	4	MEN1
BEXAROTENE	4	MEN1
IFOSFAMIDE	4	MEN1
PROGESTERONE	4	MEN1
CLOTRIMAZOLE	4	MEN1
AMINOCAPROIC ACID	4	MEN1
LATANOPROST	4	MEN1
FLUORESCEIN	4	MEN1
OXCARBAZEPINE	4	MEN1
SALMETEROL XINAFOATE	4	MEN1
AMIODARONE HYDROCHLORIDE	4	MEN1
TRICLABENDAZOLE	4	MEN1
TRYPAN BLUE FREE ACID	4	MEN1
MIGALASTAT	4	MEN1
DROPERIDOL	4	MEN1
ARIPIPRAZOLE	4	MEN1
AMOXAPINE	4	MEN1
RALOXIFENE HYDROCHLORIDE	4	MEN1
IDARUBICIN	4	MEN1
ACETAMINOPHEN	4	MEN1
OXYBUTYNIN CHLORIDE	4	MEN1
DECAMETHONIUM BROMIDE	4	MEN1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	ABCC8, KCNJ11, MEN1
B	Phased (≥1) drug, not yet approved	2	GCK, PMM2
C	Druggable family + PDB, no drug	2	EIF2S3, KSR2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	19	ZBTB20, PAX6, SALL1, SPINK1, HNF1A, HNF1B, KLF11, TLR1, TMEFF2, WFS1 (+9 more)

Undrugged target profiles

21 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
HNF1A	1	GCK
WFS1	1	ABCC8
ZBTB20	0	—
EIF2S3	0	—
PAX6	0	—
SALL1	0	—
SPINK1	0	—
HNF1B	0	—
KLF11	0	—
TLR1	59	—
TMEFF2	0	—
TLR10	0	—
TLR6	28	—
KSR2	28	—
THADA	0	—
ARMC9	0	—
RFX6	0	—
GLIS3	0	—
PLEKHH2	0	—
INS-IGF2	0	—
INS	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6,047.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE4	513
PHASE3	501
PHASE2/PHASE3	63
PHASE2	19
PHASE1/PHASE2	4

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00135226	PHASE4	ACTIVE_NOT_RECRUITING	ASCEND: A Study of Cardiovascular Events iN Diabetes
NCT03520660	PHASE4	ACTIVE_NOT_RECRUITING	People With CHC Who Achieved a Sustained Virological Response Following Therapy With Direct Acting Antiviral Agents
NCT04286399	PHASE4	RECRUITING	Asian Diabetes Outcomes Prevention Trial
NCT04297592	PHASE4	ENROLLING_BY_INVITATION	Antibiotic Prophylaxis in High-Risk Arthroplasty Patients
NCT04416269	PHASE4	ACTIVE_NOT_RECRUITING	Oral Anti Diabetic Agents in the Hospital
NCT05195944	PHASE4	ENROLLING_BY_INVITATION	Semaglutide vs Sitagliptin
NCT05591339	PHASE4	ACTIVE_NOT_RECRUITING	Diabetes Diagnosis, Management, Prevention and Education in Guinea-Bissau
NCT05659147	PHASE4	ENROLLING_BY_INVITATION	Imaging Biomarkers of Pancreatic Function and Disease
NCT05702931	PHASE4	RECRUITING	Semaglutide Treatment for Hyperglycaemia After Renal Transplantation
NCT06132477	PHASE4	RECRUITING	Impact GLP-1 Agonists Following Bariatric
NCT06140537	PHASE4	RECRUITING	Efficacy and Mechanisms of Dapagliflozin in Promoting Kidney Function and Cardiovascular Health in Kidney Transplant Recipients
NCT06427889	PHASE4	RECRUITING	Treatment Effects of Two Pharmaceutical Skin Care Creams for Xerotic Feet Among Persons with Diabetes
NCT06439758	PHASE4	NOT_YET_RECRUITING	Effects of First-Line Oral Hypoglycemics in Bone Markers of Treatment Naïve Saudi Adults With Type 2 Diabetes
NCT06442280	PHASE4	NOT_YET_RECRUITING	SGLT-2 Inhibitor and High-Dose Furosemide Plus Small-Volume Hypertonic Saline Solution in Acute HF
NCT06657209	PHASE4	RECRUITING	Normal-weight Diabetes: Adipocyte-directed Therapy With Pioglitazone or Tirzepatide
NCT06709313	PHASE4	ACTIVE_NOT_RECRUITING	Effect of Chromium on Blood Sugar After Sacroiliac Joint Injection
NCT06767774	PHASE4	RECRUITING	Comparison of Pitavastatin Plus Ezetimibe Versus High-Intensity Statin Therapy on Risk of New-Onset Diabetes Mellitus
NCT06813014	PHASE4	NOT_YET_RECRUITING	Pharmacogenetics of Response to Sitagliptin (PRS)
NCT06846411	PHASE4	RECRUITING	The EMPA-FIT Study
NCT06851962	PHASE4	ACTIVE_NOT_RECRUITING	Impact of Pharmacogenetic-Guided Treatment on Type 2 Diabetes.
NCT06862739	PHASE4	RECRUITING	Glycemic Control With Triple Pathway Approach Through Empagliflozin, Linagliptin and Metformin Combination
NCT06903546	PHASE4	RECRUITING	The Effect of Propolis Administration on Cholesterol Level in Diabetic Type 2 Patients
NCT06959784	PHASE4	ENROLLING_BY_INVITATION	Assessing Incretin Therapy for Cardiovascular Risk Reduction and Diabetes Remission( ITCRDR Study)
NCT06999551	PHASE4	NOT_YET_RECRUITING	Comparison of the Efficacy and Safety of GLARGEN® Versus NPH Insulin in Diabetic Tunisian Patients.
NCT07017270	PHASE4	NOT_YET_RECRUITING	Glucagon-like-peptide-1 Receptor Agonists in Patients Receiving Maintenance Dialysis
NCT07117240	PHASE4	ENROLLING_BY_INVITATION	Evaluation of the Efficacy and Safety of GLP-1 Receptor Agonist Therapy In Steroid-Induced Diabetes
NCT07121088	PHASE4	NOT_YET_RECRUITING	Traditional Chinese Medicine Intervention for Ischemic Cerebrovascular Disease and Diabetes Mellitus: An Efficacy Comparative Study
NCT07228195	PHASE4	NOT_YET_RECRUITING	SGLT2i Therapy in Islet Transplantation (SIT)
NCT07274644	PHASE4	ENROLLING_BY_INVITATION	Effects of iGlarLixi Versus iGlar on Liver Fat Content in Patients With Type 2 Diabetes Mellitus Combined With Metabolic Dysfunction-associated Steatotic Liver Disease
NCT07323381	PHASE4	NOT_YET_RECRUITING	Effects of Henagliflozin Proline and Metformin XR on Body Composition in Geriatric Patients With Newly Diagnosed T2DM
NCT07489924	PHASE4	ACTIVE_NOT_RECRUITING	Microbiological Effect of 0.12% Chlorhexidine Digluconate and 0.05% Cetylpyridinium Chloride vs Probiotics (Lactobacillus Reuteri Prodentis) on Porphyromonas Gingivalis.
NCT07561541	PHASE4	RECRUITING	Extended Oral Antibiotic Prophylaxis in Diabetic Fracture Patients
NCT00044746	PHASE4	COMPLETED	Study Evaluating the Safety and Efficacy of Piperacillin/Tazobactam and Ampicillin/Sulbactam in Patients With Diabetic Foot Infections
NCT00069602	PHASE4	COMPLETED	Assessing Continuous Glucose Monitors in Healthy Children
NCT00079638	PHASE4	COMPLETED	Comparative Efficacy Evaluation of Lipids When Treated With Niaspan & Statin or Other Lipid-Modifying Therapies-COMPELL
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00108615	PHASE4	COMPLETED	Effects of Insulin Sensitizers in Subjects With Impaired Glucose Tolerance
NCT00117780	PHASE4	COMPLETED	Comparison of Insulin Detemir Given Once or Twice Daily in Type 1 Diabetes
NCT00120341	PHASE4	COMPLETED	Anodyne Therapy in Diabetic Sensory Neuropathy

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
INSULIN DEGLUDEC	4	65
INSULIN DETEMIR	4	64
INSULIN ASPART	4	61
ALOGLIPTIN	4	45
INSULIN HUMAN	4	45
SEMAGLUTIDE	4	27
GLIMEPIRIDE	4	26
SITAGLIPTIN	4	25
METFORMIN	4	24
SAXAGLIPTIN ANHYDROUS	4	24
ROSIGLITAZONE	4	22
INSULIN GLARGINE	4	21
CANAGLIFLOZIN ANHYDROUS	4	18
LIRAGLUTIDE	4	17
PIOGLITAZONE	4	17
REPAGLINIDE	4	16
EMPAGLIFLOZIN	4	15
GLYBURIDE	4	15
ROSUVASTATIN	4	14
DAPAGLIFLOZIN	4	11
LINAGLIPTIN	4	11
CLOPIDOGREL BISULFATE	4	9
INSULIN GLULISINE	4	8
VILDAGLIPTIN	4	8
EXENATIDE	4	7
SIMVASTATIN	4	7
ALISKIREN	4	6
AMLODIPINE	4	6
DULAGLUTIDE	4	6
INSULIN LISPRO	4	6