Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0011860 (
type 2 diabetes
)
57,723
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The
kinase suppressor of ras 2
(
KSR2
) gene resides at human chromosome 12q24, a region linked to obesity and
type 2 diabetes
(T2D). While knocking out and phenotypically screening mouse orthologs of thousands of druggable human genes, we found
KSR2
knockout (
KSR2
(-/-)) mice to be more obese and glucose intolerant than melanocortin 4 receptor(-/-) (MC4R(-/-)) mice. The obesity and T2D of
KSR2
(-/-) mice resulted from hyperphagia which was unresponsive to leptin and did not originate downstream of MC4R. The kinases AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are each linked to food intake regulation, but only mTOR had increased activity in
KSR2
(-/-) mouse brain, and the ability of rapamycin to inhibit food intake in
KSR2
(-/-) mice further implicated mTOR in this process. The metabolic phenotype of
KSR2
heterozygous (
KSR2
(+/minus;)) and
KSR2
(-/-) mice suggests that human
KSR2
variants may contribute to a similar phenotype linked to human chromosome 12q24.
...
PMID:Profound obesity secondary to hyperphagia in mice lacking kinase suppressor of ras 2. 2112 80
Kinase suppressor of Ras 2
(
KSR2
) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of
KSR2
in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in
KSR2
that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish
KSR2
as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of
KSR2
-mediated effects may represent a novel therapeutic strategy for obesity and
type 2 diabetes
.
...
PMID:KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation. 2473 52
