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SMOC1 as a therapeutic target for type 2 diabetes

ABSTRACT: Inter-tissue communication is a fundamental feature of systemic metabolic regulation and the liver is central to this process. We have identified sparc-related modular calcium-binding protein 1 (SMOC1) as a glucose-responsive hepatokine and potent regulator of glucose homeostasis. Acute administration of recombinant SMOC1 improves glycemic control and insulin sensitivity, independent of changes in insulin secretion. SMOC1 exerts its favourable glycemic effects by inhibiting cAMP-PKA-CREB signaling in the liver, leading to decreased gluconeogenic gene expression and suppression of hepatic glucose output. Over expression of SMOC1 in the liver or once-weekly injections of a stabilized SMOC1-FC fusion protein induces durable improvements in glucose tolerance and insulin sensitivity in db/db mice, without significant adverse effects on adiposity, liver histopathology or inflammation. Furthermore, SMOC1 correlates with systemic insulin sensitivity and is decreased in obese, insulin resistant humans. Together, these findings identify SMOC1 as a potential pharmacological target for the management of glycemic control in type 2 diabetes.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: Cheng Huang

LAB HEAD: Matthew J Watt

PROVIDER: PXD015767 | Pride | 2020-08-21

REPOSITORIES: Pride

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			Action	DRS
	F1CHH_20160525_Phos_CTR1.raw	Raw
	F1CHH_20160525_Phos_CTR2.raw	Raw
	F1CHH_20160525_Phos_CTR3.raw	Raw
	F1CHH_20160525_Phos_CTR4.raw	Raw
	F1CHH_20160525_Phos_CTR5.raw	Raw

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Project description:Insulin resistance represents a hallmark during the development of type 2 diabetes mellitus (T2D) and in the pathogenesis of obesity-associated disturbances of glucose and lipid metabolism 1,2,3. MicroRNA (miR)-dependent posttranscriptional gene silencing has recently been recognized to control gene expression in disease development and progression including that of insulin-resistant T2D. MiRs, whose deregulation alters hepatic insulin sensitivity include miR-143, miR-181 and miR-103/107. Here we report that expression of miR-802 is increased in liver of two obese mouse models and of obese human subjects. Inducible transgenic overexpression of miR-802 in mice causes impaired glucose tolerance and attenuates insulin sensitivity, while reduction of miR-802 expression improves glucose tolerance and insulin action. We identify Tcf2 as a target of miR-802-dependent silencing and shRNA-mediated reduction of Tcf2 in liver causes glucose intolerance, impairs insulin signaling and promotes hepatic gluconeogenesis. In turn, hepatic overexpression of Tcf2 improves insulin sensitivity in db/db mice. Thus, the present study defines a critical role for deregulated expression of miR-802 in the development of obesity-associated impairment of glucose metabolism via targeting Tcf2 and assigns Tcf2 an unexpected role in the control of hepatic insulin sensitivity. Adenoviruses (Ad5) encoding either GFP (Ad-Ctrl 1-3) or shTcf2 (Ad-shTcf2 1-4) were injected into the tail vein of C57BL/6 mice at 1x10E10 viral particles (VP) per gram bodyweight. Biotin-labeled cDNA was synthesized using GeneChip Whole Transcript Sense Labeling Assay (Affymetrix) according to vendorM-bM-^@M-^Ys instructions. After fragmentation, cDNAs were hybridized for 17h at 45M-BM-0C on Affymetrix Mouse Gene 1.0 ST Arrays. The Arrays were washed and stained in the GeneChip Fluidics Station 450 and scanned on a GeneChip Scanner 3000 7G (Affymetrix). Data intensities were log transformed and normalized with a quantile normalization method using Affymetrix Power Tools. Differentially expressed genes were identified according to statistical evidence indicated by Student's t-test and fold change statistics

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SMOC1 as a therapeutic target for type 2 diabetes

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