Evidence map›Paper›PMID 26727229›Full record

ReviewThe Journal of clinical investigation2016

The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux.

Varman T Samuel, Gerald I Shulman

Open access · bronzeAbstract readReview
PubMed Full text at PMC Publisher
In one paragraph

Review in The Journal of clinical investigation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 782 papers, 9 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
782citing papers in PubMed, 9 pooled it
98.8field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

782 citing papers in PubMed, 9 syntheses or guidelines pooled it, 1,364 citations in OpenAlex.

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722 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

2 authors at 1 institution in 1 country.

Varman T Samuel
Gerald I Shulman
Yale University · US

Funding

Yale Diabetes Research CenterP30DK045735 · NIDDK · YALE UNIVERSITY · PI Richard A Flavell · 1993 to 2026
$44.0M
Yale Mouse Metabolic Phenotyping CenterU24DK059635 · NIDDK · YALE UNIVERSITY · PI SHULMAN, GERALD I · 2001 to 2015
$8.9M
Genetic and Cellular Mechanisms of NAFLD and Hepatic Insulin ResistanceR24DK085638 · NIDDK · YALE UNIVERSITY · PI SHULMAN, GERALD I · 2010 to 2014
$6.3M
NMR STUDIES OF GLYCOGEN METABOLISM IN HUMANSR01DK049230 · NIDDK · YALE UNIVERSITY · PI SHULMAN, GERALD I · 1995 to 2014
$5.4M
Mechanisms of Lipid-Induced Hepatic Insulin ResistanceR01DK040936 · NIDDK · YALE UNIVERSITY · PI SHULMAN, GERALD I · 1989 to 2015
$5.1M
Yale Mouse Metabolic Phenotyping CenterU2CDK059635 · NIDDK · YALE UNIVERSITY · PI SHULMAN, GERALD I · 2016 to 2016
$493k
Cellular mechanisms for increased gluconeogenesis in type 2 diabetes mellitus: the role of lipid induced pyruvate carboxylase acetylation in increasing hepatic gluconeogenic capacity.I01BX000901 · VA · VA CONNECTICUT HEALTHCARE SYSTEM · PI SAMUEL, VARMAN T · 2012 to 2020
–
BLRD VA I01 BX000901NIDDK NIH HHS DK-059635NIDDK NIH HHS DK-085638NIDDK NIH HHS DK-40936NIDDK NIH HHS DK-45735NIDDK NIH HHS DK-49230NIDDK NIH HHS P30 DK045735NIDDK NIH HHS R01 DK040936NIDDK NIH HHS R01 DK049230NIDDK NIH HHS R24 DK085638NIDDK NIH HHS U24 DK059635
6 · The paper itself

Abstract

Insulin resistance arises when the nutrient storage pathways evolved to maximize efficient energy utilization are exposed to chronic energy surplus. Ectopic lipid accumulation in liver and skeletal muscle triggers pathways that impair insulin signaling, leading to reduced muscle glucose uptake and decreased hepatic glycogen synthesis. Muscle insulin resistance, due to ectopic lipid, precedes liver insulin resistance and diverts ingested glucose to the liver, resulting in increased hepatic de novo lipogenesis and hyperlipidemia. Subsequent macrophage infiltration into white adipose tissue (WAT) leads to increased lipolysis, which further increases hepatic triglyceride synthesis and hyperlipidemia due to increased fatty acid esterification. Macrophage-induced WAT lipolysis also stimulates hepatic gluconeogenesis, promoting fasting and postprandial hyperglycemia through increased fatty acid delivery to the liver, which results in increased hepatic acetyl-CoA content, a potent activator of pyruvate carboxylase, and increased glycerol conversion to glucose. These substrate-regulated processes are mostly independent of insulin signaling in the liver but are dependent on insulin signaling in WAT, which becomes defective with inflammation. Therapies that decrease ectopic lipid storage and diminish macrophage-induced WAT lipolysis will reverse the root causes of type 2 diabetes.

Indexed as

Insulin ResistanceLipid MetabolismAdipose TissueAnimalsGlucoseHumansLiverMuscle, SkeletalSignal TransductionTriglyceridesGlucoseTriglycerides

Identifiers

PMID26727229
PMCPMC4701542
OpenAlexW2230222215

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.