Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

TLDR: The mechanisms underlying the plasma glucose level-lowering effects of metformin (1,1-dimethylbiguanide) still remain incompletely understood as discussed by the authors. But, the role of AMPK has been challenged and might only account for indirect changes in hepatic insulin sensitivity.

Abstract: Despite its position as the first-line drug for treatment of type 2 diabetes mellitus, the mechanisms underlying the plasma glucose level-lowering effects of metformin (1,1-dimethylbiguanide) still remain incompletely understood. Metformin is thought to exert its primary antidiabetic action through the suppression of hepatic glucose production. In addition, the discovery that metformin inhibits the mitochondrial respiratory chain complex 1 has placed energy metabolism and activation of AMP-activated protein kinase (AMPK) at the centre of its proposed mechanism of action. However, the role of AMPK has been challenged and might only account for indirect changes in hepatic insulin sensitivity. Various mechanisms involving alterations in cellular energy charge, AMP-mediated inhibition of adenylate cyclase or fructose-1,6-bisphosphatase 1 and modulation of the cellular redox state through direct inhibition of mitochondrial glycerol-3-phosphate dehydrogenase have been proposed for the acute inhibition of gluconeogenesis by metformin. Emerging evidence suggests that metformin could improve obesity-induced meta-inflammation via direct and indirect effects on tissue-resident immune cells in metabolic organs (that is, adipose tissue, the gastrointestinal tract and the liver). Furthermore, the gastrointestinal tract also has a major role in metformin action through modulation of glucose-lowering hormone glucagon-like peptide 1 and the intestinal bile acid pool and alterations in gut microbiota composition.

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Understanding the glucoregulatory mechanisms of
metformin in type 2 diabetes mellitus
Marc Foretz, Bruno Guigas, Benoit Viollet
To cite this version:
Marc Foretz, Bruno Guigas, Benoit Viollet. Understanding the glucoregulatory mechanisms of met-
formin in type 2 diabetes mellitus. Nature Reviews Endocrinology, Nature Publishing Group, 2019,
�10.1038/s41574-019-0242-2�. �inserm-02277186�

1
Understandingtheglucoregulatorymechanismsofmetforminintype
2diabetesmellitus



MarcForetz
1,2,3
,BrunoGuigas
4
andBenoitViollet
1,2,3
*


1
INSERM,U1016,InstitutCochin,Paris,France.
2
CNRS,UMR8104,Paris,France.
3
UniversitéParisDescartes,SorbonneParisCité,France.
4
DepartmentofParasitology,LeidenUniversityMedicalCenter,Leiden,Netherlands.

*email:benoit.viollet@inserm.fr




2
ABSTRACT

Despite its position as the first‐line treatment for type 2 diabetes mellitus, the
mechanisms underlying the plasma glucose level‐lowering effects of metformin (1,1‐
dimethylbiguanide)stillremainincompletelyunderstood.Metforministhoughttoexert
itsprimaryantidiabeticactionthroughthesuppressionofhepaticglucoseproduction.
Furthermore,thediscoverythatmetformininhibitsthemitochondrialrespiratory‐chain
complex1hasplacedenergymetabolismandactivationofAMP‐activatedproteinkinase
(AMPK)atthecenterofitsmechanismofaction.However,theroleofAMPKhasbeen
challenged and might only account for indirect changes in hepatic insulin sensitivity.
Various mechanisms involving alterations of cellular energy charge, AMP‐mediated
inhibitionofadenylatecyclaseorfructose‐1,6‐bisphosphatase‐1(FBP1)andmodulation
of the cellular redox state through direct inhibition of mitochondrial glycerol‐3‐
phosphate dehydrogenase (mG3PDH) are proposed for the acute inhibition of
gluconeogenesis by metformin. Emerging evidence suggests that metformin could
improve obesity‐induced meta‐inflammation via direct and indirecteffectsontissue‐
residentimmunecellsinmetabolicorgans(thatis,adiposetissue,thegastrointestinal
tract and the liver). Furthermore, the gastrointestinal tract  also has a major role in
metformin action through modulation of glucose‐lowering hormone glucagon‐like
peptide‐1 (GLP‐1) and intestinal bile acid pool and alterations in gut microbiota
composition.





3
Keypoints

•Metforministhefirst‐linedrugfortreatmentoftype2diabetes mellitus, with an
excellent safety profile, high efficacy on glycaemic control and clear but incompletely
understoodcardioprotectivebenefits.

•Thepleiotropicpropertiesofmetforminsuggestthatthedrugactsonmultipletissues
through various underlying mechanismsratherthanonasingleorganviaanunifying
modeofaction.

• The mitochondrial respiratory‐chaincomplex 1 is a key cellular target of metformin
anditsmildandtransientinhibitionisinvolvedintheAMPK‐independentregulationof
hepatic gluconeogenesis by triggering alterations in the cellular energy charge and
redoxstate.

• Metformin might contribute to improvements in obesity‐associated meta‐
inflammationandtissue‐specificinsulinsensitivitythroughdirectandindirecteffectson
variousresidentimmunecellsinmetabolicorgans.

• The gastrointestinal tract has an important role in the action of metformin, which
modulatesbileacidrecirculationandenhancesthesecretionoftheglucose‐loweringgut
incretinhormoneglucagon‐likepeptide‐1(GLP1).

•Thegutmicrobiotarepresentsanoveltargetinthemechanismsofmetforminaction
andisinvolvedinboththetherapeuticandadverseeffectsofthedrug.



4

Introduction
Metforministhefirstlineoftreatmentinpatientswithtype2diabetesmellitus(T2DM)
asrecommendedbyclinicalguidelinespublishedbytheAmericanDiabetesAssociation
(ADA) and the European Association for the Study of Diabetes (EASD)
1,2
, which are
supportedbyprospectivestudies
3,4
andrecent2016meta‐analyses
5,6
.Theseguidelines
arebasedontheimprovedglycaemicprofileandreductionincardiovascularmortality
inducedbymetformintreatment,withouttheriskofhypoglycaemiaand/orbodyweight
gains that are associated with the use of other antidiabetic drugs
3,4,6,7
. Furthermore,
metforminisalsothefavouredantidiabeticdrugbecauseofitsgoodsafetyprofileand
minimalcost
8
.
The drug metformin is a biguanide derivate (1,1‐dimethylbiguanide hydrochloride),
whichoriginatesfromtheplantgoat’srueorFrenchlilac(Galegaofficinalis)
9
.Originally
used in medieval Europe to relieve the symptoms of diabetes mellitus, this plant
containsgalegine,anisoprenylguanidine.Althoughmono‐anddiguanidinederivatives
aretoxic,thebiguanides(twoN‐linked molecules of guanidine) synthesized from the
reactionbetweendimethylaminehydrochlorideanddicyanodiamide
10
havebeenused
forthetreatmentofdiabetes mellitussince thelate1950s(REF.
9
).Ofnote,metformin
hasbeenapprovedforuseinEuropeandCanadasince1957,althoughitwasonly
introducedintotheUSAin1995.Themorepotentbiguanides,phenformin and
buformin, were quite popular in the USA and Europe in the 1960sbutwereremoved
fromthemarketsinmostcountriesinthelate1970sowingtoanincreasedriskoflactic
acidosis
11
.Bycontrast,theincidenceoflacticacidosisassociatedwith metformin
treatmentisverylow(approximately3to10casesper100,000person‐yearsand~1.5
deathsper100,000patient‐years.),exceptinhigh‐riskgroups,particularlypatientswith
chronically impaired renal function or in acute kidney disease
8
. The most common
adverseeffectofmetforminisusuallygastrointestinalintolerance(BOX1).
Metformin is described as an anti‐hyperglycaemic agent that does not cause
clinical hypoglycaemia in patients with T2DM, nor alter glucose homeostasis in non‐
diabeticindividuals
5‐7
.Althoughmetforminhasbeenavailableforover60yearsforthe
treatmentof T2DM,theexactmechanism(s)foritseffects onbloodglucose levelsstill
remainedelusive
12
.However,severalactionshavebeenattributedtoitsabilitytolower
bloodglucose. For example,metforminactsprimarilybythesuppression of enhanced

Frequently asked questions

Q1. What are the contributions mentioned in the paper "Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus" ?

In this paper, the effects of metformin on metabolic pathways and the regulation of whole-body glucose homeostasis were investigated. 

Q2. What future works have the authors mentioned in the paper "Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus" ?

Therapeutic strategies to overcome metformin gastrointestinal intolerance include gradual uptitration of immediate‐release metformin or use of extended‐release and delayed‐release formulations of the drug217. A recent 2018 pharmacokinetic study reported the absence of significant differences in the absorption, distribution or elimination of metformin between tolerant and intolerant individuals, suggesting the involvement of local factors within the intestinal lumen or enterocytes218. Another potential mechanism by which metformin might cause gastrointestinal disturbances is by decreasing reabsorption of bile acids, leading to elevated colonic bile acid concentrations, thereby causing diarrhoea160,222. In combination with lifestyle intervention, metformin treatment is also associated with lower body weight and improved menstrual cyclicity and fertility potential239‐241 in women with obesity and PCOS237. 

Q3. What is the role of metformin in the inhibition of gluconeogenesis?

The alteration of hepatic redox potential caused by metformin probably has an important role in the inhibition of gluconeogenesis. 

Q4. What is the role of the gut microbiota in regulating glucose homeostas?

The gut microbiota also plays an important role for bile acid homeostasis, by generating unconjugated and secondary bile acids196. 

Q5. What is the role of metformin in the metabolic function of the microbiome?

In addition to the modulation of microbiome composition, metformin treatment has been reported to improve metabolic functions of the microbiomeand interactions with host metabolism. 

Q6. What mechanism has been suggested to increase glucose absorption in the upper small intestine?

a mechanism has been suggested in which metformin acts to decrease glucose absorption in the upper small intestine, which causes an increase inglucose concentrations in more distal regions of the gut. 

Q7. What is the mechanism by which intestinal glucose contribute to the release of GLP1?

The mechanism by which intestinal glucose contribute to the release of GLP1 implicates a role for SGLT1‐mediated glucose uptake in enteroendocrine cells178,179. 

Q8. What is the important explanation for the reduction of hepatic gluconeogenic?

As such, the decrease in intracellular ATP levels resulting from the inhibition of mitochondrial respiratory‐chain complex 1 could be the simplest explanation to account for the reduction of hepatic gluconeogenic flux by metformin68. 

Q9. What is the main reason for the use of metformin in T1DM?

Given the absence of metformin effects to improve blood glucose control and its minor beneficial effects, the use of metformin for patients with T1DM is questionable. 

Q10. What is the role of the immune system in the regulation of wholebody metabolic homeosta?

The immune system is now well recognized to have a key role in the regulation of whole‐body metabolic homeostasis through a variety of innate and adaptive immune cells that are present in various organs, most notably in adipose tissue and the liver98,99.