Minireviews
Copyright ©The Author(s) 2016.
World J Diabetes. Mar 25, 2016; 7(6): 122-133
Published online Mar 25, 2016. doi: 10.4239/wjd.v7.i6.122
Table 1 Role of AMP-activated protein kinase activation on cell metabolism in different organs
OrganEffectMechanism of actionRef.
LiverInhibition of anabolic pathwaysInhibition of fatty acid synthesis[27]
Inhibition of gluconeogenesis
Stimulation of ATP synthesisStimulation of Mitochondrial oxidative phosphorylation[27]
Skeletal muscleRegulation of energy expenditure during exerciseFavours the transition from glycolitic to oxidative skeletal muscle fibers[28]
Regulation of myocitic uptake and oxidation of fatty acids[21]
Enhanced glucose uptake via an increase in GLUT4 expression[21]
Increase in skeletal muscle regenerationRegulation of post-injury inflammatory response[29]
Stem cell reprogramming: Induction of proliferation, differentiation and self-renewal[21]
BoneIncrease in osteoblastogenesisIncreases MSC differentiation towards the osteoblastic lineage favouring Runx2 expression[30,37]
Decreases PPARγ expression diminishing MSC differentiation towards the adipocytic phenotype[36,37]
Decrease in osteoclastogenesisNegative regulation of RANKL expression by osteoblasts[35]
Table 2 Clinical evidences of metformin effects on bone
Study designStudy populationnOutcomeRef.
Case control studyAll subjects with bone fracture in Denmark (year 2000), vs 3-fold controls124655 fracture patients 373962 controlFracture risk = 0.81 (95%CI: 0.70-0.93)1 (for metformin)[59]
Cohort StudyRochester residents first meeting Diabetes glycaemic criteria (1970-1994)1964 diabetic patientsFracture risk = 0.7 (95%CI: 0.6-0.96)2 (for metformin)[6]
Case control studyA study nested within a cohort of 1945 diabetic Tuscany outpatients (1998-2004)83 fracture patients 249 controlFracture risk = 0.60 (95%CI: 0.34-1.08)3 (for metformin)[60]
Double-blind, randomized, controlled clinical trialRecently diagnosed, drug-naïve patients with type 2 diabetes, treated for a median of 4 yr with rosiglitazone, metformin, or glyburideRosiglitazone: n = 1456; Metformin: n = 1454; Glyburide: n = 1441Nº Fractures (%): Rosiglitazone 60 (9.30) Metformin 30 (5.08)4 Glyburide 21 (3.47)4[12]
Double-blind, randomized, controlled clinical trialRecently diagnosed, drug-naïve patients with type 2 diabetes, treated for a median of 4 yr with RSG, MET, or GLYPaired baseline and 12-mo stored serum samples from 1605 patientsIn women, CTX increased by 6.1% with RSG, decreased by 1.3% with MET (P = 0.03) In men, CTX was unchanged on RSG (-1.0%) and fell with MET -12.7% (P = 0.001)[61]
Randomized, parallel group, double-blind, multicentre studyDrug naïve, male and female patients who had an established clinical diagnosis of type 2 diabetes mellitus688 patients equally randomized to RSG/MET or METBMD at week 80: Lumbar = (-2.2) (95%CI: -3.5, -0.9) Total hip = (-1.5) (95%CI: -2.3, -0.7)5[62]
Prospective randomized study with active comparator studyForty postmenopausal diabetic women recruited from Tanta University Hospitals20 patients on metformin and 20 on sitagliptin, for 12 wkBMD was unchanged in both groups at week 12 Bone turnover markers remained unchanged from baseline in MET[63]
Prospective randomized double-blind, double-dummy with active comparatorMen with uncomplicated type 2 diabetes mellitus, aged 45-65 yr71 men were randomized to PIO once daily or MET twice dailySclerostin levels at week 24 increased by 11% in PIO-treated patients and decreased by 1.8% in MET-treated patients (P = 0.018)[64]