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Report for Clinical Trial NCT03859934

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

Metabolic Effects of Melatonin Treatment

Modern living is associated with an epidemic of type 2 diabetes mellitus (T2DM). Sleep disturbances such as insomnia or frequent awakenings are strong risk factors for T2DM with several studies indicating a central role of melatonin. Additionally, a certain single nucleotide polymorphism in the melatonin receptor gene, MTNR1B rs10830963, with an allele frequency of 30 %, is associated with increased fasting plasma glucose and T2DM. Due to treatment of, among other things, insomnia, the use of melatonin is increasing rapidly in Denmark with a 100-fold increase from 2007-2012 in children and adolescents. No previous studies have thoroughly assessed changes in glucose and fatty acid metabolism after 3 months of melatonin treatment in patients with T2DM.

NCT03859934 Metabolic Disease Insulin Sensitivity Glucose Metabolism Disorders (Including Diabetes Mellitus) Type 2 Diabetes Mellitus Blood Pressure Inflammation
MeSH: Diabetes Mellitus Insulin Resistance Metabolic Diseases Glucose Metabolism Disorders Inflammation
HPO: Diabetes mellitus Insulin resistance

2 Interventions

Name: Melatonin

Description: Melatonin treatment

Type: Drug

Melatonin

Name: Placebo Oral Tablet

Description: Placebo treatment

Type: Drug

Placebo


Primary Outcomes

Description: Insulin sensitivity is assessed by a hyperinsulinemic euglycemic clamp, unit: mg/kg/min (mg of glucose to maintain euglycemia per kilogram of weight per minuts)

Measure: Change of insulin sensitivity

Time: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment and compared afterwards with a paired T-tes

Description: Insulin secretion is assessed by an intravenous glucose tolerance test, unit: pmol/L (insulin)

Measure: Change of insulin secretion change

Time: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

Description: MTNR1a rs10830963 genotype influence on insulin sensitivity and insulin secretion (see outcome 1 + 2)

Measure: MTNR1a rs10830963 influence on change in insulin sensitivity and insulin secretion

Time: The outcome will be measured after 3 months of placebo treatment and again after 3 months of melatonin treatment

Description: Insulin signalling in muscle and adipose tissue assessed by western blot

Measure: Change of insulin signalling

Time: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

Secondary Outcomes

Description: Ambulatory blood pressure assessed with Mobil-O-graph, I.E.M., Stolberg, Germany (Unit: mmHg)

Measure: Change of ambulatory blood pressure

Time: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

Description: Arterial stiffness assessed with Mobil-O-graph, I.E.M., Stolberg, Germany (unit: m/s)

Measure: Change of arterial stiffness

Time: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

Description: Feces analysis of microbial mRNA

Measure: Change of gut microbiome

Time: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

Description: Pittsburg Sleep Quality Index Questionnaire (Points on a scale: range 0-57)

Measure: Change of sleep evaluation 1

Time: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

Description: Epworth Sleepiness Scale Questionnaire (Points on a scale: range 0-24)

Measure: Change of sleep evaluation 2

Time: After 3 months treatmentThe outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

Description: Major Depression Inventory Questionnaires (points on a scale: range 0-65)

Measure: Change of psychological health 1

Time: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

Description: World Health Organization 5 Questionnaires (points on a scale: range 0-25)

Measure: Change of psychological health 2

Time: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

Description: Ghrelin, HbA1c, GLP-1, GLP-2, GIP, free fatty acids (FFA), leptin, cytokines, adiponectin, growth hormone, cortisol, hsCRP, CD163, MBL, IGF-1 and proinsulin measured by ELISA, RIA, or routine biochemical analysis. Unit: pmol/L

Measure: Hormonal changes

Time: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

Description: Tracer technique with infusion of radioactive labeled glucose and palmitate for determination of rate of appereance. Unit: mikromol/min

Measure: Change of glucose and palmitate kinetics

Time: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

Description: Forearm model with arteriovenous differences of glucose and palmitate (Arterial glucose minus venous glucose = forearm uptake (unit mmol/l). The same applies for palmitate

Measure: Change of regional glucose and palmitate uptake

Time: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

Description: Evaluation of body composition and bone mineral density by DEXA-scan

Measure: Change of DEXA-scans

Time: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

Description: Assessment of respiratory quotient (RQ) with indirect calorimetry (unit: VCO2/VO2)

Measure: Change of assessment of respiratory quotient (RQ)

Time: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

Description: Assessment of resting energy expenditure (REE) with indirect calorimetry (Unit J/s)

Measure: Change of assessment of resting energy expenditure (REE)

Time: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

Purpose: Treatment

Allocation: Randomized

Crossover Assignment


There is one SNP

SNPs


1 rs10830963

Additionally, a certain single nucleotide polymorphism in the melatonin receptor gene, MTNR1B rs10830963, with an allele frequency of 30 %, is associated with increased fasting plasma glucose and T2DM.

MTNR1a rs10830963 influence on change in insulin sensitivity and insulin secretion.

MTNR1a rs10830963 genotype influence on insulin sensitivity and insulin secretion (see outcome 1 + 2).

3. Does the MTNR1B rs10830963 risk allele alter the insulin secretion and insulin sensitivity compared with carries of the normal variant after chronic melatonin treatment?



HPO Nodes


HPO:
Diabetes mellitus
Genes 523
PDE6A IDH3A UBR1 IER3IP1 SPINK1 HNF1B PCARE ND1 OPA1 RP1 AGPAT2 TRNS1 MMP2 TTC8 PDX1 TGIF1 TREX1 CDON CFTR MKRN3 GCK INS PPARG HYMAI COX2 XRCC4 SNRNP200 NUBPL PTRH2 CEP19 NDUFB10 PROKR2 EYS LMNA TRNQ MAPK8IP1 LEPR TCF7L2 NSMCE2 PRPF4 ARL6 RDH12 ARL3 FGF8 GCK KDSR CEL DISP1 NR2E3 NDUFAF5 ARL2BP ERGIC1 PLAGL1 PRPF31 PNPLA6 NDUFV2 COX3 PRCD RLBP1 WFS1 KLF11 TRNL1 PDX1 NDUFA11 BLK KCNJ11 GPD2 SLC19A2 DHDDS MLXIPL LEP CLIP2 BMP2 BRCA2 TRNF IFT140 LMNA RP2 REEP6 NDUFS2 PDX1 PDE4D LIG4 RETN CNGA1 GLI2 NDP PNPLA2 EDA CYTB LHX1 PRSS1 NPM1 IFIH1 TBL2 ALMS1 GCK PRPH2 HAMP DCAF17 ABCC8 SNORD115-1 PRPF8 ENPP1 GUCA1B MEN1 MST1 NEUROD1 POMGNT1 HNF4A PTPN1 PPP1R3A FXN AIP KIAA1549 IGF2BP2 NKX2-5 EIF2S3 COX1 SLC29A3 ND5 SUFU CDKN2A HERC2 FXN CYP19A1 STAT3 MKKS SOX2 LIPC INSR GTF2I TDGF1 GCGR HMGA2 TWNK HFE TRNH HLA-DRB1 CORIN PRPF6 ZNF408 FGFR1 PROM1 FOS ZMPSTE24 PEX1 CPA1 HNF4A NPAP1 NDUFAF3 DLL1 BEST1 TRNK TRNL1 POLG CAV1 XRCC4 ND2 TUB CP SLC2A2 KRAS EFL1 NDUFS1 HNF1A SIX3 POLR3A RP9 TRNE AKT2 NODAL PPARG XRCC4 ND1 NDUFS4 GATA6 WRN DCAF17 TTC7A AKT2 RBP3 POC1A PAX4 RTEL1 NDUFA6 TRNS1 KCNJ11 INSR GJB3 INS CASR USP8 MAK FOXC2 FOXP3 HNF1B GATA3 IMPDH1 APOA5 LIPE TRNL1 LEMD3 IL6 PRKAR1A FGFR1 NDN COX1 FAM161A HESX1 INSR NRL NDUFS6 ABCC8 TRNC CFTR GJA1 PRKACA NDUFB9 TRNW COX3 TTPA GPR101 PLAGL1 TIMMDC1 GJA1 WRAP53 RNASEH2A HNF4A COX2 PAX4 FOXRED1 PAX4 DKC1 RRM2B SMAD4 BLK TMEM126B ND5 NDUFAF1 FLT1 KCNJ11 MAFA GATA6 IL2RA CLCNKB NDUFAF2 CTRC PPARG OFD1 IFT172 SPINK1 PRKAR1A RPGR ATM SNORD116-1 OTX2 NDUFA1 ZFYVE26 NDUFB3 BAZ1B PRSS2 BSCL2 ABCC8 INS WFS1 IFT88 PDE6B GAS1 ABCC8 ABCC8 RGR PALLD ND4 STOX1 GNAS NEK2 RFC2 CA4 HYMAI CTRC LIPE RHO MMP14 SCAPER NOP10 ITPR3 GCK SLC19A2 NHP2 HNF1B CRB1 PEX6 TWNK TRNQ NEUROD1 GTF2IRD1 ABCC8 ND6 DNAJC3 POLD1 GJB4 SPINK1 PARN BSCL2 VANGL1 SLC29A3 PDE11A PTPN22 PTF1A BRAF AHR PWRN1 HYMAI TRNV GLRX5 USB1 HLA-DQB1 ITCH SBDS TRNK GPR35 PRSS2 PROK2 STAT1 NSMCE2 CTNS PIK3R1 NDUFAF4 CDHR1 ZFP57 ATP6 TRNW PTF1A CTNNB1 AIP EIF2AK3 POLA1 GCK TRNE ELN NEUROG3 CISD2 GLIS3 DNAJC21 CAVIN1 ELMO2 PTCH1 ROM1 ZFP57 BBS2 LEPR LRP6 KCNJ11 PRKACA PRPF3 SLC25A4 DNM1L GCK HJV LRAT WFS1 HNF1B TP53 PNPLA2 ELN IRS2 NDUFV1 ND6 PRSS1 CERKL CLRN1 PPARG BBS2 MOG TOPORS ARNT2 FOXH1 RAC1 HNF4A PLIN1 TP53 TRNF NDUFB11 EIF2AK3 CFTR SNRPN USH2A KCNJ11 HNF1A STAT3 C8ORF37 APOE FUZ LMNB2 IGF1R TRNS2 LMNA IPW POLG2 PDX1 TERC SLC16A2 INS CAV1 NDUFS7 AR LMNA HGSNAT KLF11 SEMA4A FOXP3 CIDEC CTC1 PLIN1 IDH3B PCNT PEX10 GCK SPINK1 APPL1 HNF1A ZIC2 ABCA4 FBN1 ZNF513 TRNS2 CRX STUB1 NEUROD1 KLHL7 CISD2 PSTPIP1 ALMS1 LMNA PDX1 LIMK1 HNF1A RPE65 BRCA1 RNASEH2B CCDC28B STAT1 AHI1 AIRE ARMC5 NDUFS3 AGBL5 PDE4D TULP1 SHH DHX38 IL2RA HMGA1 CEL NDUFS8 ATM DNAJC3 INS MAGEL2 HNF1A EDA2R HFE MKRN3-AS1 SLC12A3 SLC30A8 UBR1 ND1 IMPG2 KCNJ11 PWAR1 CNOT1 ADAR BLM PDE8B PDX1 HNF4A IRS1 RNASEH2C INSR PIK3R1 CDH23 BBS1 TCF4 ZMPSTE24 ZBTB20 KIZ TINF2 KCTD1 WFS1 SRP54 APPL1 ND3 WFS1 PRSS1 SPATA7 AGPAT2 HBB MERTK WRN KCNJ11 PALB2 HNF1A LMNA PAX4 SARS2 SLC7A14 SOX3 MC4R PDE6G LMNA ARHGEF18 SAG AMACR MTNR1B CP CNBP PLCD1 CTRC FSCN2 TERT SAMHD1 CNGB1
Insulin resistance
Genes 122
LIPC KCNJ11 HNF1A GCGR STAT3 BSCL2 HSD3B2 ABCC8 AGPAT2 INS LMNA LMNB2 LMNA PDX1 ABCC8 ABCC8 INS CAV1 FOS ZMPSTE24 LMNA HYMAI LIPE BSCL2 CIDEC PLIN1 PPARG HYMAI CAV1 XRCC4 ADCY3 SLC2A2 CEP19 IGFALS LMNA MAPK8IP1 TCF7L2 DBH NEUROD1 NSMCE2 AKT2 PPARG XRCC4 IGF1 GATA6 NEUROD1 GCK AKT2 POLD1 PAX4 BSCL2 ALMS1 LMNA PDX1 PMM2 KCNJ11 HNF1A PTF1A HYMAI PLAGL1 HNF1B KLF11 NSMCE2 PIK3R1 BLK LIPE KCNJ11 GPD2 HMGA1 CEL INSR INSR ZFP57 CAV1 LEP ABCC8 SLC12A3 SLC30A8 EIF2AK3 LMNA GCK PDX1 RETN PDX1 CAVIN1 HNF4A IRS1 PIK3R1 ZFP57 PLAGL1 LEPR KCNJ11 ZMPSTE24 GCK MFN2 WFS1 ALMS1 APPL1 DCAF17 ABCC8 PAX4 ZMPSTE24 HSD11B1 AGPAT2 ENPP1 IRS2 HNF4A WRN PTPN1 PPP1R3A LMNA PAX4 PPARG IGF2BP2 KCNJ11 LMNA MTNR1B CLCNKB PPARG CAVIN1 EIF2AK3 CYP19A1