Gestational diabetes from A to Z

Table 1 Risk factors for gestational diabetes mellitus defined by the expert groups[12-15]

NICE[14] and SIGN[15]

BMI > 30 kg/m2

Previous history of macrosomic baby ≥ 4.5 kg

Previous history of GDM

Family history of diabetes (first-degree family member with diabetes)

Ethnic backgrounds

South Asian (India, Pakistan or Bangladesh)

Black Caribbean

Middle Eastern (Saudi Arabia, United Arab Emirates, Iraq, Jordan, Syria, Oman, Qatar, Kuwait, Lebanon or Egypt)

ADIPS[13]

Moderate risk factors for GDM

Ethnic backgrounds: Asian, Indian, Aboriginal, Torres Strait Islander, Pacific Islander, Maori, Middle Eastern, and non-White African

BMI 25-35 kg/m2

High risk factors for GDM

Previous history of GDM

Previous history of high blood glucose

Age ≥ 40 yr

Family history of diabetes (1st degree relation with diabetes or a sister with GDM)

BMI > 35 kg/m2

Previous history of macrosomic child ≥ 4.5 kg

PCOS

Medications: Corticosteroids, antipsychotics

ADA[12]

BMI > 25 kg/m2

No physical activity

1st degree relation with diabetes

Ethnic backgrounds (African-American, Latino, Native-American, Asian-American, Pacific Islander)

Previous macrosomic child > 9 lb

Previous history of GDM

Hypertension

HDL-C < 0.90 mmol/L and/or triglyceride > 2.82 mmol/L

PCOS

HbA1c ≥ 5.7% and previous IGT or IFG

Signs of insulin resistance such as acanthosis nigricans

History of CVD

ADA: American Diabetes Association; HDL-C: High-density lipoprotein cholesterol; IFG: Impaired fasting glycaemia; IGT: Impaired glucose tolerance; NICE: National Institute for Health and Clinical Excellence; PCOS: Polycystic ovarian syndrome; SIGN: Scottish Intercollegiate Guidelines Network; ADIPS: Australasian Diabetes in Pregnancy Society; BMI: Body mass index; CVD: Cardiovascular disease; GDM: Gestational diabetes mellitus; HbA1c: Glycosylated haemoglobin.

Table 2 Various diagnostic criteria for gestational diabetes mellitus and cut-off values

Diagnostic criteria	Sample	WVB (mg/dL)	VP
O’Sullivan and Mahan (Women screened using 3-h 100 g OGTT and two cut-off values are required to diagnose GDM)[28,31]	Fasting	90	90 mg/dL
	1 h	165	165 mg/dL
	2 h	143	145 mg/dL
	3 h	127	125 mg/dL
NDDG criteria (Women screened using 3-h 100 g OGTT and two cut-off values are required to diagnose GDM)[32]	Fasting	90	105 mg/dL
	1 h	170	190 mg/dL
	2 h	145	165 mg/dL
	3 h	125	145 mg/dL
Carpenter and coustan criteria (Women screened using 3-h 100 g OGTT and two cut-off values are required to diagnose GDM)[33]	Fasting	90	95 mg/dL
	1 h	165	180 mg/dL
	2 h	143	155 mg/dL
	3 h	127	140 mg/dL
WHO 1999 criteria (Women screened using 2-h 75 g OGTT and one cut-off value is required to diagnose GDM)[5]	Fasting		126 mg/dL
	2 h		140 mg/dL
Recent IADPSG criteria (GDM) (Women screened using 2-h 75 g OGTT and one cut-off value is required to diagnose GDM)[8]	Fasting		92 mg/dL
	1 h		180 mg/dL
	2 h		153 mg/dL
Recent IADPSG criteria (Overt diabetes) (Women screened using 2-h 75 g OGTT and one cut-off value is required to diagnose GDM)[8]	Fasting		126 mg/dL
	HbA1c		≥ 6.5%
	RPG		200 mg/dL

GDM: Gestational diabetes mellitus; RPG: Random plasma glucose; VP: Venous blood; WHO: World Health Organization; WVB: Whole venous blood; HbA1c: Glycosylated haemoglobin; IADPSG: International Association of Diabetes and Pregnancy Study Groups; NDDG: National Diabetes Data Group; OGTT: Oral Glucose Tolerance Test.

Table 3 Etiology and pathophysiology of gestational diabetes mellitus

Insulin resistance

Pregnancy and obesity as states of low grade inflammation[48,49]

Adipocytokines

↓ Adiponectin[51-53]

↑ TNF-α[55-58]

↑ IL-6[56,62-64]

↑ Leptin[56,58,65,66]

↑ AFABP[79]

↑ RBP-4[69]

?↑ Resistin[54,62,72]

?↑ Visfatin[76,77]

? Novel adipocytokines (Vaspin, Apelin and Omentin)[50]

Endothelial function and angiogenic growth factors[74,80,81]

↓ EPC

↓ SOD

↑ eNOS

↑ PAI-1

↑ sEng

↑ sICAM-1

↑ sVCAM-1

↑ t-PA

↑ PLGF

↑ sFlt-1

Proteomics biomarkers

Haptoglobin, protein SMG8 and apoptosis inducing factor-1[83]

Apolipoprotein CIII[84]

Peptides precursors of clusterin, isoform 1 of fibrinogen alpha chain and apolipoprotein CII[85]

Glycosylated fibronectin[86]

Transthyretin–retinol binding protein-retinol complex[87]

Pancreatic β-cell dysfunction

Autoimmunity[92]

Glucokinase gene defect[93]

AFABP: Adipocyte fatty acid-binding protein; eNOS: Endothelial nitric oxide synthase; sEng: Soluble endoglin; sFlt-1: Soluble fms-like tyrosine kinase-1; sICAM-1: Soluble intercellular adhesion molecule-1; sVCAM-1: Soluble vascular cell adhesion molecule-1; SOD: Superoxide dismutase; t-PA: Tissue plasminogen activator; TNF-α: Tumor necrosis factor-α; RBP-4: Retinol-binding protein-4; EPC: Endothelial progenitor cells; hPGH: Human placental growth hormone; hPL: Human placental lactogen; IL-6: Interleukin-6; PLGF: Placental growth factor; PAI-1: Plasminogen Activator Inhibitor type-1.

Table 4 Genetic variants studied in relation to gestational diabetes mellitus

Gene	Location	Variant	Association
Genes related to insulin secretion
ABCC8	11p15.1	tagGCC allele of exon 16 and the AGG allele of the R1273R	Significant[97]
KCNJ11	11p15.1	E23K	Significant[98]
UCP-2	11q13	UCP2-866G> A	Controversial[98]
MT-ND1	mtDNA	T3398C mutation	Significant[100]
TCF7L2	10q25.3	rs7903146	Significant[101,102]
GCK	7p15.3-p15.1	rs1799884 (-30G/A)	Significant[105-107]
HNF4A	20q13.12	rs2144908, rs2425637 and rs1885088	No association[105]
HNF1A	12q24.2	rs1169288, rs1800574	No association[105,108]
Genes of insulin and insulin receptors
INS	11p15.5	INS-VNTR class-III allele	Controversial[110,111]
INSR	19p13.3-p13.2	INSR allele-1 Kpn I RFLP	Significant[112]
IGF2	11p15.5	IGF2 Bam HI RFLP	Significant[112]
IGF2BP2	3q27.2	rs4402960	Significant[113-115]
IRS1	2q36	rs1801278 (Gly972Arg)	Controversial[98,107]
Genes of insulin resistance
PPARG	3p25	rs1801282	No association[107]
PPARGC1A	4p15.1	rs8192678	No association[101,118]
ADRB3	8p11.23	rs4994 (Trp64Arg)	Controversial[101,194,119-121]
SLC2A1	1p34.2	SLC2A1 Xba I RFLP	No association[112]
ADIPOQ	3q27	rs1501299	No association[101]
FOXC2	16q24.1	-512C allele	No association[101]
HLA genes
HLA	6p21	DR3 and DR4	Controversial[122,123,125]
HLA	6p21	DR3-DQ2/X, DR4-DQ8/X with positive autoantibodies	Associated[124]
HLA	6p21	DR7-DQ2/X, DR9-DQ9/X and DR14-DQ5/X	Associated[124]
HLA	6p21	DQB1 alleles	Associated[111]
Other genes
CAPN10	2q37.3	SNP-19, SNP-43, SNP-44, SNP-63)	No association[98,101]
HFE	6p21.3	C282Y in Northern and Central European women	Associated[127]
HFE	6p21.3	H63D	No association[127]
MBL2	10q11.2	rs1800450 (Gly54Asp)	Significant[128]
MBL2	10q11.2	rs5030737 (Arg52Cys)	No association[128]
SERPINE1	7q22.1	-675 4G/5G	Could be associated[130]

ABCC8: ATP-binding cassette transporter sub-family C member 8; ADIPOQ: Adiponectin ADRB3 adrenergic receptor β3; CAPN10: Calpaine 10; FOXC2: Forkhead box C2; GCK: Glucokinase; HFE: Haemochromatosis; HLA: Human leukocyte antigen; HNF4A: Hepatocyte nuclear factor 4 alpha; HNF1A: Hepatocyte nuclear factor 1 alpha; IGF2BP2: Insulin-like growth factor-2 mRNA-binding protein-2; IGF2: Insulin-like growth factor 2; IRS1: Insulin receptor substrate 1; INS: Insulin; INSR: Insulin receptor; KCNJ11: Potassium channel inwardly rectifying subfamily J member 11; MBL2: Mannose binding lectin 2; MT-ND1: Mitochondrial NADH dehydrogenase-1; PPARG: Peroxisome proliferator-activated receptor gamma; PPARGCIA: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; RFLP: Restriction fragment length polymorphism; SERPINE1: Serpin peptidase inhibitor, clade E, member 1; SLC2A1: Solute carrier family 2 (facilitated glucose transporter), member 1; SNP: Single nucleotide polymorphism; TCF7L2: Transcription factor 7-like 2; UCP-2: Uncoupling protein-2; VNTR: Variable number of tandem repeats.

Table 5 The ACOG recommendations of the caloric requirements, composition and distribution throughout the day in pregnant women with diabetes[167]

Caloric requirements
	Normal BMI	30-35 kcal/kg per day
	< 90% of Normal BMI	30-40 kcal/kg per day
	> 120% of Normal BMI	24 kcal/kg per day
Caloric composition
	Complex, high-fiber CHO	40%-50%
	Proteins	20%
	Unsaturated fats	30%-40%
Caloric distribution
	Breakfast	10%-20%
	Lunch	20%-30%
	Dinner	30%-40%
	Snacks	Up to 30%

BMI: Body mass index; CHO: Carbohydrates.