Long-term Changes in Glucose Metabolism After Gestational Diabetes

A Double Cohort Study

Hanna Huopio; Heidi Hakkarainen; Mirja Pääkkönen; Teemu Kuulasmaa; Raimo Voutilainen; Seppo Heinonen; Henna Cederberg

BMC Pregnancy Childbirth. 2014;14(296)

Abstract and Introduction

Abstract

Background: Gestational diabetes (GDM) has been associated with an elevated risk of type 2 diabetes in women after the pregnancy. Recognition of the factors differentiating the women at highest risk of progression to overt disease from those who remain normoglycemic after gestational diabetes is of key importance for targeted prevention programmes. To this aim, we investigated the incidence and risk factors of prediabetes and type 2 diabetes with a view to the underlying pathophysiological mechanisms in a long-term follow-up of women with a history of gestational diabetes.

Methods: 489 women with GDM and 385 normoglycemic controls attended a follow-up study after pregnancy (mean follow-up time 7.3, SD 5.1 years) in Kuopio, Finland. Glucose tolerance was evaluated with an oral glucose tolerance test, insulin sensitivity by Matsuda insulin sensitivity index (ISI), and insulin secretion by Disposition Index 30 (DI30).

Results: GDM increased risk of pre-diabetes and diabetes (HR 3.7, 95% C.I. 2.8–4.7 and HR 40.7, 95% C.I. 5.3–310.1, respectively, after adjustment for confounding factors) and was associated with both increased fasting (P < 0.001) and 2-hour plasma glucose (P < 0.001) during OGTT at the follow-up study. This effect was attenuated when adjusted for Matsuda ISI but abolished after adjustments with DI30 suggesting insulin secretion is the key defect leading to type 2 diabetes after GDM pregnancy. Increase in waist circumference and weight after pregnancy predicted the development of hyperglycemic conditions in women with a history of GDM (P < 0.001, and P = 0.002, respectively).

Conclusions: Pre-diabetic stages after GDM pregnancy are frequent and reflect the progressive risk of type 2 diabetes in long-term follow-up. Hyperglycemia after GDM pregnancy results from beta cell failure and inability to compensate the increased insulin resistance by insulin secretion. Importantly, increase in waist circumference and as well as weight gain during the follow-up is associated with progression to prediabetes and type 2 diabetes in women with a history GDM.

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Abstract and Introduction
Background
Methods
Results
Discussion
Conclusions
References

Table 1. Clinical characteristics of the women with gestational diabetes and controls at index pregnancy and the follow-up study
	GDM patients (n = 489)		Controls (n = 385)		P
	Mean	SD	Mean	SD	P
*Index pregnancy*
Age at delivery (yrs)	32.0	5.9	29.6	5.3	<0.001
Parity	1.1	1.3	0.7	0.9	<0.001
Primipara/multipara (%)	36.6/63.4		54.5/45.6		<0.001
Waist (cm)	91.3	13.4	86.3	11.7	<0.001
BMI in the first trimester (kg/m2)	26.4	4.8	24.1	3.8	<0.001
Duration of the pregnancy (weeks)	39.3	1.5	39.5	1.7	0.095
Birth weight of the child (g)	3648	545	3579	570	0.065
Follow-up study*
Age at follow up (yrs)	37.8	7.2	38.4	6.3	0.200
Follow-up time (yrs)	6.0	4.4	9.0	5.5	<0.001
Family history of diabetes (%)	81.0		71.5		0.001
Current smoker (%)	18.8		13.6		0.040
BMI (kg/m²)	28.4	5.5	26.9	4.9	<0.001
HbA1c [mmol/mol (%)]	36 (5.5)	5	35 (5.3)	3	<0.001
Fasting plasma glucose (mmol/l)	5.6	0.5	5.3	0.4	<0.001
30-min plasma glucose (mmol/l)	8.0	1.7	7.1	1.5	<0.001
2-h plasma glucose (mmol/l)	6.0	1.7	5.5	1.2	<0.001
Fasting plasma insulin (pmol/l)	79.2	55.6	63.2	43.1	<0.001
30-min plasma insulin (pmol/l)	507.0	355.6	439.0	266	0.013
2-hour plasma insulin (pmol/l)	351.4	327.1	278.5	242.4	<0.001
P-glucose area under the curve (mmol/l*min)	832.6	160.3	749.6	130.6	<0.001
P-insulin area under the curve (pmol/l*min)	40880.3	28499.6	34414	21656	<0.001
HOMA-IR	2.9	2.1	2.2	1.6	<0.001
Matsuda ISI (mg/dl, mU/l)	5.7	3.2	7.1	3.6	<0.001
Disposition Index	167.4	65.1	206.3	77.6	<0.001

*Individuals diagnosed with type 2 diabetes during the follow-up time (n = 15) were not included in HbA1C and oral glucose tolerance tests. HOMA-IR, homeostatic model assessment of insulin resistance. P-values < 0.05 are indicated in bold font.

Table 2. Association between gestational diabetes and the risk of prediabetic stages at the follow-up study
	IIFG			IIGT			IFG + IGT			Prediabetes
	(N = 267)			(N = 26)			(N = 40)			(N = 333)
	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P
Model 1	3.1	2.4–4.0	<0.001	7.8	2.9–21.6	<0.001	4.7	2.2–10.0	<0.001	4.0	3.1–5.1	<0.001
Model 2	3.2	2.5–4.3	<0.001	7.8	2.8–21.7	<0.001	3.7	1.7–7.9	0.001	3.8	3.0–4.9	<0.001
Model 3	3.0	2.3–4.0	<0.001	7.7	2.7–21.4	<0.001	3.5	1.6–7.6	0.001	3.6	2.8–4.6	<0.001
Model 4	3.1	2.4–4.1	<0.001	7.6	2.7–21.3	<0.001	3.1	1.4–6.9	0.004	3.7	2.8–4.7	<0.001

Cox proportional hazard model comparing the association of GDM with prediabetic stages vs NGT. IIFG, isolated impaired fasting glucose, IIGT, isolated impaired glucose tolerance, IFG + IGT, combined impaired fasting glucose and impaired glucose tolerance; HR, Hazard ratio: CI, confidence interval. P-values < 0.05 are indicated in bold font.
Model 1: unadjusted.
Model 2: Adjusted for age, BMI.
Model 3: Adjusted for age, BMI, parity.
Model 4: Adjusted with age, BMI, parity, smoking, physical activity.

Table 3. Association between gestational diabetes and plasma glucose levels at the follow-up study
Variable at follow-up study	B	SE	P	P*	P**	P***
Fasting plasma glucose (mmol/l)	0.27	0.03	<0.001	<0.001	<0.001	0.063
2-hour plasma glucose (mmol/l)	0.54	0.10	<0.001	<0.001	0.011	0.803
Glucose AUC (mmol/l)	83.04	10.84	<0.001	<0.001	<0.001	0.011

Linear regression analysis, individuals with diabetes diagnosed between index pregnancy and follow-up study are excluded, N = 385 controls and 474 patients with GDM. AUC, area under the curve. P-values < 0.05 are indicated in bold font.
P, unadjusted.
P*, adjusted for age, BMI, follow-up time, parity, smoking, physical activity.
P**, adjusted for age, BMI, follow-up time, parity, smoking, physical activity, Matsuda ISI.
P***, adjusted for age, BMI, follow-up time, parity, smoking, physical activity, Disposition Index.

Table 4. Comparison of women with normal and abnormal glucose tolerance at the follow-up study visit among those affected by gestational diabetes
	NGT (n = 228)		AGT (n = 246)		P
	Mean	SD	Mean	SD	P
Age at delivery (years)	31.3	5.9	32.6	5.9	0.016
Number of deliveries	1.1	1.4	1.2	1.2	0.550
Age at follow-up study (years)	36.3	7.0	38.6	7.0	<0.001
Follow-up time (years)	5.2	4.0	6.3	4.5	0.008
Waist (cm)	87.0	12.3	94.0	12.6	<0.001
BMI in the first trimester (kg/m2)	25.6	4.6	26.9	4.6	0.001
BMI in the end of pregnancy (kg/m2)	30.1	4.4	31.2	4.5	0.013
Weight increment during pregnancy (kg)	12.3	6.2	12.2	5.9	0.993
BMI at follow-up study (kg/m2)	26.6	4.9	29.5	5.2	<0.001
Change in weight during follow-up time (kg)	1.6	7.3	5.5	8.1	0.002
Change in BMI during follow-up time (kg/m²)	1.1	2.7	2.6	3.0	<0.001
Current smoker (%)	21.8		15.6		0.090
Physical activity (%)	82.7		83.5		0.816
Family history of diabetes	79.9		81.5		0.669
HbA1c [mmol/mol (%)]	35 (5.3)	3	37 (5.5)	4	<0.001
Matsuda ISI (mg/dl, mU/l)	6.8	3.3	4.6	2.8	<0.001
Disposition Index	201.8	61.1	133.0	48.9	<0.001

NGT, normal glucose tolerance; AGT, abnormal glucose tolerance (includes both prediabetes and type 2 diabetes). Subjects diagnosed with type 2 diabetes between the index pregnancy and the follow-up visit were excluded. P-values < 0.05 are indicated in bold font.