Discussion of main findings

In this dissertation, we found that one in two South Asian and one in five Nordic women had actionable HbA1c 1-3 years after GDM. The high prevalence and the ethnic differences were well captured by applying the ADA recommended HbA1c cut-offs of 39 mmol/mol (5.7%).

Lack of integrated healthcare services with an established recall system for follow-ups, tailored information about future diabetes risk and with focus on emotional health were key behavioural factors behind South Asian and Nordic women’s suboptimal follow-up after GDM. Lower disposition index, lower fasting hepatic insulin clearance, and higher peripheral insulin levels in South Asian compared to Nordic women were important pathogenetic factors behind South Asians increased T2D risk.

In our study population of women with previous GDM, we found both a high prevalence and significant ethnic differences in the proportion of women with prediabetes or diabetes short time after delivery. This increased risk of T2D after GDM is supported by several seminal meta-analyses (41, 42, 97, 98). The absolute risk increases steadily over time and is higher in non-white populations (41, 42). The relative risk, however, plateaus after 10 years and is higher in white populations (43, 98). These diverging statements reflect that prevalence rate of T2D short time after delivery is lower in white than in non-white women without GDM, and hence, the calculated relative risk appears ‘falsely’ higher in white populations. Accordingly, it is important to consider the study design, study period, methods, definitions and

calculations of variables used when interpreting or comparing studies, as these are factors that can largely influence the results and conclusions. Diagnostic criteria for GDM and prediabetes have changed throughout the history, and still differ worldwide (99). This make it difficult to compare studies across countries and ethnicities. We, therefore, provided results with

different prediabetes criteria, with and without HbA1c measurements. In the Nordic population, we found that 22% had an actionable ADA-HbA1c ~1.5 years after GDM.

Comparable studies in white women ~1-2.5 years after GDM show an actionable HbA1c

prevalence of 16-19%. In the South Asian population, we applied the combined OGTT and HbA1c data, as comparable HbA1c studies are scarce. We found that 87.8% of the South Asian

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women qualified for the prediabetes or diabetes diagnosis compared to 57.7% in a recent study from India with similar design (45). Some of the differences in the prevalence rates can be attributed to different cut-off levels for diagnosing GDM. We applied higher cut-off levels that are associated with higher conversion rates to prediabetes and diabetes (100, 101).

Notably, by applying the combined ADA criteria, we found that 65.7% of the Nordic women had prediabetes or diabetes compared to 18.4% in a comparable Irish study (102).

Notwithstanding the differences in diagnosing GDM, this prevalence rate was unexpectedly high.

These high prevalence rates of prediabetes or diabetes in South Asian and Nordic women gave rise to a discussion of how to diagnose prediabetes and diabetes. Bearing in mind that we accepted a single abnormal glucose value as diagnostic for prediabetes and diabetes, isolated peaks of glucose may have contributed to ‘falsely’ higher prevalence rates. This assumption is supported by a recent study from Germany, reporting that OGTT-based glucose tolerance fluctuated between glucose categories over time (103). Notably, such isolated glucose peaks would most likely not translate into higher HbA1c levels. Advantageous of HbA1c testing is that it can be done without fasting, it is easy for patients to perform, and it is the best test analytically (14). More important, HbA1c predicts micro- and macrovacular complications better than fasting and 2h glucose values from an OGTT (18, 19). In contrast to this argument, current literature (100, 102, 104), consistent with our data, reports HbA1c as less sensitive than the combined OGTT and HbA1c measurements in diagnosing prediabetes and diabetes.

Additionally, a recent review of diabetes epidemiology in the US reports HbA1c as less specific compared to OGTT measurements in diagnosing diabetes among South Asian populations (66). This is at variance with our data suggesting that HbA1c efficiently detected the absence of diabetes when it was not present (specificity of 100%) in both ethnic groups.

These results, however, assume that OGTT is the gold-standard test for diagnosing diabetes.

We indicated that ADA-HbA1c measurements alone appropriately identified women with increased prediabetes or diabetes risk after GDM, and also captured the higher risk in South Asian compared to Nordic women.

Another topic debated related to the use of HbA1c across ethnicities is whether ethnic

differences in the haemoglobin molecule or in the lifespan of erythrocytes could affect HbA1c

levels. Importantly, the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial of 12 527 people reported similar relationship between HbA1c and FPG across ethnic groups, and therefore, suggested the use of HbA1c throughout the world (105).

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Notwithstanding this high risk of future T2D after GDM, a large proportion of women do not attend the healthcare follow-ups after delivery to evaluate their future diabetes risk and implement preventative measures (46, 47). To understand this epistemological ignorance, several studies have reported on behavioural factors facilitating or interrupting

health-promoting behaviours (48, 49). We also discussed such factors in paper I, but additonally we tried to understand mechanisms behind women’s suboptimal follow-up. Therefore, we applied Lipsky’s theory on street-level bureaucracy (52) as a support in the analysis, and to discuss our findings.

Lipsky’s theory describes mechanisms behind and how to counteract the gap between SLB’

intentions and actions, i.e., unwanted behaviours. SLB are defined as public employees (such as police, teachers or healthcare providers) working in circumstances with more load than they can cope with provided by their agency (commonly the government). To reduce unwanted behaviours, Lipsky’s theory suggests policymakers to build on whole-system changes rather than trusting one person’s ability to make changes. It stimulates discussion between the decision-maker and the decision-taker, and suggests a supportive leadership to avoid SLB bend rules with an intention to meet the need of their clients, although, this action often serves to preserve unwanted behaviours (52, 53).

In paper I, we implemented a modified version of Lipsky’s theory to understand women's

‘unwanted’ responses to current GDM guidelines, and how these influence GDM follow-up.

We recognised the postpartum women as the public employee, the child or family as her clients, and the public healthcare system as the agency. Lipsky postulates five main reasons for unwanted behaviours that reflected our five main themes and explained mechanisms behind women’s suboptimal follow-up after GDM.

(i) Lack of resilience and emotional distress (= SLB are sensitive to claims, due the constant negotiation between policymakers and clients (52)) made women resistant to further follow-up after GDM. The constant self-negotiation, between a normal lifestyle and maintaining a strict blood glucose regime recommended by healthcare providers, resulted in emotional distress. Several reports have linked emotional distress to suboptimal follow-up after GDM (48, 49). Therefore, an interesting and novel finding, retrieved from the health and disease beliefs in our study, was that a positive attitude and resilience might effectively buffer against emotional distress independent of ethnicity. In accordance with Lipsky’s theory (52) and others (48, 106), a supportive approach that builds on women’s coping strategies, and

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addresses emotional health would be beneficial to improve women's adherence to follow-ups after GDM.

(ii) Time constraints (= SLB are often caught between inadequate resources and a heavy workload (52)) made women resistant to follow-ups and to physical activity independent of ethnicity. Consistent with current literature (48, 49, 77), we suggest that to improve women’s adherence to follow-up the healthcare services should try to combine women’s and children’s healthcare appointments. Several lifestyle intervention studies in high-risk populations show reduced T2D risk if weight loss is obtained, both in general (63, 107) and after GDM (65).

Interestingly, a recently published study showed no effect of lifestyle intervention in South Asian women after GDM (64). These women, however, did not obtain weight loss during the trial that may explain the disappointing results. We, therefore, still recommend physical activity as a preventive measure. Notwithstanding that previous studies show inconsistent data regarding factors promoting physical activity (75), and our study is unable to answer this question, this may be a key area for further studies.

(iii) ‘Caught between a rock and a hard place’ (= SLB’ service for dependent clients) is a phrase that reflected the dual pressure from healthcare providers, and the family or the child (= ‘clients’) that often were ranked as first priority, particularly among South Asian women (77). This dual pressure made it easier for women to maintain commonly debated

motivational barriers (48, 49) such as denial of their diabetes diagnosis, prioritising of other obligations such as family, and maintain the perception that exercise beyond daily work is secondary in importance.

(iv) Postpartum abandonment (= a lack of routine makes it challenging to measure

performance and promotes unwanted coping strategies (52)) was strongly emphasised, and reflects current guidelines that hold women themselves responsible for booking an

appointment for follow-up after a GDM pregnancy (13). This gave women the opportunity to rationalise themselves away from their future diabetes risk (108). Therefore, we recommend a more organised public healthcare with establish recall systems for follow-ups and reiterating of lifestyle recommendations, consistent with a recently published Norwegian study (109) and previous literature (48, 49). We, in accordance with others (49, 106), also recognised social support from family and healthcare providers as important to improve follow-ups after GDM.

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(v) Insufficient guidance (= vague organisational expectations can easily give rise to misunderstandings) about women’s increased diabetes risk and ethnicity-specific diabetic-friendly diets were revealed. National websites with understandable and tailored information about future T2D risk, including alternative GDM recipes for different ethnicities, were therefore suggested. These findings are consistent with previous literature (48, 49, 75, 77), and Lipsky's request for understandable goals (52).

Fig. 9. Insights into mechanisms behind unwanted health behaviours after GDM. The identified themes in light of Lipsky's theory indicate the need to focus on specific coping strategies and more organised public healthcare to improve women's adherence to follow-ups after GDM. Figure from article 1 (110). GDM, gestational diabetes mellitus.

Taken together, although using Lipsky’s theory is uncommon in healthcare models, it may help us to understand that in circumstances with a heavy workload and time constraints it is human to choose the easiest way out, although this may preserve unwanted behaviours (Fig.

9). Therefore, the challenge is to make guidelines that can counteract such unwanted health behaviours that assist women in rationalising themselves away from their future diabetes risk.

Accordingly, when designing strategies to improve women's adherence to follow-up after

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GDM, it is important that these guidelines are useful for the women who will apply them, as they finally decide whether the guidelines will be implemented or not.

In paper 3, we sought for pathogenetic factors behind the South Asian women’s higher risk of prediabetes and T2D after GDM. Our most important finding was lower beta cell function (estimated by the disposition index) in South Asian compared to Nordic women, both for the normoglycaemic and the prediabetes and diabetes groups. Notably, South Asian

normoglycaemic women tend to fall off the disposition curve regressed on comparable Nordic women, approaching women with prediabetes or diabetes (Fig. 10). Interestingly, this was only present when calculating the disposition index by pre-hepatic insulin (rather than peripheral) levels. An animal study also showed discrepancy in the estimates of disposition index when accounting for hepatic insulin clearance (71). Our findings imply that estimates of beta cell function based on peripheral insulin levels may mask an early beta cell dysfunction.

Although, a lower beta cell function has been reported in women with previous GDM, this finding in normoglycaemic women was novel.

In the normoglycaemic groups, fasting and 2h OGTT values did not differ between the ethnic groups, but AUC for glucose values were higher among the South Asian women. This, in addition to a delayed glucose peak, also reflected a lower beta cell function in South Asian

Fig. 10. The disposition index curve.

The hyperbolar relationship between early pre-hepatic (IGI) insulin secretion, and insulin sensitivity (Matsuda-ISI) in South Asian vs. Nordic women by different glucose categories. The blue line was regressed on Nordic women with normal glucose tolerance (blue triangle).

South Asian normoglycemic women (red cross) tended to ‘fall off the curve’ and cluster to the lower left, resembling South Asian (red light square) and Nordic women with prediabetes or diabetes (blue light circle). Data are means.

IGI: insulinogenic index, ISI: insulin sensitivity index.

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compared to Nordic normoglycaemic women. The beta glucose sensitivity, reflecting the relationship between pre-hepatic insulin and glucose levels, is normally expected to increase with higher glucose levels (27). We, however, did not find any difference in beta glucose sensitivity between the ethnic groups, which further supported a lower beta cell function in South Asian than comparable normoglycaemic Nordic women.

Another important finding was the lower fasting hepatic insulin clearance in South Asian compared to Nordic women, regardless of glucose tolerance group. We speculate that reduced hepatic insulin clearance and the resulting increased peripheral insulin levels act to

compensate for failing beta cells. This theory is supported by a study in Japanese men using euglycaemic clamp (70). The authors showed that individuals with reduced insulin clearance had normal hepatic, but lower muscle insulin sensitivity. They suggest that the lower insulin clearance may compensate for a mild muscle insulin resistance, and thereby maintains normoglycaemia. Another possibility is that the increased peripheral insulin levels due to lower hepatic insulin clearance contribute to higher insulin resistance, and the development of T2D (26).

Our study results showed lower hepatic insulin sensitivity among South Asian than comparable Nordic women. This was supported by higher glucose values in South Asians during the first hour of the OGTT, when the hepatic glucose production was expected to be maximally suppressed. Moreover, our research group (111) has previously reported that South Asian individuals with T2D have higher hepatic glucose production during a euglycaemic clamp. Others have also discussed the linkage between intra-hepatic fat and progression to T2D in South Asian populations (58). An unsettled issue is how lower hepatic insulin clearance relate to hepatic insulin resistance. Our study design is not suited for further evaluation of this.

Taken together, our data showed that South Asian women have lower hepatic insulin

clearance and higher hepatic insulin resistance compared to comparable Nordic women; both factors resulted in higher peripheral insulin levels. Due to the cross-sectional nature of our study, and as we did not directly measure hepatic glucose production, we cannot address in which order these factors appear, or their relative importance with respect to peripheral insulin levels. However, the ongoing DIASA 2 and 3 trials in our research group include euglycaemic clamps with measurements of hepatic glucose production, and will hopefully provide data that can better address these questions.

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In paper 3, we found lower muscle and whole-body insulin sensitivity in South Asian than in Nordic normoglycaemic women, confirming previous literature that reports higher peripheral insulin resistance in South Asian individuals years before their diabetes diagnosis (55). This is in accordance with the fat compartment hypothesis that says that South Asian individuals have reduced capacity to store fat in healthy compartments, and are more prone to central fat accumulation. Accordingly, Nordic women were allowed a greater weight gain before putting on central fat (i.e., similar waist-to-height ratio) than comparable South Asian women. This is consistent with a recent study comprising ~1.5 million people followed over 6.5 years, where the age and sex-adjusted incidence of T2D in South Asian individuals developed at a lower BMI cut-off level than comparable European individuals (BMI 23.9 vs 30.0 kg/m²) (62).

To develop strategies that could counteract the high prevalence of prediabetes or T2D after GDM, we sought for risk factors before, during, and short time after the index pregnancy. In paper II, we suggested that HbA1c should be used as the outcome variable (rather than fasting or 2h OGTT values). To the best of our knowledge, this study was, therefore, the first trial that looked for variables predicting actionable HbA1c. Not surprisingly, South Asian ethnicity appeared as a strong risk factor for actionable HbA1c, in addition to GDM before the index pregnancy, use of glucose-lowering drugs in pregnancy, higher age, and higher in-pregnancy fasting glucose levels. Although these risk factors were consistent with previous literature, all these studies assume that the OGTT is the gold-standard test for diagnosing prediabetes or diabetes (100, 112, 113). Therefore, it was reassuring to find consistent predictors for glucose deterioration regardless of criteria used (112, 114, 115). More importantly, all these risk factors might be linked to overweight and obesity. Accordingly, in paper II and III, we found that waist-to-hip ratio and weight-to-height ratio were important risk factor for glucose deterioration. Further, to clarify how much of the ethnic differences in the estimated glucometabolic indexes were mediated through central fat accumulation (waist-to-height ratio), we performed mediation analyses. Through these novel analyses, we found that ~25-40% of the differences in insulin sensitivity between South Asian and Nordic women were explained through central fat accumulation. Waist-to-height ratio, however, did not explain ethnic differences in disposition index or fasting hepatic insulin clearance. Although, the latter findings were disappointing, they may be key areas for future research.

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