The results of this prospective cohort study support the concept that the development of T2D in high-risk individuals is indeed multifactorial and that the involved pathophysiological mechanisms are closely linked. Subjects with first-degree relatives with T2D thus have unfavorable body composition as well as reduced insulin sensitivity, beta cell dysfunction, dyslipidemia and, at the trend level, exhibit markers of adipose tissue cell hypertrophy and dysfunction prior to developing IGT/T2D.
Previous cross-sectional studies have demonstrated impairments in glucose metabolism in non-diabetic FDR compared with control groups. Results from the RISC study indicated insulin resistance and beta cell dysfunction in response to an oral glucose challenge, and suggested that beta cell dysfunction is the major defect determining diabetes development in diabetic offspring . The Botnia study concluded that subjects with a family history of T2D displayed lower disposition indices and lower physical fitness, independent of level of physical activity, as well as an impaired capacity of beta cells to compensate for an increase in insulin resistance imposed by an increase in BMI . Results from the EUGENE2 study have also suggested associations between specific genes contributing to dysfunctional beta cells or insulin resistance [8, 9].
Prospectively, it was recently shown in the control group of the ACT NOW trial, that HbA1c and markers of beta cell dysfunction (insulin secretion/insulin resistance index after an OGTT) predicted the development of T2D in patients with IGT during 2.4 years of follow-up . In a Danish population-based study of patients with IGT or IFG the results of fasting laboratory measures and an OGTT showed that hypertension, higher BMI, serum triglycerides and plasma glucose levels predicted T2D during a 3.5 year follow-up period . In a similar study based on OGTT and four years of follow-up, Moromoto et al. proposed that disturbances in insulin secretion had a greater impact on the incidence of type 2 diabetes than insulin resistance in a Japanese population . In the current prospective study with the primary aim to evaluate pathophysiological mechanisms in FDR, we confirm and extend the previous results using state of the art methodology (intravenous glucose tolerance tests and euglycemic hyperinsulinemic clamp) for more exact determination of insulin secretion and insulin sensitivity .
Several studies have proposed that adipose tissue dysfunction may contribute to insulin resistance. Key characteristics for a dysfunctional adipose tissue are cellular hypertrophy, impaired adipocyte differentiation and a pro-inflammatory adipokine secretion pattern in addition to remodeling and tissue fibrosis . Recent publications by our group have confirmed that this association is found also among FDR to T2D patients. Yang et al. concluded that adipocyte cell size, a well-known predictor of later development of T2D , in addition to BMI, is associated with reduced insulin sensitivity in FDR . Furthermore, in a later publication we could show that healthy and normal glucose tolerant FDR had increased HOMA-IR, adipocyte hypertrophy, adipose tissue inflammation and slightly reduced serum adiponectin levels compared to healthy controls in spite of no difference in BMI or percent body fat .
In the present study we show at the trend level that markers of adipocyte dysfunction such as adipocyte cell size and circulating IL-6 are further altered in FDR with manifest IGT (however, not reaching statistical significance), strengthening the concept of adipose tissue dysfunction as a contributor to the development of insulin resistance and T2D. Interestingly, in a detailed study of obese individuals with or without insulin resistance Kloting et al. demonstrated that insulin sensitive obesity was characterized by smaller adipocytes, higher secretion of adiponectin and reduced adipose tissue inflammation, in fact, the strongest predictor of insulin sensitivity was the combination of adiponectin and cellular markers of inflammation, markers that were distinctive also in the present study . Importantly, Andersson et al. recently concluded that reversing adipose tissue dysfunction is possible by weight loss and that this correlates with reduction of the metabolic risk profile. Furthermore, the reduction in subcutaneous adipocyte volume associate more strongly with improvement of insulin sensitivity compared to fat mass reduction per se .
In our study serum adiponectin levels did not significantly differ between the group of FDR developing IGT/T2DM and the group of FDR remaining NGT. However, Onat et al. showed that serum adiponectin levels did in fact not diminish linearly with increasing BMI . The authors concluded that high serum adiponectin in certain populations fail to exhibit anti-inflammatory properties, and that gender, partially explained by sex hormone binding globulin levels in women, influenced the correlation between serum adiponectin levels and anti-inflammatory markers . This hypothesis could possibly contribute to explaining why serum adiponectin did not reach statistical significance in our study population.
It is important to note, that in this study we have studied subcutaneous adipose tissue biopsies, as opposed to visceral adipose tissue. The latter has been extensively studied and there is consensus today regarding its major role in the development of cardiometabolic disease, including T2D. Large subcutaneous adipose tissue storages have been proposed to be less indicative of insulin resistance and its associated metabolic derangements . However, as shown by Gustavson et al., an inability to store excess energy subcutaneously is associated with the accumulation of visceral fat, and the subcutaneous adipose tissue function thus plays a role in the development of ectopic fat storage . In addition to the conclusion drawn from subcutaneous biopsy data in this study, we found that waist circumference and WHR both tended to be larger, however not reaching statistical significance, in the group that developed IGT/T2D than in the individuals with NGT at follow-up (shown in Table 3 and Table 5), i.e. indicating larger visceral adipose tissue storage.
In this study, we could also show that insulin secretion is correlated with two important markers of adipose tissue dysfunction, adipocyte hypertrophy and reduced circulating adiponectin levels, suggesting a potential cross-talk between adipose tissue and beta-cell function, potentially through endocrine regulation by one or several secreted, that was recently proposed by Cantley et al. .
Attention has been brought to the patterns of weight gain prior to the development of T2DM by The Whitehall II Cohort study . The majority of individuals that developed T2DM had only a modest weight gain during the study period, but were overweight during the entire 18 years follow-up. Two other, more extreme weight gain patters were identified and all three groups increased significantly more compared to the control group not developing T2D. FDR are at increased risk of developing overweight or obesity and are, for a given BMI, more likely to display an increased risk profile for both T2D and cardiovascular disease compared to healthy controls without family history of T2D . Higher body fat percentage and waist hip ratio were the strongest predictors for development of IGT and T2D from normoglycaemia at baseline.
Interestingly, high physical activity was a risk factor of IGT/T2D in this cohort, which may seem counterintuitive at first. However, our research group is working on a cross-sectional study on the same cohort of individuals, comparing them to a control group without heredity for T2D, and the preliminary results show that high physical activity is more prevalent in the FDR group than among the controls. This could be due to a selection bias, where the FDR recruited from the general population are aware of their cardiometabolic risk profile, and thus succumb to a physically active lifestyle to minimize the risk of disease. However, Mozaffarian et al. showed a u-shaped relationship between physical and the risk of atrial fibrillation, reminding about the complex associations between lifestyle and cardiometabolic disease .
A limitation of this study could be the measurements used to assess dyslipidemia. We evaluated neither apolipoprotein subtypes, nor size of lipoprotein particles, which could have altered the conclusions we reached, i.e., that measures of dyslipidemia did not significantly differ between normoglycemic FDR and FDR developing IGT/T2D. Studies have suggested that, e.g., serum lipoprotein[Lp](a) levels in subjects with an apparently advantageous blood lipid profile, could predict cardiometabolic disease, possibly also mediated by gender differences in autoimmune activation, and thus of interest to investigate in this cohort [38, 39].
Finally, two possible confounders are important to mention. We did not collect data on the individuals’ dietary habits, which could possibly have affected the associations studied here. Another possible confounder is the significantly longer follow-up time in the group that developed IGT/T2D than in the group that remained NGT. The IGT/T2D were thus slightly older than the NGT subjects, and as age is an important risk factor for T2D, the difference in follow-up time could have affected the metabolic differences studied. We also did not stratify our study groups by gender. As gender-specific differences have been demonstrated in several of the parameters measured in this study, this might have affected our results. However, we did account for gender differences when performing the multiple regression analysis.