In the current study, we report for the first time that cortical thinning and disrupted white matter integrity are more pronounced in early stage type 2 diabetes. Furthermore, we found that disease duration-related alterations in cortical thickness and white matter integrity were more prominent in overweight/obese type 2 diabetic individuals than in those with normal weight. A similar trend was also found in psychomotor speed performance. These findings suggest that weight status may play additive roles in type 2 diabetes-related brain and cognitive alterations.

We selected grey and white matter ROIs in the temporal, prefrontoparietal, motor and occipital regions that showed type 2 diabetes-related alterations in cortical thickness or white matter integrity. We explored whether the concomitant presence of overweight or obesity influences grey and white matter of the brain in a region-specific manner. Interestingly, region-specific interaction effects were primarily observed in the temporal region, indicating that the temporal lobe is vulnerable to the combined effects of overweight/obesity and type 2 diabetes. An exploratory analysis also suggested that the reduction in FA values in white matter tracts including the inferior longitudinal fasciculus, inferior fronto-occipital fasciculus and cingulum, which are mainly located in or pass through the temporal regions, were more pronounced in overweight/obese compared with normal-weight type 2 diabetic individuals.

Overweight/obesity and type 2 diabetes independently increase the risk of dementia [2, 28,29,30], and previous studies have shown that temporal lobe atrophy is one of the earliest neuroanatomical changes in Alzheimer’s dementia [18, 31]. Therefore, the temporal deficits specifically observed in the overweight/obese type 2 diabetes group may represent neuroanatomical substrates underlying the links among overweight/obesity, type 2 diabetes and the risk of dementia.

As pronounced deficits in the brain and in cognitive functions of people with type 2 diabetes may be potentiated by obesity, these patients can be divided into distinct prognostic subtypes according to their weight status [15, 16]. Our findings also highlight the need for early intervention aimed to reduce risk factors for overweight or obesity in type 2 diabetic individuals to preserve their brain structure and cognitive function. Furthermore, the contributory factors are unknown, our findings suggest that insulin resistance without obesity has distinct effects on the brain compared with conventional type 2 diabetes.

However, it is noteworthy that the current study did not recruit overweight/obese individuals without type 2 diabetes. Therefore, we could not determine the potential effects of overweight/obesity that are completely independent of type 2 diabetes on metabolic, brain and cognitive measures. Further studies using a more elaborate framework are recommended to better describe the independent and combined (additive, synergistic or interactive) effects of type 2 diabetes and obesity/overweight on the brain. To achieve this, we suggest using a balanced cohort comprising the following groups: normal-weight control individuals, obese individuals without type 2 diabetes, normal-weight type 2 diabetic patients and obese type 2 diabetic patients.

Interestingly, HbA 1c levels (reflecting symptom severity) seem to decrease shortly after the diagnosis of type 2 diabetes. Furthermore, preliminary correlation analyses revealed that insulin resistance may be a significant determinant of cortical atrophy in early stage type 2 diabetes. Although the underlying mechanisms have not yet been clearly identified, impaired insulin signalling and consequent effects on synaptic plasticity may link insulin resistance and cortical atrophy [32]. Insulin receptors are widely distributed in the brain and are highly abundant in the hippocampus and specific cortical areas [33, 34]. Given that the current consensus recommendation for treating type 2 diabetes aims to maintain near-normal blood glucose and HbA 1c levels, these findings suggest that it may be more important to manage insulin resistance (the underlying cause of the disease) during early stage type 2 diabetes than previously thought.

Although the final model included 1 year follow-up data, the current results may represent a cross-sectional estimation of trajectories in relation to the disease duration, rather than individual longitudinal changes. We used a linear mixed-effect model that accounted for within-individual random effects by assuming that changes occurring during the disease course are comparable among individuals [19]. This estimation was corroborated by a repeated analysis including only baseline data, which produced similar findings. Future longitudinal studies are necessary to estimate the longitudinal trajectory of brain measures in early stage type 2 diabetes.

The actual onset of type 2 diabetes often begins several years before its clinical diagnosis [35]. Thus, longitudinal follow-up of individuals with impaired glucose tolerance may be necessary to confirm the effects of overweight/obesity on the brain in individuals with type 2 diabetes. In this study, type 2 diabetic participants had not experienced previous hypoglycaemic episodes, so the potential effects of hypoglycaemia could not be determined [36].

Given that a series of studies suggest that glucose-lowering medications may have effects on the brain [37], the current findings should be interpreted with caution regarding the use of glucose-lowering medications. Specifically, glucagon-like peptide-1 receptor agonist, dipeptidyl peptidase 4 inhibitors, metformin and thiazolidinedione are known to have favourable effects on the brain [37]. Further longitudinal studies using larger cohorts are needed to discriminate and trace the potential interaction between glucose-lowering medication use and weight status on the brain in type 2 diabetic patients.

Our results suggest that a relationship exists between disease duration and metabolic measures in each diabetic group (classified according to BMI). However, as there was no information on fasting insulin and C-peptide levels in the normal-weight control group, differences in metabolic measures between the type 2 diabetic and control groups could not be determined in the present study.

The current WHO BMI cut-offs between overweight and obesity do not differ according to ethnic origin [17]. In Koreans, the overall risk of death was reported to be lowest for individuals with a BMI of 23.0–24.9 kg/m2 [38]. However, it is noteworthy that people of Asian ethnicity tend to be more vulnerable to slight increases in BMI even within the overweight range and are at a higher risk of type 2 diabetes than those of other ethnicities [39, 40]. Pre-existing functional deficits in beta cells, along with a tendency toward insulin resistance even in lean individuals, may contribute to the specific vulnerability of Asian people [17, 41]. Potential ethnic differences in brain vulnerability to type 2 diabetes and/or overweight/obesity may therefore need to be considered when interpreting the results of these studies.

This study showed that the concurrent presence of overweight/obesity was associated with cortical atrophy, disrupted white matter integrity and cognitive dysfunction in early stage type 2 diabetes. An increased awareness of overweight/obesity-related risk is necessary to prevent and manage type 2 diabetes-related brain atrophy and cognitive dysfunction from early stage type 2 diabetes onward.