In current study, we investigated case-control associations of IGP with DR as well as its severity in Chinese participants with type 2 diabetes. Firstly, our findings revealed the relationships between OGTT-derived indicators and the risk of retinopathy. HbA1c and 120-min PG value has previously been found to be independently associated with DR which conformed with our findings,[7, 22] while the evidence on the association between 180-min PG value and DR were limited which might partly depend on 120-min PG. Post-load plasma glucose peak, which was described as a risk factor of cardiovascular diseases with postprandial peak,[23] also had impact of hyperglycaemia on endothelial function and retinal vascular reactivity. Previous studies had proposed that FPG could screen high risk diabetes with microvascular events and 60-min PG could prompt the onset of DR due to theirs close connection with insulin secretion.[22, 24] By contrast, in our study no independent association between FPG and 60-min OGTT glucose concentration and presence of DR was found. However, their use of cross-sectional design and 1- or 2-h plasma glucose concentrations by Americans or Indians entails a major different finding.
Additionally, adjusting for gender, age, and potential clinical-based confounders for DR, this present study first reported the association of IGP index with the presence of any-DR, moderate NPDR, and VTDR. This finding was also consistent with the results when IGP level was considered into categorical variable. Although there is no direct evidence on IGP levels with DR, high IGP was found to be associated with several macrovascular impairments, such as aortic stiffness, carotid intima-media thickness (CIMT), and maladaptive carotid remodeling.[16, 17] Moreover, evidences showed that when CGM was unavailable, IGP could be chosen to assess GV in replacement of coefficient of variation (CV; SD / mean * 100%),[14] which was recommended as the leading measurement of variability by the international consensus of the Advanced Technologies & Treatments for Diabetes (ATTD) Congress.[25] The association between variability assessed by IGP and retinopathy was consistent with the results of the GV metrics assessed by CGM,[11, 13] while the results of some researches remained in debate and further longitudinal, population-based studies are needed to confirm our findings .[10]
Mechanistic Explanations
The biological pathway underlying the relationship between IGP and DR remains to be elucidated. In order to fill this gap, HOMA-IR which was associated with DR, was graded by quartiles, and higher level of insulin resistance increased FPG and 3-h post-load plasma glucose peak (both P value < 0.001), but decreased the level of IGP (see Figure S2 in Additional file 3). In contrast, Murata et al. got a positive correlation between glucose fluctuation and HOMA-IR due to definitional discrepancy between glucose fluctuation and IPG.[26] In our study, IGP could reflect an integrated situation of pre-load and 3-h post-load plasma glucose and seem to be related to insulin resistance, then form a relationship with DR.
In addition, DR has been traditionally recognized as a micro -vascular disease. Nevertheless, retinal neurodegeneration (neuronal apoptosis and glial activation) was also proved to be involved in the pathogenesis of DR.[27] The activation of Müller cells, the representative glial component of retina, was observed in response to GV.[28] Besides, Picconi et al. and Stem et al. demonstrated that increased glycemic excursion was connected with early structural impairments of neural retina in patients with type 1 diabetes, resulting a stable glycemic status and a decrease in GV might prevent the damage to structure and function of retina.[29, 30]
Although molecular mechanisms induced by hyperglycemia in the incidence and progression of DR have been described in previous studies, such as the hexosamine pathway, increased polyol pathway flux, protein kinase C (PKC) activation, free radicals formation and advanced glycation end (AGE) products accumulation, the metabolic mechanism of GV was unclear yet.[9] Some evidences indicated that oscillating glucose played a more destructive role on oxidative stress and endothelial function than sustained hyperglycemia.[31, 32] And a further mechanism revealed oscillating glucose left a metabolic memory, which suggested the persistence of intracellular pro-oxidant environment after plasma glucose normalization.[33] More observational and experimental evidence for the effect of GV on retinopathy was expected.
Clinical Relevance
Diabetes mellitus causes some macrovascular complications such as cardiovascular diseases (CVD) as well as microvascular complications such as retinopathy, nephropathy, and neuropathy, of which, DR is a major cause of vision loss in middle-aged and elderly people. Previous study reported that IPG was associated with aortic stiffness, which is an independent determinant of CVD. Currently, we found that after adjustment for relevant confounders risk of DR was increased with IGP increasing. Our results may imply that, even in case of well-controlled obesity, blood pressure, HbA1c, and renal function, the harmful effects of IPG on DR are still present. Future studies should investigate whether our findings translate to other microvascular complications. If they are replicated in nephropathy, and neuropathy, it would further justify therapeutic interventions that specifically target IGP.