Several studies have shown the importance of adequate glycemic control in avoiding long-term diabetic complications and that partial endogenous insulin production facilitates good glycemic control ^[1][2][1,2].

Patients with type 1 diabetes mellitus (T1DM) have an increased risk of developing other autoimmune disorders such as Hashimoto’s thyroiditis, Addison disease, atrophic gastritis, pernicious anemia, vitiligo, and celiac disease (CeD) [3]. These auto-immune diseases share a similar genetic background and are associated with autoantibodies that can be detected before the development of clinical manifestations. A coexisting autoimmune disorder can complicate diabetes management. Screening protocols have been advocated to detect these disorders [4].

CeD is an autoimmune disorder in genetically predisposed individuals precipitated by exposure to gluten, a protein found in wheat, rye, barley and others, resulting in a multisystem inflammation with enteropathy as a central feature. CeD is almost always restricted to human leukocyte antigen (HLA) HLA-DQ2 or DQ8 positive individuals. The association between T1DM and CeD dates back to 1969 [5].

The genetic risk factors associated with both diseases include HLA genes and non-HLA genes. Genetic factors contribute to about 50% of the risk of T1DM [6]. The genes most strongly associated with T1DM are HLA-DQ2 and DQ8. These HLA-alleles have been linked to an increased risk of CeD. As a result, T1DM patients are more likely to develop CeD ^[6][7][6,7].

Studies in animals support a link between gluten and T1DM. It is suggested that gluten affects the β-cells, with a possible link to the development of T1DM. Other components may exert an additional effect, such as the innate and adaptive immune systems, pro-inflammation, and gut microbiota and permeability ^{[7][8][9][10][11][12]}[7,8,9,10,11,12].

Furthermore, gliadin has been shown to affect the pancreas [13], possibly by inducing inflammation [9] and β-cell stress [10]. The incidence of T1DM in mice was reduced from 64% to 15% by applying a lifelong gluten-free diet GFD ^[12][14][12,14].

In addition to the genetic connection between T1DM and CeD, studies suggest that higher gluten consumption may escalate the incidence of T1DM. For example, a study found a proportional increase in the risk of T1DM in the offspring of pregnant women who consumed more gluten [15]. In another study, a GFD improved insulin secretion in subjects at high risk for T1DM [16]. A small study from Denmark showed significant improvement in glycemic control following a one-year GFD in 15 children with newly diagnosed T1DM [17].

There is some evidence suggesting that a GFD might positively influence T1DM pathology, onset, and clinical course [18]. However, studies in humans are rare. There is no clear evidence that a GFD can prevent the development of CeD in patients with T1DM [19]. Such an approach is not recommended as it makes future CeD diagnosis difficult [20].

Several environmental factors were studied as precipitating factors for the development of CeD or T1DM. Enterovirus infections, specifically Coxsackie, have been linked to the development of T1DM ^[21][22][21,22]. Rotavirus has been linked to an increased risk of T1DM and CeD [23]. Furthermore, altered gut permeability and microbiota seem to be factors that contribute to the development of both of these two diseases [24].

2. Micro- or Macroangiopathic Complications in Coexistent T1DM and Celiac Disease

Few studies have been published dealing with the vascular complications of T1DM in the presence of CeD. Interestingly, Bakker et al. ^[25][75] showed that retinopathy is less prevalent in T1DM patients with CeD compared to controls (T1DM patients without CeD). This could imply that a GFD has a beneficial effect on vascular complications in T1DM patients. Similar findings were observed by Picarelli et al. ^[26][76]. They studied whether CeD in patients with T1DM is associated with different expressions of hemostatic factors and if that is associated with an effect on the development of complications. They found that CeD may have a protective role in the prothrombotic state of T1DM. Patients with CeD had significantly lower cholesterol, triglycerides, HbA1c, factor VII antigen, coagulant activity, and prothrombin degradation fragments. Contrary to these studies, Pitocco et al. ^[27][77] found that the carotid intima-media layer was thicker in T1DM patients with a long duration of CeD, compared to those diabetics without CeD. Data from the Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) showed that the risk of cardiovascular disease in children with T1DM and untreated CeD may be increased by an unfavorable lipid profile (low HDL-C levels and high LDL-C values) ^[28][78]. These data underscore the fact that a strict GFD is mandatory for these young patients. A multicenter longitudinal analysis from the German-Austrian DPV (Diabetes Patienten Verlaufsdokumentation) Database investigated whether CeD associated with T1DM increases the risk of microvascular complications ^[29][79]. Nephropathy and retinopathy occurred earlier in the presence of CeD. The incidence of retinopathy and nephropathy was higher in patients with T1DM and CeD than in those without CeD. This researchtudy did not investigate the possible protective effect of a GFD on the microvascular complications in T1DM and CeD. In a case–control study ^[30][80] performed in Sheffield, U.K., T1DM patients aged > 16 years (n = 1000) were assessed for CeD. CeD was found in 3.3% of the study population. HbA1c, lipid profile, nephropathy stage, retinopathy stage, and degree of neuropathy before and after 1 year on a GFD were assessed. At the time of diagnosis of CeD, adult patients with T1DM had worse glycemic control, lower total cholesterol, lower HDL cholesterol, and a higher prevalence of retinopathy, nephropathy, and peripheral neuropathy. After following a GFD for one year, there was an improvement in the lipid profile, HbA1c, and markers for nephropathy. Of particular importance, if GFD has a protective role against the development of micro- and macroangiopathic complications, then a misdiagnosis of CeD in adult patients with T1DM would be associated with a higher prevalence of nephropathy, peripheral neuropathy, and retinopathy. Creanzo et al. ^[31][56] found that the coexistence of T1DM and CeD is associated with lower eGFR values than those with T1DM alone. These findings underscore the importance of regular screening for CeD in T1DM patients to timely detect those at risk of developing CeD. On the other hand, GFD has been shown to have a protective rather than a detrimental effect on micro- and macrovascular complications ^[25][26][75,76], even in children ^[32][33][81,82]. To summarize, there seems to be greater agreement between studies on the benefits of GFD regarding long-term vascular complications. However, there are substantial differences between these studies, and consequently, the inconsistent and inconclusive results regarding the influence of a GFD on glycemic control, insulin dose, HbA1c, glucose excretion, and hypoglycemic episodes in patients with T1DM and CeD, they could be due to the type of diet that they actually follow. A GFD could mean the use of foods rich in fats with a high glycemic index and a more unfavorable impact, or it could mean a diet based mainly on vegetables with a more favorable impact on glycemic values, HbA1c, insulin requirement, lipid profiles, and even the incidence of long-term diabetic complications. Thus, investigating the ingredients of GFD would be more interesting. Further investigations are needed to explore the mechanism by which therapy with a GFD might prevent micro- and macrovascular complications of T1DM. Theoretically, greater dietary adherence and regular assessment and coaching by an experienced dietitian might result in better and healthier eating habits.