The relationship between pancreatic fat and T2DM has been deeply investigated only in the last few years, showing a close association between these two conditions in most studies [
56‐
58], if not in all [
59,
60]. In a large cohort of nondiabetic lean individuals followed for approximately 6 years, Yamazaki et al. [
61] found that T2D might develop in individuals with fatty pancreas. A potential role of fatty pancreas and its correlation to the pathogenesis of T2DM has been further investigated by several studies, which tried to demonstrate a link among insulin resistance, compromised pancreatic β-cell function and fat accumulation in the pancreas. Using proton magnetic resonance spectroscopy (H-MRS), Begovatz et al. [
62] showed that there was no relationship between interlobular/intralobular fat storage and abnormal endocrine function, as have many other emerging studies [
23,
62,
63]. No clarifying evidence supports the hypothesis of insulin secretion impairment related to fatty parenchymal replacement, since different factors, such as the type of population (e.g., lean individuals vs. obese people), imaging technique or ethnicity, might influence the results reported below. Although lipogenesis and adipocyte differentiation are stimulated by insulin, the crosstalk among pancreatic islets, serum blood glycaemia and counterregulatory molecules (e.g., glucagon, adrenaline and noradrenaline) may be modified by the pancreatic adipose fraction. Emerging evidence [
64] in mice showed an active impairment in insulin secretion by fatty acids released by pancreatic adipocytes. On the other hand, hereditary factors have also been investigated [
29], and individuals with high genetic risk seem to have a negative association between pancreatic fat and insulin secretion, suggesting that pancreatic steatosis impairs only beta-cell function, especially in genetically determined insulin resistance. However, not only insulin secretion but also insulin resistance could be associated with pancreatic fat: in two studies [
20,
57], fatty pancreas was associated with higher insulin resistance (measured by HOMA-IR, associated with visceral fat area, triglycerides, and elevation of ALT) [
20], especially in male T2DM subjects with a shorter duration of diabetes [
57]. However, T2DM and prediabetes are complex and heterogeneous conditions with different subphenotypes [
65] based on glycaemic and lipid profiles, body fat distribution and genetic risk.