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Systemic Sonic Hedgehog (Shh) signaling is increasingly recognized as a potential regulator of adult metabolic homeostasis, yet its role in human disease remains poorly defined. In this study, we measured plasma Shh levels in two large Swedish cohorts to assess their associations with common non-communicable diseases, with a particular focus on type 2 diabetes mellitus (T2DM) and metabolic dysfunction. A population-based screen of 735 individuals revealed substantial inter-individual variability in Shh levels, with elevated levels associated with T2DM and hypertension in females but not in males. These findings were validated in a nested case–control study, where Shh levels were significantly higher in T2DM females compared to matched controls. Correlation analyses showed that Shh levels were associated with insulin resistance in both sexes but reflected different disease states with early compensatory insulin secretion in males and late β-cell dysfunction in females. Mechanistic studies using human intestinal organoids demonstrated that Shh secretion is induced by the combination of glucose and insulin, suggesting the intestine as a nutrient-responsive source of the systemic Shh. Together, these results identify Shh as a sexually dimorphic marker of metabolic dysfunction and support its functional role in glycemic control and metabolic disease.