There is growing evidence that β-cells in type 2 diabetes (T2D) are functionally heterogenous. However, little information is available on whether and how the function of T2D islets is directly related to clinical features. We studied islets isolated from 92 T2D organ donors [age: 73±9 years, M/F:55/37; body mass index (BMI): 26.2±3.6 kg/m2; Known duration of diabetes: 10±11 years]. Insulin secretion in response to glucose (g), glibenclamide (glib) and arginine (arg) was expressed as insulin stimulation index (ISI, ratio of stimulated over basal insulin release) and compared with that of islets from a large series (n=431) of non-diabetic (ND) donors. ISI from T2D islets was 1.65±0.68, 1.87±0.90 and 1.90±0.85 in response to g, glib and arg, respectively. As expected, these values were lower (p<0.01) than those obtained with ND islets (2.96±1.6; 3.16±1.72; 2.57±1.42). Based on ISI values, T2D islets were subdivided into four subgroups: group A (27%), that was responsive to all the three secretagogues; group B (21%), in which islets responded to g and glib or arg; group C (21%), with the islets not responsive to g but with maintained secretion when stimulated with glib or arg; group D (31%), in which the islets did not respond to any of the studied secretagogues. Donors’ age, BMI, duration of diabetes, length of intensive care unit (ICU) stay and blood glucose levels during ICU did not differ between the four groups. However, β-cell responsiveness to acute glucose stimulation (but not to glib and/or arg) was significantly lower with islets from patients on exogenous insulin therapy (in association with oral anti-diabetic agents or alone): (insulin therapy: 1.3±0.4, no insulin therapy: 1.7±0.72; p=0.002) The reduced β-cell glucose sensitivity of T2D islets from donors on exogenous insulin therapy indicates β-cell functional frailty independent from other main clinical features. Islet molecular analyses are ongoing to shed light on the underlying mechanisms. Supported by: PNRR-M4C2- I1.3 Project PE-00000019-HEAL ITALALIA - CUP I53C22001440006 - Spoke 8 and 539901_PRIN2022_MARCHETTI_2022L9PMZZ.