Blood Letting in High-Ferritin Type 2 Diabetes

Abstract

Iron-related insulin-resistance is improved by iron depletion or treatment with iron chelators. The aim of this study was to evaluate insulin sensitivity and insulin secretion after blood letting in patients who had highferritin type 2 diabetes and were randomized to blood letting (three phlebotomies [500 ml of blood] at 2-week intervals, group 1) or to observation (group 2). Insulin secretion and sensitivity were tested at baseline and 4 and 12 months thereafter. The two groups were matched for age, BMI, pharmacologic treatment, and chronic diabetic complications. All patients were negative for C282Y mutation of hereditary hemochromatosis. Baseline glycated hemoglobin (6.27 ؎ 0.9% vs. 6.39 ؎ 1.2%), insulin sensitivity (2.75 ؎ 1.8 vs. 3.2 ؎ 2.1 mg ⅐ dl ؊1 ⅐ min ؊1 ), and area under the curve for C-peptide (AUC C-peptide ; 38.7 ؎ 11.6 vs. 37.6 ؎ 14.1 ng ⅐ ml ؊1 ⅐ min ؊1 ) were not significantly different between the two groups of patients. Body weight, blood pressure, blood hematocrit levels, and drug treatment remained essentially unchanged during the study period. As expected, serum ferritin, transferrin saturation index, and blood hemoglobin decreased significantly at 4 months only in patients who received blood letting. In parallel to this changes, blood HbA 1c decreased significantly only in group 1 subjects (mean differences, ؊0.61; 95% CI, ؊0.17 to ؊1.048; P ‫؍‬ 0.01). AUC C-peptide decreased by ؊10.2 ؎ 6.3% after blood letting. In contrast, a 10.4 ؎ 6.4% increase in AUC C-peptide was noted in group 2 subjects at 4 months (P ‫؍‬ 0.032). At 12 months, AUC C-peptide returned to values not significantly different from baseline in the two groups of subjects. At 4 months, the change in insulin sensitivity from baseline was significantly different between the two groups (80.6 ؎ 43.2% vs. ؊8.6 ؎ 9.9% in groups 1 and 2, respectively, P ‫؍‬ 0.049). At 12 months, the differences between the two groups were even more marked (55.5 ؎ 24.8% vs. ؊26.8 ؎ 9.9%; P ‫؍‬ 0.005). When the analysis was restricted to those subjects who completed the follow-up until 12 months, results did not show differences compared with the changes observed at 4 months, except for insulin sensitivity. A statistically significant increase in insulin sensitivity was observed in the blood-letting group (from 2.30 ؎ 1.81 to 3.08 ؎ 2.55 mg ⅐ dl ؊1 ⅐ min ؊1 at 4 months, to 3.16 ؎ 1.85 mg ⅐ dl ؊1 ⅐ min ؊1 at 12 months; P ‫؍‬ 0,045) in contrast with group 2 subjects (from 3.24 ؎ 1.9 to 3.26 ؎ 2.05 mg ⅐ dl ؊1 ⅐ min ؊1 at 4 months, to 2.31 ؎ 1.35 mg ⅐ dl ؊1 ⅐ min ؊1 at 12 months). In summary, blood letting led simultaneously to decreased blood HbA 1c levels and to changes in insulin secretion and insulin resistance that were significantly different from those observed in a matched observational group of subjects with high-ferritin type 2 diabetes. The mechanisms for improvement in peripheral insulin sensitivity after blood letting should be investigated further.

Iron and insulin resistance

“…The effect of phlebotomy was observed also in patients with normal iron parameters at enrolment. Our data confirm previous results reported in literature in small groups of patients with diabetes, and with NAFLD with or without alterations of Glu metabolism [3][4][5] showing that phlebotomy is followed by a reduction of IR and an increased Ins release. The effect of iron depletion is possibly related to an improvement of Ins signalling.…”

“…3 Moreover, studies performed in small groups of patients indicate that phlebotomy is followed by a reduction of IR and an increased Ins release in diabetes, and in patients with NAFLD with or without alterations of Glu metabolism. 4 …”

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