Abnormal metabolic fate of nitric oxide in Type 1 diabetes mellitus - Milsom et al. (2002)

Key Points

  • The hemoglobin (Hb) of diabetics shows an increased affinity for nitric oxide (NO) in the non-bioavailable form HbNO

  • There is a positive correlation between HbA1c and HbNO concentrations

  • Rather than just being a marker of blood sugar control, the Hb itself might mediate the disease by altering Hb binding affinity for NO, thus impacting whole-body blood flow and oxygenation

The Breathing Diabetic Summary

We know from all of the other papers we’ve reviewed on nitric oxide (NO) that it’s huge.  It is critical to blood flow regulation and whole-body oxygenation.  Therefore, any paper related to “abnormal” nitric oxide fate in diabetics is extremely important.  Specifically, this paper set out to explore how high blood sugar impacts the binding affinity of NO to Hb, and how this in turn impacts the metabolic fate of NO in diabetic patients.

They did several experiments to accomplish this goal.  First, they exposed NO to increasing HbA1c levels (from 5.9% to 9.8%).  Then, they took blood samples from diabetics and non-diabetics to examine how the NO/Hb binding differed.  Finally, they then exposed the blood they drew from both the diabetics and controls to differing NO levels to see how the blood responded.

The authors found that once HbA1c reached 9.8%, the Hb “held on” to significantly more NO in the form of HbNO.  We saw similar results in James et al. (2004).  Also, note that NO loses its bioavailability when stored as HbNO.  Then, when they drew the blood of the diabetic patients they found higher concentrations of HbNO than those found in the control (no surprise there!).  Finally, they found that when they exposed the blood to higher NO concentrations, diabetics formed more HbNO than the control patients.  The increase in HbNO correlated positively with HbA1c values.

One awesome insight that these authors provided was related to the role of Hb in diabetes.  Right now, we typically regard HbA1c as a marker of blood sugar control.  Your doctor looks at your HbA1c to see how well you’ve been doing.  However, the glycated Hb itself (i.e., a high HbA1c) is also mediating the disease.  Rather than just being a marker of how well you’re doing, it’s also making the disease worse by increasing the Hb’s affinity for NO and thus limiting the amount of bioavailable NO throughout the rest of the body.  As we know, blood flow is a HUGE problem with diabetics, and this paper helps explain why by showing the positive correlation between HbA1c and HbNO.

Overall, this paper shows that we need to lower our HbA1c to increase bioavailable NO throughout the body.  As we know, this will lead to better blow flood, better tissue oxygenation, and reduce our risk of diabetic complications.

Abstract from Paper

Aims/hypothesis. Reduced bioavailability of endothelium-derived nitric oxide is implicated in diabetic macrovascular and microvascular disease. In patients with diabetes, we hypothesised that protein glycosylation can alter nitric oxide binding affinity of haemoglobin and plasma proteins, hence reducing nitric oxide availability and causing an alteration in nitric oxide metabolism.

Methods. Binding of nitric oxide to haemoglobin was studied across a range of glycosylation levels in vitro (HbA1c 5.9 to 9.8%). In clinical studies nitrate, nitrite, nitrosyl haemoglobin and plasma nitrosothiols were measured in venous blood from 23 patients with uncomplicated Type I (insulin-dependent) diabetes mellitus and 17 non diabetic control subjects. Samples were analysed at baseline and after nitric oxide was added ex vivo.

Results. Nitric oxide-haemoglobin binding was increased at a HbA1c greater than 8.5% compared with 5.9% (p<0.01). Basal nitrosyl haemoglobin was higher in diabetic patients compared with the control subjects (0.59±0.12 μmol/l vs 0.24±0.12 μmol/l, p<0.05). Plasma nitrosothiols, and nitrite and nitrate (NOx) concentrations were similar in diabetic patients compared with the control subjects (7.64±0.79 μmol/l vs 5.93±0.75 μmol/l, 13.98±2.44 μmol/l vs 12.44± 2.15 μmol/l, respectively). In blood from diabetic patients, added nitric oxide was metabolised preferentially to nitrosyl haemoglobin and plasma nitrosothiols, with a twofold increase in nitrosyl haemoglobin observed across all concentrations of nitric oxide (p<0.05). These preferential increases correlated positively with HbA1c.

Conclusion/interpretation. Nitrosyl haemoglobin is increased in patients with Type I diabetes. Preferential metabolism to nitrosyl haemoglobin and nitrosothiols occurs after increases in nitric oxide. Our results show an accentuated association between nitric oxide and glycosylated proteins, especially deoxygenated haem. An altered metabolic fate of nitric oxide could influence microvascular regulation and tissue perfusion.

Journal Reference:

A.B. Milsom, C.J.H. Jones, J. Goodfellow, M.P. Frenneaux, J.R. Peters, and P.E. James, (2002) Abnormal metabolic fate of nitric oxide in Type I diabetes mellitus, Diabetologia, 45, 1515–1522, DOI 10.1007/s00125-002-0956-9.