Roles of hydrogen sulfide in the pathogenesis of diabetes mellitus and its complications

Abstract

Significance: Diabetes and its complications represent a major socioeconomic problem.

Recent advances: Changes in the balance of hydrogen sulfide (H(2)S) play an important role in the pathogenesis of β-cell dysfunction that occurs in response to type 1 and type 2 diabetes. In addition, changes in H(2)S homeostasis also play a role in the pathogenesis of endothelial injury, which develop on the basis of chronically or intermittently elevated circulating glucose levels in diabetes.

Critical issues: In the first part of this review, experimental evidence is summarized implicating H(2)S overproduction as a causative factor in the pathogenesis of β-cell death in diabetes. In the second part of our review, experimental evidence is presented supporting the role of H(2)S deficiency (as a result of increased H(2)S consumption by hyperglycemic cells) in the pathogenesis of diabetic endothelial dysfunction, diabetic nephropathy, and cardiomyopathy.

Future directions: In the final section of the review, future research directions and potential experimental therapeutic approaches around the pharmacological modulation of H(2)S homeostasis in diabetes are discussed.

FIG. 1.

Schematic presentation of the three hydrogen sulfide (H₂S)-producing enzymes. H₂S is synthesized by mammalian cells tissues via two cytosolic pyridoxal-5′-phosphate-dependent enzymes responsible for metabolism of l-cysteine: cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), as well as by a mitochondrial third pathway involves the production from l-cysteine of H₂S via the combined action of 3-mercaptopyruvate sulfurtransferase (3-MST) and cysteine aminotransferase (CAT).

FIG. 2.

A working hypothesis depicting the cytoprotective and cytotoxic roles of H₂S in the β-cell during diabetes development. We hypothesize that in the early stage of diabetes development, a high-glucose-induced pancreatic CSE overexpression may serve as a protective mechanism, because it may neutralize oxidative/nitrosative stress and autoimmune attack. However, as a by-product of this process, an increase in intraislet H₂S production may lead to an inhibition of insulin production via potassium-opened ATP channels (K_ATP) channel activation, and the resulting increase in circulating glucose may lead to progressive β-cell toxicity, which, ultimately, results in a lowering of circulating insulin levels. We further speculate that—as this positive feedback cycle amplifies—local levels of H₂S may reach a threshold concentration where an autocrine-type cytotoxic response may be induced. This response may be especially prominent on a background of an oxidant-mediated and autoimmune attack against the β-cell. Ultimately, the above processes may culminate a progressive destruction (apoptosis) of the β-cells, leading to hypoinsulinemia and further hyperglycemia. ROS, reactive oxygen species; RNS, reactive nitrogen species.

FIG. 3.

Summary of the physiological actions of H₂S in blood vessels. H₂S is produced in the cardiovascular system and exerts a number of critical effects on the cardiovascular system. H₂S has been shown to induce vasodilation and inhibit leukocyte-endothelial cell interactions in the circulation. H₂S is a potent antioxidant and inhibits cellular apoptosis. H₂S also has been shown to transiently and reversibly inhibit mitochondrial respiration. Taken together, this physiological profile is ideally suited for protection of the cardiovascular system against disease states. Reproduced with permission from ref. (45).

FIG. 4.

Proposed scheme of H₂S/ROS interactions in hyperglycemic endothelial cells. In normal endothelial cells, physiological production of H₂S (as well as many other antioxidant systems) protects against oxidative stress generated by the mitochondria, and mitochondrial ROS do not spill over to the cytosolic or nuclear compartment. When cells are placed in elevated glucose, mitochondrial ROS production gradually consumes H₂S. This process, coupled with the depletion of other antioxidant defenses, eventually culminates in the spillage of ROS into the cytosolic and nuclear compartments. ROS production, ultimately, on its own, or by combining with nitric oxide (NO) to form peroxynitrite (ONOO⁻), activates multiple pathways of diabetic complications, such as the nuclear enzyme poly(ADP-ribose) polymerase (PARP), the polyol pathway, the advanced glycation endproduct system (AGE), protein kinase C (PKC), and the hexosamine system. Supplementation of H₂S can protect against these processes.

FIG. 5.

Replacement of H₂S attenuates cellular responses that lay downstream from hyperglycemic mitochondrial ROS production in bEnd.3 endothelial cells. (a) DNA strand breakage was measured in low (5.5 mM, LG) or high (40 mM, HG) glucose conditions at 7 days using the Comet assay. High glucose induced an increase in DNA strand breakage as compared with low glucose (*p<0.05) and H₂S (300 μM) afforded a significant suppression of this response (#p<0.05). In the inset, representative images are shown for the four respective groups (LG/HG with and without 300 μM H₂S). (b) Activation of the nuclear enzyme PARP was measured by detection of the poly(ADP-ribose) polymers using western blotting. High glucose induced an increase in PARP activation (*p<0.05) and H₂S (300 μM) afforded a suppression of this response (#p<0.05). In the insert a representative western blot is shown for the four respective groups (low and high glucose with and without 300 μM H₂S). Reproduced with permission from ref. (58).

FIG. 6.

CSE overexpression protects against the development of endothelial dysfunction in thoracic aortic rings placed in elevated extracellular glucose. (a) Rat aortic rings were incubated in low (5.5 mM, LG) or high (40 mM, HG) glucose for 48 h. High glucose induced a suppression of endothelium-dependent relaxant responses (*p<0.05), an effect that was attenuated in the rings overexpressing CSE (#p<0.05). n=4. (b) Depicts representative western blots and densitometric analysis for CSE in rings exposed to adenovirus expressing green fluorescent protein (GFP) or CSE. **p<0.01 shows a significant upregulation of CSE. Reproduced with permission from ref. (58).

FIG. 7.

Improvement of endothelial function by H₂S in diabetic rats ex vivo. (a) Streptozotocin-diabetic vehicle-treated rats (STZ/V) exhibit reduced blood H₂S levels (*p<0.05), an effect that is normalized by supplementation of H₂S using the H₂S-releasing minipumps (STZ/S; #p<0.05). (b) The streptozotocin-induced hyperglycemic response is unaffected by H₂S-releasing minipumps: *p<0.05 shows significant and comparable degree of hyperglycemia in STZ rats treated with vehicle or H₂S-releasing pumps, compared to initial blood glucose values. (c) The thoracic aortas of streptozotocin-diabetic rats (STZ/V) exhibit reduced endothelium-dependent relaxant function in response to acetylcholine (1 nM–30 μM; *p<0.05); supplementation of H₂S using the H₂S-releasing minipumps (STZ/S) attenuated the degree of this endothelial dysfunction (#p<0.05). Reproduced with permission from ref. (58).

FIG. 8.

Cytotoxic/cytoprotective effects of H₂S. Under low oxidative stress conditions, H₂S exerts cytoprotective effects at low concentrations, but becomes cytotoxic at higher concentrations. However, under high levels of baseline oxidative/nitrosative stress, H₂S exerts cytoprotective effects. See text for more detailed delineation of the pathways/mechanisms involved in each response.

FIG. 9.

Pathways involved in the pro-angiogenic effects of H₂S in endothelial cells. Further work needs to determine whether diabetes/hyperglycemia modulates these pathways.