Cytochrome c Oxidase Activity as a Metabolic Regulator in Pancreatic Beta-Cells.

Genya Aharon-Hananel,Carmit Mantzur,Ann Saada,Sarah Weksler-Zangen,Leonor Romero-Afrima,Itamar Raz

doi:10.3390/cells11060929

Abstract

Pancreatic β-cells couple glucose-stimulated insulin secretion (GSIS) with oxidative phosphorylation via cytochrome c oxidase (COX), a mitochondrial respiratory-chain enzyme. The Cohen diabetic-sensitive (CDs) rats exhibit hyperglycemia when fed a diabetogenic diet but maintain normoglycemia on a regular diet. We have previously reported a decreased COX activity in CDs rats and explored its relevance for type 2 diabetes (T2D). In this study, we investigated the relation between COX activity in islets, peripheral-blood mononuclear cells (PBMCs), and GSIS during diabetes development in CDs rats fed a diabetogenic diet for 4, 11, 20, and 30 days and during reversion to normoglycemia in hyperglycemic CDs rats fed a reversion diet for 7, 11, and 20 days. An oral glucose-tolerance test was performed at different periods of the diets measuring blood glucose and insulin concentrations. COX activity was determined in islets and PBMCs isolated from rats at the different periods of the diets. We demonstrated a progressive reduction in COX activity in CDs-islets that correlated positively with the decreasing GSIS (R2 = 0.9691, p < 0.001) and inversely with the elevation in blood glucose levels (R2 = 0.8396, p < 0.001). Hyperglycemia was initiated when islet COX activity decreased below 46%. The reversion diet restored >46% of the islet COX activity and GSIS while re-establishing normoglycemia. Interestingly, COX activity in PBMCs correlated significantly with islet COX activity (R2 = 0.8944, p < 0.001). Our data support islet COX activity as a major metabolic regulator of β-cells function. The correlation between COX activity in PBMCs and islets may serve as a noninvasive biomarker to monitor β-cell dysfunction in diabetes.

Highlights

Pancreatic β-cell dysfunction and the ensuing impaired glucose-stimulated insulin secretion (GSIS) are essential for the progression from pre-diabetes to diabetes [1–3]
Cohen diabetic-sensitive (CDs) rats fed with the diabetogenic diet exhibited a gradual time-dependent increase in the glucose area under the oral glucose tolerance test (OGTT) curve (AUCglucose, Figure 1A) paralleled by a timedependent decrease in AUCinsulin calculated as the insulinogenic index (Figure 1B)
This study provides evidence for a critical role of defective islet c oxidase (COX) activity as a preliminary event leading to diabetes in CD rats

Summary

Introduction

Pancreatic β-cell dysfunction and the ensuing impaired glucose-stimulated insulin secretion (GSIS) are essential for the progression from pre-diabetes to diabetes [1–3]. The rise in the ATP/ADP (Adenosine diphosphate) ratio is coordinated by oxidative phosphorylation (OxPhos) carried out by five mitochondrial respiratory chain (MRC) multimeric-enzyme complexes [3–5]. Islets from T2D donors demonstrated fused or fragmented mitochondria and a selective impairment in GSIS, while insulin secretion in response to non-fuel secretagogues was maintained [8–12]. The reduced expression of a set of OxPhos genes was demonstrated in islets of animal models of diabetes and patients with T2D [13,14], and impairment in the assembly of the MRC super-complex was observed in animal models of diabetes [15] as well as in the rectus abdominis muscle of obese individuals with T2D [16]. Mitochondrial dysfunction was demonstrated in platelets of both diabetic rats and T2D patients [17], suggesting that peripheral-blood mononuclear cells (PBMCs) may serve as a biomarker to observe the mitochondrial changes during T2D [18]

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