Despite new and effective drug therapies, insulin resistance (IR), type 2 diabetes mellitus (T2D) and its complications remain major medical challenges. It is accepted that IR, often associated with over-nutrition and obesity, results from chronically elevated oxidant stress (OS) and chronic inflammation. Less acknowledged is that a major cause for this inflammation is excessive consumption of advanced glycation end products (AGEs) with the standard western diet. AGEs, which were largely thought as oxidative derivatives resulting from diabetic hyperglycemia, are increasingly seen as a potential risk for islet β-cell injury, peripheral IR and diabetes. Here we discuss the relationships between exogenous AGEs, chronic inflammation, IR, and T2D. We propose that under chronic exogenous oxidant AGE pressure the depletion of innate defense mechanisms is an important factor, which raises susceptibility to inflammation, IR, T2D and its complications. Finally we review evidence on dietary AGE restriction as a nonpharmacologic intervention, which effectively lowers AGEs, restores innate defenses and improves IR, thus, offering new perspectives on diabetes etiology and therapy.

Advanced glycation end products (AGE) and diabetes: cause, effect, or both?

http://morelife.org/references/full_papers/14568010.pdf

Novel inhibitors of advanced glycation endproducts

Immunohistochemical detection of advanced glycosylation end-products in the peritoneum and its possible pathophysiological role in CAPD.

https://www.ajkd.org/article/S0272-6386(00)70189-2/pdf

Advanced glycation end products: A nephrologist's perspective

The incidence of diabetes, especially type 2 diabetes, is increasing at an alarming rate assuming epidemic proportions (1). Worldwide, 124 million people had diabetes by 1997, although an estimated 221 million people will have diabetes by the year 2010 (1).

https://care.diabetesjournals.org/content/diacare/29/6/1420.full.pdf

Diabetes and Advanced Glycoxidation End-Products

In patients with diabetic renal failure plasma advanced glycosylation end-products (AGE) levels are reported to be elevated and dialyzer of continuous ambulatory peritoneal dialysis (CAPD) is usually used with a high glucose concentration. Here, an immunohistochemical study on human AGE accumulation in vascular beds and peritonea of patients with chronic renal failure (CRF) or those on CAPD was undertaken. Further, the influence of aging was studied using AGE-specific monoclonal antibody. 1. AGE accumulation was observed in radial arterial walls (from vascular intima to smooth muscle layer) of diabetic patients with CRF. Even in some non-diabetic patients with CRF (n = 3/6), especially in those with a long history of CRF and dialysis treatment, similar positive staining was seen in vascular walls. No AGE staining was observed in any renal tissue of age-matched control subjects including tissue from patients with acute renal failure. 2. Although AGE accumulation was not seen in the peritonea of CRF patients with no prior CAPD therapy, it was seen in the mesothelial layers and in adjacent coarse connective tissues of peritonea from patients on CAPD (n = 6), even from as early as only 3 months of CAPD therapy. 3. AGE accumulation was observed in the vascular bed of the non-diabetic aged kidney with normal function, but not in that of the young kidney. Thus, AGE accumulation in the vascular bed may depend on the degree and term of renal impairment and on aging in addition to diabetes. AGE accumulation in the peritonea became positive following CAPD treatment, indicating that it might affect the efficiency of CAPD.

Immunohistochemical study of human advanced glycosylation end products (AGE) in chronic renal failure.

Aim: We tried to establish the significance of quantifying urinary type IV collagen (IV-C) excretion for the evaluation of renal involvement of type 2-diabetic patients. Methods: Twenty patients (13 males and 7 females; age range 31 to 69 years) with type 2 diabetes mellitus had undergone renal biopsy and relationship between the severity of morphological alteration, IV-C expression and urinary IV-C excretion were examined. Results: Urinary IV-C excretion significantly correlated with mesangial expansion score (p = 0.49, p <0.05) and tubulointerstitial injury score (p = 0.56, p < 0.05). Furthermore, urinary IV-C excretion significantly correlated with both glomerular (r = 0.56, p <0.01) and tubulointerstitial IV-C expression areas. Urinary protein excretion also correlated with mesangial expansion score and tubulointerstitial injury score. However, it did not correlate with the expression of IV-C in the kidney. Conclusions: These results suggest that urinary IV-C excretion reflects the pathogenetic process of diabetic nephropathy, which urinary protein excretion alone cannot do sufficiently. It can be concluded that urinary IV-C excretion could be a more useful marker for the evaluation of renal involvement of type 2-diabetic patients.

Urinary type IV collagen excretion reflects renal morphological alterations and type IV collagen expression in patients with type 2 diabetes mellitus.

Cardiovascular disease is one of the most common complications of dialysis and renal transplant patients, and high levels of AGE are present in end-stage renal failure. To address the potential involvement of AGE and growth factors in the pathophysiology of cardiovascular complications, we performed immunostaining using cardiac tissues from autopsy cases of patients on maintenance dialysis (10 cases), long-term surviving renal transplant patients with functioning grafts (8 cases), control subjects with normal renal function (7 cases) and non diabetic subjects with mild renal insufficiency (8 cases). We used two types of AGE-antibodies, 6D12 [monoclonal anti-AGE antibody, recognizing N epsilon-(carboxymethyl) lysine(CML)-modified AGE] (oxidative AGE) and non-CML-PA [polyclonal, not recognizing CML], and antibodies against PDGFs, PDGF receptors and TGF beta. Positive 6D12 staining was observed in the coronary arterial walls and in macrophages. The accumulation of 6D12-reactive AGE in the coronary arterial walls of maintenance dialysis patients was significantly greater than that of control subjects (p < 0.05). Renal transplantation significantly reduced this accumulation (p < 0.05). On the other hand non-CML-PA mainly detected AGE in intracardiac arterioles and neural tissues. There was little difference in the accumulation of non-CML-AGE among the four groups. PDGFs and PDGF receptors were mainly detected in vascular endothelial cells and infiltrating cells of cardiac tissues of renal transplant patients, but not of maintenance dialysis patients. TGF beta was not detected in cardiovascular tissue of transplant patients. Our results indicated that the accumulation of oxidative AGE (CML-AGE) in the cardiac vascular tissue is one of the factors for cardiovascular complications of maintenance dialysis patients, and also that renal transplantation has a reducing effect on CML-AGE accumulation. PDGFs may be involved in the cardiovascular complications after renal transplantation.

Immunohistochemical study of human advanced glycation end-products (AGE) and growth factors in cardiac tissues of patients on maintenance dialysis and with kidney transplantation.

Sodium-losing nephropathy and distal tubular damage of transplant kidneys with FK506 administration.

CULTURE of porcine pancreatic islets is considered to be difficult because of their fragility and for other unknown reasons Improvement of islet culture is very important for the purpose of pretransplant conditioning of islet allografts or xenografts From our previous experience of porcine lymphocyte culture, better results were obtained by adding fetal pig serum instead of fetal calf serum (FCS) to the culture medium In this study, therefore, we examined the effect of allogeneic and autologous porcine sera on islet culture as compared with FCS

K. Yamada

Papers

Immunohistochemical study of human advanced glycosylation end products (AGE) in chronic renal failure.

Urinary type IV collagen excretion reflects renal morphological alterations and type IV collagen expression in patients with type 2 diabetes mellitus.

Immunohistochemical study of human advanced glycation end-products (AGE) and growth factors in cardiac tissues of patients on maintenance dialysis and with kidney transplantation.

Sodium-losing nephropathy and distal tubular damage of transplant kidneys with FK506 administration.

Improvement of porcine islet culture with porcine serum.