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The results of several epidemiological studies of serum γ-glutamyltransferase (GGT) led us to hypothesise that associations of GGT within its normal range with type 2 diabetes may reflect detrimental effects of xenobiotics found in the environment, such as persistent organic pollutants (POPs). Epidemiological observations showed that serum GGT activity within its normal range strongly predicted future type 2 diabetes; the predictability of diabetes from obesity was low with GGT at the low end of the normal range; and GGT showed a positive association with known markers of oxidative stress or inflammation. Experimental findings on cellular GGT suggest that serum GGT levels within the normal range may reflect oxidative stress related to the re-synthesis of intracellular glutathione; however, this interpretation is not completely satisfying because, in its role of regenerating intracellular glutathione, GGT activity should be antioxidative. Alternatively, serum GGT activity may reflect amounts of glutathione conjugates formed during the metabolism of xenobiotics. Accordingly, we postulate a two-part hypothesis: that the association of serum GGT with type 2 diabetes reflects exposure to POPs, as these substances, which have a very long half-life, may influence diabetes risk by residing in adipose tissue as endocrine disruptors; and that POPs or similar substances may interact with obesity to cause type 2 diabetes. Supporting this hypothesis, cross-sectional investigation of background exposure to POPs in the National Health and Nutrition Examination Survey showed relationships similar to those observed for GGT, including a powerful association with prevalent diabetes and no association between obesity and diabetes for very low POP concentrations. Our hypothesis can be tested in both prospective studies and toxicological studies. [ABSTRACT FROM AUTHOR]

Thirty-five patients with Type 1 (insulin-dependent) diabetes mellitus and 90 normal subjects had renal size (renal area index) determined by X-ray and also had examination of renal biopsies by light and electron microscopy. Renal area index of 206±32 cm/1.73 m (mean±SD) in the Type 1 diabetic patients exceeded that in the normal subjects (180±25 cm/1.73 m, p<0.001). In the diabetic patients, the renal area index correlated with creatinine clearance ( r=+0.43, p<0.05), but did not correlate with urinary albumin excretion, or the electron microscopic measurements of percentage total mesangium and glomerular basement membrane width. In diabetic patients with clinical nephropathy or severe glomerulopathy on biopsy, the kidneys may remain large. Thus, renal size does not indicate the severity of diabetic renal lesions on biopsy. [ABSTRACT FROM AUTHOR]

Uninephrectomy is known to accelerate the development of both functional and morphological changes seen with experimental diabetic nephropathy in the rat. The present experiments utilized electron and light microscopic morphometric techniques to assess glomerular basement membrane width and the volumes of the total mesangium and its cellular and matrix components of inbred Lewis rats made diabetic at 6 weeks of age and uninephrectomized 9 days later. Immunofluorescent microscopy was used to evaluate IgG and C in the mesangium. The reversibility of established diabetic glomerular lesions in uninephrectomized diabetic rats after 7 months of diabetes was studied by performing intraportal transplant of neonatal pancreatic tissue. Renal biopsies were taken 2 months later in transplanted and non-transplanted animals. Islet transplantation lowered plasma glucose to normal levels (29.6 to 7.3 mmol/l) and raised plasma insulin values (6.3 to 53 μU/l). Glomerular basement membrane width in transplanted rats (268 nm) still exceeded the same measure (226 nm) in nondiabetic uninephrectomized rats. In transplanted animals volumes of the mesangium (0.51 × 10 μm) and of its cellular (0.27 × 10 μm) and matrix (0.24 × 10 μm) components remained higher than similar measures in control rats (0.32 × 10, 0.17 × 10 and 0.15 × 10 μm, respectively). Mesangial IgG in treated animals approached normal, but mesangial C remained similar to levels in non-transplanted diabetic control animals. These observations in uninephrectomized-diabetic rats contrast with previous observations in intact diabetic rats in which mesangial volumes and localization of immunoglobulins and complement returned to normal levels following islet transplantation. [ABSTRACT FROM AUTHOR]

Forty-eight mongrel dogs were made diabetic by total pancreatectomy. Fifteen untreated pancreatectomized animals survived for a mean of 7±1 (SEM) days. Thirty-three dogs were divided into five groups and received autotransplants to the spleen of pancreatic fragments dispersed by collagenase digestion for 0, 10, 15, 20 or 25 minutes. Animals transplanted with tissue digested for 0 minutes or for 10 minutes remained hyperglycaemic (mean survival 22±12 days and 28±9 days). Normoglycaemia occurred in all but one of 21 dogs transplanted with tissue digested for 15-25 minutes. Two weeks after transplantation tolbutamide and glucose tolerance curves in the group receiving tissue digested for 20 minutes most closely resembled those of normal animals. Glucose tolerance test K values in dogs receiving tissue digested for 15, 20 and 25 minutes were 1.20±0.19 percent, 1.60±0.25 percent and 0.78±0.08 percent, respectively. The K values of the transplanted animals were significantly different from the K value of 0.35±0.05 percent in the apancreatic control dogs (p < 0.001). The mean K value of the dogs transplanted with tissue digested for 20 minutes was significantly better than the value in the dogs transplanted with tissue digested for 25 minutes (p < 0.02), but was significantly less than the K value (3.30±0.27 percent) obtained in 22 normal control dogs (p < 0.005). Hyperglycaemia recurred immediately following splenectomy in 12 normoglycaemic dogs 10 weeks after transplantation and all animals died. The remaining normoglycaemic transplanted dogs survived for at least six months. Histological examination of spleens from the transplanted animals showed the presence of islet and exocrine tissue within the splenic pulp with no apparent destructive effect on surrounding splenic parenchyma. [ABSTRACT FROM AUTHOR]

We examined tissues of seven non-diabetic mongrel dogs and four diabetic beagle dogs treated with constant insulin infusion via totally implantable pumps for from 210 to 880 days. Kidney and skeletal muscle tissue from all dogs were stained with Congo Red and thioflavin-T and appropriately examined. Kidney tissues from the beagle dogs were examined by electron microscopy. No amyloid deposits were found in any of these tissues. Thus, we cannot confirm an earlier report of amyloid occurring in dogs given long-term intravenous insulin. It is concluded that amyloidosis is not a necessary complication of long-term intravenous insulin infusion in dogs. [ABSTRACT FROM AUTHOR]

The results of several epidemiological studies of serum gamma-glutamyltransferase (GGT) led us to hypothesise that associations of GGT within its normal range with type 2 diabetes may reflect detrimental effects of xenobiotics found in the environment, such as persistent organic pollutants (POPs). Epidemiological observations showed that serum GGT activity within its normal range strongly predicted future type 2 diabetes; the predictability of diabetes from obesity was low with GGT at the low end of the normal range; and GGT showed a positive association with known markers of oxidative stress or inflammation. Experimental findings on cellular GGT suggest that serum GGT levels within the normal range may reflect oxidative stress related to the re-synthesis of intracellular glutathione; however, this interpretation is not completely satisfying because, in its role of regenerating intracellular glutathione, GGT activity should be antioxidative. Alternatively, serum GGT activity may reflect amounts of glutathione conjugates formed during the metabolism of xenobiotics. Accordingly, we postulate a two-part hypothesis: that the association of serum GGT with type 2 diabetes reflects exposure to POPs, as these substances, which have a very long half-life, may influence diabetes risk by residing in adipose tissue as endocrine disruptors; and that POPs or similar substances may interact with obesity to cause type 2 diabetes. Supporting this hypothesis, cross-sectional investigation of background exposure to POPs in the National Health and Nutrition Examination Survey showed relationships similar to those observed for GGT, including a powerful association with prevalent diabetes and no association between obesity and diabetes for very low POP concentrations. Our hypothesis can be tested in both prospective studies and toxicological studies.