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Insulin treatment of diabetic rats fed a high-carbohydrate, fat-free diet produces a dramatic accumulation of hepatic lipids. However, this increase in hepatic lipids may only be a response to injections of exceptionally high doses of insulin. This study addresses this possibility. Alloxan-diabetic rats, fed a high-carbohydrate, fat-free diet, were given insulin every 12 h for 60 h at the following dosages: 1/2 unit each, 1 unit each, 2 units each, and 4 units each of regular and NPH insulins. At the end of the treatment period, liver samples were collected and used for morphological and biochemical analyses. Histologic examination revealed hepatic lipid accumulations at all insulin doses; the amount of lipid increased until maximal levels were reached at an insulin dosage of 1 + 1, which was maintained at doses of 2 + 2 and 4 + 4. Thus, hepatic lipid accumulation occurs regardless of the dosage of insulin administered to the diabetic animal. It is not simply an abnormal cellular response to excessive hormone levels. Similarly, the activity of the hepatic lipogenic enzyme, malic enzyme, increased at initial insulin dosages and reached maximal levels at 2 + 2. However, in contrast to lipid accumulation, enzyme activity decreased at the final insulin dosage of 4 + 4. Thus, there appears to be a direct relationship between increasing insulin levels and malic enzyme activity until an optimal insulin concentration is reached. After this point, excessive insulin levels do inhibit malic enzyme activity.
Anat Rec 1988 Mar
PMID:Effects of various insulin dosages on hepatic lipogenesis. 328 17

Alloxan is known to induce diabetic renal changes as well as causing nephrotoxic alterations. However, no ultrastructural study has been performed to differentiate diabetic verses toxic affects of alloxan to the tubule and/or glomerulus. Therefore the present study used the "protected" kidney model to prevent one kidney from being exposed to the alloxan while allowing the other to receive the drug immediately. In all experimental animals the right renal hilum was gently occluded for 5 minutes and then released. This was performed prior to the injection of alloxan. Subsequently, the left renal hilum was occluded at the time of, and for 5 minutes after, alloxan administration (40 mg/kg i.v.). The experimental rats were divided into three groups: untreated diabetics, diabetics treated with protamine-zinc-insulin, and alloxan-treated rats that failed to become diabetic. Three groups of controls were included: one group received an equal volume of saline diluent as the experimental rats but no clamping of either renal hilum; another group received the saline and had the left renal hilum occluded for 5 minutes; and a third group had both the right and left renal hila occluded. All animals were followed and sacrificed after 9 weeks. Endogenous creatinine clearance did not change among groups. Alloxan-treated nondiabetic rats displayed marked interstitial nephritis in unprotected kidneys, while protected kidneys were normal. The diabetic state resulted in mesangial proliferation and focal glomerular basement membrane thickening as well as glomerular capillary endothelial abnormalities and visceral epithelial foot-process fusion. The endothelial changes consisted of focal areas showing a reduction in the size of endothelial fenestrae. All glomerular changes were ameliorated by insulin treatment. We conclude: 1) alloxan per se is distinctly nephrotoxic; and 2) the glomerular endothelium and epithelium are involved early in the course of experimental diabetes.
Anat Rec 1984 Jan
PMID:The effect of alloxan, and alloxan-induced diabetes on the kidney. 671 36

Diabetes mellitus can lead to reproductive disorders that in turn result in weakened fertility brought about by morphofunctional changes in the testes and accessory sex glands. However, doubts persist concerning the basic biology of the secretory epithelial cells and the stroma of the coagulating gland of diabetic mice. Thus, the objective of the present study was to analyze the histological and ultrastructural changes associated with stereology of the coagulating gland of mice with alloxan-induced diabetes, and of spontaneously diabetic mice. Sixteen mice of the C57BL/6J strain, and eight non-obese diabetic (NOD) mice were used. The animals were divided into three groups: 1) control (C), 2) alloxan diabetic (AD), and 3) NOD. Thirty days after the detection of diabetic status in group 2, all of the animals were killed and then perfused with Karnovsky's solution through the left cardiac ventricle. The coagulating gland was then removed and processed for morphometric study by light microscopy and electron microscopy. The results showed thickening of the stroma, atrophy of secretory epithelial cells, and disorganization of the organelles involved in the secretory process in both NOD and alloxan-induced mice. Thus, it may be concluded that the coagulating gland suffered drastic morphological changes, and consequently impaired glandular function, in the presence of diabetes mellitus type I in both NOD and AD mice.
Anat Rec A Discov Mol Cell Evol Biol 2003 Feb
PMID:Effects of experimental diabetes on the structure and ultrastructure of the coagulating gland of C57BL/6J and NOD mice. 1252 88

Previous studies have shown that connexin (Cx) expression is considerably higher in the preglomerular compared to postglomerular vasculature and that these differences are accentuated during diabetes. Since nitric oxide (NO) has been reported to alter Cx expression in endothelial cells and muscle cells and NO bioavailability is altered in diabetes, we hypothesized that NO may be responsible for the changes during diabetes. Cx expression was studied using immunohistochemistry in mice in which eNOS expression was either upregulated (eNOS transgenic) or downregulated (eNOS knockout). Diabetes was induced intraperitoneally with a single dose of alloxan or multiple low doses of streptozotocin. Expression of Cx40 in smooth muscle cells of afferent arterioles was increased, while expression of Cx43 in endothelial cells of efferent arterioles was absent in eNOS transgenic mice, similar to the changes occurring in wild-type mice during diabetes. Expression of Cx40 and Cx43 in eNOS knockout mice was not different from control; however, induction of diabetes in eNOS knockout mice failed to produce any changes in Cx40 or Cx43 in either afferent or efferent arterioles. Immunohistochemistry showed that eNOS expression was increased in the endothelium of renal arterioles in wild-type diabetic and eNOS transgenic mice, but absent from arterioles of eNOS knockout mice. We conclude that changes occurring in Cx expression in afferent and efferent arterioles during diabetes may result from increased eNOS.
Anat Rec A Discov Mol Cell Evol Biol 2006 Sep
PMID:Increased eNOS accounts for changes in connexin expression in renal arterioles during diabetes. 1689 22

The purpose of this study was to determine the specific features of the morphological restructuring of the myocardium in the early stage of experimental diabetes mellitus (DM). Experimental type 1 DM rat model was developed by intraperitoneal injection of alloxan solution at a dose of 30 mg per 100 g body mass. After 1 month, 3 mL of blood was drawn by heart puncture and the plasma separated by centrifugation for biochemical analysis. Plasma glucose, insulin, and glycosylated haemoglobin in whole blood were determined. Light microscopy and morphometric studies were conducted of histological slices of the hearts of experimental animals. The investigation of heart morphology showed a statistically significant alteration in chamber wall thickness in the right auricle in rats with alloxan-induced DM. A change in cardiomyocyte diameter in myocardium slices was observed in all chambers of DM rats except for the left ventricle. Average cardiomyocyte diameter in rats with experimental DM increased by 26.6% and 15.5% in the right auricle and right ventricle, respectively, while average cardiomyocyte diameter in the left auricle decreased by 20.8%. Histological investigation of the heart following alloxan injection demonstrated, under the epicardium, distended vessels of the venous collecting microcirculatory system. Aggregation and agglutination of red blood cells and endothelial cell destruction were found in some vessels. In the early stage of DM development, structural alterations in the microcirculatory channels and myocardiocytes can be observed in the heart. These structural alterations were most evident in the right chambers of the heart.
Anat Rec (Hoboken) 2015 Feb
PMID:Morphological restructuring of myocardium during the early phase of experimental diabetes mellitus. 2525 97