bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiovascular Complications
Authors: Chobanian Aram V , Arquilla Edward R , Clarkson Thomas B , Eder Howard A , Howard Charles F , Regan Timothy J , Williamson Joseph R 
Published: September 2013

This report summarizes the current state of knowledge concerning the cardiovascular system in various animal models of diabetes and presents their major strengths and weaknesses for studying the important research questions in the field.
Nonhuman primates have many desirable features for studies on the macrovascular and cardiac complications of the disease as well as risk factor alterations, but their availability, cost, and maintenance present practical disadvantages. The spontaneous rodent models of diabetes currently are not considered very useful for cardiovscular research, but they have not been well characterized with respect to most aspects of their cardiovascular system. Alloxan-diabetic rabbits offer some promise for examining the effects of diabetes on atherogenesis, lipoprotein metabolism, and cardiomyopathy, but additional research is required to validate their usefulness. Insufficient data are available on canine and swine models of diabetes to judge their merits for cardiovascular research.
The Task Force recommends: (1) additional long-term investigations to determine the extent and severity of cardiovascular complications in the well-characterized rodent models and in diabetic rodents with multiple risk factor abnormalities; (2) further studies on the macrovascular disease and lipoprotein abnormalities of the alloxan-diabetic rabbit and the development of rabbit colonies with spontaneous diabetes; (3) increased emphasis on such potentially important but neglected areas of research in diabetic animals as the intramyocardial circulation, adventitial blood vessels, blood pressure, platelet function, blood coagulation, blood rheology, and autonomie nervous function; (4) long-term studies on the influence of control of Hyperglycemic and of insulin therapy on cardiovascular complications in diabetic animals; and (5) encouragement of use of diabetic nonhuman primates for cardiovascular research and institution of measures to increase their supply and availability by expanding current colonies, screening newly imported animals for diabetes, and establishing a visiting scientist's program allowing investigators to study diabetic primates at resource centers.
Studies on the Regulation of Insulin Binding by Liver Plasma Membranes From Zucker Fatty Rats
Authors: Clark Julia B , Keen Stacey , Clark Charles M 
Published: September 2013

The hyperinsulinemia of obese rodents has been associated with a reduced number of hepatic insulin receptors except in hepatocytes from fatty Zucker rats. We isolated liver plasma membranes from 10–11-wk-old lean and fatty Zucker rats, some of which were injected with streptozotocin 2–4 wk earlier. We have determined that although the number of hepatic insulin receptors is not reduced in young hyperinsulinemic fatty Zucker rats, the number of receptors can be increased when the hyperinsulinemia of the fatty rats is reduced by treatment with streptozotocin. In the fatty rats, this reduction in circulating insulin is accompanied by a reduction in plasma triglyceride concentration, consistent with a decreased stimulation of hepatic lipogenesis.
Competitive binding curves for insulin were obtained with isolated liver plasma membranes and 125I-insulin. Analysis of these curves for affinity and number of receptors indicated that the number of insulin receptors was unchanged for the fatty control rats relative to the lean control rats but was increased in streptozotocin-treated animals.
These data indicate that the regulation of hepatic insulin receptors is altered in the young fatty Zucker rat as characterized by a lack of downregulation of hepatic insulin receptors by hyperinsulinemia and an upregulation of hepatic insulin receptors at insulin concentrations higher than those found in lean rats. An altered state of hepatic insulin receptor regulation may be characteristic of developing obesity.
New Perspectives on the Microvasculature of the Islets of Langerhans in the Rat
Authors: Bonner-Weir S , Orci L 
Published: September 2013

The vasculature of the islets of Langerhans was studied in rats using methacrylate corrosion casts and islet reconstructions from stained serial paraffin sections. In corrosion casts, which allowed a three-dimensional view of the pancreatic vasculature, all islets had one or two afferent arterioles, which gave off numerous capillaries to form a glomerular-like network. Islets could be grouped in three classes on the basis of size. Moreover, these classes had preferential locations within the vascular tree: the smaller the islet, the more peripheral. In small islets (those less than 160 μm in diameter) efferent capillaries arose from this network and either coalesced at the periphery of the islet or passed through perinsular exocrine tissue before coalescing into venules. However, in intermediate islets (those 160–260 μm in diameter) and large islets (those greater than 260 μm in diameter) efferent capillaries usually coalesced at the edge of the islet forming an extensive fingerlike network of collecting venules over the islet. This suggested that at least in the rat a large amount of the islet tissue is directly drained by venules.
In serial paraffin sections of islets perfused with India ink and stained alternately for B-cells or for non-B-cells, the relation of the blood vessels and the organized array of different cell types making up the islet was discernible. In islets of all sizes, the afferent arterioles entered the islet of all sizes, the afferent arterioles entered the islet at discontinuities of the mantle of non-B-(glucagon, somatostatin, and pancreatic polypeptide) cells. Entering at the B-cell mass, the arterioles broke into capillaries that traversed the B-cell core before passing through the opposite non-B-cell mantle. The afferent capillaries coalesced into collecting venules outside the islet. In intermediate and large islets, the overlying collecting venule network was closely apposed to the mantle.
These anatomic findings indicate that in the rat islet only some of the efferent vessels are part of a insuloacinar portal system and that the afferent vessels reach the B-cell core without passing through the non-B-cell islet tissue.
Nutrition and Somatomedin. IX: Blunting of Insulin-Like Activity by Inhibitor in Diabetic Rat Serum
Authors: Phillips Lawrence S , Scholz Thomas D 
Published: September 2013

Poor growth in uncontrolled experimental diabetes appears due in part to increased circulating inhibitor, a factor (or factors) that blocks stimulation of growing cartilage by somatomedins. To determine if the inhibitor has other antianabolic properties, we examined effects on insulin and insulin-like action on muscle and adipose tissue. Rat epididymal fat pads were exposed to normal rat serum, somatomedins (fraction from normal rat serum) or insulin, with or without added streptozotocin-diabetic rat serum or inhibitor (fraction from diabetic serum); insulin-like activity was assessed by glucose conversion to CO2. Diabetic rat serum alone lowered glucose utilization significantly below buffer levels (P &lt; 0.01), but inhibitor alone had no effect. However, stimulation by insulin, normal rat serum, or somatomedins was decreased significantly by both diabetic rat serum or inhibitor (P &lt; 0.01); Lineweaver-Burk analysis suggested that such inhibition was noncompetitive. In incubations with rat diaphragm, neither diabetic rat serum nor inhibitor alone lowered glucose incorporation into glycogen, but both inhibited muscle stimulation by insulin (P &lt; 0.01). In in vivo studies, rats given insulin with added diabetic rat serum exhibited decreased stimulation of glucose incorporation into muscle glycogen (P &lt; 0.01) and into adipose tissue total lipids.
These observations indicate that an inhibitor in the serum of diabetic rats can brake anabolic processes is muscle (glycogen formation) and adipose tissue (glucose utilization, lipid formation). Such an inhibitor may therefore contribute to poor growth in diabetes by decreasing calorie storage due to insulin and insulin-like actions as well as skeletal elongation due to somatomedin action.
Acetone Metabolism During Diabetic Ketoacidosis
Authors: Owen O E , Trapp V E , Skutches C L , Mozzoli M A , Hoeldtke R D , Boden G , Reichard G A 
Published: September 2013

The presence and the importance of acetone and its metabolism in diabetic ketoacidosis has largely been ignored. Therefore, we studied acetone metabolism in nine diabetic patients in moderate to severe ketoacidosis.
The concentration of acetone in plasma, urine, and breath, and the rates of acetone production and elimination in breath and urine were determined and the rates of vivo metabolism were calculated. Plasma acetone concentrations (1.55–8.91 mM) were directly related and were generally &gt; acetoacetate concentrations (1.16–6.08 mM). The rates of acetone production ranged from 68 to 581 μmol/min/1.73 m2, indicating the heterogeneous nature of the patients studied. The average acetone production rate was 265 μmol/min/1.73 m2 and accounted for about 52% of the estimated acetoacetate production rate. Urinary excretion of acetone remained constant and accounted for about 7% of the acetone production rate in all patients. There was a positive linear relationship between the percentage of the acetone production rate accounted for by excretion in breath and the plasma acetone concentration. At low plasma acetone concentrations, ∼ 20%, and at high plasma acetone concentrations, ∼ 80% of the production rate was accounted for by breath acetone. In contrast, there was a negative linear relationship between the percentage of acetone production rate undergoing in vivo metabolism and plasma acetone concentration. At low plasma acetone concentrations, ∼ 75%, and at high concentrations, ∼ 20% of acetone production rate was accounted for by in vivo metabolism. Radioactivity from 2-[14C]-acetone was variably present in plasma acetone, glucose, lipids and proteins. No radioactivity was found in plasma acetoacetate, beta-hydroxy butyrate or free fatty acids or other anionic compounds. Exchange rates of acetone into other metabolites could not be estimated because of non-steady-state precursor product relationships in these patients.
Stimulatory Effect of Beta-Hydroxybutyrate on the Release of Somatostatin from the Isolated Pancreas of Normal and Streptozotocin-Diabetic Dogs
Authors: Hermansen K 
Published: September 2013

The present investigation was undertaken to ascertain whether the ketone body, beta-hydroxybutyrate (BOH), affects the somatostatin secretion from the isolated pancreas of normal and streptozotocin (STZ)-diabetic dogs. We found (1) that the addition of 10 mM DL-BOH to the perfusate augmented somatostatin secretion from the normal dog pancreas. The responses obtained were, however, modified by the prevailing glucose level with higher responses appearing at high (11 mM) rather than at zero glucose. The effect of BOH could not be attributed to changes in osmolarity, Na+, or H+ concentrations. (2) BOH at doses well within the physiologic and pathophysiologic range stimulated the secretion of somatostatin from the normal pancreas in a dose-dependent manner. The threshold concentration was close to 1 mM corresponding to 0.5 mM of the biologically active D form. (3) In the STZ-diabetic dogs, BOH (1–20 mM) elicits a dose-related enhancement of the pancreatic somatostatin secretion. In the two groups, identical D-cell responses were obtained at 3, 10, and 20 mM BOH.
The results demonstrate that physiologic levels of BOH stimulates the release of somatostatin from pancreas of normal and STZ-diabetic dogs, thereby providing support for a physiologic influence of BOH over the secretory function of the pancreatic D-cell. The possible existence of a BOH-somatostatin feed-back mechanism operating in the diabetic organism is discussed.
Nonenzymatic Browning Products: Physiologic Effects and Metabolic Transit in Relation to Chemical Structure. A Review
Authors: Finot P-A 
Published: September 2013

The Maillard reaction between reducing sugars and free amino acids and proteins occurs readily during the preparation and storage of foods. This reaction, which evolves through several steps, leads to irreversible modification of the molecules involved. The subsequent nutritional and physiologic effects are due to both the loss of the availability of essential amino acids and to the presence of the new molecules formed.
In food proteins, the reaction involving lysine is the most important nutritionally. The deoxyketosyl-lysine molecule formed in the “early” stage of the reaction is not available biologically. In the “advanced” stage of the reaction, which produces browning, the digestibility of the protein is decreased and other amino acids are destroyed.
The metabolic transit and the nutritional and physiologic effects of the different groups of substances produced are described. The deoxyketosyl derivatives are partly absorbed and excreted in the urine without biochemical modification. The premelanoidins also are partly absorbed but are metabolized in the organism; the most representative groups of derivatives are biochemically transformed into acids (hydroxymethyl furfural, reductones) or glucurono or sulfo conjugates (pyrazines, maltol) before excretion in the urine; they have antiphysiologic effects. The melanoidins (molecules of high molecular weight) are not absorbed and their effects are negligible. The possible occurrence of Maillard-type reactions in living organisms is also discussed.
Nutritional and Toxicologic Effects of Nonenzymatic Maillard Browning
Authors: Lee Tung-Ching , Pintauro S J , Chichester C O 
Published: September 2013

The Maillard nonenzymatic browning reaction is known to cause serious reduction in the nutritionai value of foods. The reduced nutritionai value does not seem to be limited to the loss of amino acids, as supplementation of the diet with those amino acids does not completely restore its biologic value. When rats were fed a browned egg albumin diet and a control diet of equal protein quality for up to 12 mo, the rats fed browned diet showed enlarged cecums, livers, and kidneys and reduced weight gain. In addition, intestinal digestive enzyme activities decreased, and serum alkaline phosphatase and serum glutamic oxaloacetic transaminase (GOT) activities increased compared to the control group. The livers of the rats fed browned protein showed histopathologic changes including fatty change and an unknown pigment accumulation. The data indicate a possible cumulative toxic effect due to the long-term feeding of Maillard browned compounds.
The mutagenic activity of Maillard browned egg albumin was also tested. No mutagenic effect was observed. The products of the nitrosation of the Amadori compound fructosyl-L-trytophan were mutagenic, however, in strains TA 1535 and TA 100 of the Salmonella/mammalian microsome mutagenicity assay.
Glucosylation of Human Collagen
Authors: Kohn Robert R , Schnider Stuart L 
Published: September 2013

Many of She debilities that characterize the aging syndrome can be explained by cross-linking of macromol-ecules such as collagen. And several of the characteristic complications of diabetes mellitus resemble age-like changes in collagen-rich tissues. In this laboratory, studies of human collagen that is not the site of lesions have revealed an age-related decrease in susceptibility to collagenase digestion and increased glucosylation of tendon collagen, both markedly increased in diabetes. An age-related decrease in solubility and an increase in glucosylation of skin collagen, both also markedly increased in diabetes, were also observed. Glucosylation of skin collagen was less than that of tendon, possibly because of the greater turnover of skin collagen. Collagen alterations in diabetes were most apparent in samples from younger adult subjects. Samples from older diabetics gave values within the range of nondiabetics, suggesting that the degree to which collagen can be cross-linked or glucosyiated is limited, and that limits may be attained at earlier ages in diabetes.
The association between glucosylation and cross-linking of collagen suggests that glucosylation may cause cross-linking, as has been shown to occur in albumin and eye lens protein.
Both the cross-linking of collagen occurring in maturation and glucosylation of protein involve the -amino group of lysine. If blood glucose is high during periods of collagen synthesis, namely during growth or fi-brosis, it is conceivable that lysine and hydroxylysine are glucosyiated rather than deaminated to form normal cross-links, and that an abnormal collagen forms that plays a role in the complications of diabetes. Control of diabetes during periods of collagen synthesis would then be a critical factor in preventing subsequent complications.
Epidemiologie studies of collagen properties, bearing on questions about the roles of genetic factors and control of diabetes in alterations in collagen and in complications of diabetes, would be feasible by the use Of skin biopsies.
Insulin Sensitivity, Binding, and Kinetics in Pancreatogenic and Type I Diabetes
Authors: Nosadini Romano , Prato Stefano Del , Tiengo Antonio , Duner Elena , Toffolo Gianna , Cobelli Claudio , Faronato Pier Paolo , Moghetti Paolo , Muggeo Michele 
Published: September 2013

Pancreatogenic diabetes (PD), secondary either to chronic calcific pancreatitis or to pancreatectomy, is characterized by higher frequency of hypoglycemic events during insulin therapy in comparison with type I insulin-dependent diabetes (IDD). Not only glucagon deficiency, but an enhanced peripheral tissue sensitivity to insulin could account for this metabolic behavior. We investigated several facets of insulin action, e.g., tissue sensitivity to insulin, insulin binding to red cells, and insulin kinetics in seven patients with PD in comparison with type I. Tissue sensitivity to insulin was evaluated by means of the glucose-insulin clamp technique as M/I × 100 ratio (mg · kg ·−1 min−1/μU · ml−1), where M is the amount of glucose infused by Biostator GCIIS to clamp BG at basal level and I is the free insulin plateau concentration achieved by a primed-constant insulin infusion.
At high BG 15 h after the last injection of regular insulin M/I × 100 was 7.79 (range 4.25–9.75) in PD and 4.20 (range 1.20–6.91) in D (P &lt; 0.05). At low and equal BG M/I × 100 was 8.55 (range 6.35–9.72) in PD and 3.42 (range 1.19–6.75) in D (P &lt; 0.01). The rate of endogenous glucose production was nearly totally suppressed in both groups of patients. Just before the two clamps, 125I-insulin specific binding to red cells was studied. The maximum specific binding was significantly higher in PD than in D at high BG (10.7 ± 1.7 vs. 7.4 ± 0.8/109 red cells) and at low and equal BG (12.4 ± 1.2 vs. 6.8 ± 0.8). Receptor concentration also was significantly higher in PD thant in D (P &lt; 0.02) while no significant differences were found in high affinity (K̄e). Insulin kinetic data were analysed by using both “Model independent” (or noncompartmental) method and compartmental modeling. Patients with PD had significantly higher (P &lt; 0.05) plasma clearance of insulin.
In conclusion, these data demonstrate that patients with PD are characterized by increased insulin binding sites associated with an increased insulin sensitivity and clearance rate in comparison with type I insulindependent diabetes.
Use of Total Lymphoid Irradiation in Transplantation of Rat Fetal Pancreases
Authors: Mullen Yoko , Shibukawa Renee L 
Published: September 2013

The objective of this study was to determine the effectiveness of total lymphoid irradiation (TLI) treatment of the induction of unresponsiveness to allogeneic whoie fetal pancreas tissues, which are highly immunogenic (control survival times in three combinations: &lt;10 days). Streptozotocin-diabetic Lewis male rats were irradiated 4–5 times a week with a daily dose of 200 rads under a lead shield covering the skull, lungs, hind legs, pelvis, and tail. The spleen, thymus, and major lymph nodes were exposed to radiation. When the desired total TLI dose was reached, the rats were injected with 1–3 × 108 donor-type aduit bone marrow cells within one day after TLL, followed by fetal pancreas transplants under the kidney capsule between 1 and 35 days after TLI. Three strain combinations with immunogenetic barriers ranging from moderate (non-Rt1) to strong (Rt1) were used to determine a minimum effective dose for the permanent acceptance of pancreas allografts.
Fischer → Lewis fetal pancreases identical at Rt1 but differing at multiple non-Rt1 loci were accepted permanently in the recipients who were treated with 1200 rads TLI and 108 donor bone marrow cells. Diabetes was permanently reversed or significantly improved. A minimum effective TLI dose in this combination was found to be 1000 rads. (Buffalo × Lewis)F1 → Lewis fetal pancreas grafts across strong Rt1 barriers required at least a total TLI dose of 2600 rads, when semiallogeneic F1 bone marrow cells were used. A higher dose (3000 rads) was required, when 1–3 × 108 of fully allogeneic Buffalo bone marrow ceils were grafted. Even then, only a part of the group of treated Lewis became unresponsive to donor tissues. Removal of the pelvic shield, however, resulted in consistent development of a high percentage of donor bone marrow chimera and permanent acceptance of allografts in Buffalo or F1 × Lewis combinations. This procedure exposed the whole pelvic area and part of the femur along with the portions exposed by the complete lead shield procedure. Donor-type bone marrow grafting, in addition to TLI, was essentiai for permanent acceptance of allografts.
Subcutaneous Peritoneal Access Device for Type I Diabetic Patients Nonresponsive to Subcutaneous Insulin
Authors: Schade David S , Eaton R Phillip , Warhol Richard M , Gregory Jay A , Doberneck Raymond C 
Published: September 2013

Three type I diabetic patients nonresponsive to subcutaneous insulin were implanted with a subcutaneous peritoneal access device. In these patients, multiple subcutaneous injections had been unable to prevent recurrent hospital admissions for diabetic ketoacidosis. The patients were responsive to intravenous insulin but had limited accessible peripheral veins. Complications of thrombosis and/or septicemia from permanent central venous catheters prevented the long-term use of this route.
The peritoneal access device was implanted subcutaneously adjacent to the umbilicus with its insulin delivery catheter terminating in the peritoneal space. Transcutaneous injection of insulin into the subcutaneous access port resulted in the same quantity of insulin entering the peritoneal space. Using a mixture of regular and protamine zinc insulin in a ration of 1:1 resulted in acute increases in plasma free insulin concentration with meals and a declining background level postprandially. All peritoneal access devices have been functioning well for at least 2 mo and in one of the implanted diabetic subjects, it has been in continuous use for 5 mo with no evidence of peritonitis or resistance to peritoneal insulin. These results suggest that a subcutaneous peritoneal access device may provide an alterative insulin delivery route for patients who are nonresponsive to subcutaneous insulin injections.