bluuebunny/crossref_metadata_2025_split huggingface dataset:
Waveform Requirements for Metabolic Normalization With Continuous Intravenous Insulin Delivery in Man
Authors: Perlman Kusiel , Ehrlich Robert M , Filler Robert M , Albisser A Michael 
Published: September 2013

Devices and methods for long-term intravenous (i.v.) insulin infusion in ambulatory patients have recently been developed. However, to date optimal waveforms for open-loop insulin administration in severely insulin deficient patients have not been defined.
We studied 7 nonobese uncomplicated type 1 diabetics aged 16.5 ± 0.2 yr who received insulin continuously for 14–23 days by central venous infusion. A pattern of i.v. insulin administration was developed and eventually refined to include a constant basal infusion rate augmented at meal time by a series of 3 pulses. The first pulse lasted 10–15 min with an infusion rate 1.5–2 times the basal rate. The second pulse was 60–100 min in duration with a rate 4–6 times the basal infusion rate. The third pulse lasted 40–100 min with an infusion rate 1.5–3 times the basal rate. Accompanying the evolution of this waveform, the mean fasting plasma glucose fell from 262 ± 40 mg/dl on conventional therapy to 92 ± 9 mg/dl during infusion with normal meal excusions (mean a.c. glucose 80 ± 3 mg/dl with a rise of 35 ± 3 mg/dl at 41 ± 3 min). Mean urinary glucose excretion decreased from 55 before to 1.9 g/day during the infusion period. Fasting serum cholesterol and triglycerides dropped from 220 ± 28 and 281 ± 94 to 138 ± 13 and 115 ± 24 mg/dl, respectively.Mean HbA, declined from 14.8% before to 10.7% at the conclusion of the infusion period. All indices of control showed improvement significant at P &lt; 0.05. There were no catheter-related complications and the system was well accepted by all subjects.
These studies confirm that continuous central venous insulin infusion with a relatively simple waveform is feasible for the prolonged normalization of glycemia and other indices of metabolic control in ambulatory adolescent diabetics.
The Diabetogenic Effects of Streptozotocin in Mice are Prolonged and Inversely Related to Age
Authors: Riley William J , McConnell Thomas J , McLaughlin Judith V , Taylor G 
Published: September 2013

Single ‘subdiabetogenic’ doses of streptozotocin (SZ), when given to young male CD-1 mice, produced a delayed onset of hyperglycemia dependent on the dose of SZ and on the age of the mice. The effect was markedly reduced or absent in older mice given the same dose of SZ per kg of body Weight. Histologic examination of the pancreas of these animals revealed that SZ induced greater damage to the islets of the young mice compared with older mice. In addition to the characteristic findings of a decrease in insulincontaining cells and an increase in glucagon- and pancreatic polypeptide-containing cells there was evidence of new islet formation.
Delayed-onset hyperglycemia was also induced in young inbred DBA/2J, C57BL/KsJ, and SWR/J mice with single SZ doses, as well as with alloxan in young CD-1 mice, indicating that the effect was not specific for CD-1 mice nor for SZ as the agent inducing β-cell injury.
The induction of β-cell autoimmunity did not appear to be important in the delayed diabetogenic effect of SZ, since insulitis was rare and followed the onset of hyperglycemia when seen, and islet cell autoantibodies were not found. Rather, SZ induced more β-cell destruction in young animals than in older mice, and the continued somatic growth of the former suggests that the delayed hyperglycemia was due to an outgrowing of a reduced insulin supply. That mild to severe diabetes could be induced by the same dose of SZ/kg, depending only on the age of mice when SZ was given, may have implications for understanding the apparent heterogeneity of human diabetes mellitus.
Increased Incidence of Congenital Malformations in the Offspring of Diabetic Rats and Their Prevention by Maternal Insulin Therapy
Authors: Eriksson Ulf , Dahlström Elisabeth , Larsson K Sune , Hellerström Claes 
Published: September 2013

Intensive care of the pregnant mother with diabetes has dramatically decreased the incidence of diabetic fetopathy. The persistently high rate of fetal and neonatal mortality in diabetic pregnancies is nowadays mainly due to the increased incidence of serious congenital malformations. However, attempts to elucidate the precise teratogenic mechanisms have been sparse, presumably because of a lack of relevant animal models. In the present study we recorded the incidence and types of skeletal malformations in live offspring of normal rats and in rats made diabetic with the B-cytotoxic agent streptozotocin (SZ) at least 2 wk before conception. In some of the diabetic animals insulin treatment was begun 1 wk after the SZ injection and continued throughout pregnancy. In addition, the fetal development was followed by assessing the calcification of the skeleton on gestational days 20 and 22 with the aid of Alazarin Red S staining.
Manifest diabetes in the pregnant rat induced a decrease in fetal weight and viability and marked retardation of skeletal maturation. In addition, about 20% of 135 viable fetuses showed skeletal malformations comprising either micrognathia or caudal dysgenesis. These defects were not found in 314 offspring of the control rats. Only two cases of caudal dysgenesis and none of micrognathia were detected among 233 offspring of the insulin-treated rats.
The present data underscore the importance of a strict differentiation in the offspring of the diabetic rat between transient development retardations and true malformations. They also demonstrate that correction of the maternal glucose intolerance is crucial for preventing the fetus from developing skeletal malformations. Altogether the data suggest that fetal malformations in the diabetic rat are attributable either to the hyperglycemia as such or to some accompanying metabolic consequence of insulin deficiency.
Nonhuman Primates as Models for the Study of Human Diabetes Mellitus
Authors: Howard Charles F 
Published: September 2013

Nonhuman primates have been used for a variety of studies on diabetes meiiitus. Spontaneous, natural forms of diabetes have been well documented in several species; there are limited data on numerous other species that indicate diabetes or a diabetes-like syndrome. The causes and manifestations of spontaneous diabetes, their prevalence, and their severity vary among species. Diabetes has also been induced in nonhuman primates with streptozotocin, alloxan, hypothalamic lesions, or pancreatectomy. The extent and severity of metabolic and hormonal abnormalities vary according to the method of induction, the individual monkey, and the species.
Metabolic, hormonal, and pathologic abnormalities present in human diabetics also occur in monkeys with either spontaneous or induced diabetes. Hyperglcemia, and impaired glucose clearance are common, lipid concentrations are elevated, and hemoglobin A1c concentrations are increased in Hyperglycemic monkeys. Monkeys may have fasting hypo- or hyperinsulinemia; insulin responses are often impaired in glucose tolerance tests. Glucagon concentrations may be increased. Aortic atherosclerosis, muscle capillary microangiopathies, cataracts, and glomeruio-sclerosis have been documented.
Primate size and longevity allow longitudinal studies with procedures that may not be feasible in smaller animals or in human beings. Nonhuman primates may be the models of choice for studies on selected aspects of diabetes and its secondary complications.
Pancreatic Content of Insulins I and II in Laboratory Rodents: Analysis by Immunoelectrophoresis
Authors: Kakita Keiji , O'connell Keith , Permutt M Alan 
Published: September 2013

The purpose of these experiments was to determine the relative proportion of insulins I and II in the pancreas of inbred strains of mice and rats, and whether this proportion would be altered by conditions known to affect insulin biosynthesis. Rapid analysis of multiple samples was accomplished by an immunoelectrophoretic method in which insulin can be detected in crude pancreatic extracts without further purification. Insulin I was found to account for 65–76% of total pancreatic content in C3H/HeJ, C57BL/6J, and CD2F1 mice. Glucose injection produced a significant increase in insulin content, which was completely accounted for by insulin I, although fasting for 2 days had no effect. In all three strains there was either no change or a decrease in content of insulin II, while insulin I increased 77–83% (P &lt; 0.05) of the total pancreatic insulin.
To determine the effects of chronic hyperglycemia, the content of insulins I and II was measured in the pancreas of obese hyperglycemic mice and compared with that of lean littermates. Insulin content in pregnant rats was also evaluated, since pregnancy is characterized by insulin resistance and hyperinsulinemia. The results of these studies indicate that insulin I predominates in the pancreas of a variety of strains of rats and mice. More important is the observation that conditions that increase insulin production preferentially increase insulin I relative to II, suggesting independent regulation of the two genes.
Superfusion of Dissociated Pancreatic Islet Cells Attached to Cytodex Beads
Authors: Spiess Yuriko , Smith Mark A , Vale Wylie 
Published: September 2013

Pancreatic islets of neonatal were dissociated by collagenase and cultured for 3 days in the presence of Cytodex beads to allow attachment of the cells to these microcarriers. The bead-attached cells were packed in columns and superfused with a low bicarbonate medium using the same method that we had originally developed for dissociated anterior pituitary cells of the rat. The secretion of insulin, somatostatin, and glucagon by the cells was monitored by radioimmunoassays.
The cells in the superfusion system responded as expected from experiments with islet and monolayer cultures of rat pancreas in vitro and in vivo. Increasing glucose concentrations in the superfusion medium increased the release of insulin and somatostatin (SS), whereas glucagon secretory rates remained constant or decreased. A dose-response curve was established between insulin release and D-glucose in which the ED50 of D-glucose for insulin was found between 1.5 and 2 mg/ml. The phosphodiesterase inhibitor, 3-isobutyl-methylxanthine (IBMX), significantly potentiated the insulin response to glucose. Various secretagogues such as IBMX, 8-bromo cyclic AMP, and L-arginine increased insulin, somatostatin, and glucagon secretory rates in an expected manner.
The superfusion method offers the possibility to investigate the interactions of dissociated A-, B-, and D-cells and the dynamics of hormone release in short- and long-term in vitro experiments. The method is simple and avoids the problems of monolayer procedures, such as clustering of the cells and poor adherence of dissociated pancreatic islet cells to dishes.
Nonenzymatic Glycosylation and Browning in Diabetes and Aging: Studies on Lens Proteins
Authors: Monnier Vincent M , Cerami Anthony 
Published: September 2013

The nonenzymatic glycosylation of hemoglobin has served as a model for the postsynthetic modification of protein by glucose. From these studies it has been proposed that nonenzymatic glycosylation of proteins could play a role in the development of the complications associated with diabetes mellitus. The first tissue in which an attempt has been made to link nonenzymatic glycosylation and a pathologic sequela is the ocular lens and the formation of cataracts. Incubation of lens proteins with glucose in vitro leads to nonenzymatic glycosylation, intermolecular disulfide bond formation, and protein aggregates that defract light. These findings mimic the state of proteins found in the diabetic lens. With longer incubation times, these nonenzymatically glycosylated proteins can undergo further rearrangements to form yellow-brown pigments (nonenzymatic browning) that act as molecular cross-links. From a number of physical and chemical studies it appears that these pigments formed in vitro are similar to those found in senile lenses.
Thus the nonenzymatic browning of glycosylated proteins that has been described in stored foodstuffs might well be occurring in vivo. Such protein modifications, which are essentially irreversible, could have significant effects on the aging of long-lived proteins and the general aging process of biologic systems.
Gastric Parietal Cell and Other Autoantibodies in the BB Rat
Authors: Elder Melissa , Maclaren Noel , Riley William , McConnell Thomas 
Published: September 2013

A longitudinal study of circulating autoantibodies in the sera of 48 BB rats was performed by indirect immunofluorescence. No pancreatic islet cell, adrenocortical, or thyroid microsomal autoantibodies were found. However, autoantibodies reactive to gastric parietal cells (PCA), smooth muscle, and thyroid colloidal antigens were identified, PCA were not detected in Wistar-Furth or BB × Wistar-Furth F1 hybrid rats. The range of ages at the time of first appearance of PCA was the same as that of onset of insulin-dependent diabetes (IDD) in the BB rats, suggesting that the processes leading to PCA and IDD were occurring at the same time of life in these animals. The presence of PCA was associated with degrees of lymphocytic gastritis and with squamous metaplasia of the gastric mucosa in the oldest BB rats (9 mo of age). Levels of serum iron and vitamin B12 did not differ between PCA-positive and PCA-negative BB rats, nor was achiorhydria found in any rat studied.
The identification of PCA (and chronic gastritis) and other autoantibodies in the BB rat suggests that these animals have an underlying autoimmune diathesis.
These findings thus provide indirect support for an autoimmune pathogenesis for IDD in the BB rat.
Contribution of the Liver and Extrasplanchnic Tissues to the Hypoglycemic Action of Dichloroacetate in the Conscious Dog
Authors: Diamond Michael P , Suhrer James H , Williams Philip E , Lacy William W , Cherrington Alan D 
Published: September 2013

In a previous study, administration of sodium dichloroacetate (DCA) to 48-h fasted dogs had no effect on glucose production (Ra), utilization (Rd), or clearance, possibly because the direct effects of DCA were offset by the consequences of the fall in plasma insulin that it caused. To examine this possibility, dichloroacetate was infused (0.4 mg/kg min) for 5 h into 48-h fasted conscious dogs whose insulin and glucagon levels were “clamped” at basal values using a technique that involved the peripheral infusion of somatostatin to inhibit the endocrine pancreas and intraportal replacement of insulin (273 μU/kg·min) and glucagon (1 ng/kg·min). Metabolite balances across the liver were measured using an A-V difference technique, glucose turnover was determined using a tracer technique, and gluconeogenesis was assessed by measuring the conversion of alanine and lactate into glucose.
In the presence of fixed concentrations of insulin (14 μU/ml) and glucagon (162 pg/ml), DCA caused the conversion of alanine and lactate to glucose to fall by 73 ± 10﹪ (P &lt; 0.01), glucose production to fall by 19 ± 9﹪ (NS), glucose utilization to fall by 17 ± 8﹪ (NS), glucose clearance to increase by 55 ± 16﹪ (P &lt; 0.05), and the plasma glucose level to fall from 107 ± 10 to 56 ± 6 mg/dl (P &lt; 0.001) after 300 minutes. Thus, with the plasma insulin level fixed, DCA induced hypoglycemia through an effect on both glucose production and clearance. Since the effects of DCA in the above experiment were undoubtedly attenuated by the hypoglycemia that occurred, the experiment was repeated with the exception that glucose was infused to maintain euglycemia (113 ± 11 mg/dl). In this case, the conversion of alanine and lactate to glucose fell by 76 ± 1﹪ (P &lt; 0.01), endogenous glucose production fell 46 ± 11﹪ (P &lt; 0.01), glucose utilization rose 39 ± 14﹪ (P &lt; 0.05) and glucose clearance increased 40 ± 18﹪ (P &lt; 0.05). Normalization of the alanine and lactate levels during the last 90 min of the latter experiment failed to significantly change glucose production and enhanced gluconeogenic conversion only slightly. Thus, in the conscious 48-h-fasted dog, we conclude that: (1) DCA acts to reduce the insulin/glucagon molar ratio such that the production of hypoglycemia is prevented, (2) when the effect of the compound on the pancreas is prevented, DCA causes hypoglycemia by a reduction in hepatic glucose production and a stimulation of peripheral glucose uptake, and (3) the effect of DCA on glucose production is in part due to reduced gluconeogenic substrate supply, but is principally related to the action of DCA on intrahepatic enzymatic processes.
The Surface Concentration of H-2 Antigens on Mouse Pancreatic β-Cells and Islet Cell Transplantation
Authors: Parr Earl L , Oliver John R , King Nick J C 
Published: September 2013

Measurement of the concentration of H-2 complex antigens in the surface membrane of mouse pancreatic β3-cetls by a quantitative immunoferritin-labeling technique revealed that the antigens were present in very small amounts on the β3-cells of five strains. Å comparison of the labeling densities in the five strains suggested that β3-cells from C57BL/10Sn congenic strains have about half the H-2 antigen density of BALB/c and C3H/HeJ cells, in C57BL/10Sn mice the antigen density on β3-cells was slightly greater than that on erythrocytes, about 20% of that on thymocytes, and about 2.5% of that present on peritoneal macrophages.
Intraperitoneal allografts of C57BL/10Sn islets were uniformly rejected by B10.BR/SgSn diabetic recipients only when the islets were accompanied by 107 peritoneal lymphoid cells. When transplanted without peritoneal cells, C57BL/10Sn islets were only marginally rejectable. In a group of nine such allografts, three diabetic recipients were permanently cured and three others showed rejection times of about 30 days. Sensitization of the three mice showing permanent cures, using 107 allogeneic peritoneal cells at about 40 days after the transplant, did not cause rejection of the allografts. isogeneic transplantation of cell suspensions from dissociated islets of Langerhans was markedly less effective in controlling diabetes than intact islets, and dissociation did not obviously improve the rate of allograft survival. However, 5/19 diabetic mice receiving allografts of dissociated islet cells showed longterm reversals of diabetes that were unaffected by administration of 107 peritoneal cells at about 100 days after the transplant. Recipient mice whose diabetes was reversed by islet allografts and unaffected by specific sensitization had pancreatic insulin concentrations characteristic of diabetic mice. Our reversals of diabetes with untreated islet allografts may be due to the cleanliness of islet preparations obtained with a modified isolation technique, and to the very low density of H-2 complex antigens on C57BL/10Sn β-cells.
Estimation of the Secretion Rate of Insulin from the Urinary Excretion Rate of C-Peptide: Study in Obese and Diabetic Subjects
Authors: Meistas Mary T , Rendell Marc , Margolis Simeon , Kowarski A Avinoam 
Published: September 2013

Direct methods for measuring the secretion rate of insulin are too cumbersome for clinical application. Since C-peptide is secreted in an equimolar ratio with insulin and is excreted into the urine, measuring the urinary excretion rate of C-peptide (U-C) could serve as an indicator of its secretion rate (SR-C) if its urinary clearance (UCI-C) is constant and unaffected by plasma C-peptide concentration, body mass, or diabetes.
We measured clearance ratios of C-peptide/creatinine (CR) in the fasting state and integrated 0–1, 1–3, and 3–5 h after 100 g of glucose p.o. as well as over a full 24-h in eight obese, eight lean, and six maturity-onset diabetic subjects. CR did not differ significantly when values in the fasting state were compared with those in the postprandial periods and was therefore unaffected by plasma C-peptide concentration. Furthermore, CR was similar in the lean, obese, and diabetic subjects. SR-C, determined as the product of the metabolic clearance rate of C-peptide and its fasting or integrated plasma concentrations, correlated significantly with U-C in all the subjects (r = 0.87, P &lt; 0.0001). The correlation of U-C with SR-C in the diabetic subjects alone was also significant (r = 0.88, P &lt; 0.0001). In conclusion, our data support the use of U-C as an indirect measure of SR-C and therefore of SR-I.
Effect of Metabolic Control on Lipid, Lipoprotein, and Apolipoprotein Levels in 55 Insulin-dependent Diabetic Patients: A Longitudinal Study
Authors: Lopes-Virella Maria F , Wohltmann Hulda J , Mayfield Ronald K , Loadholt C B , Colwell John A 
Published: September 2013

Plasma lipid, lipoprotein, and apolipoprotein levels were measured in 55 insulin-dependent diabetics (20 males and 35 females) before and after 2–3 wk of intensive insulin therapy in a metabolic unit.
At the time of discharge from the metabolic unit the levels of total, low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) cholesterol as well as triglycerides, VLDL triglycerides, and apolipoprotein B (Apo B) were significantly decreased. Conversely, the levels of high-density lipoprotein (HDL) cholesterol, and apolipoprotein A1 (Apo A1) were significantly increased.
The data were further analyzed after subdividing the patients into two subgroups: (1) patients admitted in poor glycemic control (HbA1c &gt; 11%) and (2) patients admitted in fair control (HbA1c &lt; 11%). In the group admitted in poor control the changes in lipid and lipoprotein levels were similar to the ones found in the group of patients as a whole, while in patients admitted in fair control only the levels of total and VLDL triglycerides showed significant changes with control.
Patients' sex appeared to influence the magnitude of changes observed in HDL cholesterol and Apo A1, levels. In males a significant increase in both HDL cholesterol and Apo A1 was achieved after glycemic control either in the whole group or in the subgroup admitted in poor control. In the subgroup admitted in fair control HDL cholesterol levels rose but no significant change was observed in the Apo A1 levels. In females no significant change was observed with improved control in HDL cholesterol and Apo A1, either in the whole group or in the group admitted in fair control. A small but significant increase was detected in the HDL cholesterol levels of the female patients admitted in poor control, but no change was observed in the Apo A1 levels.
In conclusion, in insulin-dependent diabetics, normalization in plasma lipid, lipoprotein, and apolipoprotein levels was obtained after intensive insulin therapy.
Influence of Polyethylene Glycol Insulin on Lipid Tissues of Experimental Animals
Authors: Neubauer H Paul , Obermeier Rainer , Schöne Hans-Hermann 
Published: September 2013

Earlier investigations have revealed that polyethylene glycol-B1-insulin (PEG insulin) causes lower utilization of glucose in fat cells than does the unaltered hormone, even though the blood glucose-lowering activity of both preparations in intact animals is identical.
The present study was aimed to establish whether or not PEG insulin in regard to adipose tissues of intact animals has similar functions. Radioactive glucose was used to examine the influence of both native pork insulin and its PEG derivative on the incorporation of tracers into lipids. Male Wistar rats and male domestic rabbits received 14C- and/or 3H-labeled glucose intravenously, while the insulin preparations were administered by either the subcutaneous (s.c.) or the intravenous (i.v.) route. Under the influence of PEG insulin, diminished incorporation of 14C and/or 3H into adipose tissues was observed in all cases, yet both natural insulin and the derivative lowered the blood glucose to the same extent.
These observations allow the assumption that, by using certain modified insulins, it may also be possible to manipulate the extent of glucose metabolism by lipid tissues in diabetic patients.