bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recognition and Uptake of Human Diabetic Peripheral Nerve Myelin by Macrophages
Authors: Vlassara Helen , Brownlee Michael , Cerami Anthony 
Published: September 2013

Macrophages recognize and ingest several human proteins whose amino groups have beenmodified in vitro by specific chemical reagents. Because amino groups of human peripheral nerve myelin proteins become covalently modified in vivo by products of nonenzymatic glycosylation, we examined myelin/macrophage interactions using peripheral nerve myelin prepared from diabetic and nondiabetic patients.
Intracellular accumulation of diabetic myelin increased with concentration in an apparently saturable fashion, reaching levels 3—4 times higher than those of age-matched nondiabetic samples.Low-temperature inhibition of cellular myelin accumulation further suggested that diabetic myelin uptake was associated with adsorptive endocytosis. Macrophage recognition and accumulationof nondiabetic myelin glycosylated in vitro increased with duration of sugar incubation, to a level nearly nine times that of the same sample incubated in buffer alone. Data from competition experiments with albumin and myelin glycosylated in vitro showed that recognition of human peripheral nerve myelin proteins by macrophages is specific for proteinbound products of nonenzymatic glycosylation.
In vivo, such macrophage recognition of and interaction with nonenzymatic glycosylation products on diabetic peripheral nerve myelin could contribute to the pathogenesis of segmental demyelination.
Chlorozocin: A Diabetogenic Analogue of Streptozocin with Dissimilar Mechanisms of Action on Pancreatic Beta Cells
Authors: Mossman Brooke T , Wilson Glenn L , Craighead John E 
Published: September 2013

Chlorozotocin (chlorozocin, CLZ), the 2-chloroethyl analogue of streptozocin (STZ), was evaluated in three species of rodents. The drug is currently being used in phase II chemotherapeutic trials in man, and appears to be effective in the treatment of certain tumors. In our studies, hyperglycemia was induced in hamsters as early as 2 days after a single intraperitoneal (i.p.) injection of 30–60 mg/kg and was most striking at 4 days. Greater concentrations of CLZ (≥50 mg/kg) were required to produce hyperglycemia in CD-1 mice. Degranulation and necrosis of beta cells developed in hamsters and mice, whereas alpha and acinar cells of the pancreas revealed no morphologic changes. Hyperglycemia was not induced in rats at any concentration tested; however, animals showed abnormal carbohydrate tolerance after administration of 100 mg/kg CLZ (LD50 dosage).
The nature of damage by CLZ to beta cells was investigated both in vivo and in vitro. Pretreatment of hamsters with nicotinamide (500 mg/kg, i.p.) failed to alter the extent of CLZ-induced beta cell injury and associated hyperglycemia, but decreased the amount pf beta cell necrosis and hyperglycemia in animals receiving STZ. The nonmetabolizable sugar, 3-O-methylglucose (3–O-MG), and 3-aminobenzamide, an inhibitor of the nuclear enzyme, poly AD Pribose synthetase, prevented STZ-associated damage to beta cells in islet cell cultures, but only 3–O-MG reduced CLZ-induced toxicity. Thus, in comparison to STZ, CLZ appears to be a diabetogenic agent with different species specificity and alternative mechanisms of cytotoxicity. The glucose moiety of both drugs appears critical in the induction of beta cell damage.
Unresponsiveness to Glucose in a Streptozocin Model of Diabetes: Inappropriate Insulin and Glucagon Responses to a Reduction of Glucose Concentration
Authors: Leahy John L , Weir Gordon C 
Published: September 2013

The neonatal streptozocin (STZ) rat model of NIDDM has been previously found to have a markedly reduced insulin response to an acute increase in glucose concentration. We studied the effect of an acute reduction in glucose concentration on insulin and glucagon secretion in this model and contrasted the results with the effects of epinephrine and somatostatin using the in vitro isolated, perfused pancreas.
The reduction in perfusate glucose concentration from 11.1 to 2.8 mM caused a rapid suppression of insulin release in the control rats, but had no inhibitory effect in the STZ group. Epinephrine (55 nM) and somatostatin (110 nM) caused similar decreases in insulin secretion in both groups. The glucose reduction also caused an increase in glucagon release in the controls, but had no effect in the STZ rats. Epinephrine, however, stimulated glucagon secretion in both groups in a similar fashion, and inhibition by somatostatin was also comparable. The baseline insulin and glucagon concentrations were enhanced in a separate series of experiments by the addition of arginine (5 mM) to the perfusate, and while the insulin and glucagon responses to the glucose reduction remained lost, appropriate inhibition of insulin secretion was demonstrated in the STZ rats with epinephrine.
These data indicate that A- and B-cells in this rat model of NIDDM are selectively unresponsive to both increases and decreases in glucose concentration, while the responsiveness to nonglucose agents remains intact.
Characteristics of the Interaction of the Glucagon Receptor, cAMP, and Insulin Secretion in Parent Cells and Clone 5F of a Cultured Rat Insulinoma
Authors: Korman L Y , Bhathena S J , Voyles N R , Oie H K , Recant L 
Published: September 2013

Rat insulinoma cells, which grow in culture and secrete insulin, were used to study the mechanism of stimulation of insulin release by glucagon. The parent cell line (RIN-m) and a clone that secretes high levels of insulin (5F) had been shown to possess specific receptors for glucagon. Glucagon (1 μM) stimulated a rapid increase in cyclic adenosine 3'5'-monophosphate (cAMP) that was followed by an increase in insulin secretion in both cell lines. The concentration of glucagon necessary for half-maximal stimulation of cAMP was 50 μM in parent and approximately 0.5 μM in 5F, whereas the concentration required to inhibit binding by 50% was 0.5 nM and 30 nM, respectively. In 5F, the dose-response relationships for cAMP and insulin secretion were superimposable. The glucagon effects on insulin secretion and cAMP did not require either glucose or amino acids in the incubation media. No refractoriness to glucagon stimulation of cAMP or insulin was noted.
It may be concluded that (1) there are significant differences between glucagon binding and glucagon responses in parent cells and clone 5F, (2) there are glucagon receptors that are not coupled to adenylate cyclase, and (3) cAMP mediates glucagon-stimulated insulin release.
Long-Term Prognosis After Myocardial Infarction in Men with Diabetes
Authors: Ulvenstam Göran , Åberg Anders , Bergstrand Robert , Johansson Saga , Pennert Kjell , Vedin Anders , Wilhelmsen Lars , Wilhelmsson Claes 
Published: September 2013

Men (1306) who survived a first myocardial infarction (Ml) were studied. The mean follow-up time was 6.5 yr, and at the end of the follow-up period survival status was known for all patients. By the time of the Ml the prevalence of diabetes was 5.6%. Patients with and without diabetes were compared. There were no differences in the estimated primary or secondary risk. The cumulative survival rate 1, 2, and 5 yr after the Ml was 82, 78, and 58% among the diabetic subjects compared with 94, 92, and 82% among the nondiabetic subjects (P &lt; 0.001). The difference remained even after allowance for age and estimated secondary risk in a multivariate regression analysis. There were no differences in mortality rates among patients with type I diabetes compared with type II diabetes, nor among patients treated with diet alone, sulfonylurea, or insulin, but the numbers were small. The cumulative rate of reinfarctions after 1, 2, and 5 yr was 18, 28, and 46% in diabetic subjects and 12,17, and 27% in nondiabetic subjects (P = 0.004).
A history of diabetes was an independent secondary risk factor among male survivors of a first Ml with respect to deaths and reinfarctions.
Nonenzymatic Glycosylation Products on Collagen Covalently Trap Low-Density Lipoprotein
Authors: Brownlee Michael , Vlassara Helen , Cerami Anthony 
Published: September 2013

Advanced nonenzymatic glycosylation products capable of cross-linking proteins accumulate on collagen in vivo in proportion to time-averaged blood glucose concentration. In this report, we have evaluated the ability of advanced nonenzymatic glycosylation productsformed on collagen in vitro to covalently bind low-density lipoprotein (LDL) in a manner similar to that which occurs in human atherosclerotic lesions. At constant LDL concentration, covalent trapping increased linearly with the extent of advanced glycosylation product formation, from 1.42 ± 0.15 to 4.46 ± 0.36 μg LDL protein/mg collagen. At a constant level of collagen advancedglycosylation product, LDL binding increased as a function of increasing LDL concentration. At anLDL-cholesterol level of 103 mg/dl, covalent trapping of LDL by nonenzymatic glycosylation products on collagen averaged 3.2 times as much as control (P &lt; 0.01).
These data indicate that LDL is bound specifically by reactive products generated by nonenzymatic glycosylation of collagen, and suggest that excessive LDL trapping by hyperglycemia-induced advanced glycosylation endproducts may contribute to the accelerated development of atherosclerosis in patients with diabetes mellitus.
Abnormalities of Insulin Responses After Ambient and Previous Exposure to Glucose in Streptozocin-diabetic and Dexamethasone-treated Rats: Role of Hyperglycemia and Increased B-Cell Demands
Authors: Grill V , Rundfeldt M 
Published: September 2013

In NIDDM, B-cells are insensitive to glucose. We studied the specificity and evolution of this abnormality in 6–10-wk-old neonatally streptozocin-diabetic (STZ) and in dexamethasone-treated (DMT) rats. Not only the effect of ambient but also that of previous glucose (priming effect) was characterized in the perfused pancreas. In fed STZ, blood glucose was elevated to 9.2 ± 0.8 versus 5.3 ± 0.2 mM in control (C) rats. Ambient glucose (27 mM) in the perfusate induced a significant but reduced total response (11% of C) that was predominantly monophasic. Secretion was promptly induced (in &lt;20 s) both in STZ and C. Other nutrients, i.e., glyceraldehyde (10 mM) and α-ketoisocaproic acid (KIC) (5 mM) also induced reduced and monophasic responses, whereas, in contrast, 3-isobutyl-1-methylxanthine (IBMX) induced an enhanced response that was 3.8-fold larger than in C. In DMT, blood glucose was normal (5.4 ± 0.3 mM). Ambient glucose (27 mM) in the perfusate induced a normal first phase and a moderately reduced second phase (52% of untreated rats). DMT rats were hyperresponsive to IBMX, this agent inducing 2.5-fold higher release than in untreated rats.
Previous perfusion with 27 mM glucose enhanced twofold the effect of a second stimulation period with glucose in C. This induction of priming by glucose could not be demonstrated in fed STZ or in DMT. However, when STZ were fasted or insulin treated for 36 h, induction of priming reappeared, i.e., the second pulse of glucose evoked 2–3-fold more insulin release than the first pulse.
We conclude that partial B-cell insensitivity to glucose in STZ alters time dynamics of the insulin response, includes loss of a priming effect, is influenced by hyperglycemia, and is nutrient but not glucose specific. Results in DMT indicate that increased demands on B-cell secretion can lead to hyperresponsiveness to nonmetabolic secretagogues as well as loss of induction of priming by glucose without concomitant loss of sensitivity to ambient glucose.
Acetyl-Homocysteine-Thiolactone-Induced Increase of Superoxide Dismutase Counteracts the Effect of Subdiabetogenic Doses of Streptozocin
Authors: Papaccio Gianpaolo , Pisanti Francesco A , Frascatore Sonia 
Published: September 2013

Acetyl-homocysteine-thiolactone (CYT) is an organic thio compound that exerts free radical scavenger activity and increases superoxide dismutase (SOD) activity. Administration of 32 mg CYT kg body wt day 30 days in rats increased SOD activity in erythrocytes by 126%, and in pancreatic islets by 202%. Treatment affected only the Cu-Zn fraction of the enzyme. Transmission electron microscope observations showed that the damage to the pancreatic beta cells induced by single or multiple subdiabetogenic doses of streptozocin (STZ) (45 mg/kg body wt) was attenuated in animals treated with CYT. This protective effect was not observed with 65 mg of STZ.
The experimental results seem to support the hypothesis that pancreatic beta cells are particularly vulnerableto the effect of oxygen radicals and that the cytotoxic effect of STZ is related to free radical-induced peroxidation.
Modulatory Effect of Glucose, Amino Acids, and Secretin on CCK-8-Induced Somatostatin and Pancreatic Polypeptide Release in Dogs
Authors: Schusdziarra V , Lenz N , Schick R , Maier V 
Published: September 2013

Protein- and fat-rich test meals elicit a strong stimulatory effect on postprandial somatostatin (SLI) and pancreatic polypeptide (PP) release, whereas carbohydraterich meals rather attenuate the response of both hormones. Since there is evidence that intestinal hormones might contribute to the postprandial SLI and PP response, it was the aim of the present study to determine in dogs the effect of low-dose cholecystokinin octapeptide (CCK-8) on basal hormone levels and also during a background infusion of amino acids or glucose. In a group of six conscious dogs, sulfated CCK-8 was infused intravenously (i.v.) via a hindleg vein at stepwise increasing infusion rates of 10, 30, and 50 pmol · kg−1 · h. The infusion of CCK was applied during a background infusion of saline (2 ml/min), glucose (0.2 g/min), or an amino acid mixture (8.5%, 2 ml/min). CCK-8 had no effect on plasma insulin and glucagon. levels under all experimental conditions. Plasma SLI levels were significantly stimulated by all doses of CCK. This stimulatory effect was similar during background infusions of either saline, glucose, or amino acids, respectively.
Pancreatic polypeptide (PP) levels rose 200–300 pg/ml during CCK plus saline. This was slightly attenuated by glucose. During CCK plus amino acids, the PP response was augmented to 600–800 pg/ml. Since secretin is also released after the ingestion of a meal and intraduodenal acidification is a potent stimulus not only of secretin but also of gastric and pancreatic SLI release, the effect of secretin was examined additionally. The infusion of secretin (0.03 CU · kg−1 · h) had no effect on basal levels of SLI, PP, insulin, or glucagon and abolished the stimulatory effect of CCK-8 on SLI and PP levels. Interestingly, the concomitant infusion of glucose or amino acids together with secretin restored the stimulatory effect of CCK-8 to those levels observed in the absence of secretin. In conclusion: (1) Postprandial SLI and PP release might in part be due to the stimulatory effect of CCK-8. (2) CCK-induced PP release is attenuated by elevated plasma glucose levels and augmented by elevated levels of circulating amino acids. CCK-induced SLI release remains unaffected by either glucose or amino acids. (3) Low-dose secretin abolishes CCK-8-induced SLI and PP release. Interestingly, circulating nutrients can restore the CCK effect via as yet unknown mechanisms. (4) CCK-8 at the low doses employed has no effect on insulin and glucagon release, suggesting that its primary target cells are the pancreatic PP cells and the gastric and pancreatic D-cells rather than A- and B-cells.
The Diabetes Control and Complications Trial (DCCT): Design and Methodologic Considerations for the Feasibility Phase
Authors:   The DCCT Research Group
Published: September 2013

The Diabetes Control and Complications Trial (DCCT) is a randomized, controlled clinical trial designed to assess the'relationship between glycemic control and the development, progression, or amelioration of early vascular complications in persons with insulin-dependent diabetes mellitus (IDDM). The DCCT consists of two parallel studies: a primary prevention study and a secondary intervention study. The principal outcome in the primary prevention study is the initial appearance and subsequent progression of background retinopathy. In the secondary intervention study, the principal outcome is the progression or amelioration of preexistent minimal retinopathy.
Subjects are randomly assigned to receive either experimental or standard therapy. Experimental therapy involves the use of an intensive insulin regimen designed to maintain near-normal glycemic levels in the absence of severe hypoglycemia. Standard treatment is designed to maintain subjects free of clinical symptoms related to hyper- or hypoglycemia while receiving up to two insulin injections daily.
Two hundred seventy-eight volunteers have been enrolled in 21 centers in the United States and Canada in a preliminary study to assess the feasibility of conducting a full-scale, long-term clinical trial. Based on an external review of the feasibility study results, the DCCT will be expanded to include over 1400 subjects treated for a period of up to 10 yr. This article describes the DCCT and the considerations that led to the choice of specific design features for the feasibility phase.
HLA-DR Associations in Black Type I Diabetics in Nigeria: Further Support for Models of Inheritance
Authors: MacDonald Michael J , Famuyiwa Olufunsho O , Nwabuebo Ishmael A , Bella Andrew F , Junaid T A , Marrari Marilyn , Duquesnoy Rene J 
Published: September 2013

The distributions of HLA-A, -B, -(Bw4/Bw6), -C, -DR, -(DRw52/DRw53), and -DQ genes in 19 type I diabetics, 37 type II diabetics, and 13 nondiabetics of the Yoruba tribe in southwestern Nigeria were studied. Because no associations between type II diabetes and HLA were detected in the current study and such associations are not known to exist in most ethnoracial groups, type II diabetics plus nondiabetics were used as a group of controls for the group of type I diabetics. Trends toward associations between increased DR3 (53 versus 30% of controls) and decreased DR2 (21 versus 46% of controls) and type I diabetes were found (0.1 &gt; P &gt;0.05). The strongest HLA association with type I diabetes in Caucasians is usually with DR4. The percent of DR4-positive type I diabetes (11%) was not significantly greater that that in the controls (4%). Because the strong HLA associations with type I diabetes in American Blacks are the same as in Caucasians (i.e., increased DR3 and DR4 and decreased DR2), the genetic contribution (i.e., the lack of an association with DR4) to susceptibility to type I diabetes in most Nigerian Blacks may be different from that in most Caucasians and American Blacks.
Onset of diabetes in most of the type I subjects was after age 20, and type I diabetics were difficult to recruit for the study, in keeping with reports on the rarity of type I diabetes among Blacks in western Africa and reports of DR4, but not DR3, being correlated with an early age of onset in Caucasians. Most cases of type I diabetes in American Blacks have an onset before age 20, and the incidence of type I diabetes in American Blacks is between that in American Blacks and that in Caucasians. Thus, the current data provide additional support for the theory that most type I diabetes occurring in American Blacks is the result of the admixture of a Caucasian-derived susceptibility gene into the American Black gene pool and, in addition, suggest that the susceptibility determinant is associated with DR4.
Acetone Metabolism in Humans During Diabetic Ketoacidosis
Authors: Reichard G A , Skutches C L , Hoeldtke R D , Owen O E 
Published: September 2013

Plasma acetone turnover rates were measured with the primed continuous infusion of 2-[14C]acetone in patients with moderate to severe diabetic ketoacidosis. Plasma acetone turnover rates ranged from 1.52 to 15.9 μmol · kg−1 · min−1 (108–1038 n,mol · 1.73 m−2 min−1) and were directly related to the plasma acetone concentrations that ranged from 0.47 to 7.61 mM. The average acetoneturnover rate was 6.45 μmol kg−1 min−1 (533 μmol · 1.73 m−2 min−1), a value twice that obtained in a similar group of diabetic ketoacidotic patients via the single-injection technique of 2-[14C]acetone administration.
Degradation of urine glucose revealed that 14C from administered 2-[14C]acetone was principally located in carbons 1, 2, 5, and 6 of the glucose molecule in five of six patients. This distribution is similar to that expected from 2-[14C]pyruvate, suggesting that acetone was converted to glucose through pyruvate. In one patient, label was located predominantly in glucose carbons 3 and 4, indicating that acetone metabolism maybe different in some patients.
Acetol (1-hydroxyacetone) and 1,2-propanediol (PPD), two possible metabolites of acetone, were detected in plasma of the patients. The concentrations of Acetol ranged from 0 to 0.48 mM and of PPD ranged from 0 to 0.53 mM. The concentrations of each metabolite were directly related to the plasma acetone concentrations.
During the continuous infusion of 2-[14C]acetone, the specific activities of plasma glucose and PPD rose continuously but did not reach constant values. Estimates of theminimal percent plasma glucose and PPD derived from plasma acetone averaged 2.1 and 74%, respectively.
Effects of Intracisternal Glucose or Insulin Injections on Glucose Homeostasis in Cat
Authors: Alvarez-Buylla Ramón , Rojas Mireya , Alvarez-Buylla Elena R De , Faría Nancy 
Published: September 2013

The injection of glucose (100 mg) into the cisterna magna of intact anesthetized cats elicited immediate glycosurie and natriuresis without significant changes in blood glucose concentration. Immunoreactive insulin (IRI) increased 140% in plasma, and Na+ concentration decreased in cerebrospinal fluid (CSF). After kidney denervation there was a significant decrease in glucose and Na+ concentrations in urine. Control injections with manitol did not elicit changes in the studied parameters. Abdominal vagotomy abolished the rise in IRI levels and the decrease in Na+ concentration in CSF. Vagotomy or adrenalectomy also attenuated the glycosurie and the rise in urine Na+ concentration. The intracisternal injection of insulin (0.5 U/kg) caused first, a decrease in glucose concentration in CSF and afterwards a longer latency in plasma. Again, these responses were significantly attenuated when insulin was administered in vagotomized cats.
These experiments indicate that the nervous system, through the vagi, adrenal glands, and kidneys, plays an important role in glucose homeostasis after increasing glucose or insulin levels in the CSF above physiologic concentrations. The results obtained with a denervated kidney confirm the participation of nervous system in the effector mechanism that brings the sugar and Na+ into the urine. Evidence is presented for an interrelationship between glucose and Na+ concentrations in blood, urine, and CSF.