bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduced Pupillary Unrest: Autonomic Nervous System Abnormality in Diabetes Mellitus
Authors: Hreidarsson Astradur B , Gundersen Hans Jorgen G
Published: September 2013

Pupillary unrest (fluctuations in pupil size) was measured by infrared television videopupillography in 80 insulin-dependent diabetic patients (age 25–43 yr, diabetes duration 0–35 yr) and 26 control subjects (age 26–39 yr). In darkness, pupillary unrest was 21% less in diabetic subjects than in controls. During prolonged and brief illumination, pupillary unrest was 35 and 37% less in diabetic subjects than in controls, respectively, and in both cases the unrest was inversely correlated to the duration of diabetes. There were inverse correlations between 1) vibratory perception threshold, long-term high blood glucose levels, and severity of retinopathy, and 2) pupillary unrest in darkness and during prolonged illumination. The fractional reduction in pupil size (relative miosis) was 19% less during prolonged illumination in diabetic subjects than in controls and was positively correlated to the pupillary unrest in both groups. For a given fractional reduction in pupil size during illumination, diabetic subjects still had a smaller unrest than controls. Pupil size in darkness was 19% smaller in diabetic subjects than in controls, and in diabetic subjects it was positively correlated to the unrest in darkness and during prolonged and brief illumination. None of the pupillary abnormalities showed correlation to biomicroscopic changes in the iris. The autonomic nervous system abnormalities reflected in the pupil in longstanding diabetes are 1) a reduction in pupillary unrest in light and in darkness, more pronounced in light, 2) a reduction in the ability to maintain miosis in continuous light, and 3) a reduction in size.
Specific Macrophage Receptor Activity for Advanced Glycosylation End Products Inversely Correlates With Insulin Levels In Vivo
Authors: Vlassara Helen , Brownlee Michael , Cerami Anthony
Published: September 2013

A high-affinity macrophage receptor has been shown to mediate the removal of proteins modified by advanced nonenzymatic glycosylation end products (AGEs) in both animals and humans. To characterize the effect of diabetes on this receptor system, resident peritoneal macrophages from experimentally induced and genetically diabetic mice were studied. Binding and degradation of radioiodinated AGE-bovine serum albumin (AGE-BSA) were determined from saturation kinetics and compared with glucose and insulin levels of each subgroup. Scatchard plot analysis of nondiabetic mouse macrophages has indicated 1.5 × 105 receptors/cell, with a binding affinity of 1.7 × 107 M−1. The in vitro exposure of macrophages to either elevated glucose or insulin concentrations failed to demonstrate a short-term regulatory effect on AGE-receptor function. However, macrophages from hypoinsulinemic alloxan-induced diabetic mice indicated a two- to threefold increase in AGE-receptor number per cell (2.98 ± 0.25 × 105/cell), and macrophages from C57BL/KsJ (db/db) mice showed an almost threefold greater receptor number (2.86 ± 0.2 × 105/cell), with binding affinity remaining essentially unchanged (1.24 ± 0.05 × 107 and 1.21 ± 0.07 × 107 M−1, respectively). In addition, a moderate increase (25–30%) of 125I-labeled AGE-BSA degradation was observed in these two insulin-deficient diabetic macrophage groups compared with the normal control group. In contrast, macrophages from hyperinsulinemic and hyperglycemic C57BL/6J (db/db) mice demonstrated a distinct reduction in both AGE-receptor number (0.67 ± 0.03 × 105/cell) and binding affinity (0.37 ± 0.03 × 107 M−1), with a decrease of AGE-BSA degradation of ∼50% compared with the control group. This study provides evidence for a specific insulin-sensitive mechanism that modulates the function of the macrophage AGE receptors. High peripheral insulin levels may thus adversely affect the receptor-mediated clearance of nonenzymatically glycosylated proteins from sites of diabetic tissue damage.
Are Disturbances of Sorbitol, Phosphoinositide, and Na+-K+-ATPase Regulation Involved in Pathogenesis of Diabetic Neuropathy?
Authors: Greene Douglas A , Lattimer Sarah A , Sima Anders A F
Published: September 2013

Alterations in myo-inositol and phosphoinositide metabolism, induced by hyperglycemia and prevented by aldose reductase inhibitors, are implicated in impaired Na+-K+-ATPase regulation in peripheral nerve and other tissues prone to diabetic complications by an increasing range of scientific observations. However, the precise role of these related metabolic derangements in various stages of clinical complications is complex. For instance, it appears that these biochemical defects may play a role not only in the initiation of diabetic neuropathy but also in its later progression. Therefore, full appreciation of the potential pathogenetic role of altered phosphoinositide metabolism in diabetic complications requires detailed studies of both the earliest and the more mature stages of these disease processes.
Are Reduced Lung Volumes in IDDM Due to Defect in Connective Tissue?
Authors: Bell Derek , Collier Andrew , Matthews David M , Cooksey Elizabeth J , McHardy G J Ross , Clarke Basil F
Published: September 2013

Lung volumes were measured by spirometry and helium-dilution technique in 28 young adult men with insulin-dependent diabetes mellitus (IDDM) of long duration and compared with 16 age- and height-matched adult men without diabetes. Reduced values for forced expiratory volume at 1 s, vital capacity, functional residual capacity, total lung capacity, residual volume, and single-breath carbon monoxide transfer factor were found for the IDDM patients compared to the control subjects. The results are consistent with reduced lung volumes in IDDM patients and did not correlate with the presence or absence of mild cheiroarthropathy but may relate to duration of diabetes.
Adenosine is Required for Myocardial Insulin Responsiveness In Vivo
Authors: Law William R , McLane Michael P , Raymond Richard M
Published: September 2013

The adenosine-receptor antagonist 8-phenyltheophylline (8-PTH) was used to study the role of endogenous adenosine in modulating insulin-stimulated myocardial glucose uptake (MGU) in vivo. Dogs were surgically instrumented under pentobarbital sodium anesthesia to measure hemodynamics and obtain blood samples for determinations of oxygen and glucose concentrations. Myocardial uptake of these substances was calculated as the product of the appropriate arterial–coronary sinus differences and circumflex blood flow. The response to insulin was determined with the hyperinsulinemic-euglycemic clamp technique. During insulin infusion, MGU increased from 3.12 ± 0.8 to 9.20 ± 1.8 mg/min (mean ± SE). In contrast, insulin failed to increase MGU when 8-PTH was being infused into the circumflex artery. These results demonstrate that some degree of adenosine-receptor–mediated activity is required for insulin to stimulate myocardial glucose uptake. It is suggested that the presence of adenosine at its receptor may be an important factor during conditions in which myocardial insulin resistance may develop.
Functional Characteristics of Rat Pancreatic Islets Maintained in Culture After Exposure to Human Interleukin 1
Authors: Eizirik Décio L , Strandell Eva , Benutzen Klaus , Sandler Stellan
Published: September 2013

Recent observations suggest a role for interleukin 1 β (IL-1) in the autoimmune β-cell destruction observed in type I (insulin-dependent) diabetes mellitus. We investigated the acute and long-term effects of IL-1 on pancreatic β-cell function in vitro. Rat pancreatic islets were isolated and kept in tissue culture for 5 days. The islets were subsequently transferred to media containing RPMI-1640 plus 1% human serum with or without human recombinant IL-1 β (300 pM) and cultured for another 48 h. The islets were examined either immediately after IL-1 exposure (day 0) or after an additional 6-day culture period without IL-1. On day 0, IL-1 was found to totally inhibit glucose-stimulated insulin release, partially inhibit glucose oxidation, and induce a decrease in islet DNA content. However, these islets were able to release insulin after stimulation with glucose plus theophylline, although the absolute rate of insulin secretion was lower than that of the control group. After 6 days in culture, the insulin-secretory response to glucose and the glucose oxidation rates of the IL-1-pretreated islets were completely restored, but there remained a reduced islet DNA content. We conclude that IL-1 is cytotoxic to islet β-cells. However, surviving β-cells are able to recover their functional capacity after a period of inhibited function.
Beneficial Effects of Verapamil in Diabetic Cardiomyopathy
Authors: Afzal Nasir , Ganguly Pallab K , Dhalla Ken S , Pierce Grant N , Singal Pawan K , Dhalla Naranjan S
Published: September 2013

It has been suggested that the occurrence of an intracellular Ca2+ overload may result in the development of diabetic cardiomyopathy, which is associated with depletion of high-energy phosphate stores and a derangement of ultrastructure and cardiac dysfunction. Accordingly, the effects of verapamil, a Ca2+ antagonist, on cardiac function, ultrastructure, and high-energy phosphate stores in the myocardium were evaluated in rats made diabetic by an intravenous injection of streptozocin (65 mg/kg). Four weeks after the induction of diabetes, the animals were treated with three doses (2, 4, or 8 mg kg−1 day−1) of verapamil for 4 wk until they were used for the measurement of different parameters. Untreated diabetic animals had slower heart rates, depressed rate of contraction and rate of relaxation, lower peak left ventricular systolic pressure, and elevated left ventricular diastolic pressure. All of these changes were significantly improved in diabetic rats receiving verapamil treatment. The beneficial effects of verapamil were more evident with higher doses (8 mg · kg−1 · day−1) than with the lower doses (2 mg · kg−1 · day−1). The diabetic animals also showed alterations in myocardial high-energy phosphate stores and exhibited evidence of ultrastructural damage; these abnormalities were improved by verapamil treatment without affecting their hyperglycemic status. Our results demonstrate that verapamil is capable of preventing diabetes-induced myocardial changes and support the involvement of Ca2+ in the cardiac pathology during diabetes.
Secretin-Induced Exocrine Secretion in Perfused Pancreas Isolated From Diabetic Rats
Authors: Okabayashi Yoshinori , Otsuki Makoto , Ohki Atsushi , Nakamura Takahiko , Tani Satoshi , Baba Shigeaki
Published: September 2013

Exocrine secretory function in response to 10 pM to 10 nM synthetic secretin was evaluated in perfused pancreas isolated from control, streptozocin-induced diabetic (STZ-D), alloxan-induced diabetic (ALX-D), and insulin-treated STZ-D rats. In STZ-D rats, the basal rate of pancreatic juice flow was significantly increased (10.3 ± 1.0 μl/20 min) compared with control rats (4.4 ± 0.2 μl/20 min). The basal rate of amylase output as well as pancreatic amylase content were significantly decreased to <5% of control values. The basal rates of protein and trypsinogen outputs were similar in both groups. In both control and diabetic rats, secretin caused a dose-dependent increase in exocrine secretion. Secretin (10 pM to 10 nM) induced 1.1- to 11.7-fold increases in exocrine secretion in STZ-D rats. These increases were significantly lower than the 2.1- to 20.8-fold increases in control rats. Furthermore, there was no significant increase in exocrine secretion from STZ-D rats in response to 10 pM secretin, although this concentration of secretin caused a significant increase in control rats. Secretin-induced exocrine secretion in ALX-D rats was similar to that in STZ-D rats. In insulin-treated STZ-D rats, the basal rates of pancreatic secretion were not significantly different from those of control rats. Secretin, at a concentration of 10 pM, caused a significant increase in juice flow (from 8.6 ± 1.6 to 30.7 ± 2.0 μl/20 min), protein output (from 227.9 ± 47.3 to 661.0 ± 127.5 μg/20 min), and trypsinogen output (from 37.4 ± 5.3 to 125.8 ± 27.6 μg/20 min), but not in amylase output (from 247.9 ± 57.2 to 327.4 ± 80.6 Somogyi units/20 min). Pancreatic juice flow from insulin-treated STZ-D rats in response to 10 nM secretin (40.3 ± 2.0 μl/20 min) was similar to that of control rats (46.5 ± 5.5 μl/20 min), whereas protein and enzyme outputs in response to 10 nM secretin were significantly reduced compared with those of control rats. This study indicates, therefore, that the sensitivity to secretin is reduced in the diabetic rat pancreas. In addition, this change is, in part, reversible by insulin treatment.
Insulin-Receptor and Apolipoprotein Genes Contribute to Development of NIDDM in Chinese Americans
Authors: Xiang Kun-San , Cox Nancy J , Sanz Nancy , Huang Peggy , Karam John H , Bell Graeme I
Published: September 2013

The frequencies of restriction-fragment-length polymorphism (RFLP) alleles as well as RFLP haplotypes at six genetic loci responsible for carbohydrate and lipid metabolism [insulin/insulin-like growth factor II complex, insulin receptor (INSR), HepG2/erythrocyte-type glucose transporter, apolipoprotein A-II, apolipoprotein B (APOB), and the apolipoprotein A-I/C-III/A-IV cluster (APOA1/C3/A4)] were compared between nondiabetic and diabetic Chinese Americans. The disease-association data suggest that genetic variation at the INSR, APOB, and APOA1/C3/A4 loci contributes to the development of non-insulin-dependent diabetes mellitus (NIDDM). The analysis of the INSR locus revealed “protective” haplotypes, and it may be possible to use two of the INSR haplotypes as genetic markers to identify individuals having a very low probability of developing NIDDM regardless of the presence of other genes conferring susceptibility to this disorder. The APOB and APOA1/C3/A4 loci appear to contribute to the development of NIDDM in individuals who are of lean/normal weight and overweight, respectively. The APOA1/C3/A4 locus may account for ∼8% of the difference between baseline and total possible risk of NIDDM in overweight individuals.
Metabolic Effect of Hemipancreatectomy in Donors: Preoperative Prediction of Postoperative Oral Glucose Tolerance
Authors: Kendall David M , Sutherland David ER , Goetz Frederick C , Najarian John S
Published: September 2013

Between November 1977 and January 1987, 55 transplantations of pancreas segments from living donors related to their recipients were performed at the University of Minnesota. A preliminary analysis of metabolic test results in donors tested 1 yr after hemipancreatectomy showed an increase in mean glucose and a decrease in mean insulin values during oral glucose tolerance tests (OGTTs) in 18 donors, a 14% increase in the mean of the mean glucose levels during 24-h metabolic profiles in 12 donors, and a decrease of 45% in the mean 24-h urinary C-peptide excretion in 21 donors. Including the studies performed postdonation, 11 of 31 (35%) donors developed an abnormal OGTT result. In a retrospective analysis, preoperative results of intravenous glucose tolerance tests (IVGTTs) and cortisonestimulated OGTTs were found to be statistically significant predictors of an abnormal OGTT after hemipancreatectomy. The mean of the 5- to 50-min IVGTT insulin values was the best predictive test. With the cutoff value set at 62 μU/ml, this test result had a sensitivity of 100% a specificity of 83%, and a positive predictive value of 75% for identifying donors who developed an abnormal OGTT. The sum of the 5- and 10-min IVGTT insulin (cutoff 140 μU/ml) had a sensitivity of 100%, a specificity of 67, and a predictive value of only 60%, whereas the Δ-insulin had values of 86, 71, and 60%, respectively. Both the IVGTT mean insulin and the sum of the 5-min and 10-min insulin test results were 100% predictive of an abnormal test (0% risk), but the IVGTT mean insulin excluded the lowest proportion of otherwise suitable donors (a low “false-alarm” rate). The IVGTT mean insulin can be used to identify or exclude potential donors who would develop an abnormal OGTT result should hemipancreatectomy be performed.
Do Donor Age and Cold-Ischemia Time Have a Detrimental Effect on Early Pancreas-Allograft Function?
Authors: Schmid Thomas , KöNigsrainer Alfred , Steiner Ekkehard , Koller Johann , Margreiter Raimund
Published: September 2013

To study the impact of donor age and cold-ischemia time (CIT) on early graft function, we retrospectively divided the donors of 51 pancreas transplants performed between 1979 and 1987 at Innsbruck University Hospital into four groups according to donor age (>45 yr and <15 yr) and CIT (>8 h and <3 h). All organs were perfused with Eurocollins solution and stored at 4°C. Fasting blood glucose levels and total amount of pancreatic juice produced over the first 3 postoperative days were recorded to assess graft function. No statistically significant difference was found between groups 1 and 2 and between groups 3 and 4. From these data, it is concluded that with the preservation method used, CIT can without a doubt be extended to at least 12 h, and a maximum donor age similar to that for the kidney can be adopted. This might not only enlarge the donor pool but also facilitate distant organ procurement.
Results of Pancreas-Transplant Registry
Authors: Sutherland David ER , Moudry Kay C , Fryd David S
Published: September 2013

From December 1966 to March 1988, 1394 pancreas transplants were reported to the International Pancreas Transplant Registry. For the 1129 cases since 1982, the overall 1-yr graft and recipient survival rates were 46 and 82%, respectively. When analyzed according to the three most common duct-management techniques, polymer injection (n = 324), intestinal drainage (n = 282), and bladder drainage (n = 462), the 1-yr function rates were 47, 45, and 54%, respectively. The graft survival rates were also similar, whether whole (n = 492) or segmental (n = 634) grafts were transplanted (47 vs. 46% at 1 yr). Graft survival rates according to preservation times were 49, 42, and 43% at 1 yr for those stored <6h (n = 694), 6–12h (n = 237), and >12h (n = 89), respectively. Immunosuppressive regimens that included both cyclosporin and azathioprine were associated with significantly (P < .03) higher graft survival rates than those that included only one of the drugs, with 1-yr graft survival rates for technically successful grafts of 67, 54, and 39% for patients treated with azathioprine plus cyclosporin (n = 602), cyclosporin without azathioprine (n = 201), and azathioprine without cyclosoporin (n = 44). Pancreas-graft survival rates differed according to whether a kidney was or was not transplanted and according to the timing of the transplant: 53, 40, and 32%, respectively, at 1 yr for cases in which a simultaneous kidney was transplanted (n = 685), a kidney had previously been transplanted (n = 201), or a kidney had never been transplanted (n = 202). Patient survival rates in the three categories were 77, 88, and 90% at 1 yr. In recipients of a pancreas-only transplant or a pancreas after a kidney from a different donor, functional survival rates were higher for bladder-drained than for enteric-drained or duct-injected grafts, whereas for recipients of a simultaneous kidney, the pancreas-graft survival rates were similar for all duct-management techniques. In recipients of simultaneous pancreas-kidney transplants (n = 685), the 1-yr kidney-graft survival rate was 69%. Loss of kidney function with continuation of pancreas funtion is uncommon, whereas loss of the pancreas with continuation of kidney function is common. Overall, the results of pancreas transplantation continue to improve. In an analysis of all cases reported to the registry for 1986–1988 (n = 604), the 1-yr patient and graft survival rates were 86 and 56%, respectively.
Pertussis Toxin–Sensitive G Protein Mediation of PGE2 Inhibition of cAMP Metabolism and Phasic Glucose-Induced Insulin Secretion in HIT Cells
Authors: Seaquist Elizabeth R , Walseth Timothy F , Nelson David M , Robertson R Paul
Published: September 2013

Although prostaglandin E2 (PGE2) is known to inhibit glucose-induced insulin secretion, it is uncertain whether PGE2 actions on the β-cell are direct, whether they are equipotent for both phases of hormone secretion, and whether the same mechanism of action prevails throughout. Study of the HIT cell, a clonai line of pancreatic β-cells, provides answers to these questions because perifusion with glucose and 3-isobutyl-1-methylxanthine stimulates biphasic insulin secretion. Perifusion with PGE2 decreased both the first and second phases of glucose-induced insulin release to 47 ± 4% of controls. Pretreatment with pertussis toxin partly prevented PGE2 inhibition to 80 ± 4% of controls for first phase and 79 ± 4% of controls for second phase. To evaluate whether the partial prevention of PGE2 inhibition seen with pertussis toxin pretreatment was caused by G1 heterotrimer association between the preincubation period and the end of perifusion, PGE2 actions were also examined during continuous treatment with pertussis toxin. Under these conditions, PGE2 inhibition of both phases was totally prevented. However, no difference was observed in membrane protein ADP ribosylation when cells were examined by sodium dodecyl sulfate–polyacrylamide gel electrophoresis after pretreatment or continuous treatment with pertussis toxin. Cyclic AMP (cAMP) accumulation was inhibited by PGE2 (from 3263 ± 153 to 1549 ± 158 fmol/106 cells) but less so after pretreatment with pertussis toxin (correlation between insulin release and cAMP accumulation during perifusion; n = 18, r = .85, P < .001). Thus, PGE2 equally inhibits both phases of glucose-induced insulin secretion and cAMP generation through a pertussis toxin–sensitive G protein–mediated direct effect on the pancreatic β-cell.
Normal Insulin-Receptor cDNA Sequence in Pima Indians With NIDDM
Authors: Moller David E , Yokota Atsushi , Flier Jeffrey S
Published: September 2013

Pima Indians have served as a model of non-insulin-dependent diabetes mellitus (NIDDM). Within this population, inherited insulin resistance is a primary determinant of abnormal glucose metabolism. The insulin receptor is regarded as a “candidate gene” that could potentially be defective in Pima Indians or other populations with NIDDM. To directly address the question of potential insulin-receptor genetic defects in Pima Indians, we isolated and sequenced insulin-receptor cDNA from two Pima Indians with NIDDM. Small amounts of lymphoblast RNA were used to generate first-strand cDNA, which was then amplified via the polymerase chain reaction (PCR). In this way, seven overlapping segments of insulin-receptor cDNA were obtained. With the exception of the alternatively spliced 36-base pair exon 11, which is not expressed in lymphoblasts, the complete coding region of the mature proreceptor was examined with a combination of direct sequencing and sequencing of subcloned PCR segments. The nucleotide sequence in both subjects was identical to previously published insulin-receptor cDNA sequences obtained from healthy subjects. These data indicate that abnormalities of insulin binding and receptor function that have been previously observed in vitro with fresh and cultured cells from Pima Indians may be consequences of the diabetic milieu and/or genetic abnormalities in molecules that interact with the insulin receptor.
Defects in Insulin-Receptor Internalization and Processing in Monocytes of Obese Subjects and Obese NIDDM Patients
Authors: Trischitta Vincenzo , Brunetti Antonio , Chiavetta Agata , Benzi Luca , Papa Vincenzo , Vigneri Riccardo
Published: September 2013

We investigated intracellular processing of the insulin-receptor complex in monocytes from 12 healthy control subjects, 11 obese nondiabetic subjects, and 13 obese patients with non-insulin-dependent diabetes mellitus (NIDDM) by measuring receptor internalization, recovery of cell-surface insulin binding after receptor internalization, and the release of intracellular intact insulin (insulin retroendocytosis). When monocytes from the three groups of subjects were exposed to 100 nM unlabeled insulin for 30 min at 37°C, the subsequent cell-surface 125I-labeled insulin binding was reduced, but the total number of insulin receptors, measured by radioimmunoassay, was not changed. These findings indicate a redistribution of insulin receptors from the surface to the cell interior. Insulin-receptor internalization was significantly lower in monocytes of obese NIDDM patients (mean ± SE 17.8 ± 4.7%) than in obese subjects and healthy control subjects (33.5 ± 4.5%, P < .05, and 34.4 ± 3.7%, P < .02, respectively). Moreover, in downregulated cells, a complete recovery of the initial insulin binding was observed in control subjects but not in obese NIDDM patients or obese nondiabetic subjects. The release of internalized insulin was also reduced in obese NIDDM patients and obese subjects (f1/2 = 49.0 ± 2.4 min, P < .02; 47.4 ± 5.7 min, P < .05; and 32.9 ± 3.8 in NIDDM patients, obese subjects, and control subjects, respectively). In the radioactivity released from monocytes of obese subjects and obese NIDDM patients, the percentage of intact insulin was higher (P < .05) than in control subjects, suggesting reduced intracellular insulin degradation in obese subjects and obese NIDDM patients. This study indicates that insulin-resistant obese subjects and obese NIDDM patients have multiple postbinding defects of the insulin-receptor intracellular processing. Among these defects, decreased insulin-receptor internalization is specifically associated with diabetic patients.
Sexual Dimorphism of Hyperglycemia and Glucose Tolerance in Wistar Fatty Rats
Authors: Kava Ruth A , West David B , Lukasik Valerie A , Greenwood M R C
Published: September 2013

Obese and lean male and female Wistar fatty rats were fed a high-sucrose (68% of calories) diet from 5 to 22 wk of age. Obese males, but not obese females, developed hyperglycemia in the fed state and were more glucose intolerant during an intragastric glucose tolerance test than obese females. Lean Wistar fatty rats did not become hyperglycemic on the sucrose diet. Obese males also showed a smaller insulin response during the glucose tolerance test than did obese females. The Wistar fatty rat is a sexually dimorphic model of non-insulin-dependent diabetes mellitus in which themale but not the female obese rats become diabetic. The diabetic condition and impaired glucose tolerance in the obese male Wistar fatty rat may be related to impaired pancreatic insulin release and peripheral insulin resistance.Obese and lean male and female Wistar fatty rats were fed a high-sucrose (68% of calories) diet from 5 to 22 wk of age. Obese males, but not obese females, developed hyperglycemia in the fed state and were more glucose intolerant during an intragastric glucose tolerance test than obese females. Lean Wistar fatty rats did not become hyperglycemic on the sucrose diet. Obese males also showed a smaller insulin response during the glucose tolerance test than did obese females. The Wistar fatty rat is a sexually dimorphic model of non-insulin-dependent diabetes mellitus in which the male but not the female obese rats become diabetic. The diabetic condition and impaired glucose tolerance in the obese male Wistar fatty rat may be related to impaired pancreatic insulin release and peripheral insulin resistance.
Exercise-Induced Fall in Insulin and Increase in Fat Metabolism During Prolonged Muscular Work
Authors: Wasserman David H , Lacy D Brooks , Goldstein Richard E , Williams Phillip E , Cherrington Alan D
Published: September 2013

The role of the exercise-induced fall in insulin in fat metabolism was studied in dogs during 150 min of treadmill exercise alone (controls) or with insulin clamped at basal levels by an intraportal infusion to prevent the normal fall in insulin concentration (ICs). To counteract the suppressive effect of insulin on glucagon release, glucagon was supplemented by an intraportal infusion in ICs. In all dogs, catheters were placed in a carotid artery and in the portal and hepatic veins for sampling and in the vena cava and the splenic vein for infusion purposes. Glucose levels were clamped in ICs to recreate the glycemic response evident in controls. In controls, insulin fell by 7 ± 1 μxU/ml but was unchanged from basal levels in ICs (0 ± 2 μU/ml). Glucagon, norepinephrine, epinephrine, and cortisol rose similarly in controls and ICs. Arterial free-fatty acid (FFA) levels rose by 644 ± 126 μeq/L in controls but did not increase in ICs (−12 ± 148 μeq/L). Arterial glycerol levels rose by 337 ± 43 and 183 ± 19 (μM in controls and ICs. Hepatic FFA delivery and fractional extraction increased by 17 ± 3 and 0.06 ± 0.02 μmol · kg−1 · min−1, respectively, in controls. In ICs, hepatic FFA delivery increased by only 1 ± 2 (μmol · kg−1 · min−1, whereas hepatic fractional extraction fell slightly (−0.03 ± 0.03). Consequently, net hepatic FFA uptake rose by 4.8 ± 1.5 μxmol · kg−1 · min−1 in controls but decreased slightly in ICs (−0.5 ± 1.1 μmol · kg−1 · min−1). At least partly because of the differences in hepatic FFA uptake, arterial β-hydroxybutyrate (50 ± 14 vs. 23 ± 8 μM) and net hepatic β-hydroxybutyrate output (2.2 ± 0.7 vs. 0.4 ± 0.3 μmol · kg−1 · min−1) rose more in controls than in ICs. In summary, the exercise-induced fall in insulin 7) is essential to the increase in FFA levels during prolonged muscular work, 2) facilitates hepatic FFA uptake by enhancing the delivery of FFAs to the liver and their extraction by the liver, and 3) enhances the net β-hydroxybutyrate output by the liver, at least in part through the effects described in 1 and 2. Hence, the exercise-induced fall in insulin is essential for the transition to the increased rate of FFA metabolism that occurs as work duration progresses.
Bedtime Insulin for Suppression of Overnight Free–Fatty Acid, Blood Glucose, and Glucose Production in NIDDM
Authors: Taskinen Marja-Riitta , Sane Timo , Helve Eero , Karonen Sirkka-Liisa , Nikkilä Esko A , Yki-Järvinen Hannele
Published: September 2013

We studied the clinical effectiveness and mechanism underlying the glucose-lowering effect of evening insulin therapy. Nocturnal profiles of blood glucose, plasma free fatty acid (FFA), glycerol, and lactate and overnight glucose kinetics ([3-3H] glucose infusion) were measured in 15 non-insulin-dependent diabetic (NIDDM) patients with a relative body weight of 128 ± 4% who were poorly controlled with oral therapy alone. The patients were studied before and 2 wk and 3 mo after bedtime insulin (23 ± 3 IU) was given in addition to oral therapy. An early-morning rise in blood glucose (>31 mg/dl = 1.5 mM) was present in two-thirds of the patients and was associated with an overnight rise in plasma FFA and an increase in glucose production (Ra) during the early-morning hours (change 0.42 ± 0.10 mg · kg−1 · min−1 P < .05, between 0300 and 0800). The overnight mean levels of blood glucose, plasma FFA, and serum insulin averaged 212 ± 9 vs. 137 ± 11 vs. 133 ± 11 mg/dl (P < .001), 674 ± 61 vs. 491 ± 57 vs. 484 ± 36 μM (P < 0.01) and 12.7 ± 1.6 vs. 18.1 ± 2.2 vs. 20.7 ± 2.4 μU/ (P < .01) before and 2 wk and 3 mo after the combination therapy. The decrements in overnight glucose and FFA levels after 2 wk of bedtime insulin therapy were closely correlated (r = .86, P < .001). The nocturnal profile of plasma lactate was similar before and during bedtime insulin therapy. The overnight mean glucose Ra fell significantly after insulin administration (2.31 ± 0.13 vs. 1.83 ± 0.09 vs. 1.83 ± 0.10 mg · kg−1 min−1 P < .01, respectively). There was a positive correlation between the overnight mean values of Ra and the plasma FFA concentration (r = .58, P < .001). These data raise the possibility the improvement in overall glycemic control by the administration of evening insulin is related to the suppression of overnight plasma FFA concentrations and to a consequent reduction in overnight glucose production.
Effects of Low Insulin Levels on Rat Embryonic Growth and Development
Authors: Travers James P , Pratten Margaret K , Beck Felix
Published: September 2013

The risk of congenital abnormality in diabetic pregnancy is about four times that for the normal population. Past clinical studies have suggested hyperglycemia and hyperketonemia as the factors responsible for these abnormalities, with no reference to the possible effects of low insulin levels. We examine the effect of hypoinsulinemia on rat embryonic growth and development in culture while normal glucose levels are maintained. With anti-insulin antibody bound to an affinity column containing cyanogen bromide-activated Sepharose 4B beads, insulin was selectively removed from the homologous culture serum eluted down the column. A culture of rat embryos from the early head-fold stage for 50 h in insulin-depleted normoglycemic homologous serum (insulin levels 0.055–0.18 ng/ml) showed retardation of growth and development when compared with control embryos. Adding physiological amounts (10 ng/ml) of insulin back into the insulin-depleted serum subsequently restored growth level to that of control embryos. We conclude that low insulin levels, encountered in newly diagnosed diabetic pregnancy, may be instrumental in increasing the risk of congenital abnormalities.
Exercise-Induced Rise in Glucagon and Ketogenesis During Prolonged Muscular Work
Authors: Wasserman David H , Spalding Jennifer A , Bracy Deanna , Lacy D Brooks , Cherrington Alan D
Published: September 2013

These experiments examined the role of the exercise-induced increment in glucagon in the control of ketogenesis during prolonged moderate-intensity (100 m/min, 12% grade) treadmill exercise. Dogs were studied during 150 min of exercise with saline infusion alone (C; n = 6) with the glucagon levels clamped at basal values (somatostatin infusion with basal glucagon replacement and the normal fall in insulin simulated; BG; n = 5) or with the normal exercise-induced rise in glucagon simulated (somatostatin infusion with the rise in glucagon and the fall in insulin simulated; SG; n = 5). Glucose was infused as needed in SG and BG to maintain the glycemic response seen in C. In all dogs, catheters were inserted into the carotid artery and the portal and hepatic veins for blood sampling and the vena cava and the splenic vein for infusions. Glucagon rose from 62 ± 5 and 57 ± 4 pg/ml at rest to 104 ± 20 and 120 ± 12 pg/ml during exercise in C and SG but did not deviate from basal in BG (56 ± 3 pg/ml). Insulin fell similarly from rest to the end of exercise in C (13 ± 2 to 5 ± 1 μU/ml), SG (11 ± 1 to 6 ± 1 μU/ml), and BG (10 ± 1 to 6 ± 1 μU/ml). In C, SG, and BG, free-fatty acid (FFA) levels rose from 941 ± 81,1240 ± 155, and 938 ± 36 μeq/L at rest to 1615 ± 149, 1558 ± 175, and 1391 ± 160 μeq/L with exercise. In C, SG, and BG, net hepatic FFA uptake was 2.9 ± 0.4, 4.6 ± 0.6, and 3.6 ± 0.3 μmol · kg−1 · min−1 at rest and rose to 7.8 ± 1.8, 7.2 ± 0.8, and 7.1 ± 1.3 μmol · kg−1 · min−1 with exercise. Arterial blood β-hydroxybutyrate levels rose from 20 ± 3 to 69 ± 25 μM and from 21 ± 4 to 66 ± 16 μM by the end of exercise in C and SG but from only 16 ± 2 to 27 ± 5 μM in BG. Net hepatic β-hydroxybutyrate output rose by 2.3 ± 0.6 and 2.9 ± 1.0 μmol · kg−1 · min−1 with exercise in C and SG compared to an increase of only 0.6 ± 0.2 μmol · kg−1 · min−1 in BG. Arterial blood acetoacetate did not increase appreciably from resting levels of 86 ± 7, 78 ± 7, and 60 ± 5 μM during exercise in C, SG, or BG. In C and SG, net hepatic acetoacetate output increased from 0.4 ± 0.1 and 0.9 ± 0.2 μmol · kg−1 · min−1 at rest to 1.7 ± 0.5 and 1.5 ± 0.3 μmol · kg−1 · min−1 by the end of exercise. In BG, acetoacetate production increased from 0.5 ± 0.1 to only 0.8 ± 0.2 μmol · kg−1 · min−1with exercise. The intrahepatic ketogenic efficiency was 0.13 ± 0.02, 0.10 ± 0.01, and 0.09 ± 0.01 at rest in C, SG, and BG. This variable was 0.16 ± 0.06 and 0.19 ± 0.04 by the end of exercise in C and SG but only 0.07 ± 0.02 in BG. These data indicate that, in normal dogs, the exercise-induced increment in glucagon is essential for the full rise in hepatic ketone output during muscular work and that this effect of the increase in glucagon is mediated by intrahepatic mechanisms.
Effect of Prostaglandin E1 Analogue TFC 612 on Diabetic Neuropathy in Streptozocin-Induced Diabetic Rats Comparison With Aldose Reductase Inhibitor ONO 2235
Authors: Yasuda Hitoshi , Sonobe Masanobu , Yamashita Makio , Terada Masahiko , Hatanaka Ikuo , Huitian Zheg , Shigeta Yukio
Published: September 2013

The effect of a newly developed oral agent, prostaglandin E1 (PGE1) analogue TFC 612, on diabetic neuropathy was studied by giving it for 6 wk to streptozocin-induced diabetic rats that had been diabetic for 3 mo and was compared with the effects of aldose reductase inhibitor ONO 2235. Although both compounds improved decreased motor nerve conduction velocity, the effect of TFC 612 continued during the 6 wk of treatment, whereas that of ONO 2235 became weaker from wk 4. The abnormality in sciatic nerve sorbitol and myo-inositol levels was reversed with ONO 2235, whereas it was unchanged with TFC 612. With the laser Doppler flowmetry technique, a decrease in the sciatic nerve blood flow in diabetic rats was shown to improve with both compounds, but TFC 612 had a greater effect than ONO 2235, and the increased lactate level of the diabetic nerve was corrected with both compounds, suggesting that both may be associated with the amelioration of ischemia in the diabetic endoneurium. Both TFC 612 and ONO 2235 partially but significantly normalized decreased fiber size in diabetic rats. On the other hand, TFC 612 completely normalized the dilated lumen area in diabetic rats, whereas ONO 2235 did not. These results suggest that the PGE, analogue TFC 612 has a significant effect on diabetic neuropathy, possibly via vasotropic action, and may be a potent compound for the treatment of diabetic neuropathy.
Capillary Basement Membrane Thickness and Capillary Density in Sedentary and Trained Obese Zucker Rats
Authors: Lash Julia M , Sherman William M , Hamlin Robert L
Published: September 2013

The purpose of this study was to determine whether the obese Zucker rat (OZR) develops diabeteslike peripheral vascular disease and evaluate the effects of exercise training (treadmill running, 15 m/min, 17% grade, 60 min/day, 5 days/wk, for 6 or 12 wk) on skeletal muscle vascular disease. Capillary density (CD) and capillary basement membrane (CBM) thickness were measured in the plantar muscle of sedentary and trained OZR and sedentary lean Zucker rats (LZRs). At 11 wk old, when profoundly obese, hyperinsulinemic, and insulin resistant, OZRs had lower CD and thicker CBM than LZRs. These characteristics are consistent with the expression of human diabetic microangiopathy and imply altered diffusion capacity due to increased diffusion distance and changes in the capillary wall. Between 11 and 18 wk of age, OZRs became hyperglycemic. No age-related changes in CD were observed in lean or obese animals, and OZRs had lower CDs than LZRs at 18 wk of age. CBM thickness decreased from 11 to 18 wk of age in both lean and obese animals, but the decline was proportionally greater in OZRs, and the CBM of obese animals was only slightly thicker than in lean 18-wk-old animals. Exercise training did not alter CD or CBM thickness in 11-wk-old animals. In contrast, training for 6 or 12 wk increased both CD and CBM thickness in 18-wk-old animals, normalizing CD but further increasing CBM thickness relative to LZRs. Correlational analysis revealed that CBM thickness is related to basal insulin concentration (r = .29, P <.05) but not to basal glucose (r = .12, P >.05). No relationship was evident for CD. OZRs have fewer capillaries and thicker CBM in skeletal muscle at 11 and 18 wk of age. In addition, exercise training may improve skeletal muscle diffusion capacity in OZRs by stimulating capillary proliferation; however, microvascular function may be further compromised by additional thickening of the CBM. The effects of exercise training on CBM thickness may depend on the corresponding changes in the basal insulin concentration.
Cardiac Performance and Plasma Lipids of Omega-3 Fatty Acid–Treated Streptozocin-Induced Diabetic Rats
Authors: Black Shawn C , Katz Sidney , McNeill John H
Published: September 2013

We studied the effect of omega-3 fatty acid (ω3FA) treatment on plasma lipids and cardiomyopathy in the diabetic rat. The ω3FA preparation used was Promega. Male Wistar rats (250–275 g) were rendered diabetic by streptozocin (STZ; 55 mg ·kg−1). Nondiabetic control rats received the vehicle alone. Two weeks after STZ or vehicle injection, control and diabetic rats were randomly assigned to either a treated or untreated group. Promega was administered at a dose of 0.5 ml · kg−1 · day−1 by oral gavage for 4 wk, after which the rats were decapitated, plasma collected, and isolated working heart performance studied. Promega treatment did not affect plasma glucose, triglyceride, or cholesterol concentrations of either the control or diabetic rats. Cardiac performance was assessed by measuring the left ventricular response to changing left atrial filling pressures (7.5–20 cm H2O). The treatment had no effect on peak left ventricular developed pressure (LVDP) or maximal rate of change of left ventricular pressure during systole (+dP/dtmax) or diastole (−dP/dtmax) in the nondiabetic control rats. LVDP and + / −dP/dt were significantly improved (P < .05) in the treated diabetic rats compared with untreated diabetic rats, although cardiac performance did not improve to the nondiabetic level. Cardiac sarcoplasmic reticulum (SR) calcium transport activity was not affected by the treatment in the control rats but was significantly improved (P < .05) in the treated diabetic rats. These data suggest that ω3FA treatment partially blocks the development of experimental diabetic cardiomyopathy, possibly by affecting SR calcium transport activity.
High-Dose Porcine Galanin Infusion and Effect on Intravenous Glucose Tolerance in Humans
Authors: Gilbey Stephen G , Stephenson Judith , O'halloran Domhnall J , Burrin Jacqueline M , Bloom Stephen R
Published: September 2013

The neuropeptide galanin inhibits glucose-stimulated insulin release in dogs and rodents and has been proposed as having a role in the control of insulin release in humans. The effect of infused galanin on intravenous glucose tolerance in humans was investigated by giving an intravenous glucose tolerance test (0.5 g glucose/kg body wt) alone and with infusions of synthetic porcine galanin at high-dose levels (80 and 160 pmol · kg−1 · min−1) to seven healthy male volunteers. The results showed no effect of galanin infusion on plasma glucose or serum insulin, although a rise in serum growth hormone even in the face of the intravenous glucose load confirmed the potent growth hormone-stimulating effect of galanin. These results suggest that caution should be exercised in extrapolating a physiological role for galanin in humans from the results of animal studies.
Mean Glomerular Volume and Rate of Development of Diabetic Nephropathy
Authors: Bilous Rudolf W , Mauer S Michael , Sutherland David E R , Steffes Michael W
Published: September 2013

We studied kidney glomerular structure and function in two groups of type I (insulin-dependent) diabetic subjects with 14–16 yr (group 1, n = 16) and 24–26 yr (group 2, n = 13) duration of diabetes and compared them to a group of 18 nondiabetic subjects with similar age ranges. Within each diabetic group, subjects were selected for normal kidney function (urinary albumin excretion <40 mg/24 h, normal blood pressure, creatinine clearance >90 ml · min−1 · 1.73 m−2) or for nephropathy (urinary albumin excretion >200 mg/24 h). Morphometric analysis of glomeruli revealed a significantly larger mean glomerular volume in subjects with nephropathy (group 2). Mesangial volumes were significantly greater in the nephropathic than the normoalbuminuric diabetic subjects in each group, but filtration surface per glomerulus was constant among all subjects. The percentage of sclerosed glomeruli was also significantly increased in the nephropathic subjects compared with the subjects with normal kidney function, in whom sclerosed glomeruli did not exceed 8%. In addition, there was a significant correlation between percentage of globally sclerosed glomeruli and glomerular volume in group 2 (rs = .79, P < .01) but not group 1 (rs = −.20, NS) subjects. Thus, glomerular size or individual capacity for glomerular expansion may determine the rate of progression of the loss of kidney function in subjects destined to develop diabetic nephropathy.
Evidence That Downregulation of Hexose Transport Limits Intracellular Glucose in 3T3-L1 Fibroblasts
Authors: Whitesell Richard R , Regen David M , Pelletier Diana , Abumrad Nada A
Published: September 2013

Measurements of initial glucose entry rate and intracellular glucose concentration incultured cells are difficult because of rapid transport relative to intracellular volume and a substantial extracellular space from which glucose cannot be completely removed by quick exchanges of medium. In 3T3-L1 cells, we obtained good estimates of initial entry of [14C]methylglucose and D-[14C]glucose with 1) L-[3H]glucose as an extracellular marker together with the [14C]glucose or [14C]methylglucose in the substrate mixture, 2) sampling times as short as 2 s, 3) icecold phloretin-containing medium to stop uptake and rinse away the extracellular label, and 4) nonlinear regression of time courses. Methylglucose equilibrated in two phases—the first with a half-time of 1.7 s and the second with a half-time of 23 s; it eventually equilibrated in an intracellular space of 8 μl/mg protein. Entry of glucose remained almost linear for 10 s, making its transport kinetics easier to study (Km = 5.7 mM, Vmax = 590 nmol · s−1 · ml−1 cell water). Steadystate intracellular glucose concentration was 75–90% of extracellular glucose concentration. Cells grown in a high-glucose medium (24 mM) exhibited a 67% reduction of glucose-transport activity and a 50% reduction of steady-state ratio of intracellular glucose to extracellular glucose.
Contribution of Abnormal Muscle and Liver Glucose Metabolism to Postprandial Hyperglycemia in NIDDM
Authors: Mitrakou Asimina , Kelley David , Veneman Thiemo , Jenssen Trond , Pangburn Thomas , Reilly James , Gerich John
Published: September 2013

To assess the role of muscle and liver in the pathogenesis of postprandial hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM), we administered an oral glucose load enriched with [14C]glucose to 10 NIDDM subjects and 10 age- and weight-matched nondiabetic volunteers and compared muscle glucose disposal by measuring forearm balance of glucose, lactate, alanine, O2, and CO2 (with forearm calorimetry). In addition, we used the dual-lable isotope method to compare overall rates of glucose appearance (Ra) and disappearance (Rd), suppression of endogenous glucose output, and splanchnic glucose sequestration. During the initial 1–1.5 h after glucose ingestion, plasma glucose increased by ∼8 mM in NIDDM vs. ∼3 mM in nondiabetic subjects (P < 0.01); overall glucose Ra was nearly 11 g greater in NIDDM than nondiabetic subjects (45.1 ± 2.3 vs. 34.4 ± 1.5 g, P < 0.01), but glucose Rd was not significantly different in NIDDM (35.1 ± 2.4 g) and nondiabetic (33.3 ± 2.7 g) subjects. The greater overall glucose Ra of NIDDM subjects was due to 6.8 g greater endogenous glucose output (13.7 ± 1.1 vs. 6.8 ± 1.0 g, P < 0.01) and 3.8 g less oral glucose splanchnic sequestration of the oral load (31.4 ± 1.5 vs. 27.5 ± 0.9 g, P < 0.05). Although glucose taken up by muscle was not significantly different in NIDDM and nondiabetic subjects (39.3 ± 3.5 vs. 41.0 ± 2.5 g/5 h), a greater amount of the glucose taken up by muscle in NIDDM was released as lactate and alanine (11.7 ± 1.0 vs. 5.2 ± 0.3 g in nondiabetic subjects, P < 0.01), and less was stored (11.7 ± 1.3 vs. 16.9 ± 1.5 g, P < 0.05). We conclude that increased systemic glucose delivery, due primarily to reduced suppression of endogenous hepatic glucose output and, to a lesser extent, reduced splanchnic glucose sequestration, is the predominant factor responsible for postprandial hyperglycemia in NIDDM.