bluuebunny/crossref_metadata_2025 huggingface dataset:
Training Adaptations in Skeletal Muscle of Juvenile Diabetics
Authors: Costill D L , Cleary P , Fink W J , Foster C , Ivy J L , Witzmann F
Published: September 2013

Skeletal muscles from 12 male, juvenile-onset diabetics (JD) and 13 nondiabetics (ND) were studied to determine the effects of endurance training on mitochondrial enzyme activities, lipoprotein lipase (LPL) activity, and the oxidation of lipids (14C-palmityl CoA) in vitro. Ten weeks of endurance running (30 min/day, 5 days/wk) resulted in 11.0 and 12.9% gains in aerobic capacity for the JD and ND groups (P > 0.05), respectively. Both groups showed significant (P < 0.05) increases in muscle LPL, carnitine palmityl transferase, succinate dehydrogenase, and hexokinase activities with training. Though the pretraining capacities for 14C-palmityl CoA oxidation were similar for both ND and JD groups, the diabetics showed a 41% greater improvement in the measurement of muscle lipid oxidation after training than did the ND group. The principal finding of this research was that skeletal muscle of juvenile diabetics who are in moderate insulin balance shows adaptations to endurance training that are similar to those of nondiabetic men.
Decrease in Insulin Receptors During Friend Erythroleukemia Cell Differentiation
Authors: Ginsberg Barry H , Brown Thomas , Raizada Mohan
Published: September 2013

The Friend erythroleukemia cell has an insulin receptor with all the properties of mammalian insulin receptors: rapid, reversible, and saturable binding of insulin; specific for insulin and insulin analogs; inversely proportional to temperatures; sharply pH dependent (optimum = 8.0); and demonstrated ligand-induced accelerated dissociation consistent with negative cooperativity. There were 17,200 sites per cell. After induction by dimethylsulfoxide, 80% of the cells became benzidine positive (i.e., contained hemoglobin). The receptor concentration dropped to 4300 sites per cell, while the remaining receptors retained all the initial binding characteristics. This loss of receptors could not be attributed directly to either dimethylsulfoxide or changes in cell size. Thus, during the process of differentiation, the concentration of insulin receptors in the Friend erythroleukemia cell decreases.
The Correlation of Arteriosclerosis Obliterans with Lipoproteins in Insulin-Dependent and Non-Insulin-Dependent Diabetes
Authors: Beach Kirk W , Brunzell John D , Conquest Loveday L , Eugene Strandness D
Published: September 2013

Risk factors for arteriosclerosis, such as age, duration of diabetes, sex, and plasma lipoprotein levels, were correlated with the presence of arteriosclerosis obliterans (ASO) as determined by noninvasive methods in 485 of 506 subjects studied with diabetes mellitus.

The diabetic subjects were separated into two major groups for analysis: insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). The NIDDM group was subdivided into those treated by diet (NIDDM-D), sulfonylureas (NIDDM-S), and insulin (NIDDM-I).

Overall, lipoprotein levels in the diabetics were higher than in an age- and sex-adjusted nondiabetic group. Cholesterol levels were elevated in all females and HDL cholesterol levels were depressed in diet- and sulfonylurea-treated females. VLDL levels were most elevated in diet-treated subjects followed by sulfonylurea-treated subjects; VLDL levels in insulin-treated subjects were not elevated.

The prevalence of ASO is related to different factors in each group. In IDDM and NIDDM-I subjects, VLDL triglyceride, LDL cholesterol, and duration of diabetes or age are important risk indicators. By contrast, in NIDDM-S subjects, age alone is the significant risk indicator, and in NIDDM-D subjects, inverse HDL cholesterol correlated with ASO. While males have a higher prevalence of ASO than females, the difference is not statistically significant in any group. Other possible factors, such as hypertension, smoking, and obesity, were not considered in this initial analysis.
Metabolic Effects of Sodium Dichloroacetate in Normal and Diabetic Dogs
Authors: Ribes Gérard , Valette Guy , Loubatières-Mariani Marie-Madeleine
Published: September 2013

The effects of acute and chronic administration of sodium dichloroacetate (DCA) were studied in the normal and diabetic dog. In the normal dog, a single oral injection of DCA (150 mg/kg) provoked a rapid decrease of the lactate, pyruvate, and triglyceride concentrations and a progressive decrease of blood glucose. These effects lasted longer than 24 h.

In the alloxan-diabetic dog deprived of insulin for 72 h, DCA induced a decrease of blood glucose, lactate, and pyruvate concentrations as well as of glucosuria. In these ketotic animals, the plasma lipid compounds and the blood and urinary ketone bodies were not significantly changed by DCA.

In the normal dog, the chronic administration of DCA (150 mg/kg daily for 7 days) provoked a decrease in blood glucose, lactate, pyruvate, and oxaloacetate concentrations, which returned to starting values only within 2 to 5 days after the end of the treatment, depending on the compounds studied. A decrease of cholesterol was also noted. During the chronic administration of DCA, blood β-hydroxybutyrate and acetoacetate concentrations strongly increased.

When treated with insulin alone, the alloxan-diabetic dogs had a high blood glucose concentration; the blood lactate, pyruvate, and oxaloacetate concentrations did not differ significantly from those of the normal animals, however. In these diabetic dogs, the lipid compounds and, particularly, the ketone compounds were increased. The addition of DCA (75 mg/kg daily for 7 days) provoked a drop in blood lactate, pyruvate, and oxaloacetate levels, and a reduction of blood glucose and plasma cholesterol, triglyceride, and total lipids was also noted. Blood β-hydroxybutyrate and acetoacetate concentrations, which were already high at the start, were not affected when DCA was associated to insulin. This addition of DCA provoked a rapid and marked reduction in glucosuria, which was concomitant with an increase in urinary β-hydroxybutyrate and acetone.
The Glucose Intolerance of Acute Pancreatitis: Hormonal Response to Arginine
Authors: Solomon Solomon S , Duckworth William C , Jallepalli Panduranga , Bobal Mary Alice , Iyer Ramamurthi
Published: September 2013

Patients with acute pancreatitis were studied by arginine infusion at 48–72 h, 7–10 days, and 18–21 days after onset of their illness. Plasma glucose, insulin, and glucagon values were determined. Acute pancreatitis was characterized by fasting hyperglycemia and hyperglucagonemia, associated with relative hypoinsulinemia. Arginine stimulation early in the disease (48–72 h) demonstrated hyperglycemia and hyperglucagonemia, which normalized by 18–21 days. Both phases of the normal biphasic insulin response to arginine were decreased during the initial arginine infusion. By 18–21 days, although the first phase was completely normal, the second phase of insulin secretion remained depressed.

Acute pancreatitis is associated with damage to both the endocrine and exocrine pancreas. Glucose intolerance seen with this disease appears to be the result of hyperglucagonemia and relative hypoinsulinemia. Although the healing process at 3 wk is associated with return of plasma glucose and glucagon concentrations to normal, the impaired second phase insulin secretion persists.
Clinical Segmental Pancreas Transplantation Without Duct Anastomosis in Diabetic Renal Allograft Recipients
Authors: Sutherland David E R , Goetz Frederick C , Najarian John S
Published: September 2013

Segmental pancreatic allografts with unligated ducts were transplanted intraperitoneally to five diabetic patients who had received renal allografts more than 2 yr earlier. One patient is alive with a functioning graft 10.5 mo later. Two patients rejected their grafts at approximately 2 and 3 mo but are alive 8–9 mo later after resumption of exogenous insulin therapy. In both patients, carbohydrate metabolism was nearly normal during the period of graft function. Two patients died of infectious complications between 1 and 2 mo after transplantation. The main hazard of pancreas transplantation relates to the immunosuppression necessary to prevent rejection, setting the stage for infectious complications. Technically, pancreas transplantation is a feasible and efficient procedure, and, if better methods are developed for preventing rejection, it should be applicable to patients prone to develop secondary complications of diabetes.
Isolating the Elusive Islet
Authors: Scharp David W , Downing Richard , Merrell Ronald C , Greider Marie
Published: September 2013

The lack of a technique that allows mass isolation of intact, viable human islets is part of the reason that islet transplantation has not become available to the human diabetic. This report outlines the history of islet isolation and presents two new technical modifications that have been developed in the dog. Many of the current problems in islet isolation are presented, including the difficulty in obtaining enough human pancreatic tissue with minimal warm-ischemia time; inadequate distention of the pancreas to provide sufficient disruption for maximal enzymatic reaction to release intact islets; inefficient chopping methods; the use of collagenase of variable composition; different digestion methods for obtaining isolated islets; and inefficient methods for separating and purifying the islets from the ductal, acinar, and fibrous components. The first new modification involves distention of the dog pancreas through the venous system of the gland rather than the ductal system. This results in improved intralobular disruption, which improved the yield of isolated dog islets by permitting more efficient collagenase digestion. The second new modification eliminates the concept of isolating intact islets: the dog pancreas is digested by trypsin to a single-cell preparation that is partially purified by Ficoll gradients; further purification of the endocrine cells results from selective aggregation using rotational culture. This process produces pseudoislets that contain all the islet cell types and can be kept in culture for up to 4 wk, releasing their hormones in response to appropriate stimuli. These modifications may assist in the struggle to isolate the elusive human islet for safe and effective islet transplantation in the diabetic patient.
Red Cell Sorbitol: An Indicator of Diabetic Control
Authors: Malone John I , Knox Gail , Benford Stephen , Tedesco Thomas A
Published: September 2013

Intact human erythrocytes accumulate intracellular sorbitol in response to the medium's glucose concentration during in vitro incubations. Sorbitol was identified and measured both enzymatically and by gas-liquid chromatography. The sorbitol produced is most likely a result of the activity of aldose reductase, since (1) a low glucose concentration in the medium elicits this response, and (2) this activity is completely blocked by tetramethylene glutaric acid, a specific inhibitor of aldose reductase. Erythrocyte sorbitol levels in insulin-dependent diabetics are clearly above those of nondiabetics after an 8 h fast. A good correlation exists between red cell sorbitol content and coincident plasma glucose concentrations. Individual exceptions to this rule exist, however, and suggest that red cell sorbitol levels may provide information about in vivo polyol pathway activity that may be important in the pathogenesis of diabetes-associated complications.
Epinephrine-induced Hypoaminoacidemia in Normal and Diabetic Human Subjects: Effect of Beta Blockade
Authors: Shamoon Harry , Jacob Ralph , Sherwin Robert S
Published: September 2013

To evaluate the effect of epinephrine on the circulating amino acids, we infused epinephrine into normal human subjects and juvenile-onset diabetic patients given a constant basal infusion of insulin. Epinephrine infusion produced an identical 350–400 pg/ml rise in plasma epinephrine in both groups. In normal subjects, epinephrine caused a progressive 26% reduction in total circulating amino acids, despite unchanged levels of plasma insulin. This effect was most pronounced for the branched amino acids, which fell by 40% (P < 0.001). Plasma alanine was the only amino acid which failed to decline. Similarly, infusion of epinephrine in the insulin-infused diabetics produced a 23% fall in total amino acids, a 37% decline in branched chain amino acids, but no change in plasma alanine. Saline infusion in the insulin-infused diabetics had no effect on plasma amino acid concentrations. In addition, when epinephrine was infused into two insulin- withdrawn diabetics, a comparable hypoaminoacidemic response was observed. The infusion of propranolol in both normal and diabetic subjects totally prevented the epinephrine-induced fall in plasma amino acids.

It is concluded that (1) increments in epinephrine similar to those observed in stress cause a decline in circulating amino acids (except alanine) which is greatest for the branched chain amino acids; (2) this hypoaminoacidemic effect occurs in the absence of a rise in plasma insulin and diabetic subjects, as well; and (3) epinephrine-induced changes in amino acid regulation are prevented by β-adrenergic blockade. Our findings suggest that, in contrast with glucose and fat metabolism, epinephrine and insulin may have similar, rather than antagonistic, effects on plasma amino acid metabolism.
Arteriosclerosis Obliterans and Associated Risk Factors in Insulin-dependent and Non-insulin-dependent Diabetes
Authors: Beach Kirk W , Strandness D Eugene
Published: September 2013

The prevalence of arteriosclerosis obliterans (ASO) of the legs was determined by a battery of noninvasive tests in 141 insulin-dependent and 289 non-insulin-dependent diabetic subjects and in 64 other subjects. The prevalence of detectable ASO ranges from 18% in the younger IDDM group to 41% in the diet-treated NIDDM group.

The prevalence of ASO increases 7.5% per decade, appears to increase 6.5% in the age-adjusted IDDM group, 9% in males, 19% in those with hypertension, and 12% in smokers. No consistently significant correlations with fasting glucose, glycosylated hemoglobin, or obesity were found. After accounting for the effect of smoking, the increased risk for ASO in males becomes nonsignificant.
Hypersecretion of Pancreatic Somatostatin in the Obese Zucker Rat: Effects of Food Restriction and Age
Authors: Trimble Elisabeth R , Herberg Lieselotte , Renold Albert E
Published: September 2013

Islets of 5-mo-old obese Zucker rats secreted 50% more somatostatin (SRIF) in response to 8.3 mM or 16.7 mM glucose than did islets from lean controls; the islet SRIF contents of obese and lean rats were similar. As expected, islets of obese rats demonstrated a greater basal and a fivefold greater glucose-induced insulin release and also a twofold greater insulin content than did islets from lean rats. Obese rats were pair fed with lean animals from the age of 9 wk until killed, when 5 mo old. While this curtailed the weight gain of obese rats to that of lean controls, it caused no reduction in the per cent body weight found in the form of lipid. The responses of the pancreatic delta and beta cells to pair feeding were markedly different. Pair feeding caused no alteration in either SRIF content or glucose-induced SRIF release, while the expected reductions in both islet insulin content and glucose-induced insulin secretion were observed.

Islets from older obese Zucker rats (15–18 mo old) had four to five times greater contents of both SRIF and insulin than did islets from age-matched lean controls. The obese rats of this age had a moderate glucose intolerance. SRIF secretion from the islets of such rats was distinctly greater than from those of lean controls at all glucose concentrations tested (range, 1.0–16.7 mM). The delta cells of the older obese rats had lost their sensitivity to glucose, while those of lean controls remained sensitive. Beta cells of islets from both obese and lean 15-mo-old rats remained glucose sensitive. Under all conditions tested, secretion of SRIF and insulin was greater from islets of obese than lean rats.

The results demonstrate a marked difference in pancreatic delta and beta cell responses to pair feeding in the obese Zucker rat. At present, the roleplayed by hypersecretion of pancreatic SRIF in the obesity syndrome of the Zucker rat remains obscure.
Use of a High Voltage Technique to Determine the Molecular Requirements for Exocytosis in Islet Cells
Authors: Pace Caroline S , Tarvin John T , Neighbors Ann S , Pirkle James A , Greider Marie H
Published: September 2013

Pancreatic islet cells were subjected to high voltage discharges, which induced pore formation in the plasma membrane. This technique was used to determine the molecular requirements of intracellular sites involved in the control of insulin release in β-cells. Islets, preloaded with 86Rb+ and then shocked, released 92% of the radioisotope within 1 min as compared with only a 55% loss from nonshocked islets. Exposure of the islets to 14C-urea and 3H-sucrose at 0 to 10 min after exposure to high voltage discharges indicated that 68% of the intracellular space was occupied by sucrose, whereas sucrose was excluded from nonshocked islet cells. The pores in the plasma membrane resealed about 30 min after their initial formation, as was indicated by the cellular exclusion of sucrose.

The Ca++ concentrations yielding half-maximal and maximal secretory responses from shocked islets were 0.05 × 10−6 M and 0.35 × 10−6 M, respectively; the presence of 16.7 mM glucose did not alter these values. In intact islets, a variation of extracellular Ca++ (only in the presence of 16.7 mM glucose) generated a dose-response curve yielding half-maximal and maximal secretory responses at 2.0 × 10−3 M and 4.0 × 10−3 M, respectively. The total amount of insulin released from shocked islets was three times that released from nonshocked islets during a 15 min incubation period. The addition of 1 or 5 mM ATP during an initial shock and incubation period did not augment the secretory response to 0.05 × 10−6 M Ca++, but the presence of ATP was necessary, or the islets would not respond to 0.35 × 106 M Ca++ during a subsequent shock and incubation period. The presence of 1.0 mM 3-phosphoglycerate or phosphoenolpyruvate augmented the secretory response to 0.05 × 10−6 MCa++ only in the presence of 1.0 mM ATP. Glucose-6- phosphate or fructose-1,6-diphosphate had no influence on the secretory response to Ca++ in the presence of ATP. An increase in Mg++ from 1.0 to 10 mM reduced the secretory response to 0.35 × 10−6 M Ca++ by 63%. Islets, subjected to the high voltage discharges and allowed 30 min to reseal, exhibited a normal secretory response to 16.7 mM glucose. The results indicate that the high voltage technique induces reversible pore formation in β-cells to introduce ions and solutes into the intracellular environment so that the factors controlling exocytosis can be determined.
Banting Lecture 1980: of Pregnancy and Progeny
Authors: Freinkel Norbert
Published: September 2013

A profile characteristic of fuel economy in the mother during normal pregnancy has been delineated. The evidence indicates that pregnancy changes the metabolism of every class of foodstuff. The mechanisms by which the conceptus may be implicated are reviewed. The gestational interactions create a pattern of “accelerated starvation” whenever food is withheld, especially in late pregnancy, and they tend to “facilitate anabolism” when food is ingested. The consequent heightened metabolic oscillations during the shuttlings from fed to fasted state provide a basis for more aggressive therapy with exogenous insulin when endogenous insulin is lacking in pregnancy. It is emphasized that developing fetal structures may be exquisitely attuned to fine alterations in maternal fuel economy and that pregnancy complicated by diabetes may merely exaggerate these normal dependencies since maternal insulin affects all maternal fuels. The manifest changes in the offspring of mothers with. even the mildest limitations in insulin reserve, i.e., gestational diabetes, attest to the sensitivity of the relationships. It is suggested that concepts of teratogensis should be expanded to include alterations occurring subsequent to organogenesis during the differentiation and proliferation of fetal cells. Such changes could cause long-range effects upon behavioral, anthropometric, and metabolic functions. It is hypothesized that all of these could constitute expressions of fuel-mediated teratogenesis and that the potentialities should be incorporated into any evaluation of the outcome of pregnancy in gestations attended by disturbances in maternal fuel metabolism.
Insulin Does Not Act by Causing a Change in Membrane Potential or Intracellular Free Sodium and Potassium Concentration of Adipocytes
Authors: Stark Robert J , Read Peter D , O'doherty Josephine
Published: September 2013

The influence of insulin on the intracellular free sodium and potassium ion concentrations ([Na+]i, [K+]i) and resting membrane potential of rat epididymal adipocytes was examined to determine its potential for mediating insulin's action on other cellular processes. Direct intracellular measurements of [Na+]i, [K+]i, and the resting membrane potential were made using ionselective and conventional microelectrodes. The use of these microelectrodes enabled us to continuously monitor these parameters in the same cell before, during, and after periods of insulin stimulation of up to 20-min duration. The electrical potentials measured in these experiments remained unchanged when the cells were stimulated with insulin (0.01, 0.1, or 1.0 mU/ml). Varying the extracellular glucose concentration had no effect on these results. Our results provide the first direct measurement of [Na+]i and [K+]i in adipose tissue and clearly demonstrate that the response to insulin's association with its receptors on the cell surface and subsequent action on hexose transport and cellular metabolism does not involve a change in membrane potential or intracellular sodium and potassium ions.
The Relationship of Intracytoplasmic Movement of Beta Granules to Insulin Release in Monolayer-cultured Pancreatic Beta-Cells
Authors: Kanazawa Yasunori , Kawazu Shoji , Ikeuchi Masatoshi , Kosaka Kinori
Published: September 2013

To study the mechanism of insulin release, we examined β-granule movement in the cytoplasm of monolayer-cultured B-cells. The majority of the granules do not move, while about 2% of the granules moved per minute. The velocities of 90% of the moving granules exceeded 0.4 μm/s and showed saltatory type of movement. This movement may have a role in transport of the beta granule from Golgi to B-cell membrane.

We studied the mechanism of this movement using colchicine. Granule movement decreased exponentially by treatment with colchicine (10−6 M to 10−4 M). Almost 60 min was necessary to get a full inhibitory effect of colchicine on granule movement.

Colchicine (10−8 M to 10−4 M) inhibits insulin release in a dose-dependent manner. Maximum inhibition of insulin release (by about 40%) by colchicine (10−4 M) required 60 min. Granule movement also decreased when insulin release was inhibited by lowering glucose from 16.5 mM to 2.7 mM. Thus, granule movement participates in the mechanism of insulin release and may be related to the microtubular system.
Somatostatin Release from the Isolated, Perfused Diabetic Rat Pancreas: Inverse Relationship Between Pancreatic Somatostatin and Insulin
Authors: Kadowaki Seizo , Taminato Tomohiko , Chiba Tsutomu , Goto Yasuo , Nozawa Masumi , Seino Yutaka , Matsukura Shigeru , Fujita Takuo
Published: September 2013

The changes in pancreatic somatostatin content and release were studied in streptozotocin (STZ)-diabetic rats. Male Wistar rats were treated with a graded dose of STZ (group I, 0; II, 25; III, 50; IV, 75 mgμkg), which produced various grades of diabetic rats four weeks later. The pancreatic somatostatin content increased in proportion to the dose of STZ (1,189 ± 31; II, 222 ± 20; III, 343 ± 4; IV, 515 ± 36 ngμg wet wt), while graded reductions of insulin content were observed. Significant increases in glucagon content were found only in groups III and IV. Pancreatic somatostatin release increased during arginine infusion (19.2 mM) dose dependently, (I, 543 ± 36; II, 946 ± 64; III, 1229 ± 55; IV, 2186 ± 150 pg/15 min), and it correlated with the graded decreases of insulin release. The glucagon release induced by arginine, however, did not change significantly.

These results indicate that pancreatic somatostatin content and release increased in STZ-diabetic rats in proportion to the degree of insulin deficiency.
Insulinopenic Diabetes After Rodenticide (Vacor) Ingestion: A Unique Model of Acquired Diabetes in Man
Authors: Karam John H , Lewitt Peter A , Young Clinton W , Nowlain Robert E , Frankel Barbara J , Fujiya Hiroshi , Freedman Zachary R , Grodsky Gerold M
Published: September 2013

A clinical syndrome, characterized by acute diabetic ketoacidosis associated with a toxic neuropathy, developed in five men who intentionally ingested a recently introduced rodenticide (Vacor) containing N-3-pyridylmethyl-N'-p-nitrophenyl urea (RH-787). A 7-yr-old boy, who accidentally ingested this poison, died within 14 h.

Marked insulinopenia, without a reduction in glucagon levels, suggested a specific beta-cytotoxic effect, which was supported after autopsy in three cases by histopathologic evidence of extensive beta cell destruction. Lethal effects in rats prevented investigation of RH-787's diabetogenicity in vivo; however, studies in isolated rat islets confirmed a direct inhibitory effect, which was prevented by concomitant incubation with nicotinamide, suggesting a mechanism of action similar to that of streptozotocin.

We detected islet cell-surface antibodies in two of four patients studied.

These findings indicate that this nongenetic, acquired form of insulinopenic diabetes, which has persisted in the surviving patients for up to 3 yr, presents a unique opportunity to test in man the concept that hyperglycemia and the accompanying metabolic consequences of insulinopenia can induce diabetic microangiopathy in the absence of genetic predisposition.
Differential Binding of Insulin to Human Arterial and Venous Endothelial Cells in Primary Culture
Authors: Bar Robert S , Peacock M L , Spanheimer R G , Veenstra R , Hoak J C
Published: September 2013

The properties of 125I-insulin binding were assessed in endothelial cells prepared from the veins and the arteries of human umbilical cords. The endothelial nature of both the arterial and venous cultures was documented by the presence of characteristic endothelial features, including Weibel-Palade bodies, factor VIII antigen, and morphology. Both arterial and venous cells possessed typical receptors for insulin on the basis of specificity of binding, curvilinear Scatchard plots, affinity profiles, pH dependency, and dissociation kinetics. Arterial cells bound at least 2.5 times more insulin than did venous cells, whether studied at 4 h, 24 h, or 72 h after in vitro plating. We conclude that (1) specific receptors for insulin are present on human arterial as well as human venous endothelial cells and (2) the concentration of insulin receptors varies among endothelial cells derived from different vascular sources.
Insulin Recoverable from Tissues
Authors: Eng John , Yalow Rosalyn S
Published: September 2013

In this report we describe the insulin concentrations in plasma and in brain, kidney, liver, heart, and other tissues of rabbits and dogs as well as of rats and mice of different strains. In the larger animals, insulin concentrations in the brain never exceeded plasma levels. In rats, brain concentration averaged no more than twice plasma levels, compared with the 25-fold tissue:plasma ratio reported by others. Since there is no reason to believe that the biosynthetic mechanisms are different in the brains of large and small mammals, Our results suggest that the insulin found in the brain is due in part to that in vascular spaces and perhaps also to that crossing the blood-brain barrier, diffusing through the brain and then concentrating on brain receptor sites. In our preliminary abstract we reported that kidney and liver concentrations in rabbits and dogs exceeded plasma levels but noted no pattern of relationship between tissue and plasma concentrations. However, we have observed that when hyperinsulinism persists, as in a dexamethasone-treated dog or hyperphagic, obese rodents, the insulin content of some organs, particularly the kidney, does reflect plasma levels. In rats and mice, the insulin concentrations in kidney extracts appear to increase linearly with plasma levels. Liver and heart insulin concentrations initially appear to increase with plasma but then plateau, suggesting a saturable mechanism. We believe that insulin extractable from tissues reflects binding of insulin to receptors and that the total content of insulin receptors in a tissue may be the sum of unoccupied receptor sites, as measured in receptor assays, and the sites occupied by insulin extractable from the tissue.
Stimulation of Counterregulatory Hormonal Responses in Diabetic Man by a Fall in Glucose Concentration
Authors: DeFronzo Ralph A , Hendler Rosa , Christensen Niels
Published: September 2013

The effect of a falling plasma glucose concentration, from one hyperglycemic to another lower, yet still hyperglycemic, level, on the release of counterregulatory hormones was examined in nine diabetic subjects. The fasting plasma glucose concentration (201 ± 22 mg/dl) was lowered at the rate of 2.3 ± 0.3 mg/min with an exogenous insulin infusion and maintained between 100 and 110 mg/dl for an additional 60 min employing the glucose clamp technique. During the phase of rapidly falling glucose concentration, or shortly thereafter while the plasma glucose was being maintained at or above 100 mg/dl, eight of nine diabetics released growth hormone, five of nine released cortisol, six of nine released epinephrine, and five of nine released norepinephrine. No subject demonstrated any increase in plasma glucagon. One subject experienced a frank hypoglycemic reaction when her plasma glucose concentration had decreased to 149 mg/dl. In contrast, control subjects did not demonstrate the release of any counterregulatory hormones despite a similar rate of decline in plasma glucose concentration. These results indicate that diabetic subjects with fasting hyperglycemia have an upward resetting of the glucostat at which counterregulatory hormones are released and provide direct support for the clinical observation of hypoglycemic reactions in some diabetics with “normal” or high plasma glucose concentrations.
Streptozotocin-induced Diabetes in Athymic and Conventional BALB/c MICE
Authors: Beattie G , Lannom R , Lipsick J , Kaplan N O , Osler A G
Published: September 2013

Spleen cells from conventional BALB/c or athymic mice with streptozotocin (SZ)-induced hyperglycemia failed to raise blood sugar levels when injected into athymic or thymus-sufficient recipients. Passive transfer efforts were unsuccessful despite variations in donor-recipient pairs with respect to age, thymic function, or time after sensitization of donor mice. Athymic mice develop hyperglycemia following SZ but fail to mount an inflammatory lymphocyte infiltration. In contrast, the heterozygotes show a marked cellular response, which seems to follow the onset of hyperglycemia. The injection of spleen cells from thymus-sufficient mice to athymic recipients confers immunologic competence on the latter as tested by antibody formation to sheep erythrocytes.
Continuous Subcutaneous Infusion of Insulin in the Management of Diabetes Mellitus
Authors: Champion M C , Shepherd G A A , Rodger N W , Dupre J
Published: September 2013

Control of glycemia by means of continuous subcutaneous infusion of insulin (CSII) was examined in insulin-dependent diabetes mellitus (IDDM). A battery-powered portable infusion pump was employed to deliver insulin at a constant basal rate designed to maintain plasma glucose within the normal range in the postabsorptive state, and empirically determined supplementary infusions of insulin were delivered before meals by the same system with the objective of maintaining excursions of plasma glucose within the normal range during absorption of a meal. The effects of CSII were compared with those of optimized conventional treatment using twice daily injections of mixed intermediate-acting and crystalline insulins in the same groups of volunteers in short term (1 wk) studies in hospital and in longer term (1 to 7 mo) studies with unrestricted activity under normal conditions after leaving hospital. The control of glycemia obtained with CSII in hospital was closely approximated by optimized conventional treatment under these conditions. In studies in hospital, continued infusion of insulin by the CSII program at basal rates with omission of meals and with vigorous exercise did not result in hypoglycemia. Abrupt cessation of CSII for 12 h overnight resulted in moderate ketoacidosis, which was rapidly corrected on resumption of insulin infusion. After the subjects were discharged from hospital, their mean postabsorptive plasma glucose concentrations and mean excursions of plasma glucose after ingestion of meals were maintained within normal limits with CSII but not with optimized conventional therapy. The control of glycemia with CSII was associated with significant reduction of daily dose of insulin by comparison with conventional treatment. During CSII, plasma free immunoreactive insulin (IRI) concentrations were in the normal range in the postabsorptive state. The supplementary doses of insulin before meals with the CSII program were shown to be essential for control of glycemia and were associated with dose-related increments of plasma free IRI, which were detectable within 15 min of delivery, rose to peaks at between 60 and 90 min, and declined to baseline at between 3 and 4 h. It is concluded that the management of IDDM by CSII is effective and safe and provides normalization of mean diurnal plasma glucose concentration through prolonged unrestricted activities under everyday conditions. The treatment can be maintained by the unaided subject and permits the undertaking of long term studies of its effects on the complications of diabetes mellitus.
Impaired Glycogen Synthase Activating System in Human Diabetic Polymorphonuclear Leukocytes
Authors: Goldstein David E , Curnow Randall T
Published: September 2013

The effects of diabetes mellitus on glycogen synthase and its activating system (synthase phosphatase) were studied using human polymorphonuclear leukocytes (PMN). PMN were obtained from control subjects and diabetic patients by a gradient sedimentation technique. Enzyme activities of synthase-I and total synthase were not statistically different in diabetic and control cells. For measurement of endogenous synthase phosphatase, cells were sonicated in 50 mM Tris buffer (pH 7.5) and incubated at 30°C. Conversion of endogenous synthase-D to -I was linear for 20 min and maximal by 30 min. The rate of conversion of synthase-D to -I and the maximum percent synthase-I attained were decreased in homogenates of diabetic cells. There was no correlation between the plasma glucose concentration and the rate of conversion of synthase-D to -I. Synthase phosphatase activities were also measured using a purified synthase-D substrate. Under these experimental conditions, glycogen synthase phosphatase activities did not differ in control and diabetic cells. These results are consistent with a diabetes-induced defect in conversion of endogenous synthase-D to -I at the level of the synthase enzyme rather than at that of the activating phosphatase.
Impaired Responses of Catecholamines, Growth Hormone, and Cortisol to Graded Exercise in Diabetic Autonomic Neuropathy
Authors: Hilsted Jannik , Galbo Henrik , Christensen Niels Juel
Published: September 2013

Six juvenile diabetics [age, 31 ± 2 yr ( and SEM); duration of diabetes, 15 ± 4 yr], who showed signs of autonomic neuropathy (decreased beat-to-beat variation in heart rate during deep breathing), and seven control patients of similar age (27 ± 1 yr) and duration of diabetes (14 ± 2 yr) performed graded exercise on an ergometer cycle 3 h after breakfast and subcutaneous administration of insulin.

Plasma epinephrine increased significantly in both patient groups and was not significantly different at exhaustion [0.43 ± 0.17 ng/ml (neuropathy) vs. 1.07 ± 0.28 ng/ml (controls), P < 0.1]. Plasma norepinephrine levels increased significantly in control patients but not in autonomic neuropathy, and they were significantly different at exhaustion [1.43 ± 0.34 ng/ml (neuropathy) vs. 2.51 ± 0.26 ng/ml (controls), P < 0.05]. The relationships between plasma norepinephrine and epinephrine levels, respectively, and relative work load (expressed as oxygen uptake—in per cent—of individual maximal oxygen uptake) were shifted to the right in patients with autonomic neuropathy, indicating impaired sympathetic activity.

A significant decrease in plasma glucagon levels was found at low work loads (50 W and 75 W) in control patients but not in patients with autonomic neuropathy. At exhaustion, plasma glucagon levels were similar to resting levels in both patient groups. At exhaustion, plasma growth hormone and cortisol levels were significantly above preexercise levels only in control patients (50.5 ± 7.9 mU/L and 23.5 ± 2.9 ug/100 ml, respectively), and they were higher in these patients, P < 0.025 and P < 0.005, respectively, than in patients with autonomic neuropathy (24.4 ± 8.4 and 12.8 ± 1.6, respectively). Metabolic responses were similar in the two patient groups, as judged from plasma concentrations of glucose, lactate, free fatty acids, glycerol, and beta-hydroxybutyric acid.

In conclusion, diabetics with decreased beat-to-beat variation in heart rate displayed impaired responses of catecholamines, indicating a defective sympathoadrenal outflow, and of other glucoregulatory hormones during graded exercise.
Hagfish Insulin: The Discrepancy Between Binding Affinity and Biologic Activity
Authors: Emdin Stefan O , Sonne Ole , Gliemann Jørgen
Published: September 2013

Hagfish insulin exhibits a binding affinity of about 25% of that of pig insulin in rat adipocytes and IM-9 lymphocytes, even though its relative biologic potency is only about 5% in adipocytes. The dissociation rate constant of hagfish insulin is about half that of pig insulin, and the association rate constant is about one eighth. A longer time is, therefore, required for hagfish insulin to reach a steady state of binding. Failure to reach steady state is the probable reason why some previous results suggested a relative binding affinity of hagfish insulin of the same magnitude as the relative biologic potency.
Pancreatic Islets: A Tissue Rich in Serotonin
Authors: Bird Janice L , Wright Eugene E , Feldman Jerome M
Published: September 2013

Despite the fact that exogenous serotonin is an inhibitor of insulin secretion in a variety of species, many investigators doubt that endogenous serotonin plays a role in the regulation of insulin secretion. This is because, with the exception of the guinea pig, most animals do hot demonstrate histochemical evidence of serotonin in their pancreatic islets. In this study, the serotonin content of collagenase-isolated golden hamster islets was compared with the serotonin content of other hamster tissues known to contain serotonin. In the serotonin assay, serotonin was converted to N-acetyl serotonin by N-acetyltransferase; the latter is converted to tritiated melatonin by hydroxyindole-o-methyltransferase and tritiated S-adenosylmethionine. In control hamsters, the mean ± SEM serotonin concentration in μmol/kg wet weight of islets (26.3 ± 9.00) was greater than that of pancreas (4.0 ± 0.84), anterior pituitary (6.3 ± 1.53), median eminence (2.5 ± 0.69), and cerebral cortex (1.9 ± 0.30). There was no significant increase in tissue serotonin after the administration of the monoamine oxidase inhibitor tranylcypromine. When the serotonin precursor 5-hydroxytryptophan alone was given to hamsters, there was a 22-, 31-, and fivefold increase in islet, pancreatic, and anterior pituitary serotonin, respectively. When 5-hydroxytryptophan was given to hamsters after tranylcypromine administration, there was a 58-, 73-, 14-, and 10-fold increase in islet, pancreatic, anterior pituitary, and median eminence serotonin, respectively. Tissue serotonin decreased after administration of reserpine but not after administration of p-chiorophenylalanine. Exposure to collagenase did hot alter the serotonin concentration of pancreas or cerebral cortex in control or drug-treated hamsters. Hamsters receiving tranylcypromine plus 5-hydroxytryptophan had a higher plasma glucose concentration (266 ± 19 versus 116 ± 8 mg/dl), lower plasma insulin concentration (19 ± 3 versus 46 ± 8 μU/ml), and lower plasma insulin/glucose ratio (0.06 ± 0.01 versus 0.40 ± 0.06) than control hamsters. The present study demonstrates that animals whose islets do not have histochemical evidence of serotonin may have a high concentration of serotonin by chemical analyse that large increases in islet serotonin concentration probably inhibit pancreatic insulin secretion.
Impaired Granulocyte Adherence in Mildly Diabetic Patients: Effects of Tolazamide Treatment
Authors: Bagdade J D , Walters E
Published: September 2013

Granulocyte adherence in 10 of 15 untreated asymptomatic hyperglycemic diabetic outpatients (mean fasting glucose ± SEM, 289 ± 16 mg/100 ml) was 62 ± 7% of control values. After treatment (2–4 wk) with tolazamide (500 mg daily), adherence to the nylon fiber columns employed in this study returned to control levels in the seven patients whose fasting glucose levels fell, (mean, 192 ± 16 mg/100 ml) and deteriorated in the three in whom fasting hyperglycemia worsened. Results of this study indicate that, even in some mildly diabetic patients, a reduction in granulocyte.adherence similar to that found in insulin-dependent diabetics may impair the inflammatory response.
Glucose and Insulin Responses to Oral Glucose in Overt Non-insulin-dependent Diabetics With and Without the Islet Cell Antibody
Authors: Gray R S , Irvine W J , Cameron E H D , Duncan L J P
Published: September 2013

Plasma insulin, glucose, and insulin/glucose responses to a 50-g oral glucose tolerance test (OGTT) were compared in 14 islet cell antibody (ICAb) positive non-insulin-dependent diabetics (NIDDM), 14 matched ICAb negative NIDDM, and 14 ICAb negative nondiabetic controls. Both groups of NIDDM exhibited marked carbohydrate intolerance with insulinopenia. Despite having significantly higher plasma glucose concentrations during the study, the ICAb positive NIDDM had significantly lower insulin levels, and thus lower insulin/glucose ratios, than the ICAb negative NIDDM both in the fasting state and in response to the OGTT. Similarly, ICAb positive NIDDM had higher integrated glucose responses (ΔG), lower integrated insulin responses (ΔI), and lower (Δ/ΔG values than ICAb negative NIDDM. Three ICAb negative and seven ICAb positive NIDDM subsequently required insulin treatment.

These findings show that ICAb positive NIDDM suffer from a greater disturbance of B-cel1 function than do matched ICAb negative NIDDM.
Effects of Intraportal Islet Transplantation on the Transplanted Tissue and the Recipient Pancreas: I. Functional Studies
Authors: Trimble E R , Karakash C , Malaisse-Lagae F , Vassutine I , Orci L , Renold A E
Published: September 2013

It is well known that, in diabetes, there is an abnormality of both pancreatic beta and alpha cell secretion. Since islet transplantation can markedly improve the diabetic state in streptozotocin-treated rats, we investigated the effects of intraportal transplantation on the beta and alpha cell secretion of the transplanted tissue. In addition we examined the effects of transplantation on the hormone content of both the transplanted tissue and the endogenous pancreas.

Animals were examined 6 and 20 wk after transplantation. Isolated perfusions of the islet-containing livers showed that both glucagon and insulin secretion could be promptly stimulated by arginine. The hormone content of the livers at death revealed that, while the insulin content of transplanted tissue was well maintained, there was a marked reduction in glucagon content. An increase in pancreatic glucagon content was found in rats with untreated diabetes of five months' duration; this was partially or fully prevented by islet transplantation. There was also a moderate increase in insulin content of the pancreases of animals that received islet transplants.
Clearance Rates of Metabolizable and Nonmetabolizable Sugars in Insulin-infused Dogs and in Exercising Dogs
Authors: Issekutz B
Published: September 2013

Dogs with indwelling arterial and venous catheters were trained to run on a treadmill (slope, 15% speed, 100 m/min). The clearance rates (CR) of 3H-inulin, 3-3Hglucose (G), 14C-L-arabinose (L-A), 14C-D-xylose (D-X), 14C-3-methyl-O-glucose (3-m-G) and 2-deoxy-glucose (2-d-G) were measured using the primed constant infusion tracer technics. With the exception of glucose, all substances were excreted in the urine; therefore the CR is the sum of the urinary clearance rate (UCR) plus the tissue clearance rate (tCR). By measuring CRinuMn and the concentration of 3H-inulin in the urine, the flow rate of urine and the UCR and tCR of the simultaneously infused 14C-sugars were calculated. Infusion of insulin (1.5 mU/kg min) and glucose (6 mg/kg min) into the resting dog raised plasma insulin to 60–40μU/ml at normoglycemia. The tCR of all sugars was increased: G>2-d-G>3-m-G>D-X>L-A. There was a great discrepancy between the phosphorylable (G, 2- d-G) and the nonmetabolizable sugars (3-m-G, D-X, LA). Insulin increased tCR of glucose almost threefold, and it was estimated that 27% of the increase could be ascribed to the unassisted direct effect of membrane- transport (3-m-G) and 55% if the glucose could be phosphorylated but not metabolized further (2-d-G). Exercise decreased plasma insulin by almost 50%, hepatic glucose production rose more than twofold, and the tCR-glucose more than 21/2-fold. The tCR of L-A remained unchanged and that of the other sugar derivatives was increased by the run in the following order G>2-d-G>3-m-G>D-X. It was estimated that only 16% of the increase of tCR-glucose could be ascribed to the effect of exercise on the membrane-transport if it was not assisted by the hexokinase, and 53% with the help of the enzyme but without the accelerated glycolysis. It is concluded that, under physiologic conditions, a relatively small fraction (16–20%) of the twoto threefold increase of glucose utilization can be ascribed to a direct membrane effect if the activity of flux-generating steps towards either glycogen formation (insulin) or glycolysis (exercise) is accelerated.