bluuebunny/crossref_metadata_2025 huggingface dataset:
Beta Cell Function During Insulin or Chlorpropamide Treatment of Maturity-onset Diabetes Mellitus
Authors: Turner R C , Holman R R
Published: September 2013

Maturity-onset diabetic patients usually have raised overnightfasting plasma glucose levels associated with “normal” basal plasma insulin levels. The basal hyperglycemia is proportional to the degree of insulin deficiency. Basal insulin or C-peptide levels become subnormal if normal fasting plasma glucose levels are attained with insulin. Basal hyperglycemia is probably a compensatory response to maintain near-normal basal insulin levels. A logical therapy of maturity-onset diabetes is to produce basal normoglycemia by means of a constant basal insulin supplement, which can be provided by ultralente Insulin. The reduced insulin response of diabetics to intravenous glucose is slightly increased when basal normoglycemia is established, suggesting that the high plasma glucose levels compromise beta cell function. The insulin response to meals in a mild diabetic is not affected by mild hyperglycemia but can be depleted if gross hyperglycemia occurs. Maintenance of normoglycemia then allows beta cell “recovery”. In mild diabetics (c.<9 mmol per liter basal plasma glucose), chlorpropamide sufficiently stimulates beta cell secretion so that basal normoglycemia can be produced. The C-peptide response to meals is improved, whereas comparable reduction of the plasma glucose with insulin does not alter the meal response. Thus basal normoglycemia can be produced by “resting’ beta cells with a basal insulin supplement or by stimulating them with sulfonylurea therapy.
The Functional State of Sympathetic Nerves in Spontaneously Diabetic Mice
Authors: Giachetti Antonio
Published: September 2013

I investigated biochemical parameters of sympathetic nerve function in spontaneously diabetic mice (C57 BL/KsJ db/db) and in their lean littermates. The concentration of norepinephrine (NE) in organs innervated by sympathetic nerves was significantly reduced in the heart, kidney, and salivary glands of mice (24 weeks old) with severe diabetic-like symptoms (blood glucose > 300 mg./100 ml.). In the spleen, vas deferens, and adrenal glands of the same animals the NE levels were not changed in relation to control. Other measurements of NE in young (six weeks old) diabetic mice revealed no differences between diabetic and nondiabetic controls.

The turnover of NE, a measure of the functional state of sympathetic nerves, decreased significantly in the heart and salivary glands of 24-week-old mice but remained unchanged in the kidney and spleen. In young, diabetic mice the rates of NE turnover in several organs were similar to those found in age-matched controls. The hearts of 24-week-old diabetic mice contained significantly less dopamine-β-hydroxylase (DBH), an intraneuronal enzyme active in the terminal step of NE biosynthesis. The kidney of the same animals was hypertrophic and showed a massive elevation of monoamine oxidase (MAO), an enzyme that degrades NE to inactive products.

Other experiments showed that the regeneration of sympathetic neurons that follows the reversible chemical denervation with 6-hydroxydopamine was comparable in diabetic and nondiabetic animals. It appears that mice with spontaneous diabetes show changes of sympathetic nerve function similar to those noted in diabetic patients with autonomic neuropathy.
Serum Lipids and Lipoproteins in Insulin-treated Diabetes: Demonstration of Increased High Density Lipoprotein Concentrations
Authors: Nikkilä Esko A , Hormila Pirkko
Published: September 2013

In view of the high incidence of coronary heart disease in insulin-dependent diabetes, we determined cholesterol and triglyceride concentrations in serum and in three major lipoprotein fractions of 170 nonuremic middle-aged diabetic patients who had been treated with insulin for a minimum of 10 years. In addition, postheparin plasma lipoprotein lipase activity was measured in a subsample of the diabetic subjects. The diabetics had serum cholesterol and triglyceride concentrations similar to those of nondiabetic control subjects of the same age and sex. However, the concentration of high density lipoprotein (HDL)-cholesterol was significantly higher in both male and female diabetic patients than in respective controls (P < 0.001). Male patients with poor diabetic control or with overweight had elevated triglyceride and very low density lipoprotein (VLDL)-triglyceride concentrations, whereas the patients with good diabetic control had significantly lower triglyceride and VLDL-triglyceride concentrations than did nondiabetic subjects. Overweight diabetic patients also had elevated serum cholesterol and LDL-cholesterol concentrations. The HDL-cholesterol of diabetic subjects, on the other hand, was not dependent on the degree of diabetic control or on the relative body weight. Diabetic patients had higher lipoprotein lipase activity in postheparin plasma than did normal subjects of corresponding age and sex. The HDL-cholesterol concentration showed a significant positive correlation with postheparin plasma lipoprotein lipase activity.

We conclude that the average serum lipid and lipoprotein pattern of insulin-treated chronic diabetic patients is not more. atherogenic than that of nondiabetic subjects of similar age and sex. On the contrary, the increase of HDL-cholesterol observed in the diabetic subjects should make them less liable to develop coronary heart disease. Thus, the excess cardiovascular disease that is associated with insulin-dependent diabetes must be accounted for by other factors.
Protective Effects of Ketogenic Diets on Signs of Hypoglycemia
Authors: Johnson William A , Weiner Michael W
Published: September 2013

The effects of diet-induced ketosis on the signs of hypoglycemia were investigated. Lard, medium chain triglycerides, or 1,3-butylene glycol comprised 43 per cent of the diet fed to mice. The diet containing lard or medium chain triglycerides greatly protected the animals from the manifestations of acute insulin-induced hypoglycemia. Furthermore, both diets protected the animals from the effects of repeated insulin injections (every eight hours) for 10 days. In contrast, 1,3-butylene glycol had no protective effects. These experiments suggest that ketogenic diets may be of value in the treatment of recurrent hypoglycemic conditions.
Antibodies to Nucleic Acids in Juvenile-onset Diabetes
Authors: Huang Shih-Wen , Maclaren Noel Keith
Published: September 2013

Antibodies to single stranded (SS-) and double stranded (DS-) DNA and RNA were determined by a passive microhemagglutination assay in sera from 80 children with juvenile-onset diabetes mellitus (JDM) and 129 children with asthma. The latter group was chosen for comparison with the JDM group because of their increased susceptibility to viral infection and the nonautoimmune nature of the disease. We found that JDM patients had increased titers of antibodies to SS-DNA (61.3 per cent), synthetic polyadenylicpolyuridylic acid (Poly A-U) (78.8 per cent), synthetic polyinosinicpolycytidylic acid (Poly I-C) (62.5 per cent), and DS-RNA of statolon virus (51.3 per cent) and reovirus (27.3 percent), respectively, in contrast to asthmatics (15.5, 34.9, 3.9, 20.2, and 2.3 per cent, respectively) or to healthy controls. The difference of the incidence of antibodies among the groups is statistically significant (P < 0.001). Presence of SS-DNA antibody found in two thirds of cases of JDM further support the increased prevalence of autoimmune phenomenon in that disease. Furthermore, the increased prevalence of DS-RNA antibodies in patients with JDM, found especially in cases of recent onset, is suggestive of an active immune response against the underlying viral replications that may have led to beta cell injury in islets of pancreas.
Clinical and Etiologic Heterogeneity of Idiopathic Diabetes Mellitus
Authors: Fajans Stefan S , Cloutier Michael C , Crowther Robert L
Published: September 2013

We have chosen to discuss the clinical and etiologic heterogeneity of diabetes in man, since in recent years there has been an accumulation of evidence from many centers, including our own, that idiopathic or primary diabetes mellitus is not a single disease entity. What we call diabetes mellitus appears to consist of a number of heterogeneous syndromes characterized by a continuum of metabolic changes secondary to insufficient insulin action and by various tissue changes referred to as the chronic complications of diabetes.
Assessment of Methods for Estimating Autonomic Nervous Control of the Heart in Patients with Diabetes Mellitus
Authors: Bennett Terence , Farquhar Iain K , Hosking David J , Hampton John R
Published: September 2013

A comparison of the cardiac responses to a variety of maneuvers that modify cardiac vagal tone was made in nondiabetic and diabetic subjects. We concluded that assessment of heart rate variability by reference to standard deviation of R-R intervals is unhelpful; that a single deep breath is a more potent stimulus for heart rate change than repeated deep breaths in diabetic subjects; and that measurement of this response together with the bradycardia evoked by the Valsalva maneuver obviate the need to perform invasive investigations, such as the estimation of baroreflex sensitivity, or tedious procedures, such as apneic face immersion. In a small number of subjects, heart responses to lower body, negative pressure provided information not forthcoming from other tests.
A High-performance Liquid Chromatography Method for Hemoglobin A1c
Authors: Davis J E , Mcdonald Jay M , Jarett Leonard
Published: September 2013

Hemoglobin'A1c (HbA1c) is a glycosylated derivative of hemoglobin and is one of a family of derivatives whose concentrations are elevated in patients with diabetes mellltus. Published methods for the measurement of HbA1c are relatively tedious and require modest amounts of blood. A high-performance liquid Chromatographie (HPLC) method for the determination of HbA1c is presented. The method is rapid (20 minutes), precise (coefficient of variation of 5-10 per cent), uses small amounts of sample (3μI.), and can be automated. A sample-preparation technique using filtration was developed that shortened and simplified preparation of venous blood and allowed use of capillary samples. HbA1c was measured by this method in three age-stratified groups of controls and a group of insulin-requiring juvenile diabetics. There was clear separation of HbA1c values between all normals (5.9 ± 1.3, 5.6 ± 0.7, 7.1 ± 0.9 per cent) and the diabetics (12.1 ± 2.4 per cent). Use of this method can facilitate large-scale clinical investigations and permit biochemical investigations of the metabolism and formation of hemoglobin A1c where small sample sizes are necessary.
Mechanism of Barbituric-acid Protection Against Inhibition by Alloxan of Glucose-induced Insulin Release
Authors: Weaver Daniel C , Mcdaniel Michael L , Lacy Paul E
Published: September 2013

Isolated rat islets were maintained in a simple static incubation system and were exposed to alloxan for a period of five minutes. Alloxan inhibited subsequent glucose-induced insulin release in a dose-dependent manner at 37° C, with 650μM alloxan producing 94 per cent inhibition of insulin release. Barbituric acid, a compound structurally related to alloxan, provided complete protection (at 37° C) against this inhibition of insulin release when present during the alloxan exposure. At 23° C, barbituric acid was shown to be absent from the intracellular space of the islet yet still protected completely against alloxan inhibition of insulin release. Thus, barbituric acid apparently provided protection against alloxan in the extracellular medium. By fluorometric and Chromatographie analyses, it was determined that barbituric acid reacted rapidly with alloxan to produce a new compound. These findings indicate that barbituric acid protected against alloxan by a chemical reaction in the medium.
Insulin-dependent Childhood Diabetes: Normal Viability of Cultured Fibroblasts
Authors: Rosenbloom Arlan L , Rosenbloom Edith K
Published: September 2013

Cultured skin fibroblasts from clinically normal offspring of two parents with non-insulin-dependent diabetes have demonstrated premature senescence as a decreased ability of cells to establish colonies when inoculated at low density (plating efficiency). The present study tested the hypothesis that there is an inherent cellular defect affecting viability of diabetic cells in insulin-dependent diabetes. Four insulin-dependent patients, aged 12 to 19 years, included two with joint contracture, skin changes, and growth failure; one with thyroiditis and past history of nephrosis; and one with a family history of insulin dependency. Ten control subjects, aged 10 to 52 years, had negative family histories and normal oral glucose tolerance tests.

Number of cells per confluent dish correlated significantly with donor age (p < 0.001) at 30 and 40 in-vitro generations. The patients' cells' mean confluent density did not differ from that of five age-matched controls. Plating efficiency correlated with donor age at 30 in-vitro generations (p < 0.001); plating efficiency of cells from the youngsters with diabetes was virtually identical to that of control cells at 20, 30, and 40 generations.

In this small series of two subjects with in-vivo growth failure, one with associated autoimmune disease and another with familial insulin-dependent disease, cultured fibroblasts demonstrated normal viability and the hypothesis of a cellular growth defect was not confirmed.
Observations on the Value of Mass Indiscriminate Screening for Diabetes Mellitus Based on a Five-year Follow-up
Authors: Genuth Saul M , Houser Harold B , Carter James R , Merkatz Irwin R , Price J Waide , Schumacher O Peter , Wieland Ralph G
Published: September 2013

Persons screened for diabetes in 1969 by a two-hour post-Giucoia capillary blood glucose determination (cutoff 140 mg./100 ml.) were retested in 1974. In matched positive/negative pairs, the relative risk for diabetes five years later was 22 times greater in the positive subjects. However, about half the 1969 positive subjects retested negative in 1974. Sixty per cent of these had had 1969 blood glucose concentrations less than 180 mg./100 ml. and 70 per cent had already failed to retest positive in 1969. In contrast, of the 1969 positive subjects who had evidence of diabetes in 1974, 60 per cent had 1969 blood glucose concentrations greater than 180 mg./ 100 ml. and 75 per cent had retested positive in 1969. Treatment status (diet versus medication) in 1974 of the 1969 positive subjects was related to the degree of hyperglycemie exhibited in 1969 and in 1974 as well as to the impregnation of the diagnosis into the patient by his physician.

We conclude that the misassignment (intentional or unintentional) of a diagnosis of diabetes mellitus to borderline hyperglycemie individuals occurs with sufficient frequency in indiscriminate mass screening programs to question their value. Efforts now expended in such programs should be directed to targeted populations to improve individual and public benefits.
Ketoacids and the Insulin Receptor
Authors: Misbin Robert I , Pulkkinen Andrea J , Lofton Steven A , Merimee Thomas J
Published: September 2013

The binding of insulin to a specific receptor on IM-9-cultured human lymphocytes was studied in vitro under conditions simulating diabetic ketoacidosis. Compared with control incubations at pH 7.4, binding was reduced by 19 per cent at pH 7.1 and by 48 per cent at pH 6.8. Addition of β-hydroxybutyrate, at concentrations similar to those seen clinically, “restored” insulin binding toward normal. We suggest that, by counteracting the effects of acidosis, ketoacids themselves maintain normal insulin-receptor binding in diabetic ketoacidosis. These data also illustrate that small molecules, present in vivo, can significantly alter the interactions between a hormone and its receptor in vitro.
[125I] Glucagon Binding by Liver Membranes from Young and Adult Rats
Authors: Lockwood Dean H , Elizabeth East L
Published: September 2013

We have previously shown that adipocytes from adult (between four and five months old) rats have reduced glucagon binding and glucagon-stimulated lipolytic activity when compared with cells from young (1.5 months old) animals. In the present study we measured specific [125I] glucagon binding by purified liver plasma membranes isolated from young and adult rats. When expressed on the basis of membrane protein content, 5'-nucleotidase activity, or specific [125I] insulin binding, the extent of [125I]glucagon binding by liver membranes was not influenced by aging. Furthermore, the degree of [125I] glucagon degradation was the same in both membrane preparations. These data describe a unique condition in which glucagon binding and hormone sensitivity diminish in one tissue but remain unaltered in another.
Synthetic Fragment of Human Growth Hormone with Hyperglycemic Properties: Residues 44–77
Authors: Lostroh Ardis J , Krahl M E
Published: September 2013

Peptides homologous to Cys53 44–77 and Cys53 52–77 of the human growth hormone molecule were prepared by solid-phase synthesis and tested by our acute glucose tolerance test in ob/ob mice. Peptide 44–77, as either the Acm-Cys53 or Cam-Cys53 derivative, adversely affects glucose tolerance at doses of 100 to 150 nmol. Peptide 52–77 is nonhyperglycemic. Other diabetogenic properties are being tested.
Selective Calcification of Pancreatic Islets of Langerhans: An Unusual Association with Hypercalcemia and Diabetes Mellitus
Authors: Cotelingam James D , Hellstrom H Richard
Published: September 2013

An unusual and extensive calcification of islets of Langerhans was found at autopsy in a man, 58 years old, who developed myeloma and, subsequently, hypercalcemia and diabetes. Although the islet cell calcification appears to be related to the hypercalcemia, the pathogenesis of the calcification is not clear, as primary metastatic calcification of pancreatic islets due to hypercalcemia does not occur. In support of this, a retrospective study of pancreatic tissue from 52 hypercalcemic patients with parathyroid adenoma and 34 patients with multiple myeloma, who frequently have hypercalcemia, did not reveal islet calcification.

The islet calcification is ascribed to primary islet cell degeneration and necrosis, with hypercalcemia playing an augmenting but crucial role. It is considered that the combination of islet degeneration and calcification resulted in the diabetic state.
The Immunohistopathology of Glomerular Antigens: III. Increased Mesangial Actomyosin in Experimental Diabetes in the Rat
Authors: Scheinman Jon I , Steffes Michael W , Brown David M , Michael Mauer S
Published: September 2013

Antisera to rat smooth muscle actomyosin (AMY) and myosin localize in the rat glomerular mesangium. The width of mesangial staining for AMY is increased in rats diabetic for four months (p < 0.01) and seven months (p < 0.0005) compared with age-matched controls. Mesangial AMY staining of unilaterally nephrectomized control animals was moderately increased after seven months, whereas unilaterally nephrectomized diabetic rats had prominently increased AMY mesangial width at four months, when they were compared with intact diabetic animals (p < 0.05).

Thus, a distinctive alteration that is found in human diabetic nephropathy also occurs in experimental (streptozotocin) diabetes in the rat. Further, this alteration appears to be accelerated by the changes in nephron hemodynamics resulting from unilateral nephrectomy. While the function of mesangial AMY is unknown, it may be related to intrarenal regulation of glomerular ultrafiltration, which appears to be altered in diabetic nephropathy in man.
Effects of Chronic Glucagon Excess on Hepatic Metabolism
Authors: Boden Guenther , Wilson Robert M , Owen Oliver E
Published: September 2013

To investigate the effect of chronic hyperglucagonemia on hepatic metabolism, we have studied net splanchnic glucose and ketone body production rates in a patient with glucagonoma before and after complete tumor resection. Preoperatively, immunoreactive glucagon (IRG) concentration was high (1,800 pg. per milliliter) and the molar insulin/glucagon (I/G) ratio was low (0.4). Arterial free fatty acid (FFA) concentration (0.74 mM) and net splanchnic FFA uptake (0.27 mmole per minute) were normal. However, 48 per cent of the net splanchnic FFA uptake was utilized for net splanchnic ketone body production, which was four times (0.52 mmole per minute) greater than normal. Postoperatively IRG (40 to 150 pg. per milliliter) and the molar I/G ratio (> 1.0) were both normal. Arterial FFA concentration and net splanchnic FFA uptake were unchanged (0.67 mM and 0.27 mmole per minute, respectively). However, only 19 per cent of the net splanchnic FFA uptake was utilized for net splanchnic ketone body production, which had declined to 0.19 mmole per minute. These data suggest that chronic hyperglucagonemia in this patient had a stimulating effect on ketogenesis.

Preoperatively, the net splanchnic glucose production rate was 0.56 mmole per minute and could be accounted for entirely by gluconeogenesis from lactate (83 per cent), pyruvate (9 per cent), glycerol (14 per cent), and alanine, glutamine, and glutamate (8 per cent). The abnormally large contribution of lactate to gluconeogenesis was an effect of inappropriately elevated lactate concentration (0.88 mM) and increased blood flow (2,400 ml. per minute). Postoperatively the net splanchnic glucose production rate was 0.67 mmole per minute, of which 51 per cent could be accounted for by gluconeogenesis. The data provide no evidence for an effect of chronic hyperglucagonemia on splanchnic glucose production. However, they do not exclude a small stimulating glucagon effect on gluconeogenesis from amino acids.
The Effect of Hyperglucagonemia on Blood Glucose Concentrations and on Insulin Requirements in Insulin-requiring Diabetes Mellitus
Authors: Clarke William L , Santiago Julio V , Kipnis David M
Published: September 2013

The effect of elevated glucagon concentrations on insulin requirements and on blood glucose concentrations was studied in five insulin-requiring diabetic subjects during feedback control of hyperglycemia with an automated glucose-controlled insulin infusion system (artificial endocrine pancreas) for six to eight hours. Two levels of hyperglucagonemia were induced by means of constant intravenous infusion. Raising plasma glucagon concentrations to levels reported in poorly controlled diabetics (450 to 665 pg. per milliliter) did not alter total insulin requirements or blood glucose concentrations. Higher glucagon concentrations (850 to 1,050 pg. per milliliter) caused a modest (26 per cent) increase in insulin requirements and only a slight increase in mean blood glucose concentrations. These studies demonstrate that the degree of hyperglucagonemia found most frequently in insulin-requiring diabetics does not increase insulin requirements or decrease insulin effectiveness in patients given insulin in amounts appropriate to maintain euglycemia.
Equilibrium Binding Assay and Kinetic Characterization of Insulin Antibodies
Authors: Goldman José , Baldwin David , Pugh William , Rubenstein Arthur H
Published: September 2013

A simple and precise equilibrium binding assay has been developed for the quantitation of circulating insulin antibodies. This procedure differs from previously reported methods in that (1) serum samples were deinsulinized in order to avoid endogenous insulin's interfering with the binding assay, (2) l25I-monoiodoinsulin was used to prevent artifacts resulting from variability in ligand binding due to excessive iodination, and (3) separation of free and bound insulin was accomplished by rapid precipitation of the hormone-antibody complexes without disturbing the binding equilibrium. This approach prevented dissociation and underestimation of the bound species.

In agreement with previous reports, two classes of antibody sites (high-affinity-low-capacity and low-affinity-high-capacity) were demonstrated in the sera of insulin-treated diabetic patients. No consistent differences existed in the association constants and/or binding capacities for insulins of bovine, porcine, and human origin, even though the immunogenic stimulus for antibody formation in these patients was treatment with commercial preparations of bovine and porcine insulins. Thus, higher affinities and/or binding capacities for human versus bovine and porcine insulins does not provide evidence for an autoimmune origin of insulin antibodies, as has been previously proposed. Significant differences in the antibody-binding capacities for all three species of insulin were found in individual serum samples, and underestimation of antibody titers may occur if only one species of the hormone is used.

Kinetic studies on the dissociation of the insulin-antibody complexes revealed two classes of dissociating sites, in agreement with the equilibrium binding data. The corresponding dissociation rate constants were large enough to implicate the release of insulin from the pool of antibody-bound hormone as a possible hypoglycemic mechanism in some diabetic patients.
Impaired Granulocyte Adherence: A Reversible Defect in Host Defense in Patients with Poorly Controlled Diabetes
Authors: Bagdade John D , Stewart Mary , Walters Elwanda
Published: September 2013

When the ability of granulocytes from 10 poorly controlled diabetic patients with fasting hyperglycemia and no evidence of ketoacidosis (mean fasting glucose 293 ± 20 mg. per 100 ml.; mean ± S.E.M.) to adhere to a nylon fiber column was assessed, the number of adherent granulocytes from whole blood was only 53 ± 6 per cent of the values observed in controls. After antidiabetic treatment for one to two weeks and lowering of fasting glucose levels (mean 198 ± 29 mg. per 100 ml.), adherence improved significantly (p <0.01) in the diabetics; however, their values were still subnormal (diabetic 74 per cent ± 8 of control; p < 0.02). Adherence values before and after treatment correlated with the fasting glucose level (r = 0.88, p <0.001).

These findings suggest that, in addition to previously reported abnormalities in migration and the ingestion and killing of bacteria, granulocyte adherence may also be impaired in poorly controlled diabetic patients. This functional abnormality correlates directly with the fasting glucose and is reversed by insulin treatment. A defect of this type may compromise the normal inflammatory response in some diabetics and impair their capacity to resist infection.
Characteristics of Human Erythrocyte Insulin Receptors
Authors: Gambhir Kanwal K , Archer Juanita A , Bradley Carole J
Published: September 2013

Highly specific insulin receptors have been identified on human erythrocytes. A modification of the monocyte insulin radioreceptor technique permitted distinct separation of human erythrocytes with their bound insulin from the free insulin. When incubated with 80 pg. per milliliter of 125I-insulin (pH 8.0, 3.5 hours, 15 ° C.), erythrocytes from 17 normal volunteers specifically bound 10 per cent (± 1.450 S.D.) of the total 125I-insulin. Less than 15 per cent of the total 125I-insulin bound was nonspecific. Binding of 125I-insulin to human erythrocytes was dependent on pH and temperature. Less than 5 per cent of the insulin available to the plasma membrane was degraded. Both calcium and magnesium enhanced 125I-insulin binding by 100 per cent but had no synergistic effect when mixed in a 1:1 molar ratio.

Scatchard analysis of the binding data resulted in a curvilinear plot with characteristics typical of negative cooperative interactions between receptor sites and with an unoccupied site affinity constant of 0.1 × 108 M-1. Human erythrocytes have 2,000 insulin binding sites per erythrocyte with 14 sites per square micrometer of surface area. The readily available human erythrocyte, thus, has both specific insulin binding sites and binding characteristics similar to other human cell types. These studies have provided the basis for further clinical investigation of polypeptide hormone receptors on human erythrocytes.
Relation of Insulin Release to Cyclic AMP Content in Rat Pancreatic Islets Maintained in Tissue Culture
Authors: Rabinovitch Alexander , Cuendet Guy S , Sharp Geoffrey W G , Renold Albert E , Mintz Daniel H
Published: September 2013

This study was designed to elucidate the role of adenosine 3′, 5′-monophosphate (cAMP) in the decreased glucose-induced insulin release observed in cultured pancreatic islets. Freshly coUagenase-isolated rat islets and islets that had been maintained in tissue culture medium for two to 140 hours (six days) were incubated for one hour with 3H-2-adenine, and insulin release and islet 3H-cAMP accumulation were measured in subsequent short-term (3 to 60 minutes) incubations.

There was a progressive decrease in the stimulatory effect of 20 mM glucose on insulin release in islets that had been cultured for 2, 4, and 20 hours, and, after 20 to 140 hours of culture, glucoseinduced insulin release was about one-third that in freshly isolated islets. Similarly, 20 mM glucose stimulated a threefold increase in 3H-cAMP content in fresh islets, but did not increase 3H-cAMP in islets cultured for four to 140 hours. Basal insulin release and islet 3H-cAMP levels were two- to threefold higher in islets cultured for 44 hours in 16.7 mM glucose rather than in 5.6 mM glucose. However, the sensitivity and capacity of glucose-induced insulin release were less in islets cultured in medium with either 5.6 or 16.7 mM glucose than in freshly isolated islets, and glucose did not further increase islet 3H-cAMP levels in the cultured islets. By contrast, 3-isobutyl-l-methylxanthine (IBMX, 1 mM) increased insulin release and 3H-cAMP content in both fresh and cultured islets. Glucagon (10 μM) increased insulin release and 3H-cAMP content in cultured islets better than in fresh islets; and glucagon (10 μM) plus IBMX (1 mM) increased insulin release and islet 3H-cAMP content similarly in fresh and cultured islets.

It is concluded that there is rapid and, apparently, selective loss in the short-term action of glucose to increase the cAMP content in islets maintained in vitro, and this may account for the impaired insulin-releasing action of glucose observed in cultured islets.
Stimulatory Effects of Prostaglandins E-l, E-2, and F-2-Alpha on Glucagon and Insulin Release In Vitro
Authors: Pek Sumer , Tai Tong-Yuan , Elster Alan
Published: September 2013

The effects of prostaglandins (PG) E1, E2, and F2 upon the release of glucagon and insulin from the isolated perfused rat pancreas were investigated. In the presence of 5.6 mM glucose the release of both glucagon and insulin was stimulated by PGF2α at several concentrations ranging from 2.8 × 10−8 M to 3.6 × 10−6 M. Ten-minute perfusions of 1.4 × 10−6 M PGE1 or 2.8 × 10−7 M PGF2α evoked biphasic release of both islet hormones, and they augmented their biphasic release induced by 10 mM L-arginine. The addition of 5 mM fumarate, glutamate, and pyruvate permitted PGE2 to stimulate insulin release at a concentration as low as 1.1 × 10−9 M. The failure of 10−6 M oleic acid to elicit hormone release suggested that these effects of PGs were not nonspecific effects of long-chain fatty acids. In the absence of glucose, in response to 2.8 × 10−7 M PGE1 or PGE2 or PGF2α, the magnitudes of glucagon release were similar to or slightly greater than those seen with 5.6 mM D-glucose, but the release of insulin failed to occur. In the presence of 16.7 mM glucose, in response to 1.4 × 10−6 M PGE2 and 2.8 × 10−7 M PGF2α, the release of glucagon was blunted and that of insulin unchanged as compared with the secretory responses seen in the presence of 5.6 mM D-glucose.

These data indicate that administered PGs can stimulate acutely the release of glucagon and insulin at pharmacologic concentrations as well as at concentrations similar to those found in pancreatic tissues and effluent.

These observations are in keeping with the hypothesis that PGs of the E and F series may play a role in the regulation of secretion of glucagon and insulin.
Determination of Insulin Requirements in Brittle Diabetic Patients by the Artificial Pancreas
Authors: Lambert A E , Buysschaert M , Marchand E , Pierard M , Wojcik S , Lambotte L
Published: September 2013

An extracorporeal system (called the artificial pancreas) infused insulin and/or glucose at rates regulated by feedback control of the continuously monitored blood glucose. This system was capable of restoring the circadian blood glucose profile of 11 brittle diabetics to within a physiologic range. These patients made two stays of one week each in the hospital, during which the M-value and the MAGE index (used as indexes of blood glucose control and of glycemic fluctuations) were measured. The first stay was just before their connection to the artificial pancreas, while the patients were being given their usual insulin dosage; the second stay occurred one to nine months later. The day after connection of the artificial pancreas, the patients received a new insulin regimen, calculated according to the daily insulin profile infused by the artificial pancreas, consisting of two daily injections of a mixture of short-acting and intermediate-acting insulins. This regimen was essentially characterized by an increased proportion of regular insulin in the daily dose of from 31.2 ± 5.8 per cent (mean ± S.E.M.) before to 56.1 ± 3.0 per cent after artificial pancreas, p < 0.01, and a reduction of the percentage of the dose given in the morning of from 68.1 ± 5.9 to 52.6 ± 2.8 per cent, p < 0.025. These changes of insulin dosage caused a noticeable decrease of the M-value, from 69.5 ± 8 to 53.1 ± 4.4 (p < 0.02), but the MAGE index was not significantly affected (187 ± 20 versus 162 ± 14). Thus, the artificial pancreas could be helpful in the clinical management of brittle diabetics by providing a more precise estimate of the patient's insulin needs (particularly those of short-acting insulin), leading to a better control of blood glucose.
Effects of Pancreatic Islet Transplantation on the Increased Urinary Albumin Excretion Rates in Intact and Uninephrectomized Rats with Diabetes Mellitus
Authors: Mauer S Michael , Brown David M , Matas Arthur J , Steffes Michael W
Published: September 2013

The effects of reduced renal mass and of islet transplantation on urinary albumin excretion (UAE) rates in diabetic rats were examined. Increased UAE rates were noted two months after the induction of streptozotocin diabetes in 100-gm. inbred Lewis rats. Over the subsequent seven months, UAE rates remained constant in controls but were increasing in diabetic rats at the end of this time. Uninephrectomized nondiabetic rats had increasing UAE with time as compared with intact controls. Uninephrectomized diabetic rats had greater UAE than their respective controls, and the magnitude of this difference increased over the nine-month period of these studies. Uninephrectomized and intact rats, diabetic for seven months, were cured of the diabetic state by neonatal pancreatic tissue administered via the portal vein. Within one month of transplantation, UAE values decreased in these animals as compared with their pretransplant values and, within two months, were no longer different from values in their respective nondiabetic controls. In contrast, untreated uninephrectomized and intact diabetic rats increased their UAE over these same two months. At two months posttransplant, glomerular mesangial thickening was decreased in transplanted uninephrectomized and intact diabetic rats when compared with their respective untreated diabetic littermates.

Thus, the albuminuria of diabetes in rats is reversed by pancreatic islet transplantation. It is unclear whether this reversal is primarily due to improvement in functional or structural abnormalities in glomeruli of diabetic rats.
Inhibition of Glucagon Secretion by Diazoxide In Vitro
Authors: Urdanivia Enrique , Pek Sumer , Santiago Josephine C
Published: September 2013

The effect of diazoxide on the secretion of glucagon and insulin was studied using the isolated perfused rat pancreas. The perfusate concentration of D-glucose was kept constant at 5.6 mM. Five secretagogues of both glucagon and insulin—10 mM L-arginine, 5 mM L-leucine, 1.4 μM prostaglandin F2α, 100 nM bovine growth hormone, and 10 mM theophylline—were administered individually in the presence or absence of 325 μM diazoxide. Basal secretion of glucagon or insulin was not discernibly affected by diazoxide. With diazoxide the secretion of glucagon was (a) abolished completely in response to L-arginine or L-leucine; (b) inhibited partially in response to prostaglandin F2α; (c) unaltered in response to growth hormone; and (d) unchanged or, at times, enhanced in response to theophylline. On the other hand, the secretion of insulin induced by each of these agents was inhibited effectively by diazoxide. Conclusions: (a) Diazoxide inhibits the secretion of glucagon as well as insulin in response to certain secretagogues independent of any changes in prevailing levels of glucose, (b) At the concentration tested, diazoxide is a more potent and consistent inhibitor of the release of insulin than of glucagon.
Effects of Fasting on Gluconeogenesis from Alanine in Nondiabetic Man
Authors: Chiasson J L , Atkinson R L , Cherrington A D , Keller U , Sinclair-Smith B C , Lacy W W , Liljenquist J E
Published: September 2013

The present study was designed to determine the effect of fasting on gluconeogenesis from alanine. This process was measured by combining the infusion of l4C-alanine with the A-V difference technique. Normal subjects were studied after 12 and 48 h of fasting and obese subjects were studied after 18 days of therapeutic starvation. After a 12-h fast the hepatic venous 14C-alanine specific activity was 34% lower than the arterial 14C-alanine specific activity, which was consistent with a dynamic exchange of alanine between the intestine and the plasma and with a net release of unlabeled alanine by the intestine. Under these conditions the net splanchnic alanine uptake (106 μmol/min) would underestimate the actual hepatic extraction of alanine, which could be estimated as at least 147 μmol/min. After 48 h and 18 days of fasting, the 14C-alanine specific activity equaled that in the arterial plasma, indicating cessation of intestinal release of alanine into the portal circulation. Under these circumstances, net splanchnic alanine uptake would equal net hepatic alanine extraction. Thus, actual hepatic alanine ëxtraction rates at 48 h and 18 days of fasting were 134 and 94 μmol/min, respectively.

In the face of a decreasing hepatic alanine extraction with fasting, gluconeogenesis from alanine increased by 100% (from 41 to 82 μmol/min) after 48 h of fasting. After 18 days of starvation 51 /μmol/min of alanine was converted to glucose, a rate still 25% higher than after a 12-h fast.

We concluded: (a) fasting is associated with a gradual decrease in hepatic alanine extraction; (b) however, gluconeogenesis from alanine is increased after 48 h and 18 days of fasting due to a more efficient intrahepatic conversion of alanine to glucose.
Regranulation of Islets of Langerhans and Normalization of In Vivo Insulin Secretion in ob/ob Mice Treated with Oxytetracycline
Authors: Bégin-Heick Nicole , Heick H M C , Norman Margaret G
Published: September 2013

Oxytetracycline (OTC) treatment was associated with regranulation of the islet cells and increased pancreatic insulin content in the ob/ob mouse. This was accompanied by an improvement of the in vivo insulin secretory response to glucose. Because of the wide-ranging effects of OTC on other membrane-related functions, it is postulated that this compound may exert its effect by altering the composition of cellular membranes.
Effect of Norepinephrine on Insulin, Glucagon, and Somatostatin Secretion in Isolated Perifused Rat Islets
Authors: Sorenson Robert L , Elde Robert P , Seybold Virginia
Published: September 2013

The rate of insulin, glucagon, and somatostatin secretion was measured from isolated rat islets maintained in a perifusion system. The effect of norepinephrine (NE) was simultaneously determined on the release rate of all three hormones. Norepinephrine was employed at an acute dose of 10 μM and in graded doses from 1 nM to 10 μM in the presence of high (22 mM) and low (1.4 mM) glucose concentrations. Under both high and low glucose conditions, insulin secretion was maximally inhibited at 10 μM NE concentration and was significantly depressed at 100 nM NE concentration. Under both high and low glucose conditions, glucagon release was maximally stimulated at 10 μM NE concentration and was significantly elevated at 10 nM NE concentration: Under high and low glucose conditions, somatostatin release was inhibited by 10 μM NE concentration and was significantly depressed at 100 nM NE concentration. During the initial maximal stimulation of glucagon, NE inhibition of somatostatin and insulin was prevented, possibly by the high level of glucagon released. A paracrine effect of glucagon on beta and delta cells is proposed.
Persistence of Ketosis Despite Suppression of Lipolysis by 16, 16-Dimethylprostaglandin E2 in Experimental Diabetic Ketoacidosis in Rats
Authors: Axelrod Lloyd , Slowman Sally D , Lloyd-Jones Peter , Martin Donald B
Published: September 2013

We studied the effect of suppression of lipolysis on ketogenesis in rats with established diabetic ketoacidosis (DKA) using 16, 16-dimethylprostaglandin E2 (DMPGE2) as an antilipolytic agent.

DMPGE2 produced a dose-related reduction in plasma free fatty acid (FFA) levels and a reduction in plasma glycerol levels after an intravenous injection of up to 2 μg/kg body weight in animals with streptozotocin-induced DKA. In contrast, doses of PGE2 varying from 2 to 500 μg/kg body weight intravenously failed to suppress lipolysis and some doses were lipolytic. In nondiabetic rats, DMPGE2 produced a fall in the FFA and glycerol levels and a concomitant reduction in the plasma ketone levels.

When DMPGE2, 2 μg/kg body weight, was administered intravenously every 30 min for 4 h to rats with DKA, the plasm FFA level fell from 2.86 ± 0.36 meq/L at time 0 to 0.78 ± 0.07 meq/L at 4 h; the final value was lower than that found in fed, nondiabetic, nonketotic rats studied under the same conditions. However, the plasma ketone levels remained elevated in response to DMPGE2 (8.36 ± 0.46 mM at time 0; 7.19 ± 0.17 mM at 4 h). In contrast, insulin produced a rapid and marked fall in both the FFA and the ketone levels in comparable animals.

When DMPGE2 was administered together with insulin to rats with DKA, the plasma FFA level fell to the same low level achieved with insulin alone. Nevertheless, DMPGE2 impaired the effect of insulin on the total plasma ketone level. When both agents were given concurrently, the total plasma ketone level fell from 10.26 ± 0.99 mM at time 0 to 5.32 ± 1.67 mM at 4 h; with insulin alone, the total plasma ketone level fell from 8.47 ± 0.84 mM at time 0 to 0.78 ± 0.23 mM at 4 h. DMPGE2 also interfered with the response of the plasma glucose level to insulin.

Conclusions: (1) DMPGE2 is a potent antilipolytic agent in vivo, as well as in vitro. This efficacy contrasts with the absence of an antilipolytic effect of PGE2 in vivo, although both substances suppress lipolysis in vitro. This discrepancy may be explained by the fact that DMPGE2, unlike PGE2, is not rapidly metabolized in the pulmonary circulation. (2) DMPGE2 has an effect on ketogenesis, in addition to its antilipolytic effect, in animals with DKA but not in normal animals. This may be enhancement of hepatic ketogenesis, interference with the peripheral disposal Of ketones, or both.
Serum Protein-bound Hexose in Diabetes: The Effect of Glycemic Control
Authors: Kennedy Allan Laurence , Kandell Thomas W , Merimee Thomas J
Published: September 2013

To determine whether the carbohydrate content of serum proteins is related to overall glycemic control, we studied serum protein-bound hexose and glycosylated hemoglobin [HbA1(a+b+c)] in 37 ambulant diabetic patients and 32 nondiabetic controls. Proteinbound hexose was correlated with HbA1(a+b+c) in the diabetic patients (r = 0.36, P < 0.025). The mean protein-bound hexose level of the diabetic patients was greater than that of the controls (190.8 versus 174.7 mg/dl, P < 0.01), but diabetic patients with HbA1(a+b+c) < 12% had a mean protein-bound hexose similar to the controls. In nine of the diabetic patients, mean protein-bound hexose and HbA1(a+b+c) were significantly reduced during a period of intensive outpatient care, while two major serum glycoproteins, haptoglobins and alpha-1-antitrypsin, were unchanged. Our findings support the hypothesis that increased glycosylation of serum proteins may occur in diabetes mellitus; this abnormality in serum protein-bound hexose may be corrected by close attention to overall glycemic control.
Nonenzymatic Glucosylation of Serum Proteins in Diabetes Mellitus
Authors: McFarland Kay F , Catalano Edward W , Day James F , Thorpe Suzanne R , Baynes John W
Published: September 2013

The extent of nonenzymatic glucosylation of serum protein in control and diabetic subjects was measured by a chemical procedure using thiobarbituric acid. A mean value of 0.81 (±0.21 SD) nmol glucose per milligram serum protein was observed in the control group. Diabetics displayed elevated levels of glucosylated serum proteins, up to 4 nmol glucose per milligram protein. Glucosylation of serum protein correlated strongly with fasting blood sugar (r = 0.71), percent hemoglobin A1 (r = 0.79), and percent glucosylated albumin (r = 0.99). There was no overlap between control and diabetic groups, i.e., within 3 SD of the mean of controls. These studies indicate that the assay for glucosylated serum protein appears to be an especially sensitive indicator of the degree of hyperglycemia in diabetes.
Effect of Acetate on Hypoglycemic Seizures in Mice
Authors: Urion David , Vreman Hendrik J , Weiner W
Published: September 2013

In order to determine the effects of acetate on signs and symptoms of hypoglycemic seizures, Swiss Webster albino mice were injected intraperitoneally with solutions of NaCI, NaHCO3, NH4CI, Na-acetate, or NH4-acetate, followed by subcutaneous injection of 7 U of insulin/kg body wt. Administration of Na- or NH4-acetate delayed and reduced the incidence of hypoglycemic reactions. Reinjection with Na-acetate or repeated injections with NH4-acetate caused a return to normal behavior patterns for 60 and 75%, respectively, of the affected hypoglycemic experimental animals. Injections of control animals with NaHCO3 or NH4CI showed that the results were not due to alkalosis or acidosis. Acetate administration significantly increased plasma acetate and citrate, but not glucose, lactate, β-hydroxybutyrate, or acetoacetate concentrations. The results indicate that intraperitoneal administration of acetate directly acted to prevent signs of hypoglycemia from occurring and reversed its manifestations when they were present. The protective effect of acetate suggests that it may serve as a fuel for the brain.
Insulin Inhibition of Lipolysis of Human Adipocytes: The Role of Cyclic Adenosine Monophosphate
Authors: Burns Thomas W , Terry Boyd E , Langley Paul E , Robison G Alan
Published: September 2013

To gain information on the manner in which insulin suppresses lipolysis in man, isolated adipocytes, prepared from subcutaneous adipose tissue, were incubated with insulin (100 μU/ml) alone and in combination with isoproterenol (10−7 M or 10−8 M). Cyclic AMP concentration was measured at 60 min; glycerol release, used as an index of lipolysis, was determined at 45 and 75 min. Insulin consistently reduced both basal and stimulated cyclic AMP and glycerol release: the degree of suppression of each was comparable. In subsequent experiments, the ability of insulin to suppress glycerol release stimulated by isoproterenol, theophylline, and dibutyryl cyclic AMP (dbcAMP), respectively, was compared. Insulin substantially reduced the raised levels of cyclic AMP and glycerol release prompted by isoproterenol and theophylline, but it had little effect on increases caused by dbcAMP. These findings support the view that reduction in cyclic AMP is an important component in the regulation of fat mobilization by insulin.