bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduced Sulfation of Liver Heparan Sulfate in Experimentally Diabetic Rats
Authors: Kjellén Lena , Bielefeld David , Hook Magnus
Published: September 2013

Analyses by anion exchange chromatography indicate that heparan sulfate proteoglycans isolated from the livers of experimentally diabetic rats have a reduced net negative charge as compared with heparan sulfate proteoglycans from control rats. In contrast, the size of the normal and diabetic proteoglycans are indistinguishable as are the size of individual polysaccharide chains when compared by gel chromatography. The reduced net negative charge of heparin sulfate from diabetic rats is shown to be caused by a reduced number of sulfate groups present in the diabetic heparan sulfate. Results are presented suggesting that one of the biosynthetic enzymes; the N-deacelylase, which tentatively has been identified as a regulatory enzyme affecting the sulfate content of the polysaccharide chains, may be inhibited in the diabetic rat.
Review of Criteria for Diagnosis of Diabetes Mellitus Based on Results of Follow-up Study
Authors: Ito Chikako , Mito Kazuyo , Hara Hitoshi
Published: September 2013

Comparison of the 75-g oral glucose tolerance test (OGTT) method was made with the conventional 50-g method in a fixed population followed for 1–17 yr. The possibility of using the results in establishing the diagnosis of diabetes mellitus was also considered. The following results were obtained: (1) The 75-g method showed significantly higher 2-h and 3-h postchallenge plasma glucose (PG) and immunoreactive insulin values. (2) The two methods showed good correlation in PG values at various time periods, and there was no difference between the two at ½ h and 1 h. The 2-h standard value of 200 mg/dl used to diagnose diabetes with the 75-g method was equivalent to 180 mg/dl by the 50-g method. The upper limits of normals were 140 mg/dl and 120 mg/dl, respectively, for the two tests. (3) Those subjects diagnosed as diabetic on the basis of fasting plasma glucose (FPG) values of 140–149 mg/dl only had a high rate of reverting to normal over time. The frequency of “nondiabetic” plasma glucose values after glucose loading steadily decreases as FPG increased, with separation into two asymptotic lines at 150 mg/dl level. Thus, the logical value for diagnosis of diabetes when based only on FPG value is considered to be 150 mg/dl. (4) A smaller number of individuals had 2-h PG values that satisfied criteria for diagnosis of diabetes mellitus, but ½-h and 1-h values that were <200 mg/dl. Nevertheless, follow-up of these subjects showed a high development rate of diabetes. Thus, the ½-h and 1-h values are not considered necessary to establish diagnosis of diabetes mellitus.
Peripheral Neuropathy in Rats Induced by Insulin Treatment
Authors: Sidenius Per , Jakobsen Johannes
Published: September 2013

The effect of sustained insulin-induced hypoglycemia on peripheral nerve function and structure was examined in rats. After a period of hypoglycemia (<2.5 mmol/L) of at least 72 h, axonal degeneration and reduction of the maximal amplitude of the evoked muscle action potential occurred, the two abnormalities being correlated negatively (r = −0.99, 2P = 0.00097). One of five rats developed paresis of both hindlegs as well as nerve damage and perikaryal alterations of lower motor neurons.
Lack of Glucagon Response to Hypoglycemia in Type I Diabetics After Long-Term Optimal Therapy with a Continuous Subcutaneous Insulin Infusion Pump
Authors: Berqenstal R M , Polonsky K S , Pons G , Jaspan J B , Rubenstein A H
Published: September 2013

Counterregulatory hormonal responses were studied in six patients after 4–18 mo treatment with a continuous subcutaneous insulin infusion pump. In response to insulin-induced hypoglycemia, significant increases in epinephrine, norepinephrine, cortisol, and growth hormone were measured in all subjects, while in five of the six patients glucagon levels did not increase at all. The persistence of these abnormal glucagon responses despite long-term optimal glucose controlsuggests that they are not due to hyperglycemia perse, but are due rather to a specific alpha cell abnormality. The high incidence of asymptomatic hypoglycemia in these patients emphasizes that caution is necessary to avoid serious hypoglycemia when striving for near-normal glucose control with insulin infusion pump therapy.
Demonstration of a Relationship Between Level of Physical Training and Insulin-stimulated Glucose Utilization in Normal Humans
Authors: Rosenthal Mark , Haskell W L , Solomon Robert , Widstrom Anders , Reaven Gerald M
Published: September 2013

The relationship between level of physical training and in vivo insulin-stimulated glucose utilization was investigated in 33 healthy nonobese subjects. Status of physical training was estimated by maximal oxygen consumption (VO2 max) during graded bicycle ergometry, and insulin action by the insulin clamp technique. Within the study population we defined a significant (r = 0.63, P < 0.001) correlation between these two variables. This relationship was independent of age and obesity and accounted for over 40% of the variance in insulin-stimulated glucose utilization among these subjects. In addition, significant correlations existed between VO2 max and the plasma glucose (r = −0.35, P < 0.05) and insulin (r = −0.37, P < 0.05) responses to an oral glucose load. These results suggest that differences in level of physical training play a regulatory role in control of in vivo insulin action.
Interaction Between Glucose and Dehydroascorbate Transport in Human Neutrophils and Fibroblasts
Authors: Bigley R , Wirth M , Layman D , Riddle M , Stankova L
Published: September 2013

Dehydroascorbate (DHA) competitively inhibits the uptake of 2-deoxy-D-glucose and of3-O-methyl-D-glucose by human blood neutrophils; 2-deoxyglucose and 3-0-methylglucose competitively inhibit dehydroascorbate uptake Ratios of Km to KI are near unity for each of these I gands. Exposure of cultured human fibroblasts to insulin enhances cytochalasin B-inhibitable uptake of DHA and of 2-deoxyglucose, both to the same degree. These observations suggest that DHA transport is mediated by glucose transport systems in human neutrophils and fibroblasts.
Insulin Binding and Removal by Livers of Genetically Obese Rats
Authors: Karakash Clairette , Jeanrenaud Bernard
Published: September 2013

Livers from 9–10-wk-old genetically obese and hyperinsulinemic (fa/fa) rats contained more DNA, proteins, and lipids than livers of age-matched controls. Actually, the increase in liver mass of fa/fa rats was mainly due to an increased cell number. On perfusion with insulin (1.75–16 nM), ivers of obese fa/fa rats removed 35–40% less insulin per gram tissue than control livers. When calculated on a per organ basis, removal capacity was, however, similar in livers of control and obese fa/fa rats. The binding of 125I-insulin to as well as the insulin removal by isolated hepatocytes was also assessed. contrary to previous unexpected data in which the downregulation of insulin receptors by hyperinsulinemia was reported not to prevail in hepatocytes from obese fa/fa rats, it was found that the binding capacity of hepatocytes from fa/fa rats was decreased by 45% without alteration of the binding affinity. Moreover, in hepatocytes from obese fa/fa rats, both binding and removal of insulin were lowered to an analogous extent. It is concluded that livers of obese fa/fa rats behave, with regard to insulin binding and removal, as those of other hyperinsulinemic obese animals.
Minimal Increases in Glucagon Levels Enhance Glucose Production in Man with Partial Hypoinsulinemia
Authors: Lins Per-Eric , Wajngot Alexandre , Adamson Ulf , Vranic Mladen , Efendić Suad
Published: September 2013

In man a small dose of somatostatin (50 (μg/h) suppressed moderately basal insulin (5 μU/ml) and glucagon (40 pg/ml) levels. This resulted in a short-lasting hypoglycemia, which was then followed by marginal hyperglycemia throughout the experiment. The addition of a minimal dose of glucagon (0.50 ng/kg/min) to somatostatin normalized basal glucagon levels and resulted in a significant and sustained hyperglycemia. During the first 2 h, hyperglycemia was mainly due to increased glucose production, whereas later on it was maintained by decreased glucose uptake. We conclude that, in man moderately deprived of insulin, even a marginal change in glucagon level induces a long-lasting hyperglycemia.
Splanchnic and Peripheral Disposal of Oral Glucose in Man
Authors: Katz Lee D , Glickman Morton G , Rapoport Stanle , Ferrannini Eleuterio , DeFronzo Ralph A
Published: September 2013

Oral glucose (92 g) was administered to 22 healthy, young volunteers undergoing hepatic vein catheterization, and net splanchnic glucose output (SGO) was measured during the basal period and for 4 h after glucose ingestion. In the basal state, SGO averaged 1.90 ± 0.11 mg/min · kg. After glucose, SGO rose to a peak value of 6.65 ± 0.83 mg/min · kg at 30 min and returned to baseline by 3 h. Total SGO over 4 h was 69 ± 4 g; assuming complete absorption of the load, this amount represented 75% of the oral glucose.

In a subgroup of six subjects, leg glucose uptake was simultaneously quantitated by femoral vein catheterization and leg blood flow measurement. In the postabsorptive state, glucose uptake by one leg was 24 ± 8 mg/min and increased to a mean value of 76 ± 7mg/min during the 4 h after glucose ingestion. Overall, 18 ± 2 g/4 h of glucose were taken up by one leg, which extrapolates to a total body muscle uptake of 65 ± 4 g over 4 h.

We conclude that in normal man, well over 2/3 of an oral glucose load escapes splanchnic removal, and that the peripheral tissues quantitatively play the dominant role in glucose disposal.
In Vitro Control of T-Lymphocyte Insulin Receptors by In Vivo Modulation of Insulin
Authors: Helderman J Harold , Pietri Angel O , Raskin Philip
Published: September 2013

The mechanism for carbohydrate intolerance related to insulin resistance is under intense study. Some have suggested that environmental modulation of plasma insulin concentrations may influence cellular mechanisms that could result in diminished receptor binding and thus create insulin resistance. We have employed the T-lymphocyte model to explore this possibility. Two groups of studies were performed. In the first, relative hyperinsulinemia was created in patients with type I diabetes mellitus by means of continuous subcutaneous insulin infusion by a portable insulin infusion device. In response to an elevation of “free” plasma insulin from 14 ± 2 to 26 ± 3 μU/ml there was a progressive fall in the number of insulin receptors that developed on freshly isolated, then lectin-treated, cultured T-lymphocytes (6552 ± 377 to 3241 ± 348 sites/cell) after 14 days of hyperinsulinemia. Neither the level of lectin stimulation, as ascertained by 3H-thy-midine uptake, nor the time course of response to PHA was altered by the insulin therapy. In the second study, plasma insulin was reduced in normal-weight subjects and in nondiabetic obese subjects (nearly twice ideal body weight) by means of a 4-day fast. In response to a fall in plasma insulin of 35 ± 6 to 19 ± 3 μU/ml, insulin receptor number on freshly isolated, then cultured and stimulated, lymphocytes rose from 2796 ± 379 sites/cell to 6453 ± 893 sites/cell. Again, neither a change in lectin responsiveness nor a change in the time course of PHA response accounted for the change in these data. The relationships between the direction and magnitude of changes in in vivo plasma insulin levels in both studies were analyzed together. There was a strong (r = 0.94; P < 0.001) inverse relationship between changes in plasma insulin levels and the ultimate number of insulin receptors displayed on cultured lymphocytes. We conclude that in vivo insulin modulation is important for the regulation of the appearance of insulin receptors on cultured T-lymphocytes. Since the T-cell does not bear an insulin receptor in the circulation, the regulatory signals cannot be passed to this cell by the binding event itself. These data are not explained by a shift in a subset of lymphocytes present or by alterations in the degree of cell activation induced by PHA. The T-lymphocyte capacity to synthesize insulin receptors appears to be set, in part, by ambient plasma insulin concentrations.
Reciprocal Gastropancreatic Modulations for the Release of Somatostatin-like Immunoreactivity, Glucagon, and Insulin in the Rat
Authors: Marre M , Miller J , Helman A M , Assan R
Published: September 2013

In order to assess the interrelationships between stomach and pancreas regarding the secretions of somatostatin-like immunoreactivity (SLI), glucagon (IRG), and insulin (IRI), concentrations of the three hormones were assayed in portal plasma and portal blood flow was measured in enterectomized rats before and after the selective removal of stomach or pancreas.

Portal plasma SLI, IRG, and IRI concentrations were significantly increased by i.v. arginine in control rats (pancreas + stomach present). After gastrectomy, SLI, IRG, and IRI concentrations were, respectively, 52 ± 13% (N = 15; P < 0.005), 234 ± 40% (P < 0.001), and 119 ± 15% (NS) of the pregastrectomy values. A decreased SLI secretion, an increased IRG release, and an unmodified basal IRI release were estimated by portal flow measurement. The A- and B-cell responses to arginine in the gastrectomized rats were significantly higher than in the control rats, while the D-cell response was no longer detectable. After pancreatec-tomy, by contrast, SLI concentrations were 360 ± 75% of the prepancreatectomy values (N = 12; P < 0.001). This reflected an actual increment of SLI release, taking into account the concomitant measurement of portal blood flow. The concentrations of IRG declined by 51 ± 5% (P < 0.001) and IRI was no longer measurable. A-and B-cell responses to arginine also were no longer detectable.

These results suggest that in these experimental conditions (1) the stomach restrained pancreatic A-and B-cell responses to arginine, perhaps through the SLI released from the stomach and (2) the pancreas restrained gastric SLI secretion, perhaps through insulin.
Intravenous Infusions of Sulfated Insulin Normalize Plasma Glucose Levels in Pancreatectomized Dogs
Authors: Nomura Makoto , Zinman Bernard , Bahoric Andrej , Marliss Errol B , Albisser A Michael
Published: September 2013

Sulfated insulin (SI) differs radically from regular crystalline zinc insulin (CZI). To date, SI has been used mainly for the subcutaneous treatment of diabetics with resistance or local allergic reactions to CZI. In this regard, SI exists as a soluble monomer at pH 7.4 and is not inclined to self-association even when agitated and exposed for long periods to materials known to aggregate CZI. To compare its stability and biologic activity when used in conjunction with intravenous infusion pumps, diabetic dogs were infused portally for 140 days with SI and for 140 days with CZI. These studies demonstrated a significant improvement of glycemie control obtainable with SI compared with CZI. Mean ± SD fasting glycemias were normalized for the SI group (99 ± 19 mg/dl) and were significantly (P < 0.001) less than the mean of 148 ± 64 mg/dl for the CZI group. Mean ± SD coefficient of variation of the fasting plasma glucose concentrations was 18 ± 1% for the SI- versus 43 ± 3% for the CZI-infused dogs, both significantly greater than normal values of 4.5 ± 0.5%. Basal insulin requirements under these conditions also differed significantly (P < 0.001). The CZI group received 0.35 ± 0.07 mU/kg/min compared with 0.20 ± 0.05 mU/kg/min for the SI group1, the former resulted in mean ± SD plasma levels of 14 ± 7 μU/ml and the latter resulted in concentrations of 47 ± 12 μU/ml. Insulin clearance rates were 28 ± 11 ml/kg/min with CZI compared with 5 ± 3 ml/kg/min with SI (P < 0.001). CZI but not SI resulted in progressive obstruction of the delivery systems employed. In conclusion, porcine SI is more stable and remarkably more resistant to aggregation than regular CZI preparations. It maintains its bioactivity and affords improved long-term glycemie control when infused . v. With SI insulin requirements were reduced 1.75-fold while insulin clearance was reduced 5.6-fold compared with CZI. These findings reflect the essentially mono-meric nature of the hormone and emphasize its remarkable stability in the difficult environment presented by a portable pumping system.
Reduction of Insulin Resistance in Obese and/or Diabetic Animals by 5-[4-(1-Methylcyclohexylmethoxy)benzyl]-thiazolidine-2,4-dione (ADD-3878, U-63,287, Ciglitazone), a New Antidiabetic Agent
Authors: Fujita Takeshi , Sugiyama Yasuo , Taketomi Shigehisa , Sohda Takashi , Kawamatsu Yutaka , Iwatsuka Hisashi , Suzuoki Ziro
Published: September 2013

Effects of 5-[4-(1-methylcyclohexylmethoxy)benzyl]-thiazolidine-2,4-dione (ADD-3878, U-63,287, Ciglitazone) on glucose and lipid metabolism were examined in various animal models. ADD-3878, administered as a dietary admixture (30–186 mg/kg/day) to obese-diabetic yellow KK (KK-Ay) mice, markedly suppressed the diabetic syndromes (hyperglycemie, hypertriglyceride-mia, and hyperinsulinemia), accompanied by the reduction of insulin resistance as manifested by improvement of overall insulin sensitivity in either the insulin tolerance test òr the steady-state blood glucose test. Chronic administration of ADD-3878 for as long as 12 wk to young yellow KK mice, which were in the early stage of diabetes and obesity, depressed age-dependent rises in blood glucose, plasma triglyceride, and insulin without exerting any effect on obesity.

When orally administered to obese Zucker-fatty rats, ADD-3878 decreased plasma insulin and triglyceride in a dose-dependent manner (5–100 mg/kg/day). The treated rats showed increased tolerance and decreased insulin secretion in response to oral glucose. The glycemie response to insulin and the steady-state plasma glucose were also normalized in the treated rats. Chronic administration of ADD-3878 to young fatty rats for as long as 12 wk decreased the dose-dependent rises in blood glucose, plasma triglyceride, and insulin without exerting any effect on body weight.

ADD-3878 had no effect on glucose and lipid metabolism of young Sprague-Dawley rats and mild strepto-zotocin-diabetic rats. However, in old Sprague-Dawley rats that were moderately insulin resistant and hyperli-pidemic compared with young ones, ADD-3878 decreased plasma triglyceride and insulin and improved insulin sensitivity.

Five-day administration of ADD-3878 to beagle dogs with slightly impaired glucose tolerance increased glucose tolerance and suppressed postprandial rises in plasma glucose, insulin, and triglyceride.

Based on these results, ADD-3878 is effective on abnormal glucose and lipid metabolism associated with insulin resistance or obesity through reduction of peripheral insulin resistance. Therefore, ADD-3878 is expected to be useful in the treatment of hyperglycemie, hyperinsulinemia, and hyperlipemia in obese type II diabetes and Obesity.
Hyperphagia Alters Cholesterol Dynamics in Diabetic Rats
Authors: Young Nancy L , McNamara Donald J , Saudek Christopher D , Krasovsky Joseph , Lopez Deborah R , Levy Grace
Published: September 2013

Rats with streptozotocin-induced diabetes stop growing and start eating more chow. These two events elicit an interacting series of changes in cholesterol dynamics. Hyperphagia increases dietary cholesterol intake and cholesterol synthesis by the small intestine. These increases are balanced by a decrease in cholesterol synthesis in the rest of the body so that total cholesterol input is normal. With growth failure, utilization of cholesterol for formation of new tissue ceases. This decrease is balanced by an increase in bile acid synthesis by the liver. The bile acid pool in the contents of the small intestine is enlarged by hyperphagia. Despite these changes, fecal sterol excretion and total utilization of cholesterol are normal. During the course of changes in growth and food intake and the attendant changes in cholesterol flux, the total tissue cholesterol pool does not change. Therefore influx equals efflux and the systems regulating cholesterol and bile acid synthesis are responding appropriately and are themselves unperturbed by insulin deficiency. However, plasma cholesterol level increases threefold. This elevation is due to increased influx of cholesterol from the small intestine and decreased synthesis in the rest of the body, so that a larger portion of total body cholesterol influx passes through the blood.
Ciglitazone, a New Hypoglycemic Agent: I. Studies in ob/ob and db/db Mice, Diabetic Chinese Hamsters, and Normal and Streptozotocin-Diabetic Rats
Authors: Chang A Y , Wyse B M , Gilchrist B J , Peterson T , Diani A R
Published: September 2013

Ciglitazone, 5-[4-(1-methylcyclohexylmethoxy) benzyl]-thiazolidine-2,4-dione, is a new hypoglycemic agent orally active in the obese-hyperglycemic animal models. In C57BL 6J-ob ob mice, treatment with 100 mg /kg ciglitazone for 2 days elicited a drastic fall in blood glucose. It also decreased plasma insulin, triglycerides, and free fatty acids and food intake without affecting the body weight. Its hypoglycemic activity was independent of its effect on food intake. Regranulation of islet β-cells and increased pancreatic insulin content were observed in ob/ob mice treated for 41–44 days with 100 mg/kg/day ciglitazone. Ciglitazone showed no effect on food intake, blood glucose, or pancreatic islet β-cells in a group of lean C57BL/6J-+ /? mice concomitantly treated at a dose of 150 mg/kg/ day. In C57BL/KsJ-db/db mice, ciglitazone decreased blood glucose and food intake. The untreated db/db mice lost weight despite hyperphagia, whereas the cig-litazone-treated db/db mice gained weight. In the spontaneously diabetic Chinese hamsters, ciglitazone showed no significant effect on food intake, body weight, blood glucose, or insulin content in either plasma or pancreas, but it lowered plasma lipids. In normal rats, ciglitazone failed to affect fasting blood glucose but improved glucose tolerance without increasing insulin secretory response to glucose. In streptozotocin-diabetic rats, it showed no effect on blood glucose or glycemie response to exogenous insulin. The hypoglycemic activity of ciglitazone was specific for obese-hyperglycemic and insulin-resistant animals.
Evidence Against the Presence of Tight Junctions in Normal Endocrine Pancreas
Authors: Veld P A in't , Pipeleers D G , Gepts W
Published: September 2013

Tight junctional fibrils were absent in freeze-fracture replicas of rat and human islets in situ, but were easily discerned in collagenase-isolated islets. Disruption of the pancreatic gland and its exposure to trypsin were each found to induce tight junction formation in rat islets. The amount of tight junctions between islet cells declined progressively during culture, but tight junctional structures remained detectable after 1 day of culture. It is suggested that rather than being involved in normal islet cell function tight junctions provide an adaptive mechanism intended to seal and hence to protect islet microdomains against sudden perturbations in local interstitial fluid.
Effect of Genetic Background on the Therapeutic Effects of Dehydroepiandrosterone (DHEA) in Diabetes-Obesity Mutants and in Aged Normal Mice
Authors: Coleman D L , Schwizer R W , Leiter E H
Published: September 2013

Dehydroepiandrosterone (DHEA) was fed at 0.1–0.4% in the diet to genetically diabetic (db/db) or obese (ob/ob) C57BL/KsJ (BL/Ks) or C57BL/6J (BL/6) mice. Treatment of BL/Ks-db/db or oblob mice with 0.4% DHEA prevented hyperglycemia, islet atrophy, and severe diabetes associated with this inbred background, but did not affect weight gain and food consumption. Homozygous obese (ob) or diabetes (do) mice on the BL/6 background were more sensitive to DHEA, and the mild, transient hyperglycemia associated with ob or db gene expression on the BL/6 inbred background could be prevented by 0.1% DHEA. Both body weight and food consumption were decreased in BL/6 mutants maintained on 0.1% DHEA whereas this effect was not seen in BL/Ks mutants fed up to 0.4% DHEA. Early therapy with 0.4% DHEA, initiated at 2 wk of age, prevented the development of most diabetes symptoms and decreased the rate of weight gain in pups of all genotypes. In addition to therapeutic effects on both obese mutants, DHEA effected significant changes in an aging study using normal BL/6 female mice. Four weeks of DHEA treatment initiated at 2 yr of age improved glucose tolerance and at the same time reduced plasma insulin to a “younger” level. This suggests that DHEA may act in insulin-resistant mutant mice and in aging normal mice to increase the sensitivity to insulin.
Relative Roles of Insulin Clearance and Insulin Sensitivity in the Prebreakfast Increase in Insulin Requirements in Insulin-dependent Diabetic Patients
Authors: Skor Donald A , White Neil H , Thomas Lorraine , Santiago Julio V
Published: September 2013

During continuous subcutaneous or intravenous insulin infusion therapy, many patients with insulin-dependent diabetes (IDD) require more insulin in the prebreakfast period (0600–0800 h) than earlier in the morning (0100–0300 h). This study was designed to assess whether variations in insulin clearance or insulin sensitivity might contribute to overnight variations in insulin requirements. Euglycemic insulin clamp studies were performed in random sequence from 2400 to 0300 h and from 0500 to 0800 h on successive nights in 10 subjects with IDD. Insulin was infused at a rate of 40 mU/min/m2 and plasma glucose concentration was maintained at 100 mg/dl by a variable rate glucose infusion from a Biostator GCIIS (Miles Laboratories, Elkhart, Indiana). Insulin clearance was (mean ± SEM) 277 ± 41 ml/min/m2 between 0700 and 0800 h compared with 256 ± 41 ml/min/m2 between 0200 and 0300 h (P < 0.05), while glucose infusion rates were the same [3.86 ± 0.52 mg/kg/min from 0730 to 0800 h versus 3.99 ± 0.51 mg/kg/min from 0230 to 0300 h (P = NS)]. All eight patients with a previously documented prebreakfast increase in insulin requirements had higher insulin clearance at this time. These results indicate that differences in insulin clearance between the prebreakfast period and the early morning may account partially for the higher prebreakfast insulin requirements in some subjects with IDD, and the variations in insulin requirements during the night are not due to variations in insulin sensitivity.
Prevalence of Diabetes in Mexican Americans: Relationship to Percent of Gene Pool Derived from Native American Sources
Authors: Gardner Lytt I , Stern Michael P , Haffner Steven M , Gaskill Sharon P , Hazuda Helen P , Relethford John H , Eifler Clayton W
Published: September 2013

We have estimated the prevalence of non-insulin-dependent diabetes mellitus (NIDDM) in Mexican Americans and Anglos in three San Antonio neighborhoods. The age-adjusted NIDDM rates (both sexes pooled) for Mexican Americans were 14.5%, 10%, and 5% for residents of a low-income barrio, a middle-income transitional neighborhood, and a high-income suburb, respectively. In Mexican American women, though not in men, obesity also declined from barrio to suburbs. We have previously shown, however, that, although obesity is an important cause of NIDDM in Mexican Americans, there is a two- to fourfold excess in the rate of NIDDM in this ethnic group over and above that which can be attributed to obesity. We therefore speculated that genetic factors might also contribute to excess NIDDM in this ethnic group. The percent native American admixture of Mexican Americans as estimated from skin color measurements was 46% in the barrio, 27% in the transitional neighborhood, and 18% in the suburbs. The NIDDM rates in Mexican Americans thus paralleled the proportion of native American genes. Furthermore, the San Antonio Mexican American rates were intermediate between the NIDDM rates of “fullblooded” Pima Indians (49.9%), who presumably have close to 100% native American genes, and the San Antonio Anglo population (3.0%) and the predominantly Anglo HANES II population (3.1%), both of which presumably have few if any native American genes. The association of genetic admixture with NIDDM rates suggests that much of the epidemic of NIDDM in Mexican Americans is confined to that part of the population with a substantial native American heritage.
Experimental Galactosemia Produces Diabetic-like Retinopathy
Authors: Engerman Ronald L , Kern Timothy S
Published: September 2013

Six normal dogs were made galactosemic by feeding a 30% D-galactose diet, and were followed up to 5 yr. For comparison, 10 normal dogs and 10 alloxan-diabetic dogs were concurrently fed the diet less the galactose supplement. Retinopathy occurred in each of four dogs glactosemic 3 or more yr, and was absent at lesser durations of galactosemia, and from normal dogs not given the galactose supplement. The retinopathy was marked by saccular capillary aneurysms, hemorrhages, nonperfused or acellular vessels, tortuous hypertrophic capillaries, loss of capillary pericytes, and other lesions typical of diabetic patients and alloxan-diabetic dogs. In galactose-fed dogs, blood galactose varied between 0 (fasted) and 250 mg/ dl (postprandial), and gly cosy la ted hemoglobin levels became supranormal. In contrast to diabetic dogs, blood levels of glucose, free fatty acids, and branchedchain amino acids were not elevated in the galactosemic dogs, and their serum insulin seemed normal. The results suggest that the level of blood hexose is itself an important determinant of retinopathy.
Ethnic Differences in Susceptibility to Non-insulin-dependent Diabetes: A Comparative Study of Two Urbanized Micronesian Populations
Authors: King H , Zimmet P , Pargeter K , Raper L R , Collins V
Published: September 2013

Two urbanized Micronesian populations were recently studied by population-based diabetes surveys. These were Nauruans living on the island of Nauru, and Gil-bertese resident on the islet of Betio, in the Republic of Kiribati (1982 and 1981, respectively). Nauruans are known to suffer from a very high prevalence of non-insulin-dependent (type II) diabetes mellitus (NIDDM). In the present study, the effects of suspected environmental risk factors for diabetes were controlled for, in an attempt to elucidate any residual difference in the prevalence of diabetes between the two groups, which might be of genetic origin. As almost all Nauruans lead a physically inactive lifestyle, only inactive subjects in either population were selected for study. The total study sample consisted of 2306 subjects.

After further controlling for the effects of age and obesity, the odds of diabetes for Nauruans, as compared with Gilbertese, were threefold. The multiple logistic regression model showed ethnicity (i.e., being Nauruan) to be the strongest of the predictor variables examined in both sexes.

In a random subsample of approximately one-third of the total subjects (N = 694), stratified with respect to age and sex, daily intake of total energy and of three dietary components was assessed. The dietary variables were carbohydrate, fat, and dietary fiber. Fat intake was found to be a weak, but significant predictor of diabetes in females after controlling for age, although dietary fat was not predictive of diabetes after also controlling for ethnicity, or for body mass. None of the other dietary variables had any predictive power in either sex. Ethnicity was once again the most important predictor in both sexes, and remained a significant predictor after controlling for age and body mass.

This study demonstrates that obesity is not a sufficient explanation of the high prevalence of diabetes in Nauruans, and provides further support for recent evidence of heightened genetic susceptibility to type II diabetes in this Micronesian population. However, the possibility that as yet undetermined environmental influences may also be involved cannot be discounted.
The Antibody Response to Insulin Therapy: A Prospective Study in HLA-typed Insulin-dependent Diabetic Subjects
Authors: Asplin C M , Dornan T L , Raghu P K , Hansen J A , Palmer J P
Published: September 2013

There is heterogeneity within insulin-dependent diabetes meliitus (IDDM), and it has been suggested that the presence of the HLA-DR specificities DR3 and DR4 define two subsets of IDDM with clear differences in their immune response to therapeutic insulin. To test this hypothesis, we have prospectively studied the development of insulin binding antibody (IBA) in 54 subjects with newly diagnosed, classical childhood IDDM, determined seven binding constants of their IBA, and measured the presence or absence of pancreatic polypep-tide-binding antibodies after 1 yr of therapy with insulin. There were no relationships between insulin and pancreatic polypeptide antibodies and the DR3 or DR4 specificities whether these specificities were tested for alone or in combination, comparing the presence and absence of DR3 and DR4 and comparing DR3 with DR4, except that of the 33% of all subjects who developed antibodies binding pancreatic polypeptide by 1 yr, none possessed the DR3 specificity alone (P = 0.018). Thus, the hypothesis that the HLA-DR3 and -DR4 specificities are major determinants of IBA formation and, therefore, define important subsets of childhood IDDM in terms of immune response to therapeutic insulin is not substantiated by this study.
Sustained Normoglycemia in Newly Diagnosed Type I Diabetic Subjects: Short-Term Effects and One-year Follow-up
Authors: Perlman K , Ehrlich R M , Filler R M , Albisser A M
Published: September 2013

The impact on remission of normalizing blood glucose levels immediately after diagnosis of type I diabetes was studied in 14 adolescents. Accordingly, in this randomized prospective primary intervention study, 7 of the subjects (i.v. group) received insulin by continuous intravenous (i.v.) infusion via a portable preprogrammed system for 28–62 days and 7 (s.c. group) received conventional subcutaneous (s.c.) therapy. Before therapy, the two groups did not differ significantly with respect to glycosylated hemoglobin, fasting plasma C-peptide, or 24-h urinary C-peptide excretion. During the infusion period, the overall mean fasting plasma glucose (FPG) concentration for the i.v. group was 84 mg/dl with a mean coefficient of variation of 18 ± 4% (mean ± SD). During the comparable period for the s.c. group, the mean FPG was 253 mg/dl with a coefficient of variation of 30 ± 20%. Twenty-four-hour urinary glucose excretions for the two groups were 0.29 ± 0.06 (mean ± SEM) and 59 ± 11 g/day, respectively. Daily insulin requirements in the i.v. group decreased from 1.47 ± 0.19 U/kg body wt/day at the start to 0.47 ± 0.10 U/kg/day at the end of the infusion period. Notably, 10–25 days after the infusion period, 5 of 7 subjects experienced a further decrease to a low of 0.27 ± 0.01 U/kg/day. The mean peak and low requirements in the s.c. group were 0.71 ± 0.15 and 0.33 ± 0.13 U/kg/day, respectively, with the only peak requirements being significantly different (P < 0.01). No patient was able to discontinue insulin therapy. The fasting plasma C-peptide level rose significantly (P < 0.05) by 1 mo in the i.v. group, but only achieved similar levels by 4 mo in the s.c. group. In the i.v. group, 24-h urinary C-peptide excretion decreased during the first week of therapy, rose through the infusion period, and finally peaked at 60 ± 14 μg day 3–30 days later. In the s.c group, the urinary C-peptide excretion gradually increased reaching a significantly lower peak (P < 0.05) of 36 ± 8 μg day at 113 ± 38 days. Glycosylated hemoglobin levels declined significantly only in the i.v. group with 4 subjects achieving normal levels. At 1 mo after diagnosis, the i.v. group had significantly higher (P < 0.05) fasting plasma C-peptide levels and lower (P < 0.005) glycosylated hemoglobin levels than did the s.c. group. Inspite of the higher peak urinary C-peptide excretion for the i.v. group, 4 and 12 mo after diagnosis the groups did not differ in mean 24-h urinary C-peptide excretion, fasting plasma C-peptide, insulin requirements, or glycosylated hemoglobin. We conclude that sustained strict glycemie control within normal limits at diagnosis of type I diabetes does not of itself augment the remission phase.
The Dynamic Insulin Secretory Response of Isolated Pancreatic Islets of the Diabetic Mouse: Evidence for a Gene Dosage Effect on Insulin Secretion
Authors: Molina Joseph M , Premdas Francis H , Klenck Robert E , Eddlestone Geoffery , Oldham Susan B , Lipson Loren G
Published: September 2013

Expression of the autosomal recessive (db) gene in homozygous (db/db) C57BL/KsJ mice results in a severe and eventually fatal diabetic syndrome. Many studies of the diabetic mouse have used lean litter-mates (+ /?) as controls despite evidence suggesting a gene dosage effect in heterozygous animals. In order to study the gene dosage effect of the diabetes (db) gene on insulin release in the heterozygote, perifusion experiments were performed on isolated islets of Langerhans of diabetic (db/db), heterozygous (+/db), and normal (+ / +) control mice. Islets of normal controls exhibited a fivefold greater increase in insulin release than did those of diabetics in response to 16.7 mM D-glucose. The insulin secretory response of islets of heterozygotes to glucose was intermediate, being twofold greater than that of diabetics but only about half of that of normal controls. Biphasic insulin release in response to glucose was observed only in islets of normal controls. Islets of all three genotypes exhibited biphasic insulin release in response to 10 mM D-glyceraldehyde; however, overall insulin release in both heterozygotes and diabetics remained diminished as compared with the response of normal controls. This is in contrast to the situation we have previously reported in islets of fasted or aging rats in which, though manifesting defects in glucose-stimulated insulin release, the islets are able to respond normally to 10 mM D-glyceraldehyde in respect to both the dynamic secretory pattern and quantity of insulin released. Our data suggest a gene dosage effect of the (db) gene on glucose-stimulated insulin release in heterozygous (+/db) C57BL/KSJ mice.
Histologic Differentiation of Human Fetal Pancreatic Explants Transplanted into Nude Mice
Authors: Tuch B E , Ng A B P , Jones A , Turtle J R
Published: September 2013

The transplantation of human fetal pancreas has been suggested as a means of treatment of insulin-dependent diabetes in man. We have obtained human fetal pancreata during the second trimester of pregnancy and transplanted 1-mm3 explants subcutaneously (s.c.) into both diabetic and nondiabetic nude mice, some of the tissue being cultured in vitro before implantation. These implants coalesced and grew. They were removed at intervals up to 37 wk later and showed selective differentiation of endocrine tissue that normally occurs in the fetus and neonate, with formation of bipolar, mantle, and mature islets. There was growth of this endocrine tissue with significantly more islets than in the freshly stained fetal pancreas assuming an average dimension larger than 150 μm, which is the reported mean diameter of a neonatal islet. Duct and fibrous tissue remained viable, but there was no definitive acinar tissue seen. The pancreata uncultured before implantation reached a larger size than that attained by those implants cultured before being transplanted, the difference probably being the amount of ductular and mesenchymal tissue still present. Of those glands cultured before transplantation, the longer the period of culture, the smaller the size the implants reached. Culture beyond 3 wk in vitro made it difficult to macroscopically locate the implant. These data show that, in human fetal pancreas removed from its usual environment, both selective differentiation of the endocrine component and growth of the islets can OCCUr.
Glucosylation of Low-Density Lipoproteins to an Extent Comparable to That Seen in Diabetes Slows Their Catabolism
Authors: Steinbrecher Urs P , Witztum Joseph L
Published: September 2013

In previous studies we have shown that extensive glucosylation of low-density lipoproteins (LDL) (40% of lysines modified) completely blocks receptor-mediated degradation in animals and in man. Other studies indicated that in some diabetics up to 5% of lysine residues of LDL were glucosylated. The present study was done to determine if the extent of glucosylation of LDL which can occur in diabetics could alter LDL catabolism. We measured degradation by cultured normal human fibroblasts and turnover in guinea pigs of various LDLs with 2–17% of lysine residues glucosylated. Modification of as few as 2–5% of lysines decreased LDL catabolism by 5–25%, and the degree of inhibition of catabolism was linearly related to the extent of LDL glucosylation. These results indicate that the extent of LDL glucosylation that can occur in diabetes may slow LDL catabolism and hence increase plasma LDL levels.
A (3H)2-Deoxyglucose Method for Comparing Rates of Glucose Metabolism and Insulin Responses Among Rat Tissues In Vivo: Validation of the Model and the Absence of an Insulin Effect on Brain
Authors: Hom Frederick G , Goodner Charles J , Berrie Mary Ann
Published: September 2013

In 1980 we described an in vivo method for estimating the rate of glucose uptake among selected tissues during an acute insulin response. The method was based upon the same principles as Sokoloff's 2-deoxyglucose (2DG) method. We now report further examination of the basic assumptions of the model and validation of its general applicability by comparing the response of brain and other tissues to prolonged insulin infusion (while glucose is held constant) with their response to a single injection of insulin. The method provides a reproducible estimate of relative insulin response in any tissue that can be anatomically separated at death. Tissues that are minimally sensitive to insulin such as spleen, lung, skin, and gut do not display increments in the calculated value for net rate of tissue uptake of 2DG. Insulin-sensitive tissues display increased rates of uptake that are characteristic for each specific tissue, ranging in magnitude from 1.7- to 17.9-fold over basal among an array of insulin-sensitive tissues. The duration of a unit response to a sub-maximal dose of insulin also varied among the tissues, persisting for 20–30 min after plasma insulin had returned to basal in heart and for 10–20 min in the other insulin-sensitive tissues.

The method provides a reproducible measure of glucose metabolism in vivo and has been validated as a means of quantifying relative insulin sensitivity among the peripheral tissues. During steady-state conditions with plasma glucose held constant, brain glucose metabolism was unaffected by a 60-min infusion of insulin.
Thiol-dependent and Non-thiol-dependent Stimulations of Insulin Release
Authors: Ammon H P T , Abdel-Hamid M , Rao P G , Enz G
Published: September 2013

The effects of reduced glutathione (GSH) and diamide (an oxidant of GSH) on insulin release induced by glucose, glyceraldehyde, leucine, tolbutamide, glibenclamide, Ca-ionophore A-23187, isoprenaline, and db-cAMP were studied using isolated rat pancreatic islets. In the absence or presence of low glucose (5.6 mM) neither GSH (0.1 mM) nor diamide (0.1 mM) affected insulin release. Insulinotropic action of glucose (11.1 mM) and glyeraldehyde (11.1 mM), and that of tolbutamide (0.1 mg/ml) and leucine (10 mM) both in the presence of 11.1 mM glucose was further augmented by GSH and inhibited by diamide. GSH (0.05–1 mM) and diamide (0.1 mM) failed to affect the insulin secretion evoked by glibenclamide (5 μg/ml) + glucose (11.1 mM), Ca-ionophore A-23187 (50 μg/ml) + glucose (5.6 mM), isoprenaline (1 μM) + glucose (5.6 mM), and db-cAMP (1 mM) + glucose (5.6 mM).

The data suggest that the insulin-releasing capacity of glucose, glyceraldehyde, tolbutamide, and leucine depends on the redox state of islet thiols, whereas the insulin-releasing effect of glibenclamide, Ca-ionophore, isoprenaline, and db-cAMP does not. The possibility that thiol dependency is associated with those compounds increasing Ca uptake but not with compounds acting as Ca-ionophores or only by increasing intracellular cAMP is discussed.
Failure of a Midnocturnal Insulin Infusion to Suppress the Increased Insulin Need for Breakfast in Insulin-dependent Diabetic Patients
Authors: Nestler John E , Gebhart Suzanne S P , Blackard William G
Published: September 2013

Insulin requirements for meals were measured in eight insulin-dependent diabetic patients, using a closed-loop insulin infusion system. Patients required more insulin for breakfast than for an isocaloric lunch (35.7 ± 5.5 mU/kcal/3 h versus 26.9 ± 5.1 mU/kcal/3 h, P < 0.02) or an isocaloric supper (35.7 ± 5.5 mU/kcal/ 3 h versus 26.6 ± 6.6 mU/kcal 3 h, P = 0.05). To determine whether this insulin resistance at breakfast might be due to low basal insulin levels overnight, the insulin needs for breakfast were compared after an overnight fast (day 1) and after a midnocturnal (0200 h–0500 h) insulin infusion (day 2). Breakfast insulin requirements were similar on both days (35.7 ± 5.5 mU/kcal/3 h versus 37.7 ± 5.1 mU/kcal/3 h, P = NS).

Whereas nonobese diabetic patients required approximately 60% more insulin for breakfast than for other meals, obese diabetic patients in this study did not demonstrate insulin resistance at breakfast.

These findings provide a basis for the common clinical practice of allocating more insulin for breakfast than for other meals. The absence of an increased insulin need at breakfast in our obese patients cautions against a similar algorithm for obese diabetic patients. We postulate that growth hormone may be a cause for morning insulin resistance.
Characterization of the Serum from a Patient with Insulin Resistance and Hypoglycemia: Evidence for Multiple Populations of Insulin Receptor Antibodies with Different Receptor Binding and Insulin-mimicking Activities
Authors: De Pirro Roberto , Roth Richard A , Rossetti Luciano , Goldfine Ira D
Published: September 2013

The serum from a patient with lupus nephritis, insulin resistance, and hypoglycemia was studied. This serum both inhibits the binding of 125I-insulin to its receptor and has insulin-like activity on fat cells (see refs. 1 and 2). The IgG fraction from this patient's serum one-half maximally inhibited 125I-insulin binding to IM-9 cells at 1 μM, but did not markedly inhibit 125I-monoclonal antibody binding even at concentrations as high as 4 μM. The IgG was then subjected to affinity chromatography on a protein A-Sepharose column. Four protein peaks were eluted from this column by a step pH gradient from 5.5 to 2.3. Three of the four peaks inhibited 125I-insulin binding to its receptors, but none was more potent than the unfractionated IgG itself. One IgG peak, however, was able to inhibit 125I-monoclonal antibody binding at tenfold lower concentrations than the unfractionated IgG. When the ability of the four IgG fractions to stimulate 2-deoxy[3H]-D-glucose transport in rat adipocytes was studied, two fractions showed stimulatory activity. Compared with unfractionated IgG, one had a weak ability to inhibit 125I-insulin binding, but tenfold more potency to mimic insulin action. The other had a strong ability to inhibit 125I-insulin binding but less potency to mimic insulin action. These studies indicate, therefore, that the serum contains multiple populations of antibodies to the insulin receptor, or portions of the plasma membrane adjacent to the receptor, which have different biologic effects.
Absent or Delayed Preovulatory Luteinizing Hormone Surge in Experimental Diabetes Mellitus
Authors: Katayama S , Brownscheidle C M , Wootten V , Lee J B , Shimaoka K
Published: September 2013

The proestrus preovulatory luteinizing hormone (LH) surge was absent or delayed in more than 56% of untreated streptozotocin-diabetic rats. Absence of LH surge was associated with anovulation. Insulin treatment for 10–14 days restored the diminished surge and ovulation frequency. Pituitary LH release in response to exogenous gonadotropin-releasing hormone administration in diabetic rats was not different from controls. Impaired hypothalamic function may comprise the basis for the increased incidence of infertility in diabetes mellitus.