bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Stages in Diabetic Renal Disease: With Emphasis on the Stage of Incipient Diabetic Nephropathy
Authors: Mogensen C E , Christensen C K , Vittinghus E 
Published: September 2013

Alterations in renal function and structure are found even at the onset of diabetes mellitus. Studies performed over the last decade now allow definition of a series of stages in the development of renal changes in diabetes. Such a classification may be useful both in clinical work and in research activities.
Stage 1 is characterized by early hyperfunction and hypertrophy. These changes are found at diagnosis, before insulin treatment. Increased urinary albumin excretion, aggravated during physical exercise, is also a characteristic finding. Changes are at least partly reversible by insulin treatment.
Stage 2 develops silently over many years and is characterized by morphologic lesions without signs of clinical disease. However, kidney function tests and morphometry on biopsy specimens reveal changes. The function is characterized by increased GFR. During good diabetes control, abumin excretion is normal; however, physical exercise unmasks changes in albuminuria not demonstrable in the resting situation. During poor diabetes control albumin excretion goes up both at rest and during exercise. A number of patients continue in stage 2 throughout their lives.
Stage 3, incipient diabetic nephropathy, is the forerunner of overt diabetic nephropathy. Its main manifestation is abnormally elevated urinary albumin excretion, as measured by radioimmunoassay. A level higher than the values found in normal subjects but lower than in clinical disease is the main characteristic of this stage, which appeared to be between 15 and 300 μg/min in the baseline situation. A slow, gradual increase over the years is a prominent feature in this very decisive phase of renal disease in diabetes when blood pressure is rising. The increased rate in albumin excretion is higher in patients with increased blood pressure. GFR is still supranormal and antihypertensive treatment in this phase is under investigation, using the physical exercise test.
Stage 4 is overt diabetic nephropathy, the classic entity characterized by persistent proteinuria (&gt;0.5 g/ 24 h). When the associated high blood pressure is left untreated, renal function (GFR) declines, the mean fall rate being around 1 ml/min/mo. Long-term antihypertensive treatment reduces the fall rate by about 60%7 and thus postpones uremia considerably.
Stage 5 is end-stage renal failure with uremia due to diabetic nephropathy. As many as 25% of the population presently entering the end-stage renal failure programs in the United States are diabetic. Diabetic nephropathy and diabetic vasculopathy constitute a major medical problem in society today.
Capillary Basement Membranes in Diabetes
Authors: Williamson J R , Kilo C 
Published: September 2013

In discussions of vascular complications of diabetes the fact that capillary basement membranes are, in general, thickened (CBMT) in poorly controlled diabetics is no longer at issue. However, three important questions concerning the pathophysiologic significance of CBMT remain unanswered: (1) How and why do capillary basement membranes thicken in diabetes? (2) What is the functional significance of capillary basement membrane changes in diabetes? (3) What is the nature of the relationship of CBMT to other forms of diabetic vascular disease; in particular, is CBMT observed in tissues amenable to needle biopsy, i.e., skeletal muscle, useful in identifying individuals at high risk for developing clinically significant retinopathy, nephropathy, or atherosclerotic vascular disease?
In this survey, we will consider the nature of capillary basement membrane changes in diabetes and subsequently address the above questions.
Decreased Response of Mobile Calcium in Pancreatic Islets of Fasted Rats to Glucose Stimulation and Calcium Manipulation
Authors: Wolters G H J , Pasma A , Konijnendijk W 
Published: September 2013

The effect of fasting on mobile calcium in the B-cells of rat pancreatic islets was investigated in view of a possible role of calcium in the fasting-induced impairment of insulin secretion. Mobile calcium (GBHA-Ca), an ionized or readily ionizable calcium fraction, was determined histochemically with glyoxal bis (2-hydroxyanil). Fasting (24–72 h) strongly decreased the GBHACa content of islets in situ (55–60%).
Incubation of isolated islets at 2.5 mM glucose in the presence of 2.5 mM Ca2+ resulted after 15 min in stable GBHA-Ca levels, which were 25% lower in fasted than in fed islets. Glucose (15 mM) caused the GBHA-Ca content of fed islets to decrease rapidly and to rise again after 30 min. These changes did not occur after 24 or 72 h of fasting. GBHA-Ca appeared not to be displaceable with La3+.
At 2.5 mM glucose, withdrawal of Ca2+ rapidly reduced GBHA-Ca in fed and fasted islets. Glucose (15 mM) inhibited this rapid fall, and this inhibitory effect was particularly evident in fed islets.
Washing and preincubation in the absence of Ca2+ (2.5 mM glucose) largely depleted fed and fasted islets of GBHA-Ca. Reintroduction of Ca2+ at 2.5 mM glucose only partially restored the GBHA-Ca levels of fed and fasted islets. By contrast, 15 mM glucose restored the characteristic pattern of GBHA-Ca in fed islets as seen in nondepleted islets, but in fasted islets at lower levels as previously seen.
Thus, fasting decreased the GBHA-Ca content and its response to glucose stimulation. It is suggested that GBHA-Ca, which is presumably mainly localized in the secretory granules, plays a role in the initiation of insulin secretion.
Kinetics of Insulin Receptor Biosynthesis and Membrane Insertion: Relationship to Cellular Function
Authors: Marshall Stephen 
Published: September 2013

A method was developed for maintaining isolated rat adipocytes in primary culture in a viable state for several days. Using this method, the kinetics of insulin receptor biosynthesis and membrane incorporation were assessed by inactivating (&gt;95%) cell-surface insulin receptors with trypsin and then incubating cells in medium at 37°C for various times up to 44 h. The insertion of nascent receptors, into the plasma membrane was monitored by measuring the recovery of specific 125l-insulin binding activity. After trypsinization, insulin binding activity recovered at a linear rate with half of the original cell-surface receptor complement replenished by 24 h (6000 receptors or 2% of total surface receptors/h). This recovery was most probably mediated by de novo receptor synthesis, since no recovery of specific insulin binding was seen when cells were pretreated with cycloheximide for 3 h. Under conditions where protein synthesis was blocked immediately after trypsinization, however, a lag of 2–3 h was observed before receptor incorporation was inhibited. This lag suggests that insulin receptors are processed and routed within the cell for 2–3 h before being inserted into the plasma membrane. In support of this hypothesis it was found that the intracellular pool of insulin receptors (10% of the total receptor complement) could be depleted by about 80% by treating cells with cycloheximide for 3 h. Thus, it appears that most, if not the entire, intracellular receptor pool in adipocytes consists of newly synthesized receptors en route to the cell surface.
Insulin, after binding to cell-surface receptors, triggers various biologic actions in adipocytes such as glucose transport and endocytosis of insulin-receptor complexes. To determine whether nascent receptors are functional immediately on insertion, we compared the recovery of insulin binding activity after trypsinization with the ability of these cells to respond to insulin with an increase in glucose uptake and an augmented rate of insulin internalization. These data revealed a high correlation between recovery of binding and biologic responsiveness. Thus, these data indicate that immediately upon insertion, or shortly thereafter, receptors become functional and are able to mediate the biologic actions of insulin.
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.
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 &lt; 0.005), 234 ± 40% (P &lt; 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 &lt; 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 &lt; 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.
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.
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.
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 &lt; 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.
The Acute and Chronic Effects of Sulfonylurea Therapy in Type II Diabetic Subjects
Authors: Kolterman O G , Gray R S , Shapiro G , Scarlett J A , Griffin J , Olefsky J M 
Published: September 2013

Although sulfonylurea agents have been used in the clinical management of type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM) for over two decades, the mechanisms responsible for their hypoglycemie action remain controversial. We have quantitated glycemie control, endogenous insulin secretion in response to mixed meals, adipocyte insulin binding, insulin-mediated peripheral glucose disposal, and basal hepatic glucose output in 17 type II diabetic subjects before and after 3 mo of therapy with the second-generation, sulfonylurea compound glyburide in an attempt to identify the factors responsible for the clinical response to the drug. In addition, 9 subjects were treated for an additional 15 mo to see if the response to the drug changed with time.
The mean fasting serum glucose level fell from an initial value of 264 ± 17 mg/dl to 178 ± 16 mg/dl after 3 mo of drug therapy. Endogenous insulin secretion increased in all subjects, but the increase was most marked in those subjects who continued to exhibit fasting hyperglycemie (fasting serum glucose &gt; 175 mg/dl) after 3 mo of therapy. Adipocyte insulin binding was unchanged after 3 mo of therapy, while the maximal rate of peripheral glucose disposal was increased by 23%, indicating enhancement of peripheral insulin action at a postreceptor site(s). Basal hepatic glucose output showed a significant correlation with the fasting serum glucose level both before and after therapy (r = 0.86, P &lt; 0.001) and fell from 141 ±12 mg/m2/min before therapy to 107 ± 11 mg/m2/min after 3 mo of therapy. A significant correlation was also found between the decrease in the fasting glucose level and both the reduction in basal hepatic glucose output (r = 0.81, P &lt; 0.001) and the enhancement of postreceptor function in peripheral tissues (r = 0.68, P &lt; 0.005). After 18 mo of therapy, those subjects exhibiting an initial good response to the drug demonstrated a slight decrease in endogenous insulin secretion compared with the levels seen at 3 mo, adipocyte insulin binding had increased to the normal range, postreceptor function was further enhanced, and basal hepatic glucose output remained unchanged from the levels observed after 3 mo of therapy.
We conclude that (1) glyburide therapy increases endogenous insulin secretion, increases adipocyte insulin binding after 18, but not 3, mo of therapy, enhances peripheral insulin action by acting primarily at a post-receptor site, and reduces basal hepatic glucose output; (2) the increase in postreceptor function and the reduction of basal hepatic glucose output appear to be the crucial determinants of the clinical response to the sulfonylurea agent; and (3) the response pattern to sulfonylurea compounds in terms of these various parameters can vary as a function of the duration of treatment.