bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Control of Diabetes by the Artificial Pancreas
Authors: Albisser A M , Leibel B S , Ewart T G , Davidovac Z , Botz C K , Zingg W , Schipper H , Gander R
Published: December 2014

An artificial pancreas capable of maintaining blood sugar homeostasis within the physiological range is described in this paper. The blood sugar is continuously monitored and then interpreted by a minicomputer which in turn controls and implements the delivery of insulin (or glucose). The entire system is automatic and by giving insulin according to a projected blood sugar level the pattern of insulin administration is similar to the biphasic response of the normal pancreas. Five parameters for control can be selected and altered at will so that any level of normoglycemia can be maintained. Hypoglycemia is not encountered, and none of the patients experienced any side effects during or after the trials. The clinical trials involved a two-day study. On the first day the blood sugar profiles were monitored throughout the day. The patients were given their usual doses of subcutaneous insulin and ate measured meals and snacks. On the second day, they received no subcutaneous insulin; insulin was administered intravenously in accordance with the moment-to-moment requirements of the patients who were given meals the same as those of the previous day. Graphs plotted on a common time scale compare the blood sugar patterns on the two successive days and show the significant improvement in blood sugar homeostasis achieved by this artificial pancreas.
Extracellular Calcium and Acetylcholine-stimulated Insulin Secretion
Authors: Griffey Michael A , Conaway Howard H , Whitney John E
Published: December 2014

The importance and possible involvement of extracellular calcium in the stimulation of insulin secretion by acetylcholine was examined in the isolated perfused dog pancreas. Acetylcholine (SO μM) failed to stimulate insulin secretion when calcium was omitted from the perfusion medium. In the presence of tetracaine (1 mM) and magnesium (10.16 mM), conditions favoring blockade of Ca++ influx into the beta cell, acetylcholine-induced (50μM) insulin secretion was inhibited. We conclude from these observations that acetylcholine-stimulated insulin secretion is dependent upon extracellular Ca++ and an increase in Ca++ influx may be involved in this stimulation.
Diploid, Tetraploid and Octaploid Beta Cells in the Islets of Langerhans of the Normal Human Pancreas
Authors: Ehrie Michael G , Swartz Frank J
Published: December 2014

The nuclear DNA content of normal human endocrine and exocrine pancreatic cells was determined by Feulgen microdensitometry. Exocrine cell nuclei consistently yielded only diploid DNA values, while islet cell nuclei showed distinct diploid, tetraploid and octaploid classes. The existence of a strict positive correlation between nuclear size and DNA content in individual nuclei permitted the assignment of islet cell nuclei to one of three polyploid classes after staining by Gomori's modification of the Mallory-Heidenhain azan technic. It was thus determined that polyploidy is confined entirely to beta cells, while alpha and delta cells remain diploid. Although a complete analysis was made on only six adult specimens, the unequivocal volume-DNA relationship established permits the assumption, based on the observation of numerous other human pancreases, that the phenomenon is a generalized one.
Beta-Cell Insulin Secretory Response to Glucose in Odd-Carbon Number Fatty Acid-enriched Rats: Preservation During Starvation
Authors: Kim S , Pi-Sunyer F X
Published: December 2014

The adipose tissue of fifty male Sprague-Dawley rats was enriched with 26.3 per cent odd-carbon number fatty acids (OCE) by feeding a complete diet containing a 7:3 mixture of triundecanoin and corn oil for six weeks. An equal number of control animals (C) was fed a similar diet except that the fat was exclusively corn oil. After six weeks, the animals were given intravenous glucose (500 mg.) either in the fed state cr after forty-eight- or ninety-six-hour fasts. Fasting plasma glucose and immunoreactive insulin levels were higher in OCE than in C during starvation. K values of glucose disappearance after an intravenous glucose load were similar in OCE and C in the fed state; with starvation, K values were less impaired in OCE than in C. The areas under the insulin response curve on days 2 and 4 of starvation were reduced to 24 per cent and 19 per cent of the fed value in C and 73 per cent and 47 per cent in OCE. Insulin-to-glucose ratio diminished significantly with starvation in C, whereas no significant change occurred in dCE. Total pancreatic insulin was not different in fed or two- and four-day starved OCE and C animals. Thus, fasting in C appears to impair the insulin secretory response of beta cells to glucose, whereas OCE maintain significantly greater responsiveness. The sustained beta-cell sensitivity to glucose of the starved OCE animal probably is related to preservation in the beta cells of a glucose receptor or an intracellular enzymatic system.
Diabetes in Remission: Insulin Secretory Dynamics
Authors: Park Byung N , Soeldner J S , Gleason R E
Published: December 2014

Insulin secretory capacity and sensitivity to exogenous insulin were examined in eight nonobese, ketosis-prone young diabetics at the time of a clinical remission during which they could be managed without any insulin therapy.

The insulin secretory capacity of these patients was assessed with oral glucose, intravenous glucose and an oral mixed meal test. The insulin responses were variable and relatively subnormal compared to those in normal controls, but definite and substantial responses were found in the majority of the patients to all the stimuli.

When small amounts of crystalline insulin were administered intravenously to produce peripheral venous insulin levels in the physiologic range, these patients responded with a normal decrease in blood glucose and plasma free fatty acid levels suggesting maintenance of in vivo insulin sensitivity.

Since ketosis-prone, insulin-dependent diabetics are generally characterized by nearly complete failure of beta-cell function, the present finding supports the concept that clinical remission of diabetes is dependent on a functional recovery of the beta cell. Furthermore, it seems likely that no significant “insulin resistance” that often accompanies severe diabetes is present in this remission state.
Oral Glucose-stimulated Insulin Release in Nondiabetic Twin Siblings of Diabetic Twins
Authors: Gottlieb Marise S , Soeldner J Stuart , Kyner Joseph L , Gleason Ray E
Published: December 2014

A total of twenty-five monozygotic and dizygotic glucose-tolerant twin siblings of diabetic patients were compared with age-, sex-, and weight-matched groups of glucose-tolerant offspring of two diabetic parents and normal control subjects with regard to glucose, insulin, free fatty acid and growth hormone responses during a five hour oral glucose tolerance test. Few differences in mean levels of glucose, insulin or free fatty acids were found, the trend being a higher insulin level in the twin study groups. Although the numbers of subjects were small, significantly higher insulinglucose relationships were found in monozygotic females compared to normals and in dizygotic females compared to offspring and to normals. The fasting plasma free fatty acid level was highest in the twins among each of the four subgroups, possibly indicating a blunting of the antilipolytic effect of the basal insulin level in the twins.

A “paradoxic” type of growth hormone response was seen in both the twin and offspring groups compared to the respective normal groups.

It appears that alterations in insulin-glucose relationships and growth hormone response exist in potential diabetic groups that cannot be accounted for by small but important differences in age, weight, or glucose tolerance.
Effect of Phenformin on Carbohydrate Absorption in Man
Authors: Olsen Ward A , Rasmussen Howard K
Published: December 2014

Recent studies have demonstrated that phenformin inhibits intestinal glucose absorption in man. In order to determine if carbohydrate malabsorption occurs during phenformin administration we used a breath hydrogen (H2) test. This test depends upon fermentation of unabsorbed carbohydrate to hydrogen by colonic bacteria with subsequent absorption of H2 and pulmonary excretion. H2 excretion rates were measured in five normal subjects while fasting and two hours after the administration of 75 gm. of glucose. The study was repeated on the following day after the administration of 100 mg. of phenformin. There was no significant change in H2 excretion. One subject was then studied several times a day while eating a normal diet; phenformin administration did not increase H2 excretion. We conclude that the drug does not induce carbohydrate malabsorption.
One to Five Days of Continuous Intravenous Insulin Infusion on Seven Diabetic Patients
Authors: Slama Gerard , Hautecouverture Michel , Assan Roger , Tchobroutsky Georges
Published: December 2014

Regular insulin was infused from one to five days in seven adult diabetic volunteers previously treated with subcutaneous insulin three times a day. Through a catheter inserted in a peripheral vein, a small pump delivered 66 ± 10 units of insulin per day in a 131.0 ± 4.0 ml. solution at mean rates of 26 ± 4 mU./min. between meals and 373 ± 58 mU/min. during meals; 40 per cent of the total daily dose was given during the three meal periods. These rates were precalculated. Patients were ambulatory. Blood glucose was assayed every fifteen minutes for eight hours during the postprandial periods and hourly otherwise. The over-all highest mean values were observed ninety minutes after breakfast (138 ± 17 mg./100 ml.) and four hours after dinner (121 ± 18); the lowest were 73 ± 7, 64 ± 7, 72 ± 15 at the end of the three high concentration insulin infusion periods and 56 ± 7 at 6 a.m. During insulin infusions the mean values of blood glucose parameters were as follows: 89 ± 7 mg./100 ml. for the mean blood glucose level; 66 ± 9 for the mean amplitude of glycemic excursion; and 17 ± 5 for the modified Schlichtkrull's M coefficient. Insulin infusions gave significantly lower blood glucose levels during the night and at breakfast than insulin three times a day, and higher blood glucose values before lunch. Both technics gave very good control of diabetes. Insulin infusions without blood glucose monitoring are feasible for several days in ambulatory patients.
Mechanisms of Catecholamine Inactivation by the Endocrine Pancreas
Authors: Feldman Jerome M , Chapman Barbara
Published: December 2014

The present study was designed to determine if mechanisms are present in the islets of Langerhans to inactivate catecholamines. The dopamine content of the pancreatic beta cells was increased by incubating rabbit pancreas segments with L-3, 4-dihydroxyphenylalanine (L-dopa) for forty-five minutes prior to stimulation with glucose, 16.5 mM. Monoamine oxidase (MAO) inhibitors (pargyline, tranylcypromine and harmine) potentiate the inhibition of insulin secretion by increased beta cell dopamine, but not by dopamine added to the incubation media. Catechol-Omethyltransferase (COMT) inhibitors (pyrogallol and tropolone) did not potentiate the inhibition of insulin secretion from rabbit pancreas by beta cell dopamine. Isolated islets obtained from rabbits, rats, and golden hamsters contained MAO; only golden hamster, a species with a rich intrainsular adrenergic plexus, had COMT in their islets. Compounds that inhibit cellular uptake of catecholamines (cocaine, nortryptyline, and imipramine) potentiate the inhibition of insulin secretion resulting from the presence of norepinephrine in the incubation media but not the inhibition resulting from increased beta cell dopamine. The present study suggests that MAO and beta cell catecholamine uptake may play a role in the inactivation of catecholamines by the islets of Langerhans.
Carbohydrate Metabolism in Pregnancy: XI. Response of Plasma Glucagon to Overnight Fast and Oral Glucose during Normal Pregnancy and in Gestational Diabetes
Authors: Daniel Robert R , Metzger Boyd E , Freinkel Norbert , Faloona Gerald R , Unger Roger H , Nitzan Menachem
Published: December 2014

Plasma glucagon was examined after overnight fast and in response to 100 gm. oral glucose in sixteen subjects with normal carbohydrate metabolism and in ten gestational diabetics during week 30 to 40 of pregnancy and again five to eight weeks postpartum. In comparison to nulliparous, nongravid subjects, plasma glucagon after overnight fast was not significantly changed antepartum. However, on a pair-matched basis, small but significant and as yet unexplained reductions in plasma glucagon were evident during the postpartum period. Thus, hyperglucagonemia cannot be implicated in the accelerated starvation that is already manifest after overnight fast in late pregnancy, and altered basal glucagon does not constitute one of the diabetogenic factors of gestation. Following glucose administration, plasma glucagon in normal subjects subjects fell to a greater degree antepartum than postpartum. The paired observations suggest that this heightened suppressibility of circulating glucagon may be linked to the more prolonged hyperglycemia and hyperinsulinemia that occur during normal oral glucose tolerance in late pregnancy. In the gestational diabetics, oral glucose also elicited suppression of plasma glucagon antepartum, whereas suppressibility was not seen postpartum. Therefore, overt diabetogenesis in vulnerable subjects during pregnancy cannot be ascribed to lack of alpha cell suppressibility by glucose. Conversely, the exaggerated hyperinsulinemia and hyperglycemia in response to oral glucose during late pregnancy in gestational diabetics may obscure an intrinsically diminished sensitivity of their alpha cells to glucose.
Placental Transfer of Streptozotocin in the Rhesus Monkey
Authors: Reynolds W Ann , Chez Ronald A , Bhuyan Bijoy K , Neil G L
Published: December 2014

The induction of a diabetic-like state by the drug streptozotocin (Stz) has been useful for studies on the effects of maternal glucose intolerance upon the monkey fetus. However, the question of transplacental passage of Stz and its effect upon the fetus has to be considered if the drug is to be administered post-conception. Experiments in which Stz was administered maternally and then analyzed in maternal and fetal blood by disc-plate assay indicated prompt movement to the fetal circulation. Slow maternal degradation of Stz was associated with higher fetal blood levels of the compound.

Studies with 14C-streptozotocin suggest that about one half of the radioactivity present in maternal and fetal plasma following intravenous maternal administration is intact 14C-Stz; after one hour, only one fifth of the radioactivity is still associated with the Stz molecule. By the time maximum fetal levels of the drug were achieved, maternal levels of Stz had decreased to one sixth and one tenth of initial levels. Fetal levels did not exceed one half to one third of the simultaneous maternal plasma concentration, implying placental limitation to transfer of streptozotocin from mother to fetus.

No specific localization of 14C-Stz by pancreatic beta cells was observed in either paraffin or frozen-dried autoradiographic preparations. No evidence of high levels of uptake of 14C-Stz were found in pancreatic tissue in comparison to other selected fetal tissues.

Although Stz does cross the hemochorial placenta to a limited extent, it appears to have no discernible effect upon the fetal pancreas.
A Six-minute Test with Glucagon-free Insulin in the Classification of Diabetes and Prediabetes
Authors: Anderson George E
Published: December 2014

Somogyi pointed out that conventional tests for insulin tolerance are not adequate for determining sensitivity or responsiveness to insulin, since blood glucose below the fasting level rapidly initiates counter-regulatory mechanisms which promptly mask the degree of response to insulin.

The uncertainty of the period of action of the hyperglycemic factor existing in presently available crystalline insulin makes it quite impossible to appraise satisfactorily the primary influence of the administered insulin on blood glucose in respect to the promptness of initiation of action (“latent period” of Himsworth) and in respect to the unhampered degree of fall in blood glucose. It is essential, therefore, that for a good test of responsiveness these latter two factors be registered before any extensive fall in glucose has had an opportunity to excite the body's counter-effort at homeostatic readjustment. Such time would fall well within the first few minutes after injection of insulin.

The valid criticisms of tests now in vogue for sensitivity to insulin can be obviated by careful timing, using an insulin which is free of the hyperglycemic-glycogenolytic factor (HGF or glucagon). The suggested responsiveness test with glucagon-free insulin records blood glucose readings in a time period before marked reactive compensatory phenomena have come into play, namely within the first six minutes after administration of the insulin. Under such conditions, only factors already residing in the individual and actively functioning at the very time of the injection of insulin could prevent the initiation of a fall in blood glucose. These are antiinsulin factors peculiarly inherent in the individual and possibly actually creating the diabetic state in the obese adult.
The Morphogeny of the Capillary Vascular Lesions of Diabetes
Authors: Berkman James
Published: December 2014

Highly characteristic if not strictly specific alterations affect retinal and glomerular capillaries in patients with long-term diabetes. The morphologic characteristics of these lesions distinguish degenerative vascular disease in diabetic patients from that in nondiabetic individuals. Their presence differentiates the pattern of vascular degeneration in the retina and kidney from that so far demonstrated anatomically elsewhere in diabetic patients in whom these characteristic lesions occur. While there is disagreement among authorities, some regard the development of capillary lesions as an integral component and inevitable accompaniment of long-term diabetes, rather than as one of its complications. Glomerular lesions are found in about 50 per cent of patients with retinal capillary involvement and are not present in patients without retinal lesions. Conversely, if they are looked for, retinal lesions are found in practically all patients with glomerular lesions. Thus there is a definite correlation between the incidence of retinal and renal involvement. The lesions do not appear to be strictly comparable morphologically. It has been suggested that they reflect similar pathologic processes, the manifestations of which are modified by structural differences between the capillaries concerned. It may also be that the interpretability of changes in the retina and glomerulus is concerned. The capillary network visualized in flat mounts of whole retinas has a rather simple pattern. In the glomerulus, about 2.5 cm. of capillaries branch and reanastomose within the confines of a sphere about 200 microns in diameter. Our concepts of the finer details of normal glomerular structure and its alterations in disease are changing with recent advances in microscopic and histochemical technics.
Metabolism of the Serum Lipids in Diabetes and in Arteriosclerosis
Authors: Mann George V
Published: December 2014

As an experimentalist interested in arteriosclerosis, I look upon diabetes mellitus as a natural experiment in atherogenesis. This narrow view may distress clinicians engaged in the management or prevention of diabetes, but they should agree that progress in the prevention of atherosclerosis will benefit diabetic human beings most of all.

In 1947 I began a laboratory study of the effect of experimental diabetes on the development of vascular disease in animals. The premise that the presence of diabetes aggravates the vascular disease is so attractive that even after five years of fruitless work it is sometimes tempting to try again. It was not possible to demonstrate that this was a valid hypothesis. Although certain capillary lesions were demonstrated in diabetic rats, no evidences of major vessel disease were produced in either rats, dogs, or monkeys, whether fed cholesterol or not.

A second hypothesis concerning atherogenesis has been studied and contested for almost half a century and yet has eluded the critical experiment which will properly evaluate its verity. In simple terms this hypothesis states that atherosclerosis, a variant of arteriosclerosis, is a consequence of abnormal lipid metabolism. The immediate problems posed are those of describing the kind and extent of abnormal lipid metabolism necessary for this consequence, a description of the contribution or weight of abnormal lipid metabolism in this effect, and finally a description of the mechanism by which the lipid abnormality develops. There is now a great deal of acceptable information on these points, but for the present I shall consider some evidence that my associates and I have obtained in studies of diabetic human subjects. If from the relation of these observations, any suggestions or implications are made for the management of diabetes, they are fortuitous.
The Young Diabetic Panel Discussion
Authors: White Priscilla , Guest George M , Harwood Reed , Kennedy William B
Published: December 2014

Moderator White: The most important age periods in the management of the juvenile diabetic patient are infancy and adolescence. Some physicians dread the management of diabetes when the patient is under five years of age. The condition sometimes seems difficult to handle and it places extreme strain on the morale of the patients. Dr. Guest, what is your advice in regard to the diabetic infant?

Dr. Guest: In my opinion diabetic infants are not necessarily more difficult to manage than older children. I should say that the age of adolescence is a much more difficult period than that of infancy, but then of course, other problems are involved. As most of you know, I recommend the so-called “free-diet-glycosuric” regime which is a subject of continuing debate. (See editorials in Diabetes: 1:487–89, Nov.-Dec. 1952.) In our clinic we have eighteen diabetic infants with onset of diabetes under the age of two years. Of these, eight were under one year of age when symptoms were first recognized. The youngest started glycosuria at nine days of age. The diagnosis was made by the astute mother because she had another diabetic child then aged one and onehalf years. When she noted the new infant was passing a lot of urine, she tested it and found sugar. On admission to the hospital, the baby's blood sugar was 350 mg. per 100 cc. The urinalysis showed 3-plus glycosuria but no ketonuria. During twenty-four hours we determined the blood sugar every two hours and found it fluctuating between 300 and 500. Because there was no ketonuria, we felt that a period of observation before starting insulin would do no harm. After that brief period of observation the baby was given an initial dose of three units of protamine zinc insulin. During the next twenty-four hours the blood sugar fell progressively (determined at two-hour intervals) to 150 and then 100. Again, three units of protamine zinc insulin kept the blood sugar within normal range. (Let me stress the necessity for microchemical methods for following blood chemical changes in infants, whether diabetic or nondiabetic.) The baby was sent home on the fifth day, receiving two units of protamine zinc insulin daily. He was breast fed for ten months, on a demand schedule, with the dosage of protamine zinc varying from one to three units daily and solid foods offered at usual ages. (Please note that breast feeding is the ultimate in “free diet”, while it lasts!) That child is now seven years of age and has not suffered any illness that required hospitalization. His urine is rarely free of sugar, but excessive glycosuria with polyuria is likewise rare. Transient ketonuria has occurred occasionally during intercurrent infections, but has always cleared up promptly with the administration of extra doses of quick-acting insulin. The insulin requirement increased slowly with age and increasing body weight, from five units a day at one year of age, to thirty-five units (globin insulin) a day at the present time.
Primary Optic Atrophy in Diabetes Mellitus
Authors: Tunbridge R E , Paley Ronald G
Published: December 2014

In the late nineteenth century, publications on ocular complications of diabetes mellitus frequently mentioned primary optic atrophy. Clifford Allbutt in 1871 stated “atrophy of the optic discs … does undoubtedly occur in a sufficient number of cases of glycosuria to make the coexistence seem more than accidental.” In 1875 Leber quoted a number of cases recorded by other observers, but stated that he had not seen such a patient himself. In the 1927 edition of von Noorden's book on diabetes, 4 per cent of 477 diabetic patients are recorded as suffering from simple optic atrophy. More recently, Waite and Beetham (1935) found optic atrophy in 0.6 per cent of 2,002 diabetics and in 0.4 per cent of 457 nondiabetics. The only other reference in recent literature is that of Wolfram (1938) who reported from the Mayo Clinic four cases of diabetes mellitus and simple optic atrophy among siblings. This communication is concerned with two further cases.
Robert Russell Bensley, 1867–1956
Authors: Lazarow Arnold
Published: December 2014

Not “who is right, but what is right” characterized the life of Dr. R. R. Bensley. The effect of this philosophy upon the lives and attitudes of his students and their students constitutes a truly effective memorial. Dr. Bensley had the wisdom and patience to refrain from engaging in polemics, allowing time to prove his theses; he had the longevity to see many of his important discoveries first ignored, later accepted, and finally acclaimed.
Psychosocial Issues in Diabetes
Authors: Wishner William J , Young Raiann M
Published: December 2014

In the past few years, there has been an increasing awareness of the psychologic, social, and anthropologic determinants in human life as direct modifiers of human behavior in respect to chronic illness. These factors have been implicated both positively and negatively in modifying the treatment and outcome of diabetes as well as other chronic illnesses. The literature surrounding these issues unfortunately has escaped the eyes of the health care professional because, in part, of the fact that it has been published in areas of psychologic and social literature rather than in traditional medical journals. This series of reviews is designed to provide further awareness of these important issues as they affect the natural history of the disease.
Classification of Diabetes in Older Adults
Authors: Madsbad Sten
Published: December 2014

Older adults with diabetes mellitus are a heterogeneous group including juvenile- and adult-onset type I (insulindependent) diabetic patients and type II (non-insulindependent) diabetic patients, with some who are insulin requiring because of symptomatic hyperglycemia. Most older adults with newly diagnosed diabetes have type II diabetes, but the classification of patients into type I and type II diabetes is uncertain in most studies because only clinical characteristics are used. Age and weight at diagnosis are of value in classification of patients, whereas presence or absence of ketonuria at diagnosis has been shown to be of limited value. Measurements of C-peptide after stimulation appear to be the most reliable parameter in the classification of diabetes into type I or type II and with regard to whether a type II diabetic patient is insulin requiring.
Will Sulfonylurea Treatment of Impaired Glucose Tolerance Delay Development and Complications of NIDDM?
Authors: Melander Arne , Bitzén Per-Olof , Sartor Gunnar , Scherstén Bengt , Wåhlin-Boll Elisabeth
Published: December 2014

The chronic hyperglycemia of non-insulin-dependent diabetes mellitus (NIDDM) evolves gradually and is usually preceded by more transient hyperglycemia, classified as impaired glucose tolerance (IGT). Already in this phase, there is an increased risk of cardiovascular complications, and many IGT subjects, like NIDDM patients, often display several of the metabolic and circulatory disturbances that are associated with hyperglycemia, e.g., insulin resistance, hyperinsulinemia and/or hyperproinsulinemia, delayed insulin release, dyslipidemia, and hypertension. Therefore, and because untreated hyperglycemia is a self-perpetuating condition, early detection and early intervention may be necessary to prevent the progression and complications of NIDDM. This in turn would necessitate screening procedures, and the therapeutic goal should include both euglycemia and normalization of plasma insulin, plasma lipids, and blood pressure. A study in the German Democratic Republic indicated that the mortality in screening-detected NIDDM patients did not differ from that in patients detected in routine care. In a Swedish study on screening-detected NIDDM subjects, only those who had IGT rather than manifest NIDDM could maintain fasting blood glucose ≤6 mM for 5 yr by hypocaloric dietary regulation alone. In those with screening-detected NIDDM, the delayed acute insulin release and net postprandial hyperglycemia were improved by addition of glipizide, and most managed to attain and maintain fasting blood glucose ≤6 mM for ∼2 yr after such addition. However, after 4 yr, there was an increase in blood glucose, suggesting that preventive intervention either may not be possible or may have to start in the IGT phase. In another Swedish study, the combination of dietary advice and tolbutamide seemed to delay the progression of IGT to NIDDM, lower cholesterol and triglyceride levels and blood pressure, and reduce cardiovascular morbidity and mortality. However, no preventive effect was seen in two similar British studies. Moreover, only a few untreated IGT subjects progress to manifest NIDDM. Hence, routine screening for IGT and subsequent therapeutic intervention cannot be recommended, but more studies are needed.
Effects of Antihypertensive Treatment on Insulin Sensitivity With Special Reference to ACE Inhibitors
Authors: Berne Christian , Pollare Thomas , Lithell Hans
Published: December 2014

In 1984, the suspicion that pharmacological treatment may worsen the insulin resistance and associated metabolic abnormalities in lipid and carbohydrate metabolism and contribute to the relative failure of antihypertensive treatment to produce more than marginal reductions in cardiovascular morbidity and mortality led us to start a series of trials aimed at elucidating how antihypertensive drugs affect insulin sensitivity. These trials, which included assessment of insulin sensitivity by the euglycemic insulin clamp, showed that β-adrenergic blockade and thiazide diuretic treatment (hydrochlorothiazide) increase insulin resistance and basal plasma insulin, whereas Ca2+ - channel antagonists (verapamil and diltiazem), with the exception of the negative effect of nifedipine, are metabolically neutral. α-Adrenergic blockade with prazosin and angiotensin-converting enzyme (ACE) inhibition with captopril enhance insulin sensitivity. The mechanisms underlying the positive effects of ACE inhibition and β-adrenergic blockade are largely unknown, but hemodynamic factors (vasodilation) may contribute by improving the access of glucose and insulin to skeletal muscle. The drugs, which were favorable or neutral with respect to insulin sensitivity, caused no changes in lipids or glucose homeostasis. In contrast, β-blockers, except pindolol, had negative effects on triglycerides and high-density lipoprotein cholesterol, and thiazide diuretics caused adverse effects on total serum cholesterol, low-density lipoprotein cholesterol, and total and very-low-density lipoprotein triglyceride. The metabolic action of antihypertensive drugs is an important factor to consider in the choice of a proper treatment strategy in both diabetic and nondiabetic patients with hypertension.
Workshop Report: Treating Diabetes and its Complications
Authors: Fajans Stefan S , Nutting Paul
Published: December 2014

RESEARCH OPPORTUNITIES— The work group discussed research opportunities in biomedical, behavioral, and health service research on some of the complications of NIDDM. The panel chose to focus on aspects of the prevention of blindness, nephropathy, heart disease, and amputations, and aspects of gestational diabetes and diabetes in pregnancy.

The panel agreed at the onset that the best treatment of diabetes and its complications was prevention of diabetes by treating early abnormalities of glucose tolerance or impaired glucose tolerance. Primary prevention of diabetes may be achieved by treating such abnormalities by diet, exercise, or oral hypoglycemic agents. Alternatively, treatment of the earliest abnormalities of NIDDM, such as a diabetic glucose tolerance test, early in the natural history of diabetes might also be effective. These topics were discussed in more detail in the work group on the Prevention and Early Treatment of NIDDM.
Fetal Pancreas Transplantation for Treatment of IDDM Patients
Authors: Lafferty Kevin J , Hao Liming
Published: December 2014

The debate concerning use of fetal tissue in a clinical setting is relevant to the treatment of diabetes; the ban on clinical use of fetal tissue remains in force. Specifically, this issue raises questions about what has been and what can be done in the use of HFP tissue for treatment of the IDDM patient. The possibility of using such tissue was first raised by Lazarow et al. in the 1973 Banting Lecture (1). Since that time there has been much progress in our understanding of the allograft response and in studies of the growth and differentiation of the HFP. In this report, we review developments in this area and consider their implications in the current political climate.
Diabetes Patients and Their Physicians—All Eager for Knowledge From the West
Authors: Miller Leona V
Published: December 2014

During my flight to Moscow recently, I read John Steinbeck's Russian Journal. My daughter had given me the book, thinking, perhaps, that it might inspire me to keep a similar record. I have never been a journal keeper, although I often have wished that I had recorded impressions of situations and people I had encountered on my travels. I didn't keep a journal, but it did make me compare the differences and similarities of my impressions with Steinbeck's. The differences are not surprising, for he wrote of his visit to the Soviet Union shortly after World War II. He observed that the nation had many shortages of farming equipment and other types of machinery, but that the people were tremendously optimistic. They had won the war, and they were then ready to turn their efforts to supplying the needs of a peace-time population.
An Immunological Basis for Disproportionate Diabetes Risks in Children With a Type I Diabetic Mother or Father
Authors: Dosch Hans-Michael , Martin Julio M , Robinson Brian H , Åkerblom Hans K , Karjalainen Jukka
Published: December 2014

Children of mothers with type I diabetes carry a diabetes risk of ∼2.3–2.6%, whereas children of type I diabetic fathers carry a risk two to three times higher (1,2). In a follow-up study in Dallas, Texas, the discordance currently exceeds 10-fold (JD Capra, unpublished observations). Although parental imprinting or silent fetal loss have tentatively been invoked, no evidence supports such mechanisms. The hypothesis below describes an immunological mechanism that could explain this discrepancy in diabetes risk.
The Question Is Answered: Now what?
Authors: Farkas-Hirsch Ruth , Hirsch Irl B
Published: December 2014

The 1993 20th annual meeting of the American Association of Diabetes Educators (AADE) had a joyous overtone because it was the beginning of the celebration of 20 years of work and dedication. The record attendance of over 1,900 individuals listened to excellent presentations on a variety of exciting topics. Much of the meeting emphasized the recently publicized findings of the Diabetes Control and Complications Trial (DCCT). The results of the trial generated a tremendous amount of enthusiasm and optimism. It now appears that the question is finally answered.
Screening for NIDDM: Why is there no national program?
Authors: Harris Maureen I , Modan Michaela
Published: December 2014

Non-insulin-dependent diabetes mellitus (NIDDM) is a major clinical and public health problem in the U. S. The prevalence of NIDDM is 7% among all adults and reaches over 20% among those 65–74 years of age (1–3). NIDDM and insulin-dependent diabetes mellitus (1DDM) combined account for 50% of all nontraumatic amputations in the U. S., 15% of all blindness, and 35% of all end-stage renal disease (4). At least 50% of these events occur in NIDDM patients (5–7). Prevalence of neuropathy and ischemic heart disease in NIDDM and risk of death from cardiovascular disease is two to three times that of those without diabetes even after adjusting for other risk factors (8–13).
Mouse or Man: Is GAD the cause of type I diabetes?
Authors: Eisenbarth George S
Published: December 2014

Recent headlines in the national and presumably international news media have characterized the enzyme glutamic acid decarboxylase (GAD) as the cause of type I diabetes. The news accounts were stimulated by two excellent research reports that indicated that Tcells from the spleens of young NOD mice responded to GAD before other autoantigens and that intravenous injection of GAD or intrathymic injection of GAD prevented the development of diabetes (1,2).
Chronic Pontine Dysfunction Following Insulin-Induced Hypoglycemia in an IDDM Patient
Authors: Perros Petros , Sellar Robin J , Frier Brian M
Published: December 2014

Insulin-induced hypoglycemia is associated with significant morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). In addition to cognitive dysfunction, transient neurological abnormalities may result from the neuroglycopenia of acute hypoglycemia and can be protean in their manifestations. In experimental animals, the hippocampus, putamen, caudate, and cerebral cortex display the greatest vulnerability to hypoglycemic neuronal damage (1). In humans, permanent brain damage has been described in survivors of severe and protracted hypoglycemia and is usually localized to the cortex and hippocampus, sparing the cerebellum, brain stem, and spinal cord, which are more resistant to glucose deprivation (2). A man with IDDM is described who developed permanent pontine signs after an episode of severe hypoglycemia.
ACE Inhibitors and Diabetic Nephropathy
Authors: Molitch Mark E
Published: December 2014

Nineteen-ninety-three was a banner year for the demonstration of beneficial effects of interventions on outcomes in patients with diabetes and, in particular, with diabetic nephropathy. The Collaborative Study Group studying the effects of treatment with angiotensinconverting enzyme (ACE) inhibitors on the progression of diabetic nephropathy reported strongly positive results (1), hard on the heels of the publication of the results of the Diabetes Control and Complications Trial (DCCT) (2).
More Than You Ever Wanted to Know (But Need to Know) About Glycohemoglobin Testing
Authors: Goldstein David E , Little Randie R
Published: December 2014

In this issue of Diabetes Care, Koskinen et al. report that fetal hemoglobin levels are increased in diabetic patients (this issue, L.K. Koskinen et al., p. 828–831). The study design was a cross-sectional one with glycohemoglobin and fetal hemoglobin determinations for 930 diabetic and 258 control subjects. The authors found thatalmost 7% of the diabetic subjects had fetal hemoglobin levels >1% compared with only∼2% of the control subjects. Furthermore, fetal hemoglobin levels were increased moreoften in those with IDDM than in those with NIDDM.
A Diabetes Potpourri, Part 1
Authors: Bloomgarden Zachary T
Published: December 2014

The essayist Charles Lamb wrote, “The good things of life are not to be had singly, but come to us with a mixture (1).” This column and the next report on recent lectures covering topics from the etiology of type 1 diabetes to the causes of its complications, from the potential role of pancreas transplantation to the understanding of hypoglycemia in IDDM, show the breadth of research and the potential promise of new treatments in the field.
Neurophysiological Evidence for Altered Higher Brain Functions in NIDDM
Authors: Kurita Akira , Katayama Ko , Mochio Soichiro
Published: December 2014

OBJECTIVE

To investigate neurophysiological alterations of higher brain function in patients with NIDDM.

RESEARCH DESIGN AND METHODS

Auditory P300 event-related potentials were recorded in 60 NIDDM patients who had no evidence of stroke, dementia, or any other neurological illnesses. The P300 wave latencies in diabetic patients were compared with those in neurologically healthy control subjects, with consideration of clinical parameters and diabetic complications.

RESULTS

Diabetic patients had significantly longer P300 latencies than control subjects. Seven diabetic patients had pathologically prolonged P300 values. There was a trend toward longer P300 latencies in diabetic patients with retinopathy and in those with HbA1 of ≥10%; the differences between these diabetic subgroups and control subjects were both statistically significant. However, three of seven diabetic patients with abnormal P300 latencies had no retinal lesions, and no significant correlation was observed among diabetic patients between P300 latencies and HbA1 levels. Peripheral neuropathy, nephropathy, blood glucose levels, and disease duration appeared not to correlate with P300 alterations.

CONCLUSIONS

These findings suggest the presence of central nervous pathological processes in NIDDM that affect higher brain functions, as assessed by P300 latencies. Our findings also suggest that microangiopathy and metabolic derangement during the preceding 4- to 8-week period may contribute in small part to the pathophysiology of this central nervous involvement.
Glucose and Insulin Response to High Carbohydrate Meals in Normal and Maturity-onset Diabetic Subjects
Authors: Schade David S , Eaton R P , Mitchell William , Ortega Theresa
Published: December 2014

Previous studies using glucose tolerance testing demonstrated late afternoon glucose intolerance in normal subjects. To determine whether this alteration in carbohydrate metabolism also occurs with food intake, the effects of identical high carbohydrate meals on glucose tolerance were assessed in 12 normal and 5 maturity-onset diabetic subjects. A meal consisting of 60% carbohydrate, 14% protein, and 26% fat was administered for breakfast, lunch, and supper and the effects on glucose tolerance and plasma insulin concentration assessed. In normal subjects, glucose intolerance was observed during the evening meal, in association with a relative deficiency of plasma insulin secretion. In the maturity-onset diabetic subjects, glucose intolerance was observed at all meals but was exaggerated at supper. Thus, this study suggests that high carbohydrate diets composed primarily of simple sugars will result in exaggerated glucose intolerance in the late afternoon and should be avoided by maturity-onset diabetic patients.
Effects of Maternal Hyperglycemia on Fetal Development
Authors: Chez Ronald A
Published: December 2014

These comments reflect an experience obtained from examining fetal pancreatic alpha- and betacell responsiveness in the nonhuman primate, Macaca mulata. Our research studies encompassed nine years in two different institutions with two different colonies of monkeys. A maternal glucose-intolerant state was obtained through the use of streptozotocin (SZ). We found that the induced glucose-intolerant pregnant female monkey lent itself to an exploration of the fetopathy that occurs in human pregnancy associated with diabetes mellitus.
Alcohol and Diabetes
Authors: McDonald Janet
Published: December 2014

Newer concepts regarding the management of diabetes favor a diet that is more liberal in carbohydrate content and more personalized for the patient. Ideally, the end result will be improved glycemic control and fewer complications. Allowing more flexibility in the diet is a way of fostering better patient compliance. Alcohol, for example, which is frequently disallowed, can safely be included in the diet of many diabetic patients who desire a drink with meals, provided that certain guidelines are followed. Dietary substitutions can be made with relative ease. Although there are contraindications to its use by certain people, alcohol in moderation does not appear to compromise carbohydrate homeostasis in most individuals and, if early studies are confirmed, could possibly have some beneficial side-effects. More open discussion of alcohol use with patients is needed to give them the know-how to alter their diets and to inform them of the necessary precautions.
Biologic Activity and Receptor Binding Properties of Biosynthetic Human Insulin in Isolated Rat Hepatocytes and Mouse Soleus Muscle In Vitro
Authors: Fehlmann Max , Marchand-Brustel Yannick Le , Dolais-Kitabgl Jacqueline , Morin Odette , Freychet Pierre
Published: December 2014

Studies from our laboratory have shown that freshly isolated hepatocytes from the adult rat represent a suitable system to measure insulin binding to cell surface receptors and insulin biologic effects. Biosynthetic human insulin (BHI) binding to isolated rat hepatocytes was measured under steady-state conditions at 20°C and 37°C, using 125I-BHI and varying concentrations of unlabeled BHI. Control binding experiments were run in parallel with 125I-pork insulin and varying concentrations of unlabeled pork insulin. No difference between BHI and pork insulin binding could be detected at either temperature. Similar results were obtained when BHI and pork insulin binding was studied using purified liver plasma membranes. These results indicate that BHI binds to hepatocyte receptors with the same characteristics as monocomponent pancreatic pork insulin. BHI's stimulation of α-amino 14C-isobutyric acid (AIB) influx in rat hepatocytes was found to be indistinguishable from that induced by pancreatic human insulin or pork insulin: for the three insulins, maximal responses (about a twofold increase above basal) and concentrations producing a half-maximal response (EC50 ≅ 1 nM) were identical. The isolated mouse soleus is a slow twitch, red skeletal muscle, which binds insulin, and responds to the hormone, in a dose-related fashion as regards glucose transport and metabolism. BHI stimulated 2-deoxyglucose uptake to the same extent as pancreatic human insulin or pork insulin. Maximal stimulation (a fourfold increase) and concentrations which produced a half-maximal stimulation (EC50 ≅ 0.5 nM) were identical for the three insulins. These in vitro studies show that BHI has the same intrinsic activity (maximal effectiveness) and biologic potency (EC50) as pancreatic human insulin and pancreatic porcine insulin in two major target tissues of insulin, liver and skeletal muscle. Moreover, receptor-binding properties of BHI are identical to those of pork insulin in isolated rat hepatocytes and liver plasma membranes.