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PubMed2025

Evolution of the Artificial Pancreas: Components and Integration-CGMs, Insulin, and AP Systems.

The landmark Diabetes Control and Complications Trial (DCCT) showed that glucose control is critical to reducing the risk of diabetes-related complications. This chapter outlines a series of innovations and investigations that followed the DCCT, aimed at minimizing the risk of hypoglycemia while further improving glucose control. The chapter presents an example of innovations in wired enzyme technology that facilitated the movement from capillary glucose monitoring to continuous glucose monitoring (CGM) and ultimately, the first-factory calibrated CGM system. The next glycemic management innovation was to connect CGM data to an insulin pump containing an algorithm able to adjust insulin delivery based on the changing glucose levels and trends. The key features of automated insulin delivery (AID) systems, currently approved in the United States, are presented. The AID summary table includes type of pump, type and function of the insulin delivery algorithm, the data management system, and the indications for use. The next section explores the innovation of alternative routes of insulin delivery to move toward the goal of a fully automated insulin delivery system. The main trials in developing and implementing an implantable intraperitoneal programmable system are summarized. The last section explores if sensor input in addition to glucose levels such as continuous sensing of ketone, lactate, or insulin levels may provide valuable feedback to move us closer to a fully autonomous AID system. Much of this diabetes innovation and investigation work has been supported by the National Institute of Diabetes and Digestive and Kidney Diseases over that last 75 years.

Humans↗

PubMed2026

A New Highly Concentrated Insulin Aspart AT278 (500 U/mL) Demonstrates Ultra-Rapid Pharmacokinetic and Pharmacodynamic Properties in Type 2 Diabetes Regardless of BMI.

AIMS: To evaluate the pharmacokinetics, pharmacodynamics, and safety of a novel U500 insulin aspart formulation (AT278 [500 U/mL]; AT278-U500) compared with standard concentration insulin aspart (InsAsp [100 U/mL]; InsAsp-U100) and U500 human regular insulin (HumIns [500 IU/mL]; HumIns-U500). MATERIALS AND METHODS: This single-centre, randomised, double-blind crossover 12-h euglycaemic clamp study was conducted in 41 overweight and obese people with type 2 diabetes (BMI 25.0-38.7 kg/m2) receiving a single subcutaneous dose (0.5 U/kg) of AT278-U500 and InsAsp-U100. HumIns-U500 was consecutively studied open label in a 24-h clamp. RESULTS: AT278-U500 exhibited a significantly faster insulin absorption than InsAsp-U100 and HumIns-U500 (t Early50%Cmax: 9 min vs. 35 min vs. 55 min), leading to a significantly higher glucose-lowering effect within the first hour (AUCGIR,0-60min) compared with both InsAsp-U100 (treatment ratio 2.02 [95% CI 1.64; 2.50]) and HumIns-U500 (3.91 [2.89; 5.27]). When divided by median BMI (29.7 kg/m2), AUCGIR,0-60min was significantly higher with AT278-U500 in both the low-BMI and high-BMI subgroup compared to InsAsp-U100. Linear regression showed a significant inverse relationship between BMI and AUCGIR,0-60min for InsAsp-U100 (slope -0.142, p < 0.0001), whereas AT278-U500 showed no such relationship. Overall insulin exposure was similar for AT278-U500 and InsAsp-U100, while overall glucose-lowering effect was comparable across all three treatments. CONCLUSIONS: AT278-U500 maintains its ultra-rapid onset characteristics independent of BMI, representing the first ultra-rapid U500 option for prandial dosing in insulin-resistant people with type 2 diabetes requiring high-dose therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05754424.

Humans↗

PubMed1979

Protein-induced hypercalciuria: a longer term study.

Urine calcium excretion is known to be directly correlated with the level of dietary protein intake. In this experiment we examined the persistence of the hypercalciuria induced by the consumption of high protein diets, and the mechanism of the calciuric response. In a 95-day metabolic study, each of six adult male subjects received formula diets supplying 12 g nitrogen or 36 g nitrogen, and approximately 1400 mg calcium per day. Urine calcium increased rapidly and significantly from an average of 191 mg/day on the 12 g nitrogen diet to 277 mg/day on the 36 g nitrogen diet. There was no significant difference in the apparent absorption of calcium, so that overall calcium balance was -37 mg/day on the 12 g nitrogen diet, and significantly lower at -137 mg/day in subjects consuming the high protein diet. Levels of urinary hydroxyproline, serum insulin, and parathyroid hormone were not significantly increased by high intakes of protein. A decrease in the fractional reabsorption of calcium by the kidney seems to be the most likely cause of the protein-induced hypercalciuria. The consumption of high calcium diets is unlikely to prevent the negative calcium balance and probable bone loss induced by the consumption of high protein diets.

Adult↗

PubMed1978

Response of plasma triglycerides to dietary change in patients on hemodialysis.

The effect of reduction in dietary carbohydrate content of meal formula diets on plasma triglyceride concentrations was studied in 12 patients receiving chronic hemodialysis. Fasting plasma triglycerides decreased over a 10-day period in 11 of 12 patients in response to a decreased proportion of carbohydrate (from 50 to 35% of total daily calories) regardless of the type of fat used. Postprandial insulin responses were also significantly lower in the patients on the diets lower in carbohydrate. In addition, triglyceride kinetics were studied in three groups of patients. Patients with renal failure (dialyzed and undialyzed) had lower triglyceride production rates than those of control subjects, despite higher plasma triglyceride concentrations. Elevated (greater than 150 mg/100 ml) fasting plasma triglycerides are associated with lower triglyceride production rates in patients with chronic renal failure and may not be improved by conventional hemodialysis. A long-term study of the efficacy of reduction in dietary carbohydrate on plasma triglycerides is needed since routine hemodialysis does not appear to correct the lipid abnormality in patients with chronic renal failure.

Adult↗

PubMed1977

Parenteral nutrition techniques in cancer patients.

If a patient is expected to respond optimally to one or more forms of oncologic therapy, he should simultaneously be in the best possible nutritional and metabolic condition. When the alimentary tract cannot be used effectively for feeding cancer patients, parenteral nutrition can be lifesaving. Moreover, patients who are poor candidates or noncandidates for any antineoplastic therapy because of their debility or cachexia can be converted to reasonable candidates following a course of i.v. hyperalimentation. This i.v. hyperalimentation can significantly reduce the morbidity and mortality of cancer patients without stimulating tumor growth when applied conscientiously according to the established principles and techniques and when integrated with specific tumor therapy. With the use of ambulatory or home hyperalimentation techniques, normal nutritional status can be restored or maintained during prolonged periods of antineoplastic therapy on a practical and relatively economical outpatient basis. It is anticipated that specific nutrient substrate formulas and parenteral therapy techniques will be developed to maintain optimal host nutrition while adversely affecting the neoplasm.

Adult↗

PubMed1979

The role of physical exercise and training in the management of diabetes mellitus.

The effects of physical activity on blood glucose homeostasis in diabetes mellitus and the potential benefits of exercise in the treatment of diabetic patients, are reviewed. Mild physical exercise results in a fall of blood glucose levels in controlled diabetic patients; this acute effect of exercise might be used in particular to inhibit the rise of blood glucose seen in insulin-treated diabetics after food intake. In contrast, physical activity will further deteriorate the metabolic situation in decompensated diabetic patients by an increase in blood glucose and a rapid aggravation of ketosis. On the other hand exercise potentiates the blood glucose lowering effect of subcutaneously injected insulin; therefore precautions have to be taken in order to avoid hypoglycemia in insulin-dependent diabetics especially during and after more strenous exercise. In juvenile-type diabetes, physical activity can be used as an efficient therapeutic adjunct only in cooperative, well-instructed patients who are used to check their metabolic situation on a regular basis. Physical training increases the tissues' sensitivity towards (endogenous) insulin. Hence, in addition to the diet, training might represent the most appropriate treatment in maturity onset-type diabetic patients. However, direct evidence for an improvement of glucose tolerance in diabetic patients by physical training is still lacking. In order to formulate detailed, generally applicable recommendations on how to carry out a useful therapeutic program of physical exercise and/or training in diabetic patients, further clinical studies assessing the quantitative effects of physical activity on carbohydrate metabolism are needed.

Animals↗

PubMed1979

[Corticosteroid-sensitive chemical diabetes in Horton's disease].

We report 5 cases of temporal arteritis associated with a diabetes whose good evolution under corticotherapy suggests a common pathogenesis. Several hypotheses can be formulated to explain the origin of the glycemic abnormality and to understand the way corticotherapy is effective. A moderate posology could at first have a hyperplasic effect on the insulin-secreting cells, and later on a favorable action on the vascular lesion and on an immunological disorder. Any definitive conclusion cannot be evolved yet. Only a more systematical study of the glycoregulation's abnormalities in the temporal arteritis will enable to answer the many remaining questions.

Adrenal Cortex Hormones↗

PubMed1978

Amino acid derangements in patients with sepsis: treatment with branched chain amino acid rich infusions.

Sepsis is a major catabolic insult resulting in modifications in carbohydrate and fat energy metabolism, and leading to increased muscle breakdown and nitrogen loss. Insulin resistance, which develops in sepsis, decreases glucose utilization, but plasma insulin levels are sufficiently elevated to prevent lipolysis, resulting in a further energy deficit. The availability of fuels in sepsis is therefore limited, and the body resorts to muscle breakdown, gluconeogenesis, and amino acid oxidation for energy supply. Previous work has not defined, however, the exact alterations in amino acid metabolism. Therefore, the following studies were undertaken. Blood samples were drawn from fifteen patients in whom the diagnosis of sepsis was clinically established; the samples were analyzed for amino acid, beta-hydroxyphenylethanolamines, glucose, insulin and glucagon concentrations. The plasma amino acid pattern observed was characterized by an increase in total amino acid content, due mainly to high levels of the aromatic amino acids (phenylalanine and tyrosine) and the sulfur-containing amino acids (taurine, cystine and methionine). Alanine, aspartic acid, glutamic acid and proline were also elevated, but to a lesser degree. The branched chain amino acids (valine, leucine and isoleucine) were within normal limits, as were glycine, serine, threonine, lysine, histidine and tryptophan. Those patients who did not survive sepsis had higher levels of aromatic and sulfur-containing amino acids as compared to those patients surviving sepsis. On the other hand, those patients surviving sepsis had higher levels of alanine and the branched chain amino acids. In a second group of five patients with overwhelming sepsis accompanied by a state of metabolic encephalopathy, a parenteral nutrition solution consisting of 23% dextrose, and an amino acid formulation enriched with branched chain amino acids was administered. In these five patients, normalization of the plasma amino acid pattern and reversal of encephalopathy was observed. The following sequence of events may be postulated: The septic patient develops insulin resistance in the peripheral tissues, primarily muscle, while the adipose tissue is much less affected. The insulin resistance and the inability to utilize fat leads to increased muscle proteolysis. Muscle breakdown results in release into the blood of enormous amounts of various amino acids; the muscle itself is able to oxidize the branched chain amino acids, supplying the muscles' own energy requirements and alanine for gluconeogenesis. The extensive muscle proteolysis coupled with relative hepatic insufficiency occurring early in sepsis results in the appearance in the plasma of high levels of most of the amino acids present in muscle, particularly the aromatic and the sulfur-containing amino acids. The outcome of patients with sepsis might be positively affected by combined therapy with glucose, insulin and branched chain amino acids.

Amino Acids↗

PubMed1978

Demonstration of components of serum-free culture medium effecting maximum in vitro expression of mouse mammary tumor virus.

By using a chemically defined serum-free (SF) medium for propagation of Mm5mtc1 mouse adenocarcinoma cell cultures and clonal derivatives, medium components including hormones, glucose and individual amino acids were evaluated as to modulation of mouse mammary tumor virus (MMTV) porduction. Insulin, hydrocortisone and dexamethasone each increased MMTV production on a per cell basis over constitutive expression that occurs in SF medium devoid of hormones. Maximum production occurred when all three hormones were present. Hormone-stimulated virus expression also was influenced by glucose concentration. Cell growth and maximum MMTV expression increased when thyroxine, asparagine, proline and serine were omitted from the medium formulation. The resulting modified SF medium provides and ideal system for the propagation of high MMTV-producer clones and for the study of the biochemical regulation of MMTV expression.

Amino Acids↗

PubMed1979

Dietary fibre, diabetes, and hyperlipidaemia. Progress and prospects.

When diabetes and cardiovascular disease were first classed as possible fibre-deficiency diseases, laboratory and clinical evidence was lacking. Subsequent studies indicated that the gums and viscous types of fibre (e.g., guar and pectin) are more effective than other fibres in slowing carbohydrate absorption and hence in reducing the postprandial rise in blood glucose and serum insulin. This effect has longer term metabolic consequences. In addition, gums and viscous fibres reduce serum cholesterol, possibly by mechanisms other than simply increasing bile-salt loss. If these potential therapeutic effects of fibre are to be exploited, palatable formulations must be developed. The effect of fibre in whole foods should also be determined.

Anticholesteremic Agents↗

PubMed1979

Hormonal requirements for neuronal survival in culture.

The inability to grow neurons in culture in the absence of complex and undefined biological fluids (e.g. serum) has proved a major obstacle to a rigorous formulation of the growth, nutritional and hormonal requirements of the developing nervous system. We have been successful in maintaining dissociated chick dorsal root ganglia neurons in a serum-free, defined medium composed of F12 synthetic medium and, substituting for serum, a combination of hormones (insulin, PTH, triiodothyronine, TRH, somatomedin, hydrocortisone, testosterone) and other factors (transferrin). Not only were these hormones found to be sufficient for the maintenance of neurons in vitro, but, by the selective elimination of one component from the mixture, the role of specific hormones in neutral development could be grossly assessed. The elimination of insulin proved to be most inimical to neuronal survival.

Animals↗

PubMed1978

Metabolic responses to enteral and parenteral nutrition.

Seven pairs of rats were simultaneously infused with a chemically formulated nutritionally complete amino acid-glucose diet which was delivered, at the same rate, into a central vein or into a feeding gastrostomy. The intragastrically infused rats showed greater weight gain than did the intravenously infused rats. This could not be explained by fluid retention since intake and output were similar in the two groups of animals. There was a greater increase in serum immunoreactive insulin (IRI) at day 8 in the intragastrically infused animals, but a smaller increment in serum immunoreactive pancreatic glucagon (IRG) at that point. Levels of enteroglucagon or glucagon-like immunoreactivity (GLI) were maintained in the intragastrically infused rats but declined markedly in the intravenously infused rats. It is possible that the greater release of IRI seen with the intragastric amino acid-glucose feeding contributes to better disposal of nutrients and greater weight gain. The presence of nutrients in the intestinal lumen may have stimulated the release of GLI, which in turn is insulinotropic.

Amino Acids↗

PubMed1977

The effect of contraceptive steroids on hypothalamic-pituitary function.

A study was performed to obtain additional information about the effects of oral contraceptives on pituitary function. A sequential pituitary stimulation test (SST) was used to study normal control women who then received either a combination pill with 50 mug of ethinyl estradiol or an injectable or oral progestin for three weeks, after which the test was repeated. The same test was also performed on five long-term oral contraceptive users. The SST consists of measurement of growth hormone (GH), thyroid-stimulating hormone (TSH), prolactin (PRL), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) at frequent intervals after stimulation by hypoglycemia, thyrotropin-releasing hormone, and gonadotropin-releasing hormone. GH and TSH release following stimulation were unaffected by the use of contraceptive steroids, while PRL release was increased by both the combination pill and the progestin alone. LH and FSH release was decreased in the three short-term and most of the long-term users of the combination pills but was not decreased in two of the long-term users as well as in those receiving the progestin alone. These results indicate that the combination oral contraceptives have a direct effect upon the pituitary gland, causing an increase in prolactin release and a decrease in gonadotropin release. This effect varies among individuals receiving the same formulation and may be related to the development of syndrome of postpill amenorrhea-galactorrhea.

Contraceptives, Oral↗

PubMed1979

Comparison of effects of different combined oral-contraceptive formulations on carbohydrate and lipid metabolism.

Oral glucose-tolerance tests were performed and fasting serum cholesterol and triglyceride levels measured in 1628 Caucasian women taking combined oestrogen/progestagen oral contraceptives (o.c.) and 577 women not taking O.C. The former were divided into six groups according to the composition of the O.C Glucose tolerance deteriorated in all O.C. groups containing oestrane progestagens (nortestosterone-derived) or the gonane, norgestrel, but was unaltered by O.C. containing a pregnane progestagen (derived from progesterone). The greatest deterioration was with O.C. containing 75 microgram or more oestrogen, and this was associated with impairment of the early insulin response to glucose. In O.C. containing a pregnane progestagen insulin secretion was unaffected. In the remaining O.C. groups insulin secretion was increased; this was most pronounced with the O.C. containing a gonane progestagen. Serum-cholesterol was elevated only with O.C. containing 75 microgram or more oestrogen and an oestrane progestagen and tended to be lower in O.C. containing a gonane progestagen. O.C.-induced hypertriglyceridaemia was oestrogen-dose-related, and this effect was potentiated by the pregnane progestagen. The gonane progestagen antagonised oestrogen-induced hypertriglyceridaemia.

Adult↗

PubMed2025

Interleukin-6 related signaling pathways as the intersection between chronic diseases and sepsis.

Sepsis is associated with immune dysregulated and organ dysfunction due to severe infection. Clinicians aim to restore organ function, rather than prevent diseases that are prone to sepsis, resulting in high mortality and a heavy public health burden. Some chronic diseases can induce sepsis through inflammation cascade reaction and Cytokine Storm (CS). Interleukin (IL)-6, the core of CS, and its related signaling pathways have been considered as contributors to sepsis. Therefore, it is important to study the relationship between IL-6 and its related pathways in sepsis-related chronic diseases. This review generalized the mechanism of sepsis-related chronic diseases via IL-6 related pathways with the purpose to take rational management for these diseases. IL-6 related signaling pathways were sought in Kyoto Encyclopedia of Genes and Genomes (KEGG), and retrieved protein-protein interaction in the Search for Interaction Genes tool (STRING). In PubMed and Google Scholar, the studies were searched out, which correlating to IL-6 related pathways and associating with the pathological process of sepsis. Focused on the interactions of sepsis and IL-6 related pathways, some chronic diseases have been studied for association with sepsis, containing insulin resistance, Alcoholic liver disease (ALD), Alzheimer disease (AD), and atherosclerosis. This article summarized the inflammatory mechanisms of IL-6 cross-talked with other mediators of some chronic diseases in vitro, animal models, and human experiments, leading to the activation of pathways and accelerating the progression of sepsis. The clinicians should be highlight to this kind of diseases and more clinical trials are needed to provide more reliable theoretical basis for health policy formulation.

Humans↗

PubMed1976

A diagram to facilitate the understanding and therapy of mixed acid base disorders.

A diagram based on in-vivo relationships between arterial hydrogen ion activity (H+) and carbon dioxide tension (PCO2) in primary abnormalities of acid base homeostasis is presented. It is designed to facilitate the interpretation of pH data by including the 95% confidence limits described in patients with simple metabolic and respiratory acid base disorders. These bands have been formulated from observation of simple acid base abnormalities and indicate the appropriate respiratory or renal compensatory response to the primary pH defect. A plot which falls outside these limits therefore indicates the presence of a mixed acid base disorder. The diagram presents a physiological approach to clinical disorders of pH regulation demonstrating maintenance of intra-cellular fluid homeostasis during primary extracellular fluid disturbances. Diagnostic and therapeutic advantages are further illustrated and discussed in six case reports.

Acid-Base Imbalance↗

PubMedDate not supplied

The need for special foods and sugar substitutes by individuals with diabetes mellitus.

The need for special dietary products marketed for use by individuals with diabetes mellitus and the safety and efficacy of certain nutritive sweetener substitutes for sucrose are reviewed. Special foods for individuals with diabetes mellitus are not necessary to achieve the dietary objectives recommended by leading United States and European authorities. They can be achieved conveniently and at minimum expense through enlightened choices of commonly available food items. At present, specific and unique characteristics of food products with special therapeutic properties for diets of diabetic individuals cannot be delineated or defined on rational nutritional grounds. Such terms as "diet", "dietetic", and "diabetic" on food labels have no uniform meaning for consumers, and diabetologists have observed that patients tend to consume such foods without regard to their energy content. Some consumers regard the reduced-calorie and low-calorie prepared food products as convenient in diets for weight reduction and diabetes although their use in dietary management of diabetes has no therapeutic basis other than weight reduction and maintenance. When fed as pure substances to fasted subjects, the nonglucose carbohydrate nutritive sweeteners, fructose, xylitol, and sorbitol, are absorbed relatively slowly and produce less postprandial hyperglycemia and insulin response than sucrose or glucose. Adequate studies of their long-term effectiveness when ingested as part of mixed meals have not been conducted. Although these sucrose substitutes are generally considered safe, the significance of recent information on possible carcinogenicity of oral xylitol in long-term feeding studies has not been fully evaluated. In view of the lack of certain essential information on the long-term effectiveness of various diets in preventing or mitigating the chronic debilitating complication of diabetes, suggestions for future research are included.

Blood Glucose↗

PubMed1979

The influence of cell surface receptor clustering on the thermodynamics of ligand binding and the kinetics of its dissociation.

We show that an equilibrium model for the clustering, by divalent ligand, of homogeneous plasma membrane-bound divalent receptors that do not change conformation predicts Scatchard plots with positive second derivatives (concave up). The result is thermodynamically indistinguishable from predictions based upon receptors that are heterogeneous for ligand, or that change conformation in a negatively cooperative way when ligand binds. A more general formulation of the theory, which allows application to dissociation kinetics, predicts that the dissociation of labeled ligand is accelerated in the presence of excess cold ligand and, moreover, that the accelerated dissociation has at least two components. The theory is briefly illustrated by fitting five different sets of data, at several temperatures for two different systems, with parameter values that are well within physically meaningful ranges. The model presented is the simplest and least ad hoc explanation thus far proposed as the basis for the kinetic phenomena, and raises the possibility that the numerous experiments in which such data are observed are primarily minifestations of cell surface clustering.

Insulin↗