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In vivo, after subcutaneous injection, insulin glargine (21(A)-Gly-31(B)-Arg-32(B)-Arg-human insulin) is enzymatically processed into 21(A)-Gly-human insulin (metabolite 1 [M1]). 21(A)-Gly-des-30(B)-Thr-human insulin (metabolite 2 [M2]) is also found. In vitro, glargine exhibits slightly higher affinity, whereas M1 and M2 exhibit lower affinity for IGF-1 receptor, as well as mitogenic properties, versus human insulin. The aim of the study was to quantitate plasma concentrations of glargine, M1, and M2 after subcutaneous injection of glargine in male type 1 diabetic subjects. Glargine, M1, and M2 were determined in blood samples obtained from 12, 11, and 11 type 1 diabetic subjects who received single subcutaneous doses of 0.3, 0.6, or 1.2 units · kg(-1) glargine in a euglycemic clamp study. Glargine, M1, and M2 were extracted using immunoaffinity columns and quantified by a specific liquid chromatography-tandem mass spectrometry assay. Lower limit of quantification was 0.2 ng · mL(-1) (33 pmol · L(-1)) per analyte. Plasma M1 concentration increased with increasing dose; geometric mean (percent coefficient of variation) M1-area under the curve between time of dosing and 30 h after dosing (AUC(0-30h)) was 1,261 (66), 2,867 (35), and 4,693 (22) pmol · h · L(-1) at doses of 0.3, 0.6, and 1.2 units · kg(-1), respectively, and correlated with metabolic effect assessed as pharmacodynamics-AUC(0-30h) of the glucose infusion rate following glargine administration (r = 0.74; P < 0.01). Glargine and M2 were detectable in only one-third of subjects and at a few time points. After subcutaneous injection of glargine in male subjects with type 1 diabetes, exposure to glargine is marginal, if any, even at supratherapeutic doses. Glargine is rapidly and nearly completely processed to M1 (21(A)-Gly-human insulin), which mediates the metabolic effect of injected glargine.

Background Optimal glycaemic targets for patients with severe traumatic brain injury remain unclear. The primary objective of this microdialysis study was to compare cerebral metabolism with strict versus conventional glycaemic control. Methods We performed a prospective single-centre randomised controlled within-subject crossover study of 20 adult patients admitted to an academic neurointensive care unit with severe traumatic brain injury. Patients underwent randomised, consecutive 24-h periods of strict (4–7 mmol/L; 72–126 mg/dl) and conventional (<10 mmol/L; 180 mg/dl) glycaemic control with microdialysis measurements performed hourly. The first 12 h of each study period was designated as a ‘washout’ period, with the subsequent 12 h being the period of interest. Results Cerebral glucose was lower during strict glycaemia than with conventional control (mean 1.05 [95% CI 0.58–1.51] mmol/L versus 1.28 [0.81–1.74] mmol/L; P  = 0.03), as was lactate (3.07 [2.44–3.70] versus 3.56 [2.81–4.30]; P  < 0.001). There were no significant differences in pyruvate or the lactate/pyruvate ratio between treatment phases. Strict glycaemia increased the frequency of low cerebral glucose (< 0.8 mmol/L; OR 1.91 [95% CI 1.01–3.65]; P  < 0.05); however, there were no differences in the frequency of critically low glucose (< 0.2 mmol/L) or critically elevated lactate/pyruvate ratio between phases. Conclusions Compared with conventional glycaemic targets, strict blood glucose control was associated with lower mean levels of cerebral glucose and an increased frequency of abnormally low glucose levels. These data support conventional glycaemic targets following traumatic brain injury. Trial registration ISRCTN, ISRCTN19146279 . Retrospectively registered on 2 May 2014.

OBJECTIVE:--Cereal fiber intake is linked to reduced risk of type 2 diabetes in epidemiological observations. The pathogenic background of this phenomenon is unknown. Based on recent findings, we hypothesized that intake of purified insoluble oat fiber may improve whole-body insulin sensitivity. RESEARCH DESIGN AND METHODS--A randomized, controlled, single-blind, cross-over study was performed, and 17 overweight or obese subjects with normal glucose metabolism were analyzed. After consumption of nine macronutrient-matched portions of fiber-enriched bread (white bread enriched with 31.2 g insoluble fiber/day) or control (white bread) over a time period of 72 h, whole-body insulin sensitivity was assessed by euglycemic-hyperinsulinemic clamp. Energy intake was individually adjusted by providing standardized liquid meals. Hydrogen breath tests were performed to control for dietary adherence. RESULTS:--When analyzing the entire cohort, whole-body glucose disposal was improved after fiber consumption (M value 6.56 ± 0.32 vs. 6.07 ± 0.27 mg · min⁻¹ · kg⁻¹; P = 0.043). Thirteen subjects had increased hydrogen breath test concentrations after fiber consumption, indicating probable dietary adherence. Restricting analysis to these subjects, improvements in M value (6.85 ± 0.34 vs. 6.06 ± 0.32 mg · min⁻¹ · kg⁻¹; P = 0.003) and insulin sensitivity, expressed as M/I ratio (M value divided by mean serum insulin at steady state: 3.73 ± 0.23 vs. 3.21 ± 0.27; P = 0.02), after fiber consumption were more pronounced. Plasma lipids, serum magnesium, ghrelin, and adiponectin concentrations, as well as substrate utilization and body weight, were not significantly changed by fiber intake (P > 0.15). CONCLUSIONS:--Increased insoluble dietary fiber intake for 3 days significantly improved whole-body insulin sensitivity. These data suggest a potential mechanism linking cereal fiber intake and reduced risk of type 2 diabetes.

Beneficial Effects of Insulin Versus Sulphonylurea on Insulin Secretion and Metabolic Control in Recently Diagnosed Type 2 Diabetic Patients Michael Alvarsson , MD, PHD 1 , Göran Sundkvist , MD, PHD 2 , Ibe Lager , MD, PHD 3 , Marianne Henricsson , MD, PHD 4 , Kerstin Berntorp , MD, PHD 2 , Eva Fernqvist-Forbes , MD, PHD 5 , Lars Steen , MD 6 , Gunilla Westermark , MD, PHD 7 , Per Westermark , MD, PHD 7 , Thomas Örn , MD 8 and Valdemar Grill , MD, PHD 1 1 Department of Endocrinology and Diabetology, Karolinska Hospital, Stockholm, Sweden 2 Department of Endocrinology, Malmö University Hospital, Malmö, Sweden 3 Department of Medicine, Kristianstad Hospital, Kristianstad, Sweden 4 Department of Ophthalmology, Helsingborg Hospital, Helsingborg, Sweden 5 Department of Medicine, Visby Hospital, Visby, Sweden 5 Department of Medicine, Mälarsjukhuset, Eskilstuna, Sweden 6 Division of Cell Biology, Faculty of Health Sciences, Linköping, Sweden 7 Department of Medicine, Blekingesjukhuset, Karlskrona, Sweden Address correspondence and reprint requests to Michael Alvarsson, Department of Endocrinology and Diabetology, Karolinska Hospital, SE-171 76 Stockholm, Sweden. E-mail: michael.alvarsson{at}ks.se Abstract OBJECTIVE —To evaluate whether treatment with insulin in recently diagnosed type 2 diabetes is advantageous compared with glibenclamide treatment. RESEARCH DESIGN AND METHODS —β-Cell function, glycemic control, and quality of life were monitored over 2 years in 39 patients with islet cell antibody-negative type 2 diabetes diagnosed 0–2 years before inclusion in a Swedish multicenter randomized clinical trial. Patients were randomized to either two daily injections of premixed 30% soluble and 70% NPH insulin or glibenclamide (3.5–10.5 mg daily). C-peptide-glucagon tests were performed yearly in duplicate after 2–3 days of temporary withdrawal of treatment. RESULTS —After 1 year the glucagon-stimulated C-peptide response was increased in the insulin-treated group by 0.14 ± 0.08 nmol/l, whereas it was decreased by 0.12 ± 0.08 nmol/l in the glibenclamide group, P < 0.02 for difference between groups. After 2 years, fasting insulin levels were higher after treatment withdrawal in the insulin-treated versus the glibenclamide-treated group ( P = 0.02). HbA 1c levels decreased significantly during the first year in both groups; however, at the end of the second year, HbA 1c had deteriorated in the glibenclamide group ( P < 0.01), but not in the insulin-treated group. The difference in evolution of HbA 1c during the second year was significant between groups, P < 0.02. A questionnaire indicated no difference in well-being related to treatment. CONCLUSIONS —Early insulin versus glibenclamide treatment in type 2 diabetes temporarily prolongs endogenous insulin secretion and promotes better metabolic control. GADA, GAD antibody IA2, insulinoma-associated protein 2 IA-2A, IA2 antigen ICA, islet cell anitbody IAPP, islet amyloid polypeptide LADA, latent autoimmune diabetes in adults RIA, radioimmunoassay UKPDS, U.K. Prospective Diabetes Study Footnotes A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Accepted May 4, 2003. Received January 31, 2003. DIABETES CARE

In healthy older subjects, the glycaemic response to carbohydrate-containing meals is dependent on gastric emptying and intestinal absorption; when the latter is slowed, the magnitude of the rise in glucose is attenuated. The oligosaccharide α-cyclodextrin has been reported to diminish the glycaemic response to starch in young adults; this effect has been attributed to the inhibition of pancreatic amylase. We examined the effects of α-cyclodextrin on gastric emptying of, and the glycaemic and insulinaemic responses to, oral sucrose in healthy older subjects; as sucrose is hydrolysed by intestinal disaccharides, any effect(s) of α-cyclodextrin would not be attributable to amylase inhibition. A total of ten subjects (seven males and three females, age 68–76 years) were studied on 2 d. Gastric emptying, blood glucose and serum insulin were measured after ingestion of a 300 ml drink containing 100 g sucrose, labelled with 99mTc-sulphur colloid, with or without 10 g α-cyclodextrin. Gastric emptying was slowed slightly by α-cyclodextrin; this effect was evident between 135 and 195 min and was associated with a slight increase (P < 0·05) in distal stomach retention. After α-cyclodextrin, blood glucose was slightly less (P < 0·05) at 60 min, and serum insulin was less (P < 0·0005) at 90 and 120 min. There was no difference in the incremental areas under the curve (iAUC) for blood glucose, but there was a trend for the iAUC for serum insulin to be lower (P = 0·09) after α-cyclodextrin. We conclude that in a dose of 10 g, α-cyclodextrin has modest effects to slow gastric emptying of, and modify the glycaemic and insulinaemic responses to, oral sucrose, probably due to delayed intestinal carbohydrate absorption.

Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects 1 – 4 . For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action 4 , 5 ; however, the direct molecular target of metformin remains unknown. Here we show that clinically relevant concentrations of metformin inhibit the lysosomal proton pump v-ATPase, which is a central node for AMPK activation following glucose starvation 6 . We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase 7 , as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase 8 , which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels. Knockout of PEN2 or re-introduction of a PEN2 mutant that does not bind ATP6AP1 blunts AMPK activation. In vivo, liver-specific knockout of Pen2 abolishes metformin-mediated reduction of hepatic fat content, whereas intestine-specific knockout of Pen2 impairs its glucose-lowering effects. Furthermore, knockdown of pen-2 in Caenorhabditis elegans abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds PEN2 and initiates a signalling route that intersects, through ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation. This ensures that metformin exerts its therapeutic benefits in patients without substantial adverse effects. The molecular target of the antidiabetic medicine metformin is identified as PEN2, a subunit of γ-secretases, and the PEN2–ATP6AP1 axis offers potential targets for screening for metformin substitutes.

Ellagic acid (EA) is a bioactive polyphenolic compound naturally occurring as secondary metabolite in many plant taxa. EA content is considerable in pomegranate (Punica granatum L.) and in wood and bark of some tree species. Structurally, EA is a dilactone of hexahydroxydiphenic acid (HHDP), a dimeric gallic acid derivative, produced mainly by hydrolysis of ellagitannins, a widely distributed group of secondary metabolites. EA is attracting attention due to its antioxidant, anti-inflammatory, antimutagenic, and antiproliferative properties. EA displayed pharmacological effects in various in vitro and in vivo model systems. Furthermore, EA has also been well documented for its antiallergic, antiatherosclerotic, cardioprotective, hepatoprotective, nephroprotective, and neuroprotective properties. This review reports on the health-promoting effects of EA, along with possible mechanisms of its action in maintaining the health status, by summarizing the literature related to the therapeutic potential of this polyphenolic in the treatment of several human diseases.

Bioactive compounds of natural origin are gaining increasing popularity. High biological activity and bioavailability, beneficial effects on health and safety of use are some of their most desirable features. Low production and processing costs render them even more attractive. Microorganisms have been used in the food, medicinal, cosmetic and energy industries for years. Among them, microalgae have proved to be an invaluable source of beneficial compounds. Haematococcus pluvialis is known as the richest source of natural carotenoid called astaxanthin. In this paper, we focus on the cultivation methods of this green microalga, its chemical composition, extraction of astaxanthin and analysis of its antioxidant, anti-inflammatory, anti–diabetic and anticancer activities. H. pluvialis, as well as astaxanthin can be used not only for the treatment of human and animal diseases, but also as a valuable component of diet and feed.

Diminished bioavailability of nitric oxide (NO), the gaseous signaling molecule involved in the regulation of numerous vital biological functions, contributes to the development and progression of multiple age- and lifestyle-related diseases. While l-arginine is the precursor for the synthesis of NO by endothelial-nitric oxide synthase (eNOS), oral l-arginine supplementation is largely ineffective at increasing NO synthesis and/or bioavailability for a variety of reasons. l-citrulline, found in high concentrations in watermelon, is a neutral alpha-amino acid formed by enzymes in the mitochondria that also serves as a substrate for recycling l-arginine. Unlike l-arginine, l-citrulline is not quantitatively extracted from the gastrointestinal tract (i.e., enterocytes) or liver and its supplementation is therefore more effective at increasing l-arginine levels and NO synthesis. Supplementation with l-citrulline has shown promise as a blood pressure lowering intervention (both resting and stress-induced) in adults with pre-/hypertension, with pre-clinical (animal) evidence for atherogenic-endothelial protection. Preliminary evidence is also available for l-citrulline-induced benefits to muscle and metabolic health (via vascular and non-vascular pathways) in susceptible/older populations. In this review, we examine the impact of supplementing this important urea cycle intermediate on cardiovascular and metabolic health outcomes and identify future directions for investigating its therapeutic impact on cardiometabolic health.

Purpose l -Arabinose uncompetitively inhibits intestinal sucrase by forming an enzyme-inhibitor-substrate (EIS) complex. The transient period of the EIS complex affects the time span of inhibition. We determined the apparent transient period of the EIS complex of sucrase, l -arabinose, and sucrose both in vitro and in humans. Methods Intestinal acetone powder (a source of sucrase), l -arabinose, and sucrose were mixed and injected into a dialysis membrane that was placed in a sucrose solution. The production rate of d -glucose and the release rate of l -arabinose from sucrase were determined. We also investigated the suppression of blood glucose levels by l -arabinose in 21 healthy volunteers. Sucrose (40 g) was ingested with or without l -arabinose (2 g), then blood glucose values were measured, which returned to steady-state conditions within 2 h. Volunteers were then given 90 g of commercial adzuki bean jelly containing 40 g sucrose as the sucrose load, and blood glucose values were measured again. Results Addition of l -arabinose reduced the production rate of d -glucose compared to the rates measured in the absence of l -arabinose for several hours in vitro. l -Arabinose was released at a lower rate in the presence of sucrose than in its absence. Blood glucose values measured 2 h after sucrose was given with l -arabinose were significantly lower than those measured when l -arabinose was not given (Δ change in maximum value: with l -arabinose, 53.8 ± 19.7 mg/dL; without l -arabinose, 65.0 ± 17.7 mg/dL). Conclusion The EIS complex of sucrase- l -arabinose-sucrose was maintained for several hours both in vitro and in humans.