Regulation of muscle fructose 2, 6-bisphosphate levels by sulfonylureas

We examined the effect of sulfonylureas on the level of fructose 2, 6-bisphosphate (F-2, 6-P2) in muscle using a mouse hindlimb flow-through perfusion system. The F-2, 6-P2 level in muscle was increased by adding glibenclamide or tolbutamide in a dose-dependent manner. The stimulatory potency of each drug on F-2, 6-P2 formation was parallel to its hypoglycemic potency. Sulfonylurea stimulation of muscle F-2, 6-P2 formation is thought to be an important extrapancreatic action improving the deranged carbohydrate metabolism in diabetics.     

Pancreatic and extrapancreatic sulfonylurea receptors.

The hypoglycemic effect of sulfonylureas and their analogues results from their binding to a high affinity site in the B-cell plasma membrane. This site seems to be a structural component of the ATP-sensitive K(+)-channel and represents the pancreatic sulfonylurea receptor. Binding of sulfonylureas causes closure of the ATP-sensitive K(+)-channel and thereby initiates a chain of events eventually leading to the release of insulin. Diazoxide inhibits insulin secretion via opening of the ATP-sensitive K(+)-channel. Sulfonylurea receptors resembling the pancreatic receptor occur in nerve cells, cardiac muscle, skeletal muscle and smooth muscle. Neither these extrapancreatic receptors nor low affinity receptors for sulfonylureas in myocytes and adipocytes contribute to the therapeutic benefit of sulfonylureas.     

Insulin-related materials in the nervous system of vertebrates and non-vertebrates: possible extrapancreatic production

Studies from multiple laboratories with a range of methods raised the possibility that insulin production occurs naturally at extrapancreatic sites. Part A covers the presence of insulin-related materials in organisms that do not have an endocrine pancreas, including unicellular prokaryotes and eukaryotes as well as multicellular non-vertebrate animals (insects et al.) and plants. Part B covers possible production of insulin by extrapancreatic tissues of vertebrates that are remote from a source of pancreatic insulin e.g. early chick embryos and mammalian cells in culture. Part C covers possible extrapancreatic insulin production in mammals in vivo. Each section ends with an outline summary with evidence in favor of and against the hypothesis.     

绿原酸的药理学研究进展

绿原酸(chlorogenic acid,CGA)存在于多种植物之中,具有广泛的药理作用。近年来,对绿原酸的研究发展较快,目前研究表明绿原酸口服吸收率低,在血浆中主要以代谢产物的形式存在,主要经过肾脏排泄,具有抗氧化、抗肿瘤、抗菌、抗病毒、免疫调节、降糖等多种作用。对CGA的深入研究,将为我们科学制药与合理用药提供重要的理论依据。     

Hypoglycemic activity of Eriobotrya japonica seeds in type 2 diabetic rats and mice

The hypoglycemic effects of Eriobotrya japonica seeds were investigated in type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and KK-A(y) mice. The rats and mice were fed on a diet containing 10% powdered Eriobotrya japonica seeds with the coat intact for 4 months. Although the blood glucose concentration in the OLETF rats fed on the control diet without Eriobotrya japonica seeds was increased with time, the concentration in the OLETF rats fed on the diet with Eriobotrya japonica seeds was consistently low throughout the experimental period and was comparable to the level in Long-Evans Tokushima Otsuka (LETO) rats which are normal non-diabetic rats. Serum insulin was significantly lower in the OLETF rats fed on the Eriobotrya japonica seed diet than in those fed on the control diet at the termination of the experimental period. Eriobotrya japonica seeds suppressed the increment of blood glucose for 4 months and also effectively improved the glucose tolerance in the KK-A(y) mice, these actions being mainly exerted by the ethanol extract of the seeds. These results suggest that Eriobotrya japonica seeds had a hypoglycemic property and the effect is attributable to the components extracted by ethanol.     

The potential usefulness of taurine on diabetes mellitus and its complications

Taurine (2-aminoethanesulfonic acid) is a free amino acid found ubiquitously in millimolar concentrations in all mammalian tissues. Taurine exerts a variety of biological actions, including antioxidation, modulation of ion movement, osmoregulation, modulation of neurotransmitters, and conjugation of bile acids, which may maintain physiological homeostasis. Recently, data is accumulating that show the effectiveness of taurine against diabetes mellitus, insulin resistance and its complications, including retinopathy, nephropathy, neuropathy, atherosclerosis and cardiomyopathy, independent of hypoglycemic effect in several animal models. The useful effects appear due to the multiple actions of taurine on cellular functions. This review summarizes the beneficial effects of taurine supplementation on diabetes mellitus and the molecular mechanisms underlying its effectiveness.     

Taurine-diabetes interaction: from involvement to protection

Taurine is a sulfur amino acid (2-amino ethane sulfonic acid) and has been claimed for a number of beneficial actions ranging from anti-epilepsy to anti-hypertension. Taurine in diabetes has an age old story; taurine is involved in the development and protection of insulin apparatus. Taurine and insulin both have mutual stimulating actions with hypoglycemic properties. On the clinical front, taurine supplementation has an acceptable beneficial effect in platelet aggregation and, to name few more, in neuropathy, cardiomyopathy, and nephropathy to retinopathy. Recent studies have provided a role for taurine in fetal development and in blocking the transfer of diabetes from diabetic mother to offspring. A number of mechanisms for the actions of taurine have been advocated, from osmoregulation to anti-oxidation. Though sulfonylurea and recently introduced thiazolidinediones are effective, however they are not free from complications, thus there is a need to design new therapeutics. As taurine is also a sulfonyl derivative, it will be of great interest to develop taurine analogues as an alternative therapy. Considering the great involvement of taurine in diabetes, this review may provide a holistic view of taurine in diabetes and in its prevention in this century.     

Inositolphosphoglycans possibly mediate the effects of glucagon-like peptide-1(7-36)amide on rat liver and adipose tissue

Insulin-like effects of glucagon-like peptide-1(7-36)amide (GLP-1) in rat liver, skeletal muscle and fat, and also the presence of GLP-1 receptors in these extrapancreatic tissues, have been documented. In skeletal muscle and liver, the action of GLP-1 is not associated with an activation of adenylate cyclase, and in cultured murine myocytes and hepatoma cell lines, it was found that GLP-1 provokes the generation of inositolphosphoglycan molecules (IPGs), which are considered second messengers of insulin action. In the present work, we document in isolated normal rat adipocytes and hepatocytes that GLP-1 exerts a rapid decrease of the radiolabelled glycosylphosphatidylinositols (GPIs)—precursors of IPGs—in the same manner as insulin, indicating their hydrolysis and the immediate short-lived generation of IPGs. Thus, IPGs could be mediators in the GLP-1 actions in adipose tissue and liver, as well as in skeletal muscle, through GLP-1 receptors which are, at least functionally, different from that of the pancreatic B-cell. © 1998 John Wiley & Sons, Ltd.     

Effects of 9-cis- and all-trans-retinoic acids on blood glucose homeostasis in the fiddler crab, Uca pugilator

9-cis-Retinoic acid (9CRA) and all-trans-retinoic acid (ATRA) are known to be involved in the regulation of glucose homeostasis in vertebrates by inducing insulin release and expression of glucose transporter proteins. In view of the fact that both 9CRA and ATRA are endogenous to the fiddler crab, Uca pugilator, that a retinoid X receptor exists in this fiddler crab and that activities of insulin-like and insulin-like growth factor-like peptides have been reported for crustaceans, we investigated whether 9CRA and ATRA also play a role in glucose homeostasis in U. pugilator. Neither 9CRA nor ATRA was found to produce hypoglycemic effects at a dose of 10 microg/g live mass. However, 9CRA, but not ATRA, induced hyperglycemia. Such 9CRA-induced hyperglycemia was apparently mediated by the eyestalk hormone CHH since injection of 9CRA into eyestalk-ablated crabs did not result in hyperglycemia. ATRA was found to have an inhibitory effect on the recovery of blood glucose concentration following ATRA administration. Discussion on the possible mechanisms for the actions of 9CRA and ATRA was presented.     

The effect of the new oral hypoglycemic agent A-4166 on glucose turnover in the high fat diet-induced and/or in the hereditary insulin resistance of rats.

A-4166, a phenylalanine derivative, is a hypoglycemic agent, which has been shown to improve blood glucose levels mainly due to the rapid and short term stimulation of insulin release. Nevertheless, a possible extrapancreatic action of A-4166 has not yet been investigated. Therefore, insulin action (euglycemic hyperinsulinemic 6.4 mU.kg-1.min-1 clamp plus 3H-2-deoxyglucose tracer administration) was studied after 3 weeks on either standard (BD) or high fat (HF) diet in normal control (C) or in hereditary insulin resistant (hHTg) rats which were given a single dose of A-4166 (10 mg per kg BW, i.v.) 60 min after clamp commencement. HF feeding reduced the glucose infusion rate (GIR) required to maintain euglycemia to about 50% of C (p < 0.001). In hHTg rats, HF did not further pronounce the pre-existing decrease of GIR of hHTg animals fed BD. A-4166 changed GIR neither in C, nor in the hHTg group. The estimated glucose disposal (Rd) (C-BD: 32.3 +/- 1.9 vs C-HF: 25.5 +/- 1.9 mg.kg-1.min-1, p < 0.001) and glucose metabolic index (Rg') in skeletal muscles (Q. femoris: C-BD: 25.6 +/- 1.5 vs C-HF: 12.3 +/- 1.1 mmol.100 g-1.min-1, p < 0.001) were reduced by HF in control rats but were not restored by a concomitant bolus of A-4166. Nevertheless, in hHTg rats fed the HF diet a single dose of A-4166 brought back their Rd (hHTg-HF: 23.5 +/- 1.3 vs hHTg-HF plus A-4166: 31.0 +/- 3.5 p < 0.03) and Rg' (Soleus muscle: hHTg-HF: 29.2 +/- 3.2 vs hHTg-HF plus A-4166: 41.3 +/- 4.0) to values of the control group on BD. In summary, a) a single bolus administration of A-4166 to the control or to the insulin resistant hHTg rats, fed either the BD or HF diets, did not abolish the reduction of GIR required to maintain euglycemia during hyperinsulinemic clamps; b) nevertheless, A-4166 caused a significant increase of the estimated plasma glucose disposal (Rd) and skeletal muscle glucose metabolic index (Rg') of hHTG rats fed the HF diet; c) we suggest that A-4166 may have an extrapancreatic action but this needs to be proven using a long-term administration plan of A-4166.     

Cytology of papillary solid-cystic neoplasm of the pancreas presenting as an extrapancreatic mass: a case report

BACKGROUND: Papillary solid cystic neoplasm (PSCN) of the pancreas is a tumor of low malignant potential and has an excellent prognosis. Although the cytologic features are well documented, it can pose a diagnostic problem when it presents as an extrapancreatic mass. CASE: A young woman presented with a retroperitoneal mass. Sonography and computed tomography (CT) showed a partially cystic mass touching the spleen and pancreas but distinct from both organs. The CT-guided aspiration cytologic diagnosis was paraganglioma. At surgery the mass was attached to the tail of the pancreas by a pedicle. The histologic diagnosis was PSCN of the pancreas. CONCLUSION: The cytologic findings in paraganglioma and PSCN may be strikingly similar, with both showing a perivascular pattern, acinar formations, cells with a moderate amount of ill-defined cytoplasm with red granularity on May-Grünwald Giemsa stain and a uniform chromatin pattern. This may be a source of diagnostic error, particularly in a patient presenting with a retroperitoneal, extrapancreatic mass.     

GIP and GLP-1 as incretin hormones: lessons from single and double incretin receptor knockout mice

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut-derived incretins secreted in response to nutrient ingestion. Both incretins potentiate glucose-dependent insulin secretion and enhance beta-cell mass through regulation of beta-cell proliferation, neogenesis and apoptosis. In contrast, GLP-1, but not GIP, inhibits gastric emptying, glucagon secretion, and food intake. Furthermore, human subjects with Type 2 diabetes exhibit relative resistance to the actions of GIP, but not GLP-1R agonists. The physiological importance of both incretins has been investigated through generation and analysis of incretin receptor knockout mice. Elimination of incretin receptor action in GIPR-/- or GLP-1R-/- mice produces only modest impairment in glucose homeostasis. Similarly, double incretin receptor knockout (DIRKO) mice exhibit normal body weight and normal levels of plasma glucagon and hypoglycemic responses to exogenous insulin. However, glucose-stimulated insulin secretion is significantly decreased following oral but not intraperitoneal glucose challenge in DIRKO mice and the glucose lowering actions of dipeptidyl peptidase-IV (DPP-IV) inhibitors are extinguished in DIRKO mice. Hence, incretin receptor signaling exerts physiologically relevant actions critical for glucose homeostasis, and represents a pharmacologically attractive target for development of agents for the treatment of Type 2 diabetes.     

Prevention and Management of Insulin-Associated Hypoglycemia in Hospitalized Patients

Objective: To determine whether appropriate therapeutic changes in insulin doses are made to prevent and manage insulin-associated hypoglycemic events in non–critically ill hospitalized patients.Methods: This retrospective study was conducted in hospitalized adults on medical or surgical floors with insulin-associated hypoglycemia, excluding treatment with insulin infusions, insulin pumps, and parenteral nutrition. The first hypoglycemic event after 48 hours of admission was the index event. Over the 1-year study period, a total of 457 insulin-associated hypoglycemic events were included as index events.Results: An indication for an insulin dose adjustment was identified in 32 and 42% of patients on day -2 and day -1, respectively, before the index hypoglycemic event, of which 35 and 55%, respectively, had an insulin dose reduction ≥10%. Following the hypoglycemic event, 44% of patients had an insulin dose reduction of ≥20%. Therapeutic reduction of the total daily insulin dose by ≥20% was associated with increased odds of normoglycemia and lower odds of hyperglycemia but was not associated with lower odds of recurrent hypoglycemia on the day following the index hypoglycemic event. There was a high prevalence of hypoglycemic risk factors in this population, with kidney disease and nil per os status being the most prevalent contributing factors.Conclusion: Adherence to the current practice recommendation to reduce insulin doses in patients with borderline hypoglycemia and following overt hypoglycemia was modest. Further studies are needed to understand the associated risks and to define appropriate therapeutic changes for insulin treated patients with borderline and overt hypoglycemia.Abbreviations:AKI = acute kidney injuryBG = blood glucoseCKD = chronic kidney diseaseESRD = end-stage renal diseaseICU = intensive care unitNPH = Neutral Protamine HagedornNPO = nil per osOR = odds ratioTDD = total daily dose     

Bioactivity and pharmacokinetics of human proinsulin in comparison to human insulin after intravenous and subcutaneous injection

The hypoglycemic actions of human insulin (1 IU/kg b.w.) and biosynthetic human proinsulin in about equimolar amounts were studied after intravenous and subcutaneous injection in rabbits. Blood samples were taken up to four hours after injection for the determination of blood glucose and immunoreactive levels of both insulin and human C-peptide. For the determination of human C-peptide, serum taken after proinsulin injection was divided into two fractions. One was examined directly by the human C-peptide radioimmunoassay and the other after incubation with a protein-A-sepharose coupled insulin antibody to find "free human C-peptide". Proinsulin in amounts equimolar to 1 IU insulin/kg b.w., exerted a 34% stronger hypoglycemic action after subcutaneous injection than after intravenous administration (area under curve estimation). Proinsulin-induced hypoglycemia did not last longer after intravenous administration than that induced by intravenous insulin. Although subcutaneous proinsulin did not show the same maximum decrease of blood glucose compared to subcutaneous insulin, its action was significantly prolonged (up to 180 min). Specific measurement of free human C-peptide showed no evidence of conversion of proinsulin to insulin and C-peptide.     

Effect of Costus spiralis (Jacq.) Roscoe Leaves,Methanolic Extract and Guaijaverin on Blood Glucose and Lipid Levels in a Type II Diabetic Rat Model

This study aimed to isolate and identify flavonoids with hypoglycemic activity in Costus spiralis leaves. The methanolic extract (ME) was rich in flavonoids, while the powdered leaves (PL) contained considerable amounts of macro‐ and microelements. Oral acute treatment of streptozotocin (STZ)‐induced diabetic rats for 18 h with the C. spiralis PL, ME and isolated guaijaverin (GUA) lowered glycemia, improved oral glucose tolerance and inhibited liver lipid peroxidation. GUA and ME lowered plasma levels of low‐density and non‐high density lipoproteins; GUA also lowered total cholesterol levels. PL, ME and GUA did not significantly alter the plasma levels of triglycerides, high‐density lipoproteins, very low‐density lipoproteins, creatinine and aspartate transaminase, and the total protein levels in the kidney and liver tissues. Therefore, C. spiralis leaves are promising raw materials and rich sources of bioactive flavonoids for the development of novel antidiabetic drugs due to their hypoglycemic, antidyslipidemic and antioxidant actions.     

Interleukin-1 and glucose homeostasis: an example of the biological relevance of immune-neuroendocrine interactions

Interleukin-1 (IL-1), a cytokine mainly produced by monocytes-macrophages, plays a crucial role in immunological and inflammatory processes. We have recently demonstrated that IL-1 can also affect neuroendocrine mechanisms. In this paper, we refer to the capacity of IL-1 to affect glucose homeostasis. In normal mice, low doses of IL-1 induce a long-lasting hypoglycemia which is not dependent on possible insulin-secretagogue actions of this cytokine. The hypoglycemic effect of IL-1 is also observed in insulin-resistant diabetic mice. Furthermore, IL-1 seems to adjust the 'set point' for glucose regulation to a lower level. The effects of IL-1 on glucose homeostasis constitute a clear example of the biological relevance of immune-neuroendocrine interactions.     

Catecholamines in the rat brain during hypoglycemic convulsions and coma

The purpose of the study was to investigate the relation between the catecholamines: noradrenaline and dopamine in the rat brain on one hand and hypoglycemic convulsions and coma on the other. Concentrations of noradrenaline in the hypothalamus, brain stem and cerebral cortex were decreased during hypoglycemic convulsions and were lower during coma than those during convulsions. Dopamine concentration in the striatum was decreased during convulsions and coma. It was shown that the decrease in concentration of catecholamines was a result of hypoglycemia but not of insulin action itself. Clonidine- alpha 2 agonist accelerated occurrence and prolonged duration of hypoglycemic convulsions. Haloperidol-dopamine receptor blocker had no effect on the time of occurrence or duration of convulsions and coma. The results indicate that noradrenaline may exert an inhibitory influence on hypoglycemic convulsions. No evidence has been provided to support involvement of dopamine in the control of hypoglycemic convulsions and coma.     

Response of extrapancreatic immunoreactive glucagon to intraluminal nutrients in pancreatectomized dogs

To investigate the response of extrapancreatic glucagon to intraluminal stimuli, nutrients were administered to normal and pancreatectomized dogs through a stomach tube in a fully conscious state after an overnight fast. Plasma immunoreactive glucagon was determined with antisera specific and nonspecific to glucagon and was designated as IRG and total IRG, respectively. Oral glucose load elicited a decrease in plasma IRG and a remarkable rise of plasma total IRG in a group of 6 pancreatectomized dogs, as in the control dogs. When arginine was given, both plasma IRG and total IRG significantly increased in a group of 5 pancreatectomized dogs, while only total IRG rose significantly in the normal control dogs. Butter load did not reveal any changes in plasma IRG and total IRG in a group of 5 pancreatectomized dogs, whereas only total IRG increased in the normal control dogs. It is concluded that extrapancreatic glucagon responds to intraluminal administration of nutrients, as pancreatic glucagon does. In addition, gut glucagon-like immunoreactivity increased following glucose or arginine ingestion in pancreatectomized dogs. Furthermore, the failure in response of plasma IRG and total IRG to butter load in pancreatectomized animals suggests that its intraluminal hydrolysis is important in the secretion of extrapancreatic immunoreactive glucagon.     

Oxytocin increases extrapancreatic glucagon secretion and glucose production in pancreatectomized dogs

Infusion of oxytocin into normal dogs increases plasma levels of insulin and glucagon and glucose production and uptake. To determine whether infused oxytocin also increases glucagon secretion from extrapancreatic sites, pancreatectomized dogs, off insulin for 18 hr, were infused with oxytocin and plasma glucagon, and glucose production and uptake were measured using the [6-3H]glucose primer-infusion technique. The diabetic dogs, in the control period, had elevated plasma glucose and glucagon levels, an increased rate of glucose production, and a relative decrease in glucose uptake (decreased clearance). Infusion of oxytocin (500 microU/kg/min) caused a rise in plasma glucagon and glucose levels, increased glucose production, and further decreased glucose clearance. It is concluded that oxytocin can stimulate secretion of extrapancreatic glucagon, which contributes to the increased glucose production.